2008 Kaplan USMLE Step 1 Home Study Program-Brand New Volume II: General Principles Book 2

Contents

Section l: Embryology

Chapterl.Cametogenesis...

........3

Chapter 2.

Fertilization

.......7

ChapterS.

FirstWeek.

.......9

Chapter 4. Second Week

.

..........

Chapter5.ThirdWeek. Chapter6.FourthtoEighthWeeks. ChapterT. Ninth Weekto

Parturition

Chapter 8. FetalMembranes and

Chapterg. BodyCavitiesand Chapter 10.

Placenta

Mesenteries....

l1

.....15

.........19 ........25 ....29

.......35

PharyngealArchesandTheirDerivatives .........39

Chapter 11. CongenitalAbnormalities

.....

..........45

Section ll: Histology Chapter

Section

l.

Epithelium

.......53

lll: Pathology Chapter l.Ceneral

Pathology

.......61

iiitstical

vii

Section lV: Pharmacology

Chapterl.PharmacodynamicsandPharmacokinetics .......85

Chapter2.Autacoids Chapter 5. Lead Toxicity and Chelating Chapter 4. Antineoplastic

.....95

Agents

......

llj

...

|7

Agents

Section V: Behavioral Sciences Chapter l. The Basics of Behavioral

Sciences

. . . . . . 139

Chapter2.Brain-BehaviorCorrelations.... .......145 Chapter 3. Defining the

Mind

Chapter 4. Human Development and Sociocultural

...

lssues

. t5t

....

l6i

Ethia.

......19i

Chapter6.Psychopathology.

.....199

Chapter5.Medical

Section Vl: U.S. Health Care Chapter

l.

U.5. Health Care .

.

..

..241

Section Vll: Biostatistics and Epidemiology Chapter

l.

Biostatistics

..

Chapter2.Epidemiology....

fndex

viii ilitsfical

.249

....263 ..

.....26s

Gametogenesis

Cametogenesis is the process whereby specialized sex cells (gametes) are produced. Spermatogenesis refers to a series of changes through which spermatogonia differentiate into spermatozoa in the seminiferous tubules of the testes. Oogenesis refers to the series of changes

through which oogonia differentiate into oocytes in the ovaries. During gametogenesis, there are changes in DNA content and cellular morphology; these changes are the result of two processes: meiosis and morphologic maturation. During meiosis, the chromosome number and DNA content of the cell are reduced by half, and genetic recombination occurs. During morphologic maturation,

the sperm prepares for its motile role, and the egg prepares to support embryologic development. This chapter revieus the processes of meiosis, spermatogeneis, and oogenesis.

METOSTS A. Gonocyte primordia. The primitive germ cells contain consisting of 44 autosomes and two sex chromosomes.

l.

a

2n (diploid) complement of DNA,

Before the onset of meiosis, the DNA replicates, and the cell contains twice the normal

amount of DNA (4n complement).

2. Each of the 46 chromosomes is present as a pair of chromatids joined together at the centromere.

B. First meiotic division 1. During prophase of the first meiotic division, homologous chromosomes pair with each other (synapsis); each homologous pair consists of four chromatids. a. While the homologous chromosomes are paired, there is an interchange of chromatid

segments between the two paired chromosomes (crossing over) that leads to genetic

recombination. b.

In

contrast, during mitosis, homologous chromosomes do not pair, and genetic recombination does not occur.

2. The first meiotic division results in

a

pair of daughter cells, each containing 23 chromo-

somes (i.e., one member of each homologous pair) but a 2n amount each chromosome consists of two chromatids.

of DNA because

C. Second meiotic division occurs without prior DNA synthesis. During this process, each of the 23 chromosomes divides at the centromere and gives rise to two haploid (n) daughter cells, each containing 23 chromosomes and a haploid amount of DNA.

ifi8[ical

r

Embryology

Primary Spermatocyte

(46,4n) Primary Oocyte

Cell division Alignment and disjunction

Secondary Spermatocyte Secondary Oocyte

Gamete j

Figure l-1-1. Meiosis. Clinical Correlate Down syndrome (trisomy 2l) is caused by nondisjunction,

resulting in three copies of chromosome 21. Common clinical features include mental retardation, short stature, flat nasal bridge, and epicanthal folds.

iliBtical

D. Nondisjunction refers to an abnormality in either the first or second meiotic division that is characterizedby a failure of a homologous pair of chromatids to separate.

l.

The result is the production of gametes containing22 and24chromosomes instead of the

normal23. 2. Nondisjunction appears to be a more common abnormality in germ cells of women than in those of men.

Gametogenesis

SPERMATOGENESIS Spermatogenesis is the process of male gamete

formation-from spermatogonia to spermatozoa.

A. Primordial germ cells (46 chromosomes, 2n) migrate during embryonic life from the yolk sac wall into the primitive testes, where they become surrounded by the primitive supporting Sertoli cells.

B. Spermatogonia and spermatocyte formation 1. fust before puberty, the primordial germ cells (now called gonocytes) differentiate to form the spermatogonia (46 chromosomes, 2n) in the seminiferous tubules of the testes.

2. The spermatogonia divide by mitosis and ultimately give rise to the primary spermatocytes, which undergo meiosis.

in the formation of primary spermatocytes, DNA is replicated; spermatocytes then contain 46 chromosomes and a 4n amount of DNA.

a. Early

b. After a prolonged prophase, spermatocytes complete their first meiotic division, giving rise to a pair of approximately equal-sized secondary spermatocytes (23 chromo-

somes,2n). C. Spermatid formation. Secondary spermatocytes quickly begin the second meiotic division. 1. Each cell gives rise to two approximately equal-sized spermatids (23 chromosomes, n).

2. Thus, a single primary spermatocyte

gives rise

to four approximately equal-sized spermatids.

D. Spermiogenesis is the process in which the spermatids undergo morphologic differentiation to form spermatozoa. 1. This process includes loss of most of the spermatid cytoplasm, condensation of the nucleus in the sperm head, formation of the acrosome cap over the nucleus, and movement of the centrioles opposite to the acrosomal cap.

2. The spermatozoon consists of

a head, neck, and

tail.

In a Nutshell The process of spermiogenesis includes loss of most of the cell cytoplasm, condensation

of the nucleus to form the sperm head, formation of the

a. The head is formed by the nucleus and is covered by the acrosome and cell membrane.

acrosome cap over the nucleus, and movement of the

b. The neck contains two centrioles.

centrioles opposite the

c. The tail (flagellum) consists of a central axoneme composed of a pair of central microtubules and surrounded by a concentric ring of nine doublets (9 x 2 * 2 arrangement).

acrosomal cap.

(1) Proximally in the middle piece of the tail, the axoneme is surrounded by an inner layer of dense fibers and an outer layer of mitochondria arranged in a circular helix.

(2) Distally in the principal piece of the tail, the axoneme is surrounded by

dense

fibers and an outer fibrous sheath.

(3) At the terminal end of the tail, a short end piece consists only of the axoneme covered by the cell membrane.

3. Spermatozoa are released from the Sertoli cells and enter the lumina of the seminiferous tubules. a. Spermatozoa are transported from the testis via the straight tubules, rete testis, and efferent ductules to the duct of the epididymis. This process occurs as a result of the combination of fluid production by the testis, contractile elements in the testes, ciliated cells in the efferent ductules, and smooth muscle in the epididymis.

b. Spermatozoa in the epididymis undergo further maturation and acquire their potential for motiliry and fertilization.

iliii[ical

5

Embryology

!tl_l!s-F!l In males,

spermatogen6is

ooGENEsts Oogenesis is the process of female gamete

formation-from oogonia to ooc''tes.

puberty; A. Primordial germ cells. By the fifih week of f*al life, primordial germ cells migrate ftom the begins ' yolk sac wallinto the primitive ovaries and contain rt6-chromosomes and a diploid amount of before birth, enters a slage DNAof da/eloDment B. - arrsted - Oogonia and oocyte formation .; -;--.--'-;: -.'. ,, unll puDe y, and 6 not tully l. In the gonad, the primordial germ cells differentiate into oogonia (46 chromosomes, 2n). completed unless fertilization occurs' ' a. By the end of the fust trimester, the oogonia undergo several mitotic diyisions in the does not begin until

in females, oogenesis

ovanan @rtex. b. After the mitotic divisions, oogonia diferentiate to form the primary oocytes.

2. The DNA of the prirnary oocytes is then replicated, resulting in tetraploid cells (46 chromosomes, 4n). a. Th€ oocft€s then begin the prophase of their

first rneiotic division, which is nearly

complete at about the time of birth.

ltore

further divided into the following stag6: preleptotene, leptotene,zygotene,

"lnffi$:,"***T,Tl:ffilsi*s*:,:m'.?ffiffis.i",1fi.:l; occurred'

ProDhase I can be

pachytene, diplotene, and

diakinesis.

c. Primary oocytes remain

in the diplotene

stage

of prophase

I in prirnordial

follides

until puberty'

C.Maturationofprimordialfollicles

l.

At puberty, a few primordial follides begin to mature during each ovarian cycle, although only one usually fully matures.

2. Once the follicle is mature, the primary oocft€ re-enters the first meiotic division, which it completes shordy before ovulation. This division leads to the forrnation of two unequal cells: the secondary oocytc and the first polar body. a. Although both cells contain an equal number ofduomosomes (46) and DNA cont€nt (2n), the secondary oocyte receives almost all of the cytoplasm.

b. The fate of the first polar body remains uncrrtain.

3. As soon as the secondary oocyte is formed, it enters the second meiotic division and is released from the ovary during ovulation as soon as it shows spindle formation.

if fertilization occurs. If fertiliz:tion does not occur, the secondary oocyte will begin to degenerate within 12-36 hours after ovulation.

a- This division is completed only

b. Division of the secondary oocyte after fertilization produces the second polar body

and the ovum (23 chromosomes, n), which contains the female pronucleus and almost all of the cftoplasm from the secondary oocyte.

6

iii8[ical

Fertilization

Fertilization is the fusion of the male and the female gametes. lt usually occurs in the widest portion (ampulla) of the uterine tube (oviduct, fallopian tube). Once shed, the ovum is viable for about 24 hours; therefore, the fusion of sperm and egg must occur within t day of ovulation for fertilization to occur. Fertilization is a complex process that involves preparatory phases for spermatozoa, which are incapable of fertilization when they arrive in the female tract, entry of the sperm into the egg, and fusion of the male and female genetic material. This chapter reviews the events that lead up to

and complete the process of fertilization.

CAPACITATION AND ACROSOME REACTION For a spermatozoon to fertrlize the ovum, it must undergo capacitation and the acrosome reaction.

A. Capacitation

is the removal, in the female reproductive tract, of various factors that coat and cover the acrosomal portion of the sperm plasma membrane.

B. Acrosome reaction is the process of acrosome enzyme release that occurs when the spermatozoon binds to the zona pellucida of the female gamete. This reaction is required for the spermatozoon to penetrate the zona pellucida.

ENTRY OF THE SPERMATOZOON A. Inhibition of polyspermy. After the entry of one sperm into the zona pellucida and fusion of the sperm and egg cell membranes, important enzymatic events prevent polyspermy (i.e., fertilization by more than one spermatozoon). 1. Cortical reaction. Enzymes that prevent additional spermatozoa from penetrating the oocyte membrane are released from granules in the egg cortex.

2. Zona reaction. Cortical granule enzymes alter the zona pellucida, making the zona impenetrable to additional spermatozoa.

B. Continuation of meiosis. Fusion of the sperm and egg cell membranes also induces the resumption of meiosis in the oocyte. 1. The oocyte now completes the second meiotic division, which results in what is called the definitive oocyte as well as the second polar body.

2. The genetic material of the sperm and oocyte are enclosed within structures called the male pronucleus and female pronucleus.

ifitshicat

7

Embryology

Cytoplasm of oocyte

Plasma membrane of oocyte

Perivitelline space.

Second meiotic metaPhase

Zona pellucida

First polar body

"Acrosome reaction" perforations in acrosome wall and enzymes breaking down zona pellucida

Figure l-2-1 . Fertilization.

FUSION OF THE MALE AND FEMATE PRONUCLEI A. Genetic composition of the pronuclei. The female pronucleus contains 22 + X chromosomes, and the male pronucleus contains either 22 +Y or 22 + X chromosomes.

B. Zygoteformation. Fusion of the pronuclei to produc e the rygote

is considered the beginning

of embryonic development and entails the following:

l.

It restores the diploid number of chromosomes (a6) in the rygote.

2.

It

determines the sex of the embryo. An X-bearing sperm produces an XX (female) individual, whereas a Y-bearing sperm produces an XY (male) individual.

3. It triggers

iliB[ical

a series

of rapid mitotic divisions called cleavage.

First Week

After fertilization and formation of the zygote, designated as day 1 of embryogenesis, the first week

is

characterized by the mitotic divisions of cleavage, formation of the blastocyst, and implantation. This chapter discusses the events that occur during the first week of zygote development.

CTEAVAGE Cleavage is the series of cell divisions that occur as the zygote passes down the uterine tube on its way to the uterus. Cleavage begins within 24 hours of zygote formation. With each division, the daughter cells, called blastomeres, become smaller because these divisions are not accompanied by cell growth.

A. Compaction begins with the eight-cell

Note

stage.

1. In compaction, the loosely organized blastomeres flatten and are held together by tight

junctions.

Although uterine tube the

2. This process also segregates inner blastomeres from outer blastomeres. Inner blastomeres

Ter m i n

o Io

term, the synonyms oviduct and fallopian tube are

communicate closely via gap junctions.

B. Morula. By the third or fourth day, the compacted embryo contains 16-32 cells and is referred to as the morula.

commonly used.

1. The inner cells of the morula give rise to the inner cell mass.

2. The outer cells give rise to the outer cell mass.

BTASTOCYST FORMATION A. Blastocele. Once the morula is inside the uterus, fluid begins to accumulate in the intercellular

spaces

in the morula and forms a central cavity known

is

g i o An oto m i co

as the blastocele.

B. Blastocyst (Figure I-3-1). The rygote, now free of its zona pellucida, is called a blastocyst and consists of two cell groups. 1. The embryoblast (inner cell mass) projects into the cavity. The embryoblast gives rise to

the embryo proper.

2. The trophoblast (outer cell mass) forms an outer epithelial layer that surrounds the embryoblast and blastocele. The trophoblast gives rise to the fetal portion of the placenta.

ifits[ical

Embryology

Uterine stroma

Elastocyst

Uterine,epithetium

Trophoblast

f

Syncytiotrophoblast Embryoblast

{Cytotrophobtast-

Outer cell mass or trophoblast lnner cell mass or embryoblast

Figure l-3-1. Blastocyst at 5 days.

IMPTANTATION A. Normal

Clinical Correlate The presence of hCC in urine

or serum is a commonly used method for pregnancy testing.

1. Implantation begins by the end of the first week, when the trophoblast cells over the embryoblast pole invade the endometrial epithelium of the uterine body. After the embryoblast is embedded within the endometrial stroma, the surface is repaired by a blood clot, which is later replaced by epithelial overgrowth.

2. When the embryo implants, the trophoblast produces human chorionic gonadotropin (hCG). This is a hormone that maintains the corpus luteum, and its progesterone secre-

tion until the placenta begins to produce its own progesterone. B. Abnormal 1. The blastocyst may implant cervix.

in an abnormal site in the uterus near the internal os or

2. Implantation outside the uterus is referred to Clinical Correlate Due to the narrowness of

the uterine tube, ectopic tubal pregnancies that persist beyond the fifth week can rupture the tube.

as an

ectopic pregnancy.

a. Implantation of this type usually results in abortion and severe hemorrhaging during the second month of pregnanry.

b. Ectopic sites of implantation occur in the uterine tube (tubal pregnancy), on the surface of the ovary, or in the abdomen, where they often are found in the rectouterine (Douglas) pouch. C. Proliferation of the trophoblast 1. The trophoblast proliferates and differentiates into two cell layers. a. The cytotrophoblast is the single-celled layer adjacent to the embryoblast.

b. The syncytiotrophoblast is a thick outer layer that lacks cell boundaries and grows into the endometrial stroma.

2. Excessive growth of the trophoblast may result in proliferation of vesicular masses called hydatidiform moles. Moles secrete hCG and may give rise to benign or malignant tumors.

t0

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Second Week

The second week of development is characterized by continued implantation and expansion of the

synrytiotrophoblast until it surrounds the entire embryo and the uteroplacental circulation is established. During this period, the embryoblast splits into two germ layers: the epiblast and hypoblast. The blastocyst cavity is replaced first by the primary yolk sac and then by the secondary

yolk sac, and the amniotic and chorionic cavities appear.

FORMATION OF BITAMINAR DISC At the beginning of the second week, the cells of the embryoblast begin to differentiate into two layers, the epiblast and hypoblast, forming a bilaminar disc (Figure I-4-1).

A. Epiblast (primary ectoderm) consists of high columnar cells that separate from the cftotrophoblast to form the amniotic cavity. The roof of this cavity is lined by the ectodermal amnioblasts, which are adjacent to the cytotrophoblast. The remaining portion of the epiblast layer lines the floor of the cavity. During the third week, the epiblast gives rise to two germ layers: the embryonic ectoderm and mesoderm.

B. Hypoblast (primary endoderm) consists of low cuboidal cells adjacent to the blastoryst cavity. This layer contributes to the lining of the primaryyolk sac.

TROPHOBTAST DEVELOPMENT A. Extraembryonic mesoderm

l.

12, the trophoblast gives rise to the extraembryonic mesoderm, which is loosely arranged around the amnion and primitive yolk sac.

On days 11 and

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||

Embryology

Cytotrophoblast

Syncytiotrophoblast Enlarged blood vessels (sinusiods)

Amnioblasts

Amniotic cavity

Figure l-4-1. Blastocyst at 10 days.

2. Cavities within the extraembryonic mesoderm quickly fuse to form the extraembryonic coelom. The coelom divides the mesoderm into the extraembryonic somatic mesoderm, which covers the cytotrophoblast and amnion, and the extraembryonic splanchnic mesoderm, which covers the yolk sac. B. Uteroplacental

l.

circulation

The trophoblast and extraembryonic somatic mesoderm lining comprise the chorion.

2. Tiophoblastic erosion of maternal blood vessels allows blood to flow from sinusoids (enlarged, congested capillaries of the endometrium) into the lacunar or intervillous spaces that have formed in the embryonic synsftiotrophoblast. When this occurs, the primitive uteroplacental circulation is established. C. Chorionic cavity

l.

The expanded extraembryonic coelom forms the chorionic cavity on day 13.

2. The bilaminar embryo, amnion, and yolk sac are suspended in this cavity by the connecting stalk, which is a condensation of extraembryonic mesoderm that later develops into the umbilical cord. 3. At this time, the secondary (definitive) yok sac is pinched off from the primary yolk sac (Figure I-4-2).

l2

iliBtical

Second Week

Lacunar network

Maternal sinusoid

Future

connecting stalk Amniotic cavity

Extraembryonic somatic mesoderm

Secondary yolk sac

Extraembryonic coelom (chorionic cavity)

Figure l'4'2. Blastocyst at 14 days.

D. Decidual reaction. During week 2 of development, cells of the decidua, the functional layer of the pregnant endometrium, respond to implantation and progesterone secretion by enlarging

*d

"..rr*ulating

glycogen and lipid. The entire tissue becomes edematous. This

response is known as the decidual reaction.

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t5

Third Week

The third week of development is characterized by the formation of all three germ layers during the

process known as gastrulation. Thus, the bilaminar disc is converted into the triiaminar disc. lt

is

during this period that the cephalocaudal, left-to-right, and anteroposterior axes of the body are established. In addition, the notochord develops, the allantois appears as a posterior diverticulum of the yolk sac, and the trophoblast expands rapidly to form a complex set of villi that ensure the exchange of gases and nutrients between maternal and embryonic tissues.

FORMATION OF TRILAMINAR DISC A. Primitive streak 1. During the third week of development, the cephalocaudal axis of the embryo becomes defined by the primitive streak, which is a linear thickening of the ectoderm cells on the caudal part of the dorsal embryonic disc. The streak is delimited rostrally by the primitive node.

2. The epiblast cells of the primitive streak proliferate and migrate inward (invagination) between the epiblast and hypoblast layers. Initially, they replace the original hypoblast with the definitive endoderm. Migrating epiblast cells then form a third germ layer, the intraembryonic mesoderm. The remaining epiblast cells are the ectoderm. Thus, the three definitive germ layers are derived from the epiblast. B. Intraembryonic mesoderm 1. Mesodermal cells form a loosely arranged tissue known as mesenchyme. The lateral extension of mesoderm establishes direct contact with the extraembryonic mesoderm that covers the yolk sac and amnion.

2. Ectodermal and endodermal layers fuse at the cephalic and caudal ends of the embryonic disc to form the buccopharyngeal and cloacal membranes, respectively (Figure I-5-1). Migrating mesodermal cells do not penetrate these areas but pass on either side to surround them. Rostral to the buccopharyngeal membrane, the mesoderm forms the cardiogenic plate that will give rise to the heart.

ifitsttical

t5

Embryology

Amniotic ectoderm

Hensen node (primitive knot)

Embryonic ectoderm

Yolk sac

Caudal end

Embryonic entoderm Prochordaf plate Notochord

lntraembryonicmesoderm Cloacalmembrane

Figure l-5-1. Longitudinal section of embryo at 17 days.

of the primitive streak. The primitive streak usually degenerates and disappears. However, in abnormal cases, some remaining multipotent cells of the streak may give rise to sacrococcygeal teratomas, which are tumors of many cell types, found on or near the midline. More common in females than in males, these tumors may become malignant.

C. Fate

FORMATION OF NOTOCHORD A. Day

16. About this time, cells of the primitive streak migrate rostrally and form the tube-like notochordal process.

B. Day 17. By this time, the mesoderm layer and notochordal process (a mesodermal derivative) separate the ectoderm and endoderm layers entirely, with the exception of the buccopharyngeal and cloacal membranes.

C. Day f8. By this time, disintegration of the floor of the notochordal process and the fused underlying endoderm opens a transient passage, the neurenteric canal, which connects the yolk sac cavity and the amniotic cavity.

FORMATION OF AIIANTOIS On about day 16, the allantois forms as a diverticulum of the posterior wall of the yolk sac, which extends into the connecting stalk. Both the allantois and the yolk sac are responsible for early blood formation, which previously took place extraembryonically. At the beginning of the third week, angioblasts in the visceral mesoderm of the yolk sac wall form clusters and cords that become canalized. Centrally located cells give rise to primitive blood cells and cells on the periphery flatten to form endothelial cells that line blood islands.

r6

iliBtical

Third Week

TROPHOB LAST DEVETOPM ENT The chorion differentiates to form chorionic

villi during

the third week of development (Figure

l-s-z). A. Primaryvilli are formed when cords of cytotrophoblast cells migrate into the irregular processes of the syncytial layer. B. Secondary

villi

are formed when the extraembryonic mesoderm of the chorion invades the

cytotrophoblastic core of the primary villi. C. Tertiaryvilli are formed by organization of the core mesoderm into capillaries. These capillaries make contact with vessels of the connecting stalk and chorion, which, in turn, make contact with the intraembryonic circulatory system to connect the placenta to the embryo.

Sinusoids

rlonlc cavity cavlly Chorionic

TrophoblaStiC lacunar

(intervillous) network

Figure l-5-2. Diagram of trophoblast with embryo (teft) and longitudinal section of villus (right) during the third week.

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t7

Fourth to Eighth Weeks

Beginning approximately in the third week and extending through the eighth week

is

the interval known

as the embryonic period. This period of embryogenesis and organogenesis is characterized by the

cephalocaudal and lateral folding that transforms the embryonic disc into a tube and by the formation of

the organs and systems of the major external

bod

bod from

derivatives of the three germ layers. At the end of this period,

features are recognizable. The subsequent interval from the beginning of the third

month until parturition is known as the fetal period, a period of organ system maturation and

bod

groMh. This chapter revievr,s the processes that occur during the embryonic period.

ECTODERMAT DERIVATIVES A. Central nervous system (CNS) (Figure I-6-1) 1. Neural plate. At the cephalic region of the embryo, the notochord induces a thickening of ectoderm, which becomes the neural plate. The neural plate increases in length as the primitive node and primitive streak move caudally.

2. Neural groove and neural crest. Invagination of the neural plate by day 18 results in the formation of the neural groove. The lateral edges of the plate form neural folds, which join in the midline as the neural groove deepens. The edge of each fold is known as the neural crest. 3. Neural tube. The neural tube is formed as the neural folds fuse in the midline. Fusion begins in the region of the future neck (fourth somite) and proceeds in cephalic and caudal directions.

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re

Embryology

Neural plate

Neural

fold

Notochordal process

Neural

Ectoderm Mesoderm Endoderm Neural groove

Neural crest

Day 18

Neural fold Rostral neuropore Failure to close results in ancephaly, causing polyhydraminos and increased alpha{eto protein.

B--

Neural crest

ln a Nutshell

Caudal neuropore (closes at27 days)

Ectodermal Derivatives

. . .

Nervous system Otic and lens placode

Day 22

Skin, hair, nails, tooth

enamel

.

Ectodermal Neural Crest Derivatives Dorsal root ganglia Sensory ganglia of cranial nerves

. . . . .

Failure to close results in spina bifida AlPhafeto protein.

Figure l-6-1. Neural tube development (cross-section).

Pituitary and mammary glands

. .

Neural crest

Autonomic ganglia Meninges Schwann cells Adrenal medulla Melanocytes

20 iliB[ical

4. Brain and spinal cord. The cephalic end of the neural tube eventually dilates to form the forebrain, midbrain, and hindbrain. The spinal cord is formed from the remainder of the tube. Neural crest cells form the dorsal root ganglia, sensory ganglia of the cranial nerves' autonomic ganglia, meninges, Schwann cells, adrenal medullary cells, melanocytes, and ectomesenchyme of the head and neck. B. Otic placode and lens placode. Subsequent to neural tube closure, two additional ectodermal Gickenings, the otic placode and the lens placode, appear in the cephalic region of the embryo.

l.

The otic placode invaginates to form the otic vesicle, which gives rise to the organs of hearing and equilibrium.

2. The lens placode invaginates to form the lens vesicle, which forms the lens during the fifth week of development. C. Other ectodermal derivatives include skin, hair, nails, subcutaneous glands' mammary glands, pituitary gland, and tooth enamel.

Foufih to Eighth Week

MESENCHYMAT DERIVATIVES By day 17, the originally diffuse intraembryonic mesoderm becomes differentiated into three distinct regions. Paraxial mesoderm forms tissue columns on either side of the embryonic midline. This region is contiguous laterally with the intermediate mesoderm, which, in turn, is contiguous with the lateral mesoderm (Figure I-6-2).

A. Paraxial mesoderm 1.

On day 20, the paraxial

mesoderm tissue begins division into segmental blocks or somites. The first pair of somites appears in the cervical region. Subsequent pairs appear in a craniocaudal sequence, approximately three per day, unt:.J42 or 43 pairs are present by the end of the fifth week.

2. Beginning in the fourth week, each somite becomes differentiated into a ventromedial sclerotome and a dorsolateral dermamyotome. The dermamyotome further differentiates into dermatome and myotome regions (Figure I-6-2). a. Sclerotome cells migrate medially to the notochord and differentiate to form the bones, cartilage, ligaments of the vertebral column, and part of the base of the skull. b. Dermatome cells migrate laterally under the ectoderm to form the dermis and subcutaneous tissues of the skin.

c. Myotome cells give rise to skeletal muscles. B. Intermediate mesoderm. Cephalic intermediate mesoderm becomes arranged in cell clusters, which are the future nephrotomes. Caudal intermediate mesoderm forms an unsegmented mass of tissue known as the nephrogenic cord. This tissue will give rise to portions of the urogenital system.

Surface ectoderm

Paraxial rnesoderm

termediate mesoderm

ln a Nubhell Mesodermal Derivatives

al mesoderm

. Connective tissue (bone, cartilage)

Figure l-6-2. Development of mesoderm.

C. Lateral mesoderm tissues divide into two layers. 1. The somatic (parietal) mesoderm is continuous with the mesoderm covering the amnion. The somatic mesoderm and overlying ectoderm form the lateral and ventral body wall.

2. The splanchnic (visceral) mesoderm is continuous with the extraembryonic coelom on either side of the embryo. The splanchnic mesoderm and underlying endoderm form the wall of the gut. Cells facing the coelomic caviry form serous (mesothelial) membranes that line the pericardial, pleural, and peritoneal cavities.

. Muscle . Dermis . Urogenital system . Serous membranes

lining

the pericardial, pleural, and peritoneal cavities

.

Vascular $ructures, including

lymphatics

. Adrenal cortex . Spleen

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2l

Embryology

D. Other mesodermal derivatives include striated, cardiac, and smooth muscle; connective tissue, including cartilage and bone; blood cells and vessels; lymph cells and vessels; kidneys, gonads, and their ducts; the cortical portion of the adrenal gland; and the spleen.

EN

DODERMAL DERIVATIVES

A- Gastrointestinal tract. The endodermal germ layer gives rise to the gastrointestinal tract. This formation depends on the cephalocaudal and lateral folding of the embryonic disc into a tube-like gut. 1. Head and tail folds. Rapid longitudinal growth of the CNS causes the cephalic and caudal ends of the embryonic disc to bend and form the head and tail folds. a. Head fold. As a result of the head fold, the brain comes to lie cranial to the cardiogenic area and septum transversum, which contributes to the formation of the diaphragm. Part of the yolk sac becomes incorporated into the embryo as the foregut. This cavity opens into the midgut via the anterior intestinal portal and is bordered anteriorly by the buccopharyngeal membrane. This membrane forms the back of the stomodeum, or primitive mouth, which appears as a depression in the surface ectoderm. The buccopharyngeal membrane ruptures at the end of the third week to establish communication between the amniotic cavity and the primitive gut (Figure I-6-3). b. Tail fold. As a result of the tail fold, the proximal part of the allantois is incorporated into the cloaca. The distal part of the allantois remains in the connecting stalk, which fuses at the end of the fourth week with the yolk sac stalk to form the umbilical cord.

Part of the yolk sac is incorporated into the hindgut. The hindgut connects to the midgut at the posterior intestinal portal and is bordered posteriorly by the cloacal plate, which is known as the cloacal membrane at this stage. This membrane forms the floor of the proctodeum, a depression in the surface ectoderm, which divides into the urogenital and anal membranes (Figure I-6-3).

Allantois

Tailfold

Figure l-6-3. Longitudinal section of embryo showing head and tail folds at 26 days.

22

ilits[ical

Fourth to Eighth Week

2. Midgut. Continued growth of the somites causes the expanding lateral margins of the embryonic disc to bend ventrally, forming lateral folds. As a result of this folding, part of the yolk sac is taken into the embryo to form the midgut. In addition, this folding constricts the initially wide communication between the embryo and yolk sac to a narroq long vitelline duct, which eventually lies within the umbilical cord. B. Other endoderrnal derivatives include the epithelial lining of the primitive gut and the intraembryonic portions of the allantois and yitelline duct. Derivatives also include the epithelial linings of the respiratory tract, urinary bladder, urethra, tfmpanic cavity, and eustachian tube, as well as the parenchyma of t-he thyroid, parathyroids, thymus, liver, and

pancreas.

DEVETOPMENTAT CHANGES DURING THE EMBRYONIC A. Fourth

l.

PERIOD

week

Most body systems, as well

as

ttte eyes, nose, and ears, appear in rudimentary

form.

develop. 3. Arm and leg buds form small surface projections. 2. Four pairs of branchial (pharyngeal) arches

ln a Nutshell Endodermal Derivatives

. .

. . . . .

c.rdr^inrpctinat
Lining of respiratory

tra4

bladder, and urethra

4. The heart begins beating, and a primitive circulatory system connects the capillary plexuses of the yolk sac and chorion with the embryo. Partitioning of the atrium begins. Hematopoiesis still occurs in the yolk sac. 5. The crown-rump length of the embryo is approximately 5 mn. B. Fifth week 1. Parathyroids, spleen, genital ridges, and external genitals form.

2. The stomach starts to rotat€, and the midgut forms

a

loop.

3. Hand plates are distinguishable on the forelirnbs.

4. Cardiac septa form, and atrioventdcular (AV) cushions fuse. 5. Cartilage and muscle begin to form.

6. The crown-rump length is approximately 8 mm. C. Sixth week 1. Limbs subdivide into limb, forelimb, and hand or foot. Finger rays arise in the hand plate.

2. The heart is almost frrlly formed. The foramen primum closes, and the aorticopulmonary septation is complete. Hematopoiesis occurs in the liver. 3. Paramesonephric ducts are pres€nt, and sex cords start to develop. 4. Chondrification and intramembranous ossification occur in the skeletal system. 5. The crown-rump length is approximately

14

rnrn.

D. Seventh week

1. Notches app€ar between the ra)'s of the hand plate. 2. The ventricular septurn is fully formed. 3. The crown-rump length is approdmately 22 mm.

ifiBhical 2t

Embryology

E. Eighth week

l.

The head increases in size and is as large as the rest of the body. The neck region develops. The forebrain vesicle expands, and neuromuscular development permits fetal movement.

2. The body is covered with thin skin. 3. The

eyes are

directed forward instead of laterally.

4. Digits appear first on the hands and later on the feet. 5. The mesonephros is fi.rlly formed, and the metanephric duct is branching. 6.

Testes and ovaries are

visible, but external genitalia are not distinguishably different.

7. The crown-rump length is approximately 30 mm.

ESTIMATION OF EMBRYONIC AGE Methods of estimating embryonic age are based upon the mother's memory of specific reference points or upon the external appearance of the embryo.

A. Specific reference points. Estimations are made from 14 + 2 days after the onset of the mother's last menstrual period or from the day of fertilization.

B. External appearance of the embryo

l.

The number of somites can be counted. An embryo has approximately 28 somites by the end of the fourth week. As somites become less conspicuous during the second month of development, this method becomes less reliable.

2. Crown-rump length, which is measured from the vertex of the skull to the midpoint between the apices of the buttocks; the crown-heel length, which is measured from the vertex of the skull to the heel of the fooq and external features, such as the development of limbs and digits, are other measures used to estimate embryonic age.

24 iliE[ical

Ninth Week to Parturition

Beginning at the ninth week and extending until birth is the interval called the fetal period. During

this period little new differentiation occurs, but maturation of the organs and systems occurs. lt

is

also during this time that the body experiences rapid groMh. In the 30-week fetal period, the fetus grows from approximately 8 g to a birth weight of about 3,400 g. The first portion of this period characterized by a rapid growth in

is

lengh;the latter portion is characterized by a groMh in weight.

This chapter reviews the developmental processes that occur during the fetal period as well as the processes that occur during parturition.

FETAL PERIOD A. Third lunar month 1. The fetus nearly doubles in length, but growth of the head slows relative to the rest of body. The eyes and ears come to be located near their final positions, and the eyelids fuse. Lanugo (soft, downy hair) appears on the head and at the eyebrows.

2. The upper limbs nearly attain their final proportioned length, and nails begin to form. The lower limbs are less well developed. 3. The intestinal loops of the midgut withdraw from the umbilical cord into the abdominal cavity. The kidneys have begun to secrete urine, and the fetus is swallowing amniotic fluid. 4. The external genitalia are sexually distinguishable. B. Fourth and flfth lunar months 1. The fetus has a well developed chin.

2. Lanugo covers the entire body, and hair appears on the head. 3. The skin is covered with vernix caseosa, a whitish mixture of fetal sebum and dead epidermal cells that is thought to act

as

protection against the amniotic fluid. The vernix may

be held in place by the lanugo.

4. Brown fat, important in heat production, is formed. 5. The mother can recognize fetal movements, or quickening, and the fetal heart beat may be heard.

ifitshical

25

Embryology

C. Sixth lunar month 1. The skin is wrinkled. The lack of subcutaneous fat gives the skin a red color, which is due to underlying muscle and capillary blood.

2. Eyebrows and eyelashes are present, and the eyelids have opened. D. Seventh lunar month 1. Deposition of subcutaneous fat begins.

2. Until late in this period, the fetus would have difficulty surviving extrauterine life because the respiratory system is not fully developed and the CNS is just becoming able to regulate breathing.

E. Eighth lunar month

l.

The subcutaneous fat increases, and the skin appears smoother and pinker.

2. Lanugo hairs begin to be shed.

F. Ninth lunar month 1. The fetus appears plump.

2. In males, the left testis has descended into the scrotum. G. Tenth lunar month 1. More fat is deposited, bringing the percentage of white fat in the body from 3.5o/o at 6 months to 160/o at frrll term.

2. In males, both testes have descended. 3. The fetus has attained a crown-rump length of 360 mm and a weight of 3,000-3,400 half of the weight is gained in the last 3 months.

g;

BIRTH Birth usually occurs within 10-14 days of the expected date, which is considered to be 280 days from the first day of the last menstrual period in women with regular menstrual rycles or 266 days after fertilization.

A. Fetal position at birth 1. At the time of birth, the fetus is usually in a flexed position, its long axis parallel to that of the uterus and its head lowermost. Normally, the fetus is in a transverse position. In breech presentation, the breech, or rump, is lowermost.

2. The enlarged uterus, which previously had risen from the symphysis pubis to the level of the xiphoid process, has again moved downward to a position between the umbilicus and the xiphoid. The height of the uterus during pregnancy is approximately as follows: a. Four months at the symphysis pubis

b. Five months between the symphysis and umbilicus c. Six months at the umbilicus d. Eight months between umbilicus and xiphoid e. Nine months at the xiphoid process

26 liiE[ieal

Ninh Week to Parturition

B. Labor. The precise mechanism(s) that trigger(s) labor is (are) not fully understood. It is likely that a wide variety of hormones and other factors are involved. For example, increases in local prostaglandin levels as well as an increase in the local estrogen-to-progesterone ratio increase uterine contractions. In addition, oxftocin-like substances produced by the placenta upon signals from the fetal adrenal cortex, or oxytocin released from the maternal neurohlpophysis, can also stimulate contractions. These contractions are not dependent upon extrinsic innervation and are not disturbed by spinal anesthesia. Their strength and duration, however, may be regulated by oxytocin from the maternal neurohypophysis. Labor, or parturition, continues through three stages.

l.

First stage extends from onset of regular contractions until dilation of the cervix is complete. During this stage, the amniotic fluid and fetal membranes serye as a hydrostatic wedge in the cervical canal. Late in this stage, the membranes are ruptured and amniotic fluid is released. The average duration is 10-12 hours for first pregnancies (primigravidas) andT hours for later pregnancies (multiparas).

2. Second stage

is from full dilation of the cervix to complete delivery of the conceptus by combined action of uterine contractions and reflexive abdominal contractions. The average duration is 50 minutes for primigravidas and 20 minutes for multiparas.

3. Third stage is from the birth of the infant to the expulsion of the placenta, which separates from the uterine wall through the decidua basalis and attached membranes. The maternal surface of the expelled placenta is characterizedby grooves of the placental septa that divide the placenta into cotyledons. The fetal surface is characterized by the vessels associated with it. Contractions of the uterus constrict the spiral arteries and prevent excessive bleeding. The average duration is less

umbilical cord attachment and than 30 minutes. C. Abnormal fetal growth

1. Premature infants are characterized by 28-38 weeks.

a

birth weight of

2,500 g or less and a gestation

of

2. Small-for-dates infants are fi,rll-term, low-weight infants. They have wrinkled skin due to a lack of subcutaneous fat, which may be caused by placental dysfunction. 3. Infants of diabetic mothers may be abnormally heavy and large. Maternal hyperglycemia and fetal insulin secretion are thought to stimulate the growth of the fetus.

iliEf,ical

27

Fetal Membranes and Placenta

The four extraembryonic membranes are the chorion, yolk sac, allantois, and amnion. The placenta is a compound organ that incorporates the fetal chorion frondosum and the maternal decidua basalis. This chapter reviews the different extraembrvonic membranes and their functions.

CHORION A. Chorion frondosum and chorion laeve 1. In early development, secondary and tertiary chorionic villi cover the entire surface of the chorion. However, as pregnancy advances, the villi on the embryonic pole enlarge to form the chorion frondosum, whereas those on the opposite (abembryonic) pole degenerate by the third month to form the chorion laeve.

2. The decidua over the chorion frondosum is called the decidua basalis; it is tightly connected to the chorion. The decidual layer over the abembryonic pole is the decidua capsularis; this layer stretches as the chorion enlarges and subsequently degenerates.

3.

The chorion laeve fuses with the decidua parietalis, on the opposite side of the uterus, and the uterine cavity is obliterated.

B. Placenta. The placenta is established by the end of the third month. It has two components: a fetal portion formed by the chorion frondosum (including vascularized allantoic mesoderm) and a maternal portion formed by the decidua basalis.

ifitsbical

zs

Chonon trondosum

Decidua basalis

(bushy)

Chorionic cavity Ulerine cavity

Decrdua basalis

Oecidua

Inlernal os

Interuillous space

Smooth chorion Degenerating decidua capsulans Uterine cavltY

Decrd0a parielaiis

Amniochorionic membrane

Figure l-8-1 . Fetal membrane development.

l.

Placental circulation a. Maternal blood enters the intervillous spaces under pressure through 80-100 spiral endometrial arteries. The blood then flows over the surface of villi of the chorion frondosum and is drained by endometrial veins.

b. Deoxygenated fetal blood is brought to the chorionic villi by the two umbilical arteries and their branches. Orygenated blood from the placenta is returned to the fetus by venules that join to form the umbilical vein. 2.

Placental functions a.

A

gas exchange

of oxygen and carbon dioxide

as well as nutrient and electroly.te

exchange are important functions of the placenta.

b. Excretion of embryonic wastes including

CO, urea, uric acid, and bilirubin

occurs.

c. Antibody transmission in which the fetus acquires maternal IgG antibodies occurs. The fetus obtains passive immunity against some diseases such as diphtheria, smallpox, and measles, but not against chickenpox and whooping cough. d. Hormone production, including estrogens, progesterone, hCG, somatomammotropin (hCS), is also an important function.

50

iiiBhical

and chorionic

Fetal Membranes and Placenta

YOTK SAC A. Description. At the end of the second month, the yolk which continues to shrink during development.

sac is a small, pear-shaped

structure,

1. The dorsal part of the yolk sac is continuous with the primitive gut, from which the epithelium of the trachea, bronchi, lungs, and digestive system is derived.

2. The vitelline duct connects the yolk to lie within the umbilical cord.

sac

to the midgut. This duct and the yolk sac come

3. In approximately 2olo of adults, the yolk sac stalk persists as an outpouching of the ileum called Meckel diverticulum.

B. Functions of the yolk sac

l.

During the second and third week of development, a function of the yolk sac is the transfer of nutrients to the embryo from the trophoblast via the extraembryonic coelom and mesoderm.

2. The primordial germ cells originate from the yolk

sac

during the third week.

3. There is formation of blood cells and formation of blood vessels that join with the vitelline arteries and veins. The arteries arise from the dorsal aorta and eventually fuse to form the single superior mesenteric artery to the midgut.

AttANTOIS A. Description. The allantois arises as a diverticulum from the posterior yolk sac that forms the hindgut. It grows into the body stalk and, thus, is incorporated with the body stalk into the umbilical cord. The intraembryonic allantois persists as the urachus, which runs from the urinary bladder to the umbilicus. After birth, this becomes the median umbilical ligament. B. Functions of the allantois. Although the allantoic

sac is vestigial in humans, its abundantly vascularized mesoderm provides the blood vessels for the chorion to establish the definitive

chorioallantoic placenta. The allantois is responsible for the formation of the umbilical bloodvessels (two arteries, one vein).

AMNION A. Description. The amnion is the thin, nonvascular membrane that lines the amniotic cavity. It is formed from an internal ectoderm layer and an external extraembryonic mesoderm layer.

B. Amniotic fluid. The amniotic cavity is filled with fluid derived from the maternal blood, but in late pregnanry, it also contains some fetal urine. Amniotic fluid is rapidly turned over via the placental membrane. Beginning in the fifth month, it is also swallowed and returned to the circulation via the fetal gastrointestinal tract.

]. Hydramnios, or excessive amniotic fluid, is a condition often

associated with twins, maternal diabetes mellitus, anencephaly, and esophageal atresia. In the latter two cases, it may be related to the inability of the fetus to swallow.

2. Oligohydramnios, or insufficient amniotic fluid, is almost always associated with absent fetal renal function and is the cause of deformities of the skull, limbs, and trunk.

iliB[ical

5l

Embryology

C. Amniocentesis. The amniotic fluid contains fetal cells, which may be sampled by amniocentesis. Karyotyping of these cells allows detection of chromosomal abnormalities. Cell culture may be used to diagnose inborn errors of metabolism. Examination of the amniotic fluid also allows determination of the amount of fetal blood cell destruction by maternal antibodies in cases of Rh incompatibility.

D. Umbilical cord. As the embryo develops, it bulges into the amniotic cavity and is cushioned by the amniotic fluid. Growth of the embryo causes expansion of the amniotic cavity and the obliteration of the extraembryonic coelom. As a result, the amnion and chorion fuse, while the body stalk and yolk sac become incorporated into the umbilical cord.

l.

The umbilical cord initially contains the vitelline vessels, allantois, umbilical vessels, remnants of the chorionic cavity, mesenchyme of the body stalk (which is rich in glycosaminoglycans and is called Wharton jelly), and the intestinal loops (which cannot be accommodated by the abdominal cavity and are extruded in a physiologic umbilical hernia).

2. Later, the yolk sac, vitelline vessels, allantois, and remnants of the chorionic cavity are obliterated and the intestinal loops are withdrawn, leaving only the umbilical vessels and Wharton's jelly in the umbilical cord (Figure I-8-2).

Yolk sac and vitelline vessel

Amniotic cavity Connecting

Chorionic piate

Allantois

Primitive urnbilical

cavity

Figure l-8-2. Umbilical cord at 10 weeks.

,2

iiitsfical

Fetal Membranes and Placenta

TWINS A. Dirygotic (fraternal) twins represent two thirds of the total number of twins. They arise from two ova, each fertilized by a sperm, to give two zygotes. Each zygote forms its own fetal membranes, and the twins are no more similar than any pair of siblings. The placentas and chorions may or may not fuse. B. Monorygotic (identical) twins arise from a single fertilized ovum or zygote that splits. They are genetically identical, and, except in cases of the "fetal transfusion ,1-dro-"" *i.r" blood is shunted from one twin to the other through placental vessel anastomoses, they are physically and mentally similar.

l. If splitting

occurs at the two-cell stage, the twins have two amnions, two chorions, and two placentas that may or may not fuse.

2' Splitting at the inner cell mass stage, which occurs most frequently, results in twins that have their own amnion but share chorions and placentas.

3. Splitting during later stages of development results in twins that also share an amnion. These often become entangled in their umbilical cords and die. 4. Incomplete splitting causes conjoined twins. Twins that share no major organ systems may be separated surgically.

ifiB&ical ,t

Body Cavities and Mesenteries

Three potential cavities sunounded by serous membranes result from the partitioning of the

embryonic coelom: pericardial, pleural, and peritoneal. When the continuity between the extra- and intraembryonic coelom is lost, the somatic mesoderm gives rise to the parietal layers of the serous membranes, and the splanchnic mesoderm gives rise to the visceral layers. The formation of the diaphragm separates the coelom into thoracic and peritoneal portions, and subsequently the pleuropericardial membranes separate the thoracic cavity into pleural and pericardial cavities.

Double layers of the peritoneal serous membrane develop into the mesenteries. This chapter reviews the formation of the mesenteries and the body cavities that they define.

FORMATION OF COETOMIC CAVITY At the end of the third week, the lateral plate mesoderm divides into two layers: the somatic (parietal) mesoderm and the splanchnic (visceral) mesoderm. These two layers border a space known as the intraembryonic coelom. With cephalocaudal and lateral folding of the embryonic disc, the intraembryonic coelom loses its connection with the extraembryonic coelom and extends from the thoracic to the pelvic regions. Mesothelial cells of the somatic mesoderm give rise to the parietal serous membranes lining the outside of the coelomic cavities. Splanchnic mesoderm gives rise to the mesothelial covering of the abdominal organs, lungs, and heart.

DIAPHRAGM The diaphragm divides the coelom cavity into the thoracic cavity and the peritoneal cavity.

A. Development. The adult diaphragm develops from the following four structures:

l

Septum transversum is a mesodermal plate between the pericardial cavity and the vitelline duct. It forms in the neck region and moves caudally with its nerve supply as the heart descends from neck to thorax. It fuses dorsally with the mediastinum and pleuroperitoneal membranes to form the muscle and central tendon of the diaphragm.

2. Pleuroperitoneal membranes. By the seventh week, these membranes are fused with the dorsal mesentery of the esophagus and the dorsal portion of the septum transversum to form a partition between the thoracic and abdominal portions of the coelom. 3. Dorsal mesentery of foregut forms the left and right crura of the diaphragm.

4. Muscular components of lateral and dorsal body walls form the peripheral portions of the diaphragm.

ilits[ical 55

Embryology

Mnemonic C3, C4, C5 keep the

diaphragm alive.

B. Innervation. The diaphragm receives innervation from the third, fourth, and fifth cervical segments of the spinal cord. With the descent of the diaphragm to the level of the first lumbar vertebra, the phrenic nerves lengthen. The peripheral muscular elements of the diaphragm are innervated by intercostal nerves. However, the bulk of diaphragmatic muscle receives its motor supply via the phrenic nerves.

THORACIC CAVITY A. Pericardioperitoneal canals. The thoracic and peritoneal cavities

are

initially continuous via

paired pericardioperitoneal canals on either side of the foregut.

B. Pleuropericardial membranes. Lung buds grow into the canals and subsequently expand into the body wall mesenchyme. In this manner, the body wall is split into two components: the thoracic wall and the pleuropericardial membrane (a thin la,ver of mesoderm that contains the common cardinal vein and the phrenic nerve). Right and left pleuropericardial membranes fuse at the midline to divide the thoracic cavity into a pericardial cavity and two pleural cavities.

l.

The pleuropericardial membranes form the adult fibrous pericardium.

2. The connection between the thoracic and abdominal portions of the coelomic cavity

is

closed by the pleuropericardial membranes.

MESENTERIES The lateral folding of the embryonic disc causes the lateral edges of the intraembryonic coelom to fuse in the midline, which partitions the peritoneal cavity into two halves. Splanchnic mesoderm encloses the primitive gut and is suspended fiom the dorsal body wall as a doubleJayered membrane, the dorsal mesentery. The ventral mesentery is formed from the mesoderm of the septum transversum and, thus, extends for only a short distance along the gut, leaving the left and right halves of the peritoneal cavity in free communication.

A. Dorsal mesentery extends from the lower end of the esophagus to the cloacal region of the hindgut. It serves as a pathway for blood vessels, nerves, and lymphatics supplying the intestinal tract. 1. Dorsal mesogastrium is the mesentery of the stomach region. a. During the fourth week, clefts appear in the mesentery dorsal to the stomach. These clefts fuse to form the omental bursa (lesser peritoneal sac) behind the stomach.

b. During the fifth week, the spleen develops between the layers of dorsal mesentery behind the stomach. The spleen maintains connections to the dorsal body wall in the region of the left kidney (lienorenal ligament) and to the stomach via dorsal mesentery derivatives (gastrolienal ligament). c. Positional changes of the stomach cause the dorsal mesentery forming the left wall of the omental bursa to grow downward and extend over the transverse colon and small intestine as the apron-like greater omentum. The posterior layer of the omentum fuses with the anterior surface of the transverse colon.

2. Dorsal mesoduodenum is the mesentery of the duodenal region. The rotation of the stomach and duodenum and the rapid growth of the head of the pancreas cause the duodenum and the head of the pancreas to be pressed against the right dorsal body wall. The surface of the dorsal mesoduodenum fuses with the adjacent peritoneum and disappears. Therefore, the duodenum and pancreas lie retroperitoneally.

t6

ilitsUicar

Body Cavities and Mesenteries

3. Mesentery proper is the mesentery of the primitive intestinal loop. a. It originally is attached to the posterior abdominal wall in the midline. Rotation of the midgut causes the mesentery to twist around the origin of the superior mesenteric artery. The mesenteries of the ascending and descending portions of the colon press against the peritoneum of the posterior abdominal wall and fuse. These structures lie in a retroperitoneal position. The appendix and cecum retain their free mesentery. b. The transverse mesocolon fuses with the posterior wall of the omental bursa, remaining intraperitoneal, and is attached from the hepatic flexure ofthe ascending colon to the splenic flexure of the descending colon.

B. Ventral mesentery. The hepatic bud, an endodermal derivative from the foregut, grows into the ventral mesentery, which forms the fibrous capsule and connective tissue of the liver. 1. As the liver grows into the abdomen, the ventral mesentery between the liver and ventral body wall becomes stretched and membranous and forms the falciform ligament. The

free margin of the falciform ligament contains the umbilical vein, which, after birth, is obliterated to form a fibrous cord called the ligamentum teres.

2. Similarly, the ventral mesentery between the liver and the ventral stomach-duodenal border forms a membrane called the lesser omentum. The free margin of the lesser omentum contains the bile duct, portal vein, and hepatic artery.

CONGENITAT ANOMATIES A. Diaphragmatic hernia, a relatively common anomaly, is caused by failure of the pleuroperitoneal membranes to close the pericardioperitoneal canals. It occurs more frequently on the left side than on the right and may herniate through the diaphragm into the pleural caviry which, in some cases, retards growth of the lungs, displaces the heart and mediastinum to the right, and impairs initiation of respiration at birth. 1. Parasternal hernia occurs more often in the anterior portion and is caused by failure some diaphragmatic muscle fibers to develop.

of

2. Esophageal hernia is a protrusion of the stomach into the thorax and its subsequent constriction by the diaphragm. It is probably caused by

a shorter length

of the esophagus than normal.

B. Mobile cecum and colon caused by to incomplete fusion of the ascending mesocolon with the peritoneum of the posterior abdominal wall. If a long mesocolon remains, intestinal twisting (i.e., volvulus) and obstruction of the ascending colon may result. It is treated by fixation of the ascending colon to the posterior abdominal wall.

iiiBfical

,7

Pharyngeal Arches and Their Derivatives

The pharyngeal (branchial) arches contribute to the formation of the lower head and neck. In the

fourth and fifth weeks of development, these structures appear as condensations of mesenchymal tissue on the lateral walls of the foregut at the level of the pharynx. The arches are demarcated internally by the endodermally lined pharyngeal pouches and externally by the ectodermally lined pharyngeal clefts (Figure l-10-1). The mesenchyme of the arches is derived from mesoderm and neural crest.

Maxiiiary proc

Mandibular process

pn^,vnqear{i

arch6s

i; Primitive forelimb

Figure l-10-1. Fetus at 32 days showing (A) pharyngealclefts outside embryo and (B) pharyngeal pouches inside embryo.

ifiB[ical

59

Embryology

PHARYNGEAT ARCHES

Note . KememDer InaI tne lerms "pharyngeal" and "branchial" mean the same thing.

The mesenchyme core of the pharyngeal arches gives rise to the musculature of the face and neck. Each arch has its own cranial nerve and arterial components.

A. First pharyngeal (mandibular) arch

l.

Musculature

You may see the term

,,branchial',

a. Muscles of mastication: temporalis, masseter, and pterygoids

some review books. Another term that is used synonymously is "visceral" arches. used in

b. Anterior belly of the digastricus

,, , c' MYlohYoideus ,

d. Tensor tympani e. Tensor veli palatini

2. Skeletal component. The mesenchyme divides into tral mandibular process.

a dorsal

maxillary process and

a

ven-

a. The maxillary process extends anteromedially beneath the eye to give rise to the max-

illa, zygomatic, palatine, and squamous temporal bones through intramembranous ossification. b. The mandibular process gives rise to the mandible; its dorsal end (Meckel cartilage) becomes ossified to form the malleus and incus.

3. Cranial nerve component of the first pharyngeal arch gives rise to the maxillary and mandibular divisions of the trigeminal nerve (cranial nerve V). B. Secondpharyngeal (hyoid) arch

l.

Musculature a. Muscles of facial expression: orbicularis oris and occuli, platysma, auricularis, bucci-

nator, occipitofrontalis b. Stapedius c. Stylohyoid d. Posterior belly of the digastricus

2. Skeletal components. The mesenchl.rne forms

a

cartilaginous bar, called Reichert's cartilage.

a. The dorsal part of Reichert cartilage forms the styloid process of the temporal bone.

b. The intermediate part forms the stylohyoid ligament. c. The ventral part of Reichert's cartilage forms the superior part of the body of the hyoid bone.

3. Cranial nerve component is the facial nerve (cranial nerve VII) C. Third pharyngeal arch

1 Musculature includes

the stylopharyngeus

2. Skeletal components. The ventral portion persists to form the greater cornu of the hyoid bone and the inferior part of the body of the hyoid bone.

40

iiiBbicat

Pharyngeal Arches and Their Derivatives

3.

Cranial nerve component is the glossopharyngeal nerve (cranial nerve IX).

A

Arterial component of the third pharyngeal arch

is the common carotid and roots of the

internal carotid arteries. D. Fourth pharyngeal arch 1. Musculature includes the constrictors of the pharynx, the cricothyroid, and the levator

veli palatini.

In a Nutshell

2. Skeletai component includes the thyroid cartilage.

Cranial Nerve Innervation of Arches

3. Cranial nerve component is the superior laryngeal branch of the vagus nerve (cranial nerve X).

.

4. Arterial component is the right subclavian artery and the arch of the aorta.

E. Fifth pharyngeal arch. In human embryos, the fifth arch is either short lived or does not

nerve)

.

3rd arch = CN lX (glossopharyngeal nerve)

.

4th arch = CN X (superior laryngeal branch of the

3. Cranial nerve component is the recurrent laryngeal branch of the vagus nerve (cranial nerve X). 4. Arterial component includes the roots of the right and left pulmonary arteries and the ductus arteriosus.

arch = CN V (maxillary

. 2nd arch = CN Vll (facial

1. Musculature includes the intrinsic laryngeal muscles.

2. Skeletal components include the laryngeal cartilages.

st

the trigeminal nerve)

develop.

F. Sixthpharyngeal arch

I

and mandibular divisions of

vagus nerve)

. 6th arch = CN X (recunent laryngeal branch of the vagus nerve)

PHARYNGEAT POUCHES A. First pharyngeal pouch forms a diverticulum, called the tubotympanic recess, that contacts the epithelial lining of the first pharyngeal cleft, which is the future external auditory meatus. The distal portion of outpocketing widens to form the middle ear caviry and the proximal portion remains narrow to form the eustachian tube. Its lining forms the inner epithelial covering of the tympanic membrane.

B. Second pharyngeal pouch. The epithelial lining buds into the mesenchyme to form the palatine tonsil. Part of the pouch remains in the adult as the tonsillar fossa. C. Third pharyngeal pouch. The ventral wings of the paired third pharyngeal pouches give rise to the thymus, and the dorsal wings differentiate into the inferior parathyroid glands. 1. Thymus arises as a bilateral diverticulum, which grows inferiorly to the superior medi-

astinum, solidifies, and fuses. a. Endodermal cells multiply to give rise to the epithelial reticulum of the thymus as well as Hassall's (thymic) corpuscles. b. Lymphoid tissue invades the thymus by the fourth week.

2. Inferior parathyroid glands develop as a proliferation of endodermal cells and travel with the thyroid to lie on the dorsal surface of this gland.

In a Nutshell Pouch Derivatives

. Middle ear= lst pouch .

Eustachian tube

= lst pouch

. Palatine tonsil = 2nd pouch .

Thymus = 3rd pouch

. Inferior parathyroids = 3rd p0ucn

. Superior parathyroids = 4th pouch

. C cells of thyroid = 5th p0ucn

D. Fourth pharyngeal pouch. The endodermal proliferation of the dorsal wing cells gives rise to the superior parathyroid glands, which come to lie on the posterior surface of the thyroid gland.

E. Fifth pharyngeal pouch is the last of the pharyngeal pouches to develop. It forms the ultimobranchial bodies, which give rise to the calcitonin-secreting parafollicular (C) cells of the thyroid.

iiiBhical

4l

PHARYNGEAL CTEFTS Four pharyngeal clefts are present in the 5-week-old embryo. Only the fust pharyngeal cleft contributes to embryonic structures. It penetrates the underlying mesoderm, forming the external auditory meatus and the outer epithelial lining of the tympanic membrane.

OTHER PHARYNGEAT DERIVATIVES A. Tongue 1. Development a. During the fourth week, three swellings originate from the first pharyngeal arch: two lateral lingual swellings and one medial swelling, called the tuberculum impar. b. Another median swelling, the hlpobranchial eminence (copula), is formed from the mesoderm of the second through fourth arches. c. The posterior part of the fourth arch gives rise develops as the epiglottis.

to a third median sweliing, which

d. The lateral lingual swellings grow over the tuberculum impar and fuse in the midline, forming the anterior two thirds of the tongue.

2. Innervation a. The first pharyngeal arch mucosa is innervated by the lingual nerve, which is a branch of the mandibular division of the trigeminal nerve. b. The posterior third of the tongue arises from the second through fourth arches. The sensory innervation ofthis part ofthe tongue is from the glossopharyngeal nerve.

c. The epiglottis and the extreme posterior part of the tongue, fourth-arch derivatives, are innervated by the superior laryngeal nerve. d. The musculature of the tongue is innervated by the hypoglossal nerve.

3. Tongue musculature is mainly derived from occipital somites.

B. Thyroid gland originates as an endodermal mass at the level of the foramen cecum, pharyngeal diverticulum between the tuberculum impar and the copula.

a

1. As the thyroid descends in front of the pharynx, it maintains its connection to the tongue by the thyroglossal duct, which normally disappears.

2. Ectopic thyroid tissue may occasionally be found along the path of its descent. 3. The thyroid gland lies in front of the trachea during the seventh week and produces colloid by the end of the third month. C. Face, jaws, palate, and nose 1. Face and palate are formed by mesenchymal swellings, which grow and fuse during the second month. a. Mandibular processes, caudal to the stomodeum, meet lower jaw, lip, and part of the face.

in the midline to form the

b. Frontal prominence, at the upper border of the stomodeum, forms the forehead and apex of the nose. Two ectodermal invaginations, the nasal pits, divide this single mesenchymal prominence into two lateral and two medial nasal swellings. The lateral swellings become the sides of the nose. The medial swellings form the midpart of the

42 iliBticat

Pharyngeal Arches and Their Derivatives

nose, the midpart, or phi,ltrum, of the upper lip, the middle portion of the upper jaw and associated gingiva, and the primary palate.

c. Maxillary processes move medially to form the lower border of the developing orbit and push the medial nasal processes to the midline. The latter then merge with each other and the maxillary processes. The lateral nasal swellings extend from the eye to the mouth and form the nasolacrimal duct. d. Secondary palate forms from the palatine shelves, which grow out of the maxillary processes. These fuse in the midline above the tongue and anteriorly with the primary palate, which carries the incisors. Posterior outgrowths of these shelves give rise to the soft palate. Simultaneously, the nasal septum, a downgrowth of the merged medial nasal swellings, fuses with the cephalic aspect of the palate.

2. Conchae, or lateral elevations, are formed in the nasal cavities. Specialized olfactory epithelium, which sends fibers to the olfactory bulbs within the cranial caviry is formed in the roof of each cavity. The paranasal air sinuses form as outgrowths of the lateral nasal wall into the maxilla, ethmoid, frontal, and sphenoid bones. D. Teeth 1. Dental lamina. Teeth develop from outbuddings epithelial lining of the upper and lower jaws.

of the dental lamina, located in the

a. Epithelium from the outer dental layer differentiates into ameloblasts, which form

tooth enamel. b. Mesenchyme cells adjacent to the inner dental layer differentiate into odontoblasts,

which form dentin. c. Mesenchyme cells outside the tooth differentiate into cementoblasts, which produce

cementum. d. The periodontal ligament, another mesenchymal derivative, anchors the tooth into position on the alveolar bone.

2. Deciduous "milk" teeth appear 6-24 months after birth. Buds for the permanent teeth are formed during the third month.

CONGENITAT ANOMATIES A. Branchial fistula allows remnants of the second throush fourth clefts to maintain surface connection through this canal. B. Mandibulofacial dysostosis is a syndrome of malformations mainly caused by abnormal development of derivatives of the first arch. Insufficient migration of neural crest cells is an important factor. Symptoms include: 1. Bony defects of malar bone and mandible

2. Malformed ears and palate

Bridge to lmmunology

3. Defects of lower eyelid

The immunologic

C. DiGeorge syndrome is characterized by the poor development or absence of several structures, including the thymus and parathyroids. This condition is caused by abnormal development ofthe third and fourth pharyngeal pouches and associated neural crest.

consequences of DiCeorge syndrome are discussed in detail in the Clinical

lmmunology chapter of Ceneral Principles Book

1

(Volume l).

iiitshical

4t

Embryology

D. Thyroglossal cyst is a remnant of the thyroglossal duct. It is found anywhere along the migratory path of this structure but is usually close to the midline. It may be connected externally by the thyroglossal fistula.

E. Cleft lip and cleft palate are relatively common abnormalities resulting from a variety of environmental as well as genetic factors. They may be bilateral or unilateral. 1. Cleft

lip is caused by failure of the maxillary

swellings.

processes

to fuse with the medial nasal

It most often occurs on the upper lip.

2. Cleftpalate is usually associated with cleft upper lip. It is caused by the failure of the palatine shelves to fuse. Severe cleft palate may not allow the infant to suckle properly, and milk may be regurgitated through the nose or aspirated into the lungs.

u

iliii&ical

Congenital Abnormalities

Congenital malformations are structural abnormalities present at birth. Although accurate comparative international statistics about the incidence of various malformations do not exist, it

is

generally thought that 2-50lo of liveborn infants demonstrate one or more anomalies at birth and

that an addition al 2-30/0 of abnormalities are detected during the first year. Although a small percentage of congenital defects are known to be genetically determined, and others have been

shown to be caused solely by environmental factors, the majority probably result from an interplay of factors. This chapter reviews some of the most common congenital anomalies.

TERATOGENIC AGENTS Teratogenic agents are factors that cause abnormal development and congenital anomalies. In addition to the tfpes of factors involved, the time of exposure is also important. These agents are most harmfi.rl during periods of intensive differentiation.

A. During the pre-embryonic period, teratogenic agents usually cause death or abortion by impeding implantation or killing all the cells. Less likely effects are the death of a few cells followed by complete compensation of the remaining, still multipotent, cells. Interference with meiotic disjunction is another less common indirect cause of congenital anomalies. B. Teratogens are most likely to produce major malformations during the embryonic period of organogenesis. Within this period, each organ goes through its most critical stage of early differentiation. C. During the fetal period of organ growth, susceptibility decreases, and teratogens are most likely to produce minor defects. Because parts of the brain and urogenital system continue to differentiate late in pregnancy, they remain sensitive to the actions of teratogens.

CHROMOSOMAT AND GENETIC FACTORS A. Numerical chromosomal abnormalities are usually caused by nondisjunction, that is, failure of one or more pairs of homologous chromosomes to separate during meiosis. This situation typically results in germ cells of 22 and24 chromosomes, which form monosomic and trisomic zygotes of 45 and 47 chromosomes, respectively. Becaused increased maternal age increases the frequency of autosomal trisomies, they are thought to be due primarily to nondisjunction during oogenesis. Some trisomies, as well as monosomy of are compatible with life. Monosomy of an autosome is uniformly fatal.

a sex

chromosome,

iiiBhical

45

Embryology

l. Trisomy2l (Down syndrome) a. In some cases, the extra chromosome 21 is translocated or

attached to another chromosome. A carrier parent (clinically normal) with 45 chromosomes who has a translocated chromosome 21 has an increased chance of having a child with the syndrome.

b. Tiisomy 21 is characterized by mental deficienry, small skull size, upwardly slanting palpebral fissures, and a deep transverse crease across each palm. c. It is associated with an increased incidence of congenital heart defects, umbilical hernia, and duodenal atresia.

2. Trisomy 18 (Edward syndrome) is characterized by mental retardation, receding chin, abnormal skull shape, low-set ears, and flexed fingers. It is often associated with syndactyly, cardiac anomalies, and skeletal defects.

3. Trisomy 13 (Patau syndrome) is characterized by mental retardation, malformed ears, a small head, congenital heart defects, renal anomalies, cleft lip and palate, deafness, and eye defects.

4. Klinefelter syndrome (most commonly

)ffY)

a. This syndrome is characterized by sterility, small testes, degeneration of seminiferous tubules, gynecomastia, tallness, and, sometimes, mental retardation. b. Within the nucleus, a darkly staining chromatin region, or Barr body, can be found. The presence of this sex chromatin is due to the random condensation and "shutdown" of all X chromosomes except one. The Barr body is usually present only in

normal females. 5. Turner syndrome (XO) or ovarian dysgenesis a. This syndrome is characterized by the absence of ovaries, dysmenorrhea, and infantile external genitalia and mammary glands. b. No sex chromatin is present. c. Turner syndrome is often associated with short stature, webbed neck, lymphedema of the extremities, skeletal defects, no or mild mental retardation, and congenital heart defects.

B. Structural chromosomal abnormalities are usually due to chromosomal breakage caused by environmental factors. 1. Chromosomal deletions occur when a portion of the chromosome is lost. An example of this abnormality is the cri-du-chat syndrome that results from a partial deletion of the short arm of chromosome 5. Affected children have a high-pitched, cat-like cry, mental retardation, microcephaly, and congenital heart defects.

2. Fragile chromosomal sites are portions of chromosomes that are unusually susceptible to breakage. An example of this abnormality is the fragile X syndrome, in which a fragile site on the X chromosome is associated with an altered phenotype. Affected individuals are mentally retarded.

C. Single gene mutations 1. Autosomal dominant mutant gene anomalies include: a. Huntington disease b. Marfan syndrome

c. Osteogenesis imperfecta

46 iiitshieal

Congenital Abnomalities

d. Adult polyrystic kidney disease

e. Familial adenomatous polyposis

f. Familial

hypercholesterolemia

g. von Recklinghausen disease

2. Autosomal recessive mutant gene anomalies include: a. Cystic fibrosis

b. Hemoglobinopathies c. Phenylketonuria d. Thalassemias e. Albinism

f. |uvenile

polyrystic kidney disease

g. Congenital adrenal hyperplasia

3. Sex-linked mutant genes involve abnormal recessive genes on the X chromosome and consequently are expressed in males. Anomalies include: a. Hemophilia b. Duchenne muscular dystrophy

c. G6PD deficiency d. Color blindness

ENVI RON MENTAI. FACTORS

Bddge to Microbiology

Rubella, CMV, and herpes bloodstream. l. Rubella (German measles) causes malformations, which are usually the result of mater- il:.iff'||:l{'|!?t[[i nal infection during the first trimester. It may cause: principles Book I (Volume l).

A. Infectious agents can cross the placental barrier and enter the fetal

a. Cataracts and glaucoma

b. Cardiac septal defects and persistence ofpatent ductus arteriosus c. Destruction of the organ of Corti in the ear, leading to deafiress d. Microcephaly and mental retardation

2.

Syphilis is discussed

in the Spirochetes chapter, and Toxoplosmo is reviewed in the Protozoa chapter of this same volume.

Cytomegalovirus (CMV). The mother is usually asymptomatic. It is thought that only fetuses infected during late pregnancy survive and exhibit anomalies, which include: a. Microcephaly, hydrocephalus, mental retardation, and cerebral calcifications

b. Chorioretinitis and microphthalmia c. Hepatosplenomegaly

3.

Herpes simplex virus can be acquired by the fetus at birth if the mother has a genital infection. This condition leads to abnormalities, including chorioretinitis. Congenital anomalies, which result from infection in utero, include:

irntf,ical

47

Embryology

MnemOnit

a. Microcephaly and mental retardation

are sometimes referred to as "ToRCHes" organisms:

b' Microphthalmia and retinal dysplasia

Transplacental infections

' Toxoplasma . Rubella . CMV . Herpes, HIV ' Syphilis

c. Hepatosplenomegaly

4. Toxoplasma gondii,a protozoan infection, can result in anomalies such as: a. Cerebral calcification, microcephaly, hydrocephalus, and mental retardation b. Microphthalmia and chorioretinitis

5. Syphilis is caused by Treponema pallidum. Congenital syphilis can result in growth retardation and abnormal brain and skeletal development.

B. Irradiation. Aithough the evidence regarding the hazards of diagnostic levels of radiation is not definitive, large loses of radiation or exposure to atomic fallout are known to be teratogenic. Anomalies include skull defects, skeletal defects, spina bifida, microcephaly, mental retardation, cleft palate, and mutations on germ cells, which lead to congenital anomalies in future generations. C. Drugs 1. Alcohol. Exposure to alcohol can result in fetal alcohol syndrome. It is associated with a number of fetal defects, including growth retardation, abnormal brain development and CNS dysfunctions, cardiac abnormalities, facial dysmorphism, and joint defects.

2. Thalidomide is a sedative that was used widely by pregnant women from 1960 to 1962 until it was withdrawn from market. It causes anomalies such as absent or defective long bones, resulting in amelia or meromelia (i.e., total or partial absence of extremities), gastrointestinal defects, and cardiac defects. 3. Tetracycline exposure can result in teeth and skeletal abnormalities.

4. Isotretinoin exposure can result in

ear,

brain, and heart malformations.

5. Chloramphenicol exposure can cause gray baby syndrome. 6. Aminopterin and its derivative methotrexate, antitumor agents and folic acid antagonists, cause anomalies including: a. Skeletal defects b. Anencephaly, hydrocephalus

c. Cleft lip and palate d. Abortion

7. Antithyroid drugs (thiouracil, iodides, radioactive iodine) can cause goiter.

8. Environmental chemicals, such as organic mercury present in fish from polluted waters or certain fungicides sprayed on grain, cause anomalies including neurologic symptoms resembling cerebral palsy and blindness. D. Hormones 1. Progestins (e.9., ethisterone and norethisterone) may produce various degrees of masculinization of the genitalia in female embryos, including: a. Clitoral hypertrophy b. Labial fusion

c. Hypoplasia ofuterus and vagina in severe cases

4s

ilitstical

Congenital Abnormalities

2. Cortisone. Although this steroid has been shown to cause cleft palate in laboratory animals, its potential teratogenic effect in humans remains to be determined. E. Nutritional deficiencies

l.

Maternal diabetes. Abnormal changes in the carbohydrate metabolism of the mother is often the cause of abortions, stillbirths, neonatal deaths, and abnormally large infants.

2. Maternal iodine deficiency causes cretinism.

iiiii&ical

4s

sEcTroN

il

Histology

Epithelial tissue consists of a variety of celltypes with a minimal amount of extracellular material,

which together line and cover virtually all free surfaces of the body. Epithelia are derived from all three germ layers and form sheets composed of groups of cells, in one or more layers, joined by specialized adhesions. The apical surfaces of epithelia face the free surface of the

bod

or lumen of

an organ or gland, and the basal surfaces re$ on the basement membrane. Epithelial tissues are avascular so that nutrients and blood gases must diffuse

from blood vessels located in the

underlying connective tissues to the more superficially located epithelial cells. This chapter reviews

the different types of epithelium and their functions within the body.

CTASSIFICATION OF EPITHETIA A. Surface epithelia are classified on the basis of two major characteristics: the number of cell layers in the epithelium (i.e., simple or stratified) and the shape of the cells in the surface layer (i.e., squamous, cuboidal, columnar).

l.

Simple epithelia are defined as a single layer of cells in which all cells rest on the basement membrane. a. Sirnple squamous epithelium is one layer of flattened, scale-like cells (e.9., alveoli

of

Flashback to. Emlryology

lungs). In two locations, this epithelium has particulnr names:

(1) Endothelium lines the cardiovascular and ly-ph

Both endothelium and

vessels.

mesothelium are derived

(2) Mesothelium lines the pleural, pericardial, and peritoneal cavities.

from mesoderm.

b. Simple cuboidal epithelium is one layer of cells that are usually as tall as they are wide, as seen in vertical section (e.g., ducts of many glands).

c. Simple columnar epithelium is one layer of cells that are taller than they are wide, seen in vertical profile (e.g., intestinal absorptive cells).

as

2. Pseudostratified epithelium

is often considered as a variant of simple epithelium because all of the cells rest on the basement membrane, despite the fact that their nuclei appear to be stratified because some of the cells do not reach the free surface. Two important pseudostratified epitheiia are:

a. Respiratory epithelium is pseudostratified, ciliated, and columnar with goblet cells, as found in the conducting airways of the respiratory tract (e.g., trachea). b. Urothelium transitional epithelium, found in the urinary system, is also pseudostratified.

3. Stratified epithelia are defined as two or more layers of cells where only the basal layer rests on the basement membrane.

iiiBbical rI

Histology

a. Stratified squamous epithelium consists of multiple layers of cells and a surface layer of flattened, squamous cells.

Note Stratified epithelia are poorly

(l)

suited for functions of

Stratified squamous keratinizing epithelium occurs in the epidermis of the skin.

(2) Stratified squamous nonkeratinizing epithelium occurs in such

absorption and secretion due

areas as the oral

caviry esophagus, and vagina.

to their thickness. They are well suited for protective

b. Stratified cuboidal epithelium exhibits cuboidal-like surface cells (e.g., in the ducts of salivary glands).

function instead.

c. Stratified columnar epithelium exhibits columnar surface cells (e.g., in portions of the male urethra).

B. Glandular epithelia consist of single cells or groups of cells specialized for secretion. They are classified as exocrine (i.e., their secretions enter into a duct system) or endocrine (i.e., their secretions enter blood vessels). Exocrine glands are generally classified on the basis of the following four factors:

l

Number of cells a. Unicellular glands are defined as single cells interspersed among other epithelial cells of different functions (e.g., goblet cells). b. Multicellular glands occur as many adjacent secretory cells within the epithelium (e.g., surface mucous cells of stomach) or as complex glands with ducts (e.g., pancreas).

2. Duct system and secretory portion a. Simple glands have a simple, unbranched duct with tubular or acinar (alveolar) secre-

tory pieces. b. Compound glands have a branched duct system with tubular, acinar, or tubuloacinar secretory units.

3. Typeofsecretion a. Mucous glands secrete a variety of viscous mucins rich in protein and polysaccharides.

b. Serous glands secrete

a

watery fluid containing proteins.

c. Mixed glands contain both mucus and serous secretory units.

In a Nutshell

.

Merocrine-involves exocytosis; most common

form of secretion

.

Apocrine-discharge of the portion of the cell with secretory product included; e.g., lipid products of

mammary gland

.

Holocrine-discharge of whole cell; e.g., sebaceous gland

54

ifiB[ical

4. Mechanism of secretion a. Merocrine secretion involves exocytosis. The membrane of the secretory granule fuses with the plasma membrane to release the contents of the granule.

b. Apocrine secretion is the mechanism by which both the secretory product and a portion of the apical secretory cell cytoplasm are pinched off and released.

c. Holocrine secretion is the mechanism by which entire cells and their contained secretory product are released. Cellular death occurs in this process. 5. Myoepithelial cells are myoid (muscle-like) cells that contain contractile filaments and assist in the secretion of certain glands (e.g., sweat, salivary, mammary). Derived from ectoderm, they are situated between the secretory cells and their basement membranes.

Epithelium

EPITH

ELIAI SPECIAIIZATIONS

A. Apical (free) surface specializations 1.

Microvilli are apical cell surface evaginations of cell membrane with cores of microfilaments that function to increase the cell surface area available for absorption. They are covered by a thick glycocalyx coat, which gives a positive periodic acid-Schiff (PAS) appearance under the light microscope. The core of each microvillus is anchored in the apical cell qtoplasm to the terminal web, which itself is anchored to the zonula adherens of the cell membrane (Figure

II-l-1).

2. Stereocilia are elongated microvilli found at the apices of cells lining the epididyrnis, ductus deferens, and hair cells of the inner ear where they play a role in auditory sensation. 3. Cilia are apical cell surface projections of cell membrane that contain microtubules. a. Longer and coarser than microvilli, cilia are inserted on centriole-like basal bodies present below the membrane surface at the apical pole.

b. Electron microscopy reveals the structure of cilia. They contain a central pair of microtubules, which are encircled by nine pairs of microtubules that all run in the direction ofthe long axis ofthe cilia. c. The cilia move back and forth to propel fluid and particles in one direction.

4. Flagella are longer than cilia but have the same microstructure; a prominent example in the sperm, where the single flagellum provides motility.

is

B. Lateral surface specializations

l.

Zonula occludens (tight junction) occurs on the lateral cell surfaces just beneath the api-

Note

cal poles.

a. Formed by the interactions of specific integral membrane proteins of apposed cell membranes, these junctions serve as permeability seals of the paracellular compartment. b. Each contact point represents a tiny ridge that, together with other ridges, form an anastomosing network that interlocks tightly across the intercellular gap.

c. The zonula occludens network extends completely around the apical cell borders to seal the underlying intercellular clefts from contact with the outside environment. d.

In addition, it prevents leakage of materials, including ions, bidirectionally between epithelial cells.

2. Zonula adherens (adheringjunction)

lies basal to the zonula occludens. It is also like junction but serves in the attachment of adjacent epithelial cells.

In some epithelia (e.9., intestinal absorptive cells),

junctional complexesconsisting of occluding junctions, adhering junctions, and desmosomes-bridge the gap between the lateral surfaces of contiguous epithelial cells to seal and attach adjacent epithelial cells.

a

band-

ifitstical

55

Histology

3. Macula adherens (desmosome) is formed by the jrxtaposition of two disk-shaped plaques contained within the cytoplasm of each adjacent cell and joined via specific attachment proteins.

Zonula occludens

Glycoprotein Microvilli

Zonula adherens

Desmosome (macula adherens) Gap junction (nexus)

Tonofilaments_

Figure ll-1-1. Surface specializations found on simple columnar epithelial cells.

In a Nutshell

a. Intermediate filaments (tonofllaments) radiate away from the plaques.

Basement membranes

b. Desrnosomes are most common in lining membranes, are subject to wear and tear, and are considered spot welds that hold cells together.

provide elastic support, attach epithelia to the underlying connective tissues, and act as selective diffusion barriers.

4.

Macula communicans (gap junction) is an area of communication between adjacent cells that allows the passage of very small particles and ions from one cell to another.

junction consists of a hexagonal lattice of tubular protein subunits called connexons, which form hydrophilic channels connecting the cytoplasm of adjacent cells.

a. The

b. The communicating channels through the gap junction permit the direct passage of ions and small molecules between cells to conduct electrical impulses or other signals.

c. Gap junctions are the sites of intercellular communication between epithelial cells as well as between cells of other tissues that require direct communication (e.g., impulses for smooth muscle contraction).

56 iiitstical

Epithelium

C. Basal surface specializations 1. Basement membrane is a sheet-like structure that underlies virtually all epithelia. It consists of the following:

a. Basal lamina is composed of type fV collagen, glycoproteins (e.g., laminin), and proteoglycans (e.g., heparan sulfate). b. Reticular lamina is composed of delicate reticular fibers.

2. Hemidesmosomes resemble half-desmosomes and are found at sites where epithelial cells are attached to extracellular material, like the basement membrane. A complete desmosome, therefore, is found only on surfaces facing contiguous epithelial cells. In addition, intercellular attachment within desmosomes involves adhesion proteins of the cadherin variety, whereas hemidesmosomes use integrins.

ifitstical

57

SECTION

III

Pathology

Cellular iniury and inflammation are basic processes underlying all cellular and tissue changes in health and disease. These disease states may result from neoplasms, genetic or metabolic disorders,

or from the introduction of exogenous toxic materials. This chapter focuses on the underlying processes causing cellular disease states, and on the mechanisms by which the cell adapts to its external stimuli.

CEttUtAR INIURY AND ADAPTATION Pathologic processes are manifested at the cellular, organ, and whole body levels. Cell survival depends on the maintenance of homeostasis, a stable internal environment, which requires a constant supply of metabolic energy and active transport processes. Before the microscopic appearance of cell injury, critical alterations of basic biochemical pathways must occur. When this homeostatic state is disrupted sublethally, the cell first adapts to the change. If the cell is unable to firlly adapt, cell injury ensues. Injury at first causes reversible changes but may progress ultimately to irreversible injury and cell death. The ability of the cell tr organ to tolerate injury depends on the severity, duration, and type of insult and on the ad-aptive capacity of the tissue.

A.

Causes of cellular

l.

In a Nutshell Homeostatic cell I I

Metabolic changes lschemia Toxins, etc.

,/\ ,/\

Adaptation

injury

Iniury

,a"\

Hnroxia,

a lack of oxygen, leads to the inability of the cell to synthesize sufficient ATp. The loss of ATP production results in a failure of the membrane sodium pump, increased glycolysis, and progressive detachment of the ribosomes from the .o.tgh ".rdoplasmic reticulum. Hypoxia can result from:

.'t

Reversible

changes

\ lrreversible changes

a. Loss of blood supply (ischemia) due to decreased arterial flow b.

A

decrease in the oxygen-carrying capacity of the blood due to anemia or carbon monoxide poisoning; CO produces a stable complex with hemoglobin, blocking O,

transport. c. Poisoning of the enirymes of oxidative phosphorylation by toxins such as ryanide, rotenone, and antimycin A

2. Chemical injury can lead to a disruption of the physical structure of the cell or to a breakdown of the biochemical processes of the cell. For example, chemicals can alter membrane permeability or block the action of an enzyme by binding either to the enzyme or to its cofactor.

3. Physical injury, such

as

crush injuries, gunshot wounds, burns, frostbite, radiation, and

pressure changes, can lead to cell death and inflammation.

lliBhicat

6t

Pathology

4. Infections. Virtually all aspects of cellular metabolism are affected by biologic agents infecting the cell. a. Viruses invade cells, commandeer synthetic machinern and may release proteins that are toxic to host cells and cellular metabolism.

b. Bacteria release exotoxins (e.g., phospholipases) or produce endotoxins (e.g., lipopolysaccharides) from their cell walls. Both cause cell injury and possibly death. c. Viruses, bacteria, parasites, and fungi can cause the host to initiate a cellular (e.g., macrophages, T cells) or humoral (e.g., IgG, IgM) immunologic reaction to the invader.

5. Irnmunologic reactions. Although the immune response is tightly regulated, it can result in injury as manifested by an anaphylactic reaction or autoimmune diseases. Direct injurv to an organism can result from the absence of an immune reaction. 6. Genetic disorders, which can present as biochemical abnormalities, can lead to the accumulation of toxic products or the inabiliry to metabolize various compounds due to enzyme defects, such as rystic fibrosis, sickle cell anemia, and Thy-Sachs disease. Acquired genetic defects (mutations) in genes that govern cell growth and differentiation (oncogenes) may lead to the development of cancer.

7. Nutritional or vitamin deficiencies, hlpervitaminosis, inadequate calorie intake, or inadequate protein intake may all lead to cellular atrophy or even death. 8. Aging can lead to the breakdown of normal cellular machinery, ultimately leading to death of the cell. Some cells, such as gut epithelium or bone marrow stem cells, continuously renew, whereas others, such as neurons and skeletal muscle, may age and die. B. Cellular changes

during injury

1. Cloudy swelling results from disruption of the integriry of the plasma membrane. By inhibiting oxidative phosphorylation, hypoxia results in decreased AIP production. The loss of AIP affects the ouabain-AlPase, causing a failure of the membrane Na' pump. Disruption of the cells' osmotic pumps leads to an influx of Car' and water and an efflux of K'. The cells swell, and the endoplasmic reticulum becomes dilated. A-lthough initially reversible, ultimately injury to the cell becomes irreversible if AIP is not restored.

In a Nutshell Cellular Changes During Injury

.

Cloudy swelling from cell

membrane disruption

. .

products, which by themselves can have a detergent-like effect on the plasma membrane.

3. Dilation and swelling of the endoplasmic reticulum lead to detachment of ribosomes, which leads to a decrease in protein synthesis.

Membrane damage

4. Mitochondrial swelling results in an accumulation of Ca2', which uncouples oxidative phosphorylation.

Endoplasmic reticulum

5. Lysosomes rupture releases digestive enzymes

swelling

. . . .

2. Membrane damage plays a central role in the pathogenesis of irreversible injury. The membrane can be damaged from the loss of membrane phospholipids, breakdown of the cytoskeleton, production of toxic oxygen intermediates, and the production of lipid

Mitochondrial swelling Lysosomal swelling Nuclear changes Apoptosis

62

iiitshical

into autophagic vacuoles or into

the

cytosol.

6. Nuclear changes proceed from chromatin clumping to pyknosis with degeneration and condensation of nuclear chromatin. This can be followed by karyorrhexis (i.e., nuclear fragmentation) or karyolysis (i.e., dissolution of the nucleus). C. Expected pathologic changes

in cell death and injury

1. Coagulative necrosis is the most common form of necrosis in cells without large numbers of lysosomes. The cell is converted into a homogeneous, eosinophi-lic mass with loss of the nucleus but preservation of cellular shape. Coagulative necrosis typically occurs

General Pathology

after sudden ischemia, thermal injury, or toxin injury. The heart is the most common example ofan organ undergoing coagulative necrosis after an injury.

2. Liquefaction necrosis results from cellular destruction by hydrolytic enzymes involved in autolysis and heterolysis. Typically, liquefaction necrosis occurs in brain infarcts and pancreatic necrosis. Liquefaction by leukocytic enzymes is called suppuration, and the resultant fluid is called pus.

3. Caseous necrosis is a combination of coagulation and liquefaction necrosis, which produces tissue that is grossly soft, friable, and "cheese-like." Caseous necrosis is characteristic of tuberculosis, some granulomas and fungal infections, and the center of certain

malignancies.

NOte Squamous carcinomas often necrgse in the center of

4. Enqrmatic fat necrosis is caused by the action of lipases on fatty tissue. teristic of tissues adjacent to acute pancreatic necrosis. 5. Gummatous necrosis is seen in the late stage of syphilis; grossly, lative and liquefactive necrosis by its gelatinous appearance.

It

is

charac-

invasive nodules due to their rapid grOwth.

it differs from coagu-

6. Apoptosis is a specialized form of programmed cell death that is characterized by: a. Chromatin condensation and formation of cytoplasmic membrane blebs (cell surface deformities caused by cytoskeletal disruption)

b. Breakdown of DNA into nucleosome-sized fragments c. RNA and protein synthesis d. A minimal inflammatory response

D. Other cellular alterations during

l.

iojory

Intracellular accumulations a.

Lipids (1) Triglycerides (2) Cholesterol

(e.g., fatty change in liver cells)

(e.g., atherosclerosis)

(3) Complex lipids

(e.g., sphingolipid accumulation)

b. Proteins (e.g., renal epithelial cells in proteinuria) c. Glycogen and complex carbohydrates (e.g., glycogen storage diseases, mucopolysaccharidoses) d. Pigments are colored substances, either normal cellular constituents constituents, that lead to deposits.

or abnormal

(1) Exogenous pigments. Anthracotic pigmentation of the lung is secondary to inhalation of carbon dust.

(2) Endogenous pigments. Lipofuscin (wear and tear pigment), melanin, hemosiderin, and bilirubin all may accumulate either in the cells that made them or in macrophages. 2. Calcification a. Dystrophic calcification appears in areas of necrosis due to precipitation of calcium phosphate in low pH. b. Metastatic calcification caused by hypercalcemia (malignancy, hyperparathyroidism) is due to precipitation of supersaturated solutions of calcium phosphate.

ilitstiical

55

Pathology

E. Adaptive cellular responses to

iniury

1. Atrophyis a loss ofcells or cell substances, resulting in a decrease in cell and organ size. The causes of atrophy are disuse, ischemia, aging, malnutrition, and lack of hormonal or neural stimulation. Atrophy of an organ may be caused by loss of cells, a decrease in cell size, or both. is an increase in both cell and organ size. It is caused by an increased mechanical demand, such as that seen in striated muscle of weight lifters or cardiac muscle in hypertension. It can also be seen with an increased endocrine stimulation. Hypertrophy can be physiologic or pathologic. Hypertrophy of an organ may be caused by an increase in cell number (lactating breast), an increase in cell size (skeletal muscle), or both (many cancers).

2. Hypertrophy

3. Hlperplasia is an increase in the number of cells. It is often associated with hypertrophy. Some cell tfpes are unable to exhibit hyperplasia (e.g., nerve, cardiac, skeletal muscle cells). It can be physiologic or pathologic. Physiologic causes include compensatory (e.9., after partial hepatectomy), hormonal stimulation (e.g., breast development at puberty), or antigenic stimulation (e.g., lymphoid hyperplasia).

4. Metaplasia is a reversible change of one cell type to another, usually in response to irritation. It has been suggested that the replacement cell is better able to tolerate the environmental stresses. For example, bronchoalveolar epithelium undergoes squamous metaplasia in response to chronic irritation of tobacco smoke'

INFTAMMATION AND REPAIR Inflammation enables the body to resist infection. Inflammation occurs in response to injury, which can result from hypoxia, chemicals, drugs, physical agents, microbial agents, immunologic reactions, nutritional imbalances, genetic defects, or aging. The acute inflammatory response occurs over seconds, minutes, hours, and days after the initial insult, whereas the chronic inflammatory response can continue for weeks, months, and even years after the primary injury.

A. Acute inflammation 1. Cardinal signs of inflammation a. Rubor (redness)

b. Calor (heat)

Note Transudate is a protein{ree

fluid leaked to the extravascular space; exudate is fluid

containing proteins and cells leaked to the extravascular space. Transudate is usually caused by pressure differences

between the vasculature and intracellular space (e.g., pulmonary edema in CHF)

Exudate is usually caused by increased permeability of

endothelial cell barriers and chemotactic factors attractin g white blood cells (e.g., lung cancer, infection, toxins).

64 iliBfical

c. Tumor (swelling) d. Dolor (pain) e. Loss of function

2. Pathophysiology. The acute inflammatory response begins with changes in the vasculature. There is a transient vasoconstriction followed byvasodilatation ofthe affected area. Ultimately, the blood flow slows as the vasculature becomes leaky. First, there is a transudate of comparatively protein-free fluid into the extravascular space, followed by an exudate of proteins, cells, and plasma, depending on the severity of the injury' a. Vascular changes (I

is a transient vasoconstriction of arterioles followed by vasodilatation with opening of supplementary capillary beds, which leads to an increased blood flow. Vasodilatation can be mediated by histamine, bradykinin, and, prostaglandins.

) There

(2) Increased vascular permeability or vascular

leakage is caused by endothelial cell

and pericyte contraction, transiently affecting venules; direct endothelial cell injury, affecting all microvessels; leukocyte-dependent injury to vessels; and later, regenerating endothelium.

General Pathology

(3) Chemical mediators of increased vascular permeability include the vasoactive amines, histamine and serotonin, which are stored in the granules of mast cells, basophils, and platelets. They act exclusively on venules (not capillaries). The complement components C3a and C5a are both anaphylatoxins and cause the release of more vasoactive amines. Bradykinin, an end-product of the kinin cascade, can also cause pain. Leukotrienes (i.e., LTC., LID4, LIE4) also individually produce increased vascular permeability.

of the circulation, resulting from increased blood viscosity due to extravasation of fluid, allows leukocytes to marginate, roll, and then adhere to endothelium via specific receptors. These include the integrin family of glyco-

(4) Slowing

proteins (LFA-l,

CDlla/l8) on the neutrophil and intercellular adhesion

molecule (ICAM-1, CD54) on the endothelial cell. Adhesion is Ca2* dependent. (s) Leukocytes emigrate from the vasculature. The marginated, adherent cells extend pseudopods between the endothelial cells. They then move between the endothelial cells, migrating through the basement membrane toward the inflammatory stimulus. (6) Chemotaxis is the attraction of cells toward a chemical mediator that is released in the area of inflammation. Important chemotactic factors include bacterial products, such as N-formylmethionine (a prokaryotic product), LTB' many factors liberated from leukocytes, and IL-8. The two most important chemotactic factors for neutrophils are C5a and IL-8. (7) Phagocytosis. Neutrophils and macrophages engulf and destroy foreign material. The particle to be phagocytosed can be coated with serum opsonins, such as IgG and C3b. These facilitate phagocytosis by allowing the particle to bind to complement receptor I (CRl) and the Fc receptor on the surface of the cell. After the particle is engulfed, the phagocytic vacuole fuses with a lysosome, forming a phagolysosome complex. The lysosome disgorges its contents into the fused vacuole. The offending particle (e.g., a bacterium) is then broken down via the action of reactive oxygen species, acid hydrolases, neutral proteases, and lysozyme. b. Chemical mediators of inflammation. Metabolites of arachidonic acid metabolism mediate many of the important aspects of the inflammatory response. The processing of arachidonic acid occurs via two pathways:

Bridge to Biochemistry

(1) Cyclooxygenase pathway, leading to prostaglandin formation; certain prostaglandins (i.e., PGI, PGD2, PGE2, PGFr") mediate vasodilatation and pain. (2) Lipoxygenase pathway, leading to leukotriene synthesis; certain leukotrienes (i.e., LIB') are involved in chemotaxis and increasing vascular permeability. c. Actions of anti-inflammatory drugs (

1) Aspirin and the nonsteroidal anti-infammatory drugs (NSAIDs) exert their antiinflammatory effect by inhibiting prostaglandin synthesis (cyclooxygenase).

(2) Corticosteroids most likely

act by preventing the transformation of phospholipid

into arachidonic acid by inhibiting the membrane enzyme phospholi-pases. Therefore, they inhibit both prostaglandin and leukotriene synthesis. Corticosteroids also impair leukocyte migration toward an inflammatory focus and stabilize lysosomal membranes.

Linoleic acid I

Arachidonic acid

--- \

(Lipoxygenase)

\

(Cyclooxygenase)

I /l

ll

LTC4

PCC2

LTE4

PCH2

t-TDo

I

(Leukotrieneg-,"

,"\ TXA, (thromboxane)

\ PCF2' PCE2

PCD2

PCl, (prostacyclin)

iiiB[ical

65

Pathology

Note The main cellular component in acute inflammation is the

neutrophil; the main cellular component rn chronic inflammation is the monocytemacrophage.

B. Chronic inflamrnation. Acute inflammation can be resolved completely or progress to chronic inflammation. The activated monocyte-macrophage plays a central role in chronic inflammation. It secretes enzymes such as neutral proteases (i.e., elastase, collagenase) and acid hydrolases (i.e., phospholipases), which can digest connective tissue. The activated monocfte-macrophage acquires the capability in a few days of secreting various plasma proteins, such as complement components Cl to C5, reactive metabolites of oxygen, leukotrienes, prostaglandins, cytokines (i.e., IL-1, tumor necrosis factor), and various growth factors (i.e., fibroblast growth factor, epidermal growth factor, platelet-derived growth factor). Chronic inflammation occurs if the offending agent cannot be removed (e.g., nondegradable foreign bodies, parasites) or ifthe tissue is subjected to repeated episodes of acute inflammation, such as recurrent cholecystitis. 1. Composition of the cellular infiltrate a. Cellular infiltrate is primarily mononuclear with proliferation and maturation monocytes into macrophages (e.g., interferon-y).

of

b. Fibroblasts are recruited and proliferate; small vessels proliferate and subsequent collagen deposition results in fibrosis and scarring.

c. Lymphocytes, plasma cells, and eosinophils are also present in sites of chronic inflammation. d. Neutrophils are occasionally continuously attracted in chronic inflammation associated with pus.

2. Chronic granulomatous inflammation occurs if a substance cannot be completely removed (e.9., asbestos, silica, tuberculous bacilli) or if a cell-mediated reaction is initiated against an agent. It is most frequently seen in tuberculosis (caseating granulomas), sarcoid (noncaseating granulomas), or with foreign bodies. Granulomas are also seen in Crohn disease, gout, rheumatoid arthritis, and in fungal and parasitic infections. a. Granulomas are small (0.5-2 mm) and consist of aggregations of macrophages, which can be transformed into epithelioid cells with occasional multinucleated giant cells. They are often surrounded by lymphocytes as well as plasma cells and fibroblasts. b. Epithelioid cell-modified macrophages with abundant eosinophilic cytoplasm contain large amounts of endoplasmic reticulum, Golgi, and vesicles, which indicate a secretory rather than a digestive function.

C. Repair. Almost as soon as the inflammatory process begins, the repair of the damaged cells and tissues starts. Repair involves two separate processes: regeneration of the damaged tissue by cells of the same type and replacement by connective tissue. Together they constitute wound healing.

l.

Regeneration. Different tissues have different regenerative capacities. a. Labile cells regenerate throughout life. This cell type includes surface epithelial cells, such as those lining the skin, oral cavity, vagina, and cervix; hematopoietic, splenic, and lymphoid cells; and the mucosal cells of all excretory organs. b. Stable cells replicate at a low level throughout lif'e but are dormant unless stimulated by some initiating event; these include the liver, pancreas, kidney, vascular endothelium, and smooth muscle.

c. Permanent cells cannot replicate and include neurons, skeletal muscle, and cardiac muscle.

2. Replacement of a damaged area by connective tissue involves migration and proliferation of fibroblasts into the damaged area, deposition of extracellular matrix, formation of new

66

iiiE&icat

General Pathology

blood vessels, and reorganization of the connective tissue into a scar. Macrophages are usually present initially as the area is being remodeled. Neutrophils, eosinophils, lymphorytes, and mast cells can also be present.

3. Wound healing involves collagen synthesis and degradation. Various growth factors (such as PDGF, transforming growth factors [TGF] cl and B, and FGF) and cytokines (such as tumor necrosis factor [TNF] and IL-1) stimulate collagen synthesis. Collagen can be broken down by various proteases such as collagenase, which can be secreted by macrophages and neutrophils migrating into the damaged area. Wound healing may be prolonged by foreign bodies, infection, ischemia, diabetes, malnutrition, or scurvy. a. Primary union by first intention occurs when there has been little surrounding tissue damage. The wound is clean, and the wound edges are closely approximated.

(1) The wound fills with clotted blood, forming (2) Neutrophils line the wound

edge

within

(3) A thin, continuous epithelial cover

€linical Correlate Scurvy is caused by vitamin C

deficiency; because vitamin C is a necessary cofactor

for the

cross-linking of collagen, scurvy can result in impaired

wound healing because the cross-linking of collagen is

a scab.

essential for its tensile stren$h.

24 hours.

appears

within 24-48 hours.

(4) Macrophages replace neutrophils, and granulation tissue fills in the wound; the epithelial covering thickens.

(5)

By day 5, collagen fibers laid down by fibroblasts cross the incision following fib-

rin and fibronectin matrices. (6) Collagen continues to be (7) Full maturation of

synthesized, and the scar becomes increasingly avascular.

a scar requires up

to I

year.

b. Secondary union by secondary intention occurs when the two skin edges are not in contact. It requires larger amounts of granulation tissue to filI in the defect; it is characterized by significant wound contraction and is mediated by myofibroblasts.

CI RCU

TATORY DISTURBANCES

A. Edema is the presence of

excess

fluid in the intercellular

space.

It

can be localized or gener-

alized and is caused by:

1. Increased hydrostatic pressure due to venous thrombosis (local) or congestive heart failure (generalized)

2. Hypoalbuminemia, resulting in

a decreased

colloid osmotic pressure

J. Lymphatic obstruction 4. Renal retention of salt and water B. Congestion is an excessive amount of blood in an area secondary to diminished venous outflow. \Arith increasing stasis, the area acquires a purplish hue. C. Thrombosis is the solidification of a formed mass of blood components. It requires the interaction of all cells within the vasculature and endothelial cells, as well as circulating elements, such as platelets and the clotting cascade. Clotting is a balance between two opposing forces: those favoring the formation of a stable thrombus and those factors causing breakdown of the clot.

Clinical Correlate Congestion may be seen in purple-discolored legs with chronic venous stasis due

to circulatory failure.

1. Pathophysiology of thrombosis formation. Injury to the vascular endothelium releases factors that both facilitate and inhibit thrombosis.

ifiBtiical

67

Pathology

a. Facilitation (I

)

factor Exposure of tissue factor from injured cells activates

VII'

(2)ExposureofthrombogenicsubendothelialcollagenactivatesfactorXll. generation of (3) Platelets deposit and aggregate due to collagen exposure and

thrombin.

b.Inhibition (1) Increased prostaryclin (PGI.) and nitryl (No,) inhibit platelet aggregation' (2) Synthesis of plasminogen activator promotes fibrinolltic activity' 2. Sequence of events in thrombogenesis

Clinical Correlate

a. Endothelial iniury exposes subendothelial collagen'

Classic hemoPhilia

(hemophilia A) is caused bY a deficiency or reduced activitY of factor Vlll; it is charactertzed by excessive bleeding after trauma and bleeding into the

joints (hemarthrosis). PTT

rs

prolonged, but bleeding time

and PT are normal. A deficiency in von Willebrand factor causes von Willebrand disease, characterized

and factor vIII; stimulation of the b. Platelets adhere, requiring von willebrand factor the endothelium (tissue factor)' from release clotting cascade..qrri.., ti.omboplastin and synthesize thromboxane A'' c. Platelets degranulate, releasing ADP and fibrinogen, plug. Later, there is formation of d' Platelets aggregate' forming a temporary hemostatic ADR thrombin' and thromboxane' a secondary plug enmesh"d in fib'itt, requiring of capillaries' fibroblasts' and e. The thrombus retracts and organizes with proliferation infiltration by neutrophils and macrophages'

f.

flow through the thrombus is Canalization or formation of a new path for blood

accomplishedbyendothelialgrowthoverthesurfaceandthroughthethrombus' resulting in incorporation of the thrombus into the vessel'

bY

3. Additional factors favoring thrombogenesis

spontaneous bleeding from mucous membranes and

a. Endothelial injury releases abundant tissue factor'

excessive bleeding after

Predisposing factors are sites of b. changes in blood flow cause turbulence and stasis. atherosclerotic plaques' turbulence (i.e.' vessel bifurcations, valves' past stenoses)' trauma, certain malignancies, and inflammation'

trauma. Bleeding time is prolonged, but Platelet count

and PT are normal. PTT is also prolonged because von Willebrand factor serves as

a

canier for factor Vlll; von Willebrand disease therefore results in a functional factor

Vlll deficiencY.

thrombogenesis due to an alterc, State of hypercoagulability where there is increased where more inhibitors (e.g., syndrome nephrotic ation of the clott"ing -..i,orrisn1s than activators are lost) is composed of platelets and 4. Morphology of the thrombus. The head of the thrombus cells and the thrombus grows downstream. It consists of red blood

fibrin. The tail of

fibrin. Lines of Zahnare alternatiJg layers of fibrin, platelets,

an<1

RBCs

within the tail of

the thrombus. are not occlusive and affect large a. Mural thrombi are adherent to the vessel wall' They vessels, such as the heart and aorta'

frequently in coronary, cerebral' femoral' b. occlusive thrombi restrict blood flow most an atherosclerotic plaque' iliac, popliteal, and mesenteric vessels. They often overlie

(e'g'' myocardial infarct' Arterial thrombi are often occlusive and result in infhrct and tend to embolize' strokes), whereas venous thrombi rarely occlude vessels

by the absence of lines of c. postmortem clot can be differentiated from a thrombus that is not attached to the mass coagulated zahn anduy it, upf."*nce as a rubbery, vessel wall but forms a cast of the wall'

6s iliBbicat

General Pathology

5. Disseminated intravascular coagulation (DIC) begins with extensive formation of thrombi in the microcirculation, causing consumption of components necessary for hemostasis (i.e., platelets, fibrin, coagulation factors) and activation of the fibrinolytic pathways, leading to a bleeding diathesis. DIC is associated with a diverse array of clinical circumstances, such as amniotic cancer, trauma, surgery and burns.

fluid emboli, pre-eclampsia, gram-negative

sepsis,

DIC can be diagnosed by the presence of fibrin split products in the blood, low platelets, and prolonged

D. Embolism is the occlusion of a vessel (either artery or vein) by a mass. Often emboli are thrombi that have dislodged from their site of formation and have lodged in a distal site occluding blood flow.

l

Clinical Correlate

Pulmonary emboli often originate from deep vein thrombosis in the lower legs and less often from deep pelvic veins.

2. Systemic emboli are formed in the arterial circulation; most arise in the heart.

PT

and

PTT.

Note An embolus is most likely

a

thrombus that has dislodged

from its site of formation and has traveled to another site.

3. Paradoxical emboli cross over from the right side to the left side of the heart through septal defects and gain access to the systemic circulation.

4. Other types of emboli include gas emboli (e.g., Caisson disease), fat emboli (e.g., associated with bone fractures), amniotic fluid emboli, bone chips, and tumor cells. E. Infarction. If an artery or vein becomes occluded, then the acute loss of blood supply to the area can result in ischemic necrosis of the tissue. Most infarcts (99olo) result from thrombotic or embolic occlusion of an artery or vein. Clinically, common sites of infarction are myocardial, pulmonary brain, and intestinal tissue. Factors that affect the development of an infarct include: 1. Vascular supply, including collateral circulation

2. Rate of occlusion 3. Vulnerability of the tissue to hypoxia

4. Oxygen-carrying capacity of the blood

F. Shock is characterized by vascular collapse. There is a greatly

decreased perfusion of both

cells and tissue due to reduced blood volume, cardiac output, or vascular tone. Cellular injury is initially reversible, but if anoxia persists, cellular injury becomes progressive, leading to the death of cells and the patient.

l.

Cardiogenic shock results from myocardial infarction (pump failure).

2. Hyltovolemic shock results from reduced blood volume from any cause (hemorrhage,

fluid loss). 3. Septic shock results from bacterial infection, such as gram-negative septicemia, which causes the release ofvasodilatory mediators into the vasculature (lipopolysaccharides). 4. Neurogenic shock results from anesthesia or spinal cord injury.

NEOPLASMS A neoplasm is a mass of abnormal tissue whose growth exceeds and is uncoordinated with that of the normal tissues and continues in the same excessive state after cessation of the stimuli that evoked the change.

A. Definitions 1. Anaplasia is loss of cell differentiation and tissue organization.

rlPtlr..

meor cal

69

Pathology

2. Metaplasia is replacement of one type of aduit cell or tissue by another not normally present in that site. 3. Desmoplasia is excessive fibrous tissue formation in tumor stroma. 4. Dysplasia is abnormal atypical cellular proliferation. 5. Carcinoma is malignant tumor of epithelium. 6. Carcinoma in situ is malignant tumor of epithelium that shows no invasion of underlying tissue. 7. Sarcoma is nonepithelial (mesenchymal) malignant tumor.

8' Metastasis is secondary, discontinuous malignant growth, such

as a

lung metastasis of

a

colon carcinoma.

9. Grade is an estimate of the cpologic malignancy of a tumor, including the degree of anaplasia and number of mitoses. Nuclear size, chromatin content, nucleoli, and nuclearto-cytoplasmic ratio are all used.

10. Stage is the clinical estimate of the extent of spread of a malignant tumor. Low stage means a localized tumor. Stage rises as tumors spread locally then metastasize.

B. T[mormarkers

I'

Alpha-fetoprotein (AFP) is expressed in hepatoma, embryonal cell tumor of the testis, and malignant teratoma.

2. Carcinoembryonic antigen (CEA) can be seen in any tumor derived from gut epithelium or in intra-abdominal inflammation (e.g., ulcerative colitis). It is most often elevated in colon and pancreatic cancers. It is also elevated in smokers in the absence of tumor and may be elevated in some carcinomas of the lung. 3. Beta human chorionic gonadotropin (PhCG) is elevated in choriocarcinoma, hydatidiform mole, and germinoma. It is also elevated in pregnancy, forming the basis of the common pregnancy test.

4. Prostatic acid phosphatase elevations are seen in prostate tumors extending outside the capsule of the prostate (stage C or D). 5. Prostate-specific antigen (PSA) is also elevated in prostate cancer and in some cases of benign prostatic hyperplasia.

6. CA-125 fn a

t{utshell

7. CA l9-9 is elevated in pancreatic, gastric, and colon cancer.

. Carcinoid tumor _+ 5-HlM .

oat cell tumor _+

ADH,

C. Ectopic hormone production causes a paraneoplastic syndrome.

t

AC|H '

is elevated in ovarian cancer.

Squamous cell tumor

-; PTH

|::i::u serotomn'

tumors may produce 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of

2. Oat cell tumors of the lung, derived from neuroendocrine cells, may produce ectopic hormones, most frequentfintidiuretic hormone (ADH) or adrenocorticotropic hormone (ACTH). Many other small peptide hormones associated with oat cell carcinoma have been described.

3. Squamous cell carcinoma of the lung sometimes produces hypercalcemia by releasing PTH-like molecule. D. Metastasis

l.

70 iii6tical

Multiple routes to metastasis

a

a. Body cavities and surfaces (e.g., peritoneal, pleural, pericardial) may be directly seeded by tumor cells floating in fluid such as ascites or a pleural effi.rsion.

b. Hematogenous spread is also quite common for most neoplasms, common site for metastases of all kinds of cancer.

mfing

the lung

a

c. Lymphatic spread is the most common route of spread for epithelial carcinomas. d. Tiansplantation via mechanical manipulation (e.g., surgical incision, needle tracts) may occur but is relatively rare.

2. Sequence of lymphohematogenous spread a. Penetration of blood or lymphatic vessels requires detachment from neighboring cells, amoeboid movement, digestion of basement membranes, and crawling between

endothelial cells. b. Release and embolization of tumor cells requires detachment from vessel walls and other tumor cells. c. Adherence of tumor cells, which become anchored in fibrin mesh, requires cell surface receptors that bind to extracellular matrix proteins. d. Penetration of vessel walls in the metastatic site (i.e., lung) also requires altered adhesion molecules and amoeboid movement. e. Once tumor cells have crawled out of blood vessels in a new organ, they must survive

in a new environment of hormones dissimilar to the cell's original environment. Although millions of cells may be shed from a primary tumor, successful metastasis is relatively rare.

E. Theories of carcinogenesis

l.

Essentially all malignant tumors have genomic alterations at the time of diagnosis.

2. Somatic mutation refers to structural changes at the gene or chromosomal level that occur spontaneously or in response to carcinogens after germ cell line maturation. Somatic mutation produces neoplasms that are more often monoclonal than polyclonal. 3. Aberrent differentiation in cancer cells occurs in the absence of structural changes, indicating abnormalities of gene regulation affecting growth and differentiation. This may occur regardless of the stimulus inciting malignant change: chemical, viral, radiation, or spontaneous.

4. Viral infection and consequent integration of viral DNA into the host genome may lead to malignant transformation (e.g., hepatitis B genome has been found in hepatoma cells, and RNA retroviral DNA copies have been found in some lymphomas).

5. Cell selection. Carcinogens favor the expression of a pre-existing population of transformed cells that would not be clinically evident otherwise.

F. Cytology is the analysis of individual or clumps of cells to determine the degree of ana-

to analyze cells from any source: uterine, cervix, sputum, plural fluid, ascites, fine needle aspiration, joint fluid, and others. Besides staining cells on slides, cells may be analyzed by flow cftometry, a procedure in which fluorescent antibodies plasia. Cytology may be used

are reacted with cells to determine the surface markers they express. This is most often done in the case of lymphomas and leukemias. Karyotype analysis of tumors is also helpful in

showing which chromosomal regions of tumors are abnormal. Gene probe analysis defines specific gene rearrangements and can show gene expression patterns in tumors. These help

in classification.

iiits[ical

7l

Pathology

G. Carcinogenic agents

1. Chemical carcinogens may be divided into two broad groups: a. Direct-acting chemical carcinogens are mutagens that cause cancer directly, usually by modifring DNA (e.g., alkylating agents).

b. Procarcinogens require metabolic conversion strong chemical agents are procarcinogens.

to form

active carcinogens. Many

(1) They require an initiating agent and a promoter. Exposure to the initiating agent results in an irreversible cellular change, which allows the cells to produce a tumor. The promoter is an agent that increases the tumorigenic process in initiated cells. Cells may not be tumorigenic without previous exposure to an initiating agent. An initiator may cause a mutation, whereas a promoter causes increased growth rates.

(2) Potential carcinogens are screened by the Ames test, which detects any mutagenic effects on bacterial cells in culture. Mutagenicity in vitro correlates well with carcinogenicity in vivo.

2. Radiation a.

Illtraviolet radiation produces pyrimidine dimers in DNA, Ieading to transcriptional errors.

b. Ionizing radiation by x-rays and gamma rays causes chain breaks When critical genes are mutated, cancer may result.

in nucleic

acids.

3. Oncogenic viruses a. RNA oncogenic viruses produce a viral-coded reverse transcriptase allowing synthesis of DNA from a viral RNA template. The DNA can then be integrated into the host genome.

b. DNA oncogenic viruses include papovavirus, adenovirus, and herpesvirus. Infection does not necessarily result in the release of infectious virus. For example, EBV is associated with Burkitt lymphoma in Africa; HBV is associated with hepatocellular carcinoma. In both cases, viral DNA integrates into the host genome.

4. Loss of immune regulation. In patients with immune system dysfunction, an increased number of neoplasms develop, suggesting loss of the surveillance mechanism, which normally destroys neoplastic cells via recognition of "nonself" antigens.

TOXIC AND ENVIRONMENTAT CAUSES OF DISEASE A. Lead (plumbism) 1. Etiology. Plumbism is most often caused by chronic gradual accumulation; children absorb lead more readily than adults. In children, it may result from ingesting lead-based paint chips, chewing on painted furniture or painted lead pencils, and inhaling highway exhaust. Other sources of lead include improperly glazed ceramic dishes, home-fermented liquor, and contaminated drinking water. The use of lead-free paint and unleaded gasoline is reducing the incidence and severity of plumbism.

2. Pathogenesis. Lead inhibits enzymes involved in hemoglobin synthesis (including the inhibition ofiron incorporation in tetrapyrrole rings) and inhibits adenyl cyclase activity in the brain and pancreas. 3. Clinical features. There is an insidious onset.

72

iiiBiircat

General Pathology

a. Anemia is characterized by increased hemolysis, coarse basophilic stippling, and elevated free erythrocyte protoporphyrin. The anemia is hypochromic and microcytic.

b. Encephalopathy is caused by diffrrse edema, demyelination, and neuronal degeneration, which causes delirium, seizures, and coma.

c. Peripheral neuropathy

is caused by myelin degeneration, which predominantly

affects motor neurons. The radial nerve is most often affected, leading to wrist drop. d.

Renal lesions feature proximal tubular dysfunction, causing glycosuria, aminoaciduria, and hyperphosphaturia (Fanconi syndrome). It is associated with mineral-containing intranuclear inclusions in proximal tubular cells.

ln a Nutshell Key features of lead poisoning include:

. Basophilic $ippling of RBCs . Peripheral neuropathy . Lead lines in bones . Abdominal colic

e. Abdominal colic is chronic and often severe.

f. Lead lines

refer to an accumulation of lead sulfide on the gingival mucosa and epi-

physeal radiodensities on x-ray.

B. Carbon monoxide

l.

Pathogenesis. Carbon monoxide combines with hemoglobin to form carboxyhemoglobin, which cannot carry oxygen. The affinity of carbon monoxide for hemoglobin is more than 200 times greater than that of oxygen. Once formed, carbon monoxide is displaced from hemoglobin very slowly.

2. Types a. Acute toxicity. Symptoms of hypoxia are apparent when 30%o of hemoglobin is carboxyhemoglobin; coma and death ensue when 600/o is carboxyhemoglobin. The blood is cherry red, turning the lips cherry red as well. Carbon monoxide poisoning causes CNS hyperemia, edema, and focal hemorrhages with symmetric degeneration of the basal ganglia. There is loss of consciousness, coma, and death within minutes. b. Chronic toxicity. Slow poisoning causes systemic pathology with milder CNS changes. Fatty change occurs in the heart, liver, and kidney. The patient can usually recover completely.

C. Acetaminophen. Because of its widespread availability, acetaminophen has become a commonly ingested substance in accidental childhood poisonings and in suicide attempts.

Note Cigarette smoke contains carbon monoxide; the percentage of carboxyhemoglobin in smokers is proportionate to

the number of cigarettes smoked per day.

1. Pathogenesis. Hepatotoxicity is mediated by a toxic reactive metabolite, which, after depleting glutathione stores, binds to hepatocyte macromolecules.

2. Pathology. Acetaminophen toxicity causes severe centrilobular hepatic necrosis. The severity correlates with the serum drug ievel. 3. Clinical features. Patients experience nausea, vomiting, abdominal pain, and shock. Hepatic failure is not evident until 2-6 days after ingestion. 4. Theatment is gastric lavage and supportive measures; N-acetylcysteine may counteract the efFects by replenishing glutathione stores. Blood levels should be followed, and early intervention is critical. D. Salicylates are another commonly ingested toxin. They may be ingested accidentally or in suicide attempts.

l.

Pathogenesis. Initially, direct respiratory stimulation produces a respiratory alkalosis. In addition, the metabolic effects of salicylates cause a metabolic acidosis. Vomiting complicates fluid and electrolyte disturbances. Fatalities are most often due to dehydration and

Bridge to Pharmacology Becaused there is

delayed hepatic failure, acetaminophen overdoses can be treated with sulfur agents to restore reduced glutathione in the liver.

hypokalemia.

lfiBkcal

7l

Pathology

2. Pathology. Hemorrhagic gastritis, petechiae, systemic hemorrhages, and necrosis of lymphoid germinal centers occur. 3. Treatment is gastric lavage (to remove any toxin still in the stomach), activated charcoal (to neutralize toxin still in the GI tract), and hemodialysis (to directly remove excess toxin from the blood). E. Mercury poisoning is rare.

l.

Pathogenesis. Mercury inactivates enzymes (particularly cytochrome oxidases) and damages cell membranes.

2. Types

toxicity causes necrosis of gastric and colonic epithelium, acute renal tubular necrosis, and, possibly, cerebral edema.

a. Acute

b. Chronic toxicity causes excessive salivation, gingivitis, gastritis, renal tubular basement membrane thickening (which causes proteinuria and eosinophilic inclusions), and cerebral (particularly occipital) and cerebellar atrophy.

GENETIC DISORDERS A. Autosomal dominant disorders (Table III-1-1) 1. Phacomatoses. Tuberous sclerosis and von Hippel-Lindau disease are transmitted by auto-

Bridge to Pharmacology

somal dominant inheritance. Neurofibromatosis is transmitted in an autosomaldominant fashion in 500/o of cases, and 500/o of cases are sporadic mutations. 2. Familial hlaercholesterolemia

Heterozygotes are treated with HMC-CoA reductase inhibitors (e.9., lova$atin) and bile acid-

a. Clinical features. Homozygotes have more severe symptoms than heterozygotes, including xanthomas and extensive, early atherosclerosis often resulting in myocardial infarction in the second or third decade oflife.

binding resins (chole$yromine), which partially act through the indirect increase of liver LDL

3. Marfan syndrome is a connective tissue abnormaliry; approximately 850/o of cases are autosomal dominant. The incidence of sporadic cases increases with increasing paternal age.

receptors, which help to clear LDL from the blood.

a. Pathogenesis is unclear. There is probably a defect in collagen structure and possibly defective elastin or mucopolysaccharide ground substance due to mutations in the fib-

Homozygotes cannot be treated as heterorygotes because there are no functional LDL receptors. Therefore, they are treated with probucol,

whose mechanism of action

is

unctear.

FPC

1000/o

rillin glycoprotein

gene.

b. Clinical features are very variable. They include arachnodactyl)r (long, spider-like fingers), tall stature, ligamentous laxiry subluxed lens, dissecting aortic aneurysm, usually of the ascending aorta (secondary to rystic medial necrosis of the vessel wall), mitral valve prolapse, and a short life-span, often due to a ruptured aorta.

4. Familial poln>osis coli (FPC)

Clinical Correlate Nearly

b. Pathogenesis. There is a loss of feedback inhibition of cholesterol s1'nthesis caused by decreased or defective low-density lipoprotein (LDL) receptors.

of patients with

will get carcinoma of the

a. Thousands of adenomatous polyps appear, starting in the colorectum and spreading throughout the colon. Polyps first appear in the patient's rwenties, become symptomatic in the thirties, and transform to adenocarcinoma by approximately age 40.

colon by the fifth decade of life. The treatment of choice

is

to surgically remove the entire colon, usually in the second or

third decade of life.

74

iliBbicat

b. Gardner syndrome has colonic polyps with soft tissue and bone tumors.

General Pathology

Table III- r - 1. Autosomal-dominant disorders. Chromosome

Disease

Incidence

Population

Affected

Marfan

l9p

l:5,000 heterozygote

hypercholesterolemia

syndrome

1:106 homorygote

1:8,000

APCKD

l:1,250

disease

l5

1:20,000

FPC Huntington

Gene

17q

Neurofibromatosis Familial

with Defective

l6p

1:3,000

Wilms tumor

Retinoblastoma

5q

20s-40s

30s-s0s

4n 'r

Children

llp l3q

l:20,000

5. Adult polycystic kidney disease (APKC) a. Renal cysts, increasing

with age, cause progressively enlarged kidneys. The rate of

enlargement of kidneys proceeds at the same rate in affected families. b. Hypertension, renal failure, and anemia are the presenting signs, typically starting when patients are in their forties. The age of onset of symptoms also proceeds at the same rate in a given family. c. Cysts are also found in the liver, pancreas, spleen, and gonads. There is an increased risk of berry aneurysms and abnormalities of the cardiac valves. 6. Huntington disease a. This is a progressive neurologic disorder; the age affected families.

of onset tends to be the same in

b. The onset of symptoms is usually between the ages of 30 and 50 years with involuntary choreic movements (Huntington chorea), cognitive impairment, and changes in behavior. Death follows after 15-20 years. c. It is associated with degeneration of the caudate nucleus. 7. Wilms tumor a. This is an embryonal tumor, one of the most common solid tumors in children under 4, involving one or both kidneys and characterized by primitive mesenchyme and

immature tubules. Sporadic forms also occur. b. Wilm's tumor, aniridia, gonadoblastoma, and mental retardation (WAGR syndrome) are associated with a gene at chromosome 11p13.

c. This tumor often reaches enormous sizes and can be easily palpated on physical exam as a large abdominal mass.

ifiB[ical

75

Pathology

8. Retinoblastoma a. This disorder is an embryonal

tumor affecting one or both eyes. Familial forms are characterized by the inheritance of one abnormal Rb gene (13ql4) with the other normal Rb gene undergoing mutation early in the individual's life. Sporadic forms are not characterized by abnormal inherited genes but arise through spontaneous mutation of both Rb genes.

b. Osteosarcoma is associated with familial forms of retinoblastoma.

c. The Rb gene is also spontaneously mutated in other malignancies (e.g., breast cancer).

B. Glycogen storage diseases are inherited via an autosomal recessive pattern. 1. Type I (von Gierke disease) is caused by an enzyme defect in glucose-6-phosphatase. The affected organs are the liver and kidneys. The patient suffers hypoglycemic seizures within the first year, hyperlipidemia, hepatomegaly, growth retardation and failure to thrive, leading Io a 50o/o mortality rate.

2.Type

II (Pompe

disease) is an enzyme defect

in

lysosomal a-1,4-glucosidase, which

affects all organs, especially the heart and brain. Symptoms include muscle weakness and cardiac and neurologic impairment, resulting in death by age 2.

III is caused by an enzyme defect in glycogen debranching enzymes, which affects all organs. Symptoms include hepatomegaly, hypoglycemia, and growth retardation, but the disease is usually mild.

3. Type

4. Type IV is caused by an enzyme defect in branching enzymes, which affects all organs. It causes liver cirrhosis and is lethal by age 3. 5. Type V (McArdle disease) is caused by a defect in striated muscle phosphorylase, which specifically affects striated muscle. Symptoms include muscle weakness, beginning in the second or third decade, and following a mild course.

VI is caused by a defect in liver phosphorylase, which affects only the liver. Symptoms include hepatomegaly, growth retardation, and fasting hypoglycemia, but the patient lives a normal life span.

6. Type

C. Lysosomal storage diseases

l.

Mucopolysaccharidoses. Various lysosomal enzymatic defects lead to the accumulation of glycosaminoglycans throughout the body and brain. All except Hunter syndrome show autosomal recessive inheritance. a. Pathology. Storage of glycosaminoglycans occurs mainly in the endothelium, reticuloendothelium, and fibroblasts of the liver, spleen, lymph nodes, vessels, and bone marrow. Balloon cells are formed. These are distended cells with multiple small cytoplasmic PAS-positive vacuoles (lysosomes). In Hurler and Sanfilippo syndromes, lysosomes contain characteristic laminated structures on electron microscopy. Patients also have cardiac valve lesions, hepatosplenomegaly, arterial lesions in coronary and cerebral vessels. and skeletal deformities. b. Types of mucopolysaccharidoses (MPS)

(l)

MPS

I H (Hurler syndrome) is caused by a defect in u-r-iduronidase, which of heparan and dermatan sulfate. It is lethal by age 10

causes an accumulation

and is characterized by hepatosplenomegaly, dwarfism, skeletal abnormalities, mental retardation, and corneal clouding.

76 iliBf,ical

General Pathology

S (Scheie syndrome) results from a defect in the same enzyme as Hurler syndrome but is a much milder disease. Patients have a normal life span and

(2) MPS I

normal intelligence.

I

(3) MPS

H/S (Hurler-Scheie syndrome) also results from a defect in the same

enzyme as Hurler syndrome, with symptoms intermediate between Hurler and Scheie syndromes.

II

(Hunter syndrome) demonstrates an X-linked recessive inheritance pattern as a result of a defect of r-iduronate sulfatase, which causes accumulation of heparan and dermatan sulfate. Severity and life expectancy are variable. Symptoms are similar to those of Hurler syndrome except that there is no

(4) MPS

Mnemonic 'A Hunter will aim for the X." Hunter disease is the only mucopoly-saccharidosis that

corneal clouding. Patients also have retinal abnormalities and deafiress.

(5) MPS III (Sanfilippo syndrome) is a group of variable enryme defects (types A, B, C, and D) that lead to the accumulation of heparan sulfate. Patients present with mental retardation and skeletal abnormalities, but no corneal, cardiac, or Iiver abnormalities are seen. Death occurs in the second or third decade.

is

X-linked recessive.

(6) MPS IV (Morquio syndrome) causes an accumulation of keratin and chondroitin sulfate, which results in dwarfism, Hurler-like facies, and arterial lesions, but a normal intelligence. 2. Sphingolipidoses

Note

a. Tay-Sachs disease (GM, gangliosidosis type 1) is caused by a deficiency of hexosaminidase A, which leads to an accumulation of GM, ganglioside, affecting all organs but predominantly the brain, retina, and peripheral nervous system.

(1) Clinical features. The onset of symptoms begins at 6 months of

age

with

an

exaggerated startle response and progressive mental, motor, and visual deterioration, leading to death by age 3.It can be detected prenatally by amniocentesis. The highest incidence is in Ashkenazic ]ews (carrier rate is 1/30).

Sandhoff disease shows exactly the same symptoms as Tay-Sachs

and is caused

by deficiency of an enzyme that forms a complex

with hexosaminidase

A.

(2) Pathology. Characteristic pathologic findings include an enlarged brain, neuronal loss, and gliosis with enlarged neuronal lysosomes forming balloon cells. Electron microscopy shows membrane whorls and other lysosomal inclusions. The retina has swelling of ganglion cells, particularly at the edge of the macula, which appears as a cherry-red spot against a pale, swollen retina. b. Gaucher disease is caused by defects in p-glucocerebrosidase, leading to the accumulation of glucocerebroside, which affects reticuloendothelial cells and the central nervous system.

(l)

Types. Three types are recognized, which vary in severity. (a) Type I (adult) affects primarily Ashkenazic Iews (1:625) and does not involve the CNS. It causes hepatomegaly and splenomegaly as a result of the accumulation of glucocerebrosides in phagocytic cells in these organs. It is compatible with a normal life-span. (b) Type 2 (infantile) produces an acute cerebral pattern

with few systemic

manifestations. There is prominent CNS deterioration, leading to an early death.

(c) Type 3 (juvenile) produces early systemic symptoms with onset involvement in early adulthood.

of

CNS

iliEbicat

77

Pathology

(2) Pathology. All three show Gaucher cells (i.e., distended reticuloendothelial cells in the liver, spleen, lymph nodes, and marrow). Cells are filled with a PASpositive fibrillary substance. c. Niemann-Pick disease is caused by a defect in sphingomyelinase, leading to an accumulation of sphingomyelin and cholesterol in a variety of organs. There are five phenotfpes (types A-E) that are distinguished by the severity of CNS involvement and the age of onset. (

1) Clinical features. Eighty percent of

cases are tfpe A, which is characterized by extensive CNS and systemic accumulations. Patients suffer from hepatosplenomegaly, xanthomas, fever, vomiting, failure to thrive, neurologic dysfunction, and death by age 2.

(2) Pathology. Characteristic findings include enlarged "foamy"

cells filled with dis-

tended lysosomes containing sphingomyelin. d. Krabbe disease is a galactocerebrosidase deficienry that causes an accumulation of galactocerebroside. e. Metachromatic leukodystrophy is an aryl sulfatase A deficienry that causes an accumulation of sulfatide. D. Other metabolic disorders

Note Aspartame, an artificial sweetener, contarns phenylalanine and

should be avoided by phenylketonuris.

1. Phenylketonuria is a disorder resulting from an absence ofphenylalanine hydroxylase in homozygotes, which halts the conversion of phenylalanine to tyrosine, resulting in elevated levels of phenylalanine in the blood. a. Clinical features. Infants are normal at birth, but within months, develop an abnormal pattern on EEG with seizures and mental retardation. There is minimal melanin production, causing light hair and skin, and blue eyes. The urine has a musty odor as a result ofthe urinary excretion ofphenylacetic acid. Pathology can be prevented with a special diet free of phenylalanine and supplemented with tyrosine during childhood.

b. Diagnosis is by the Guthrie bacterial inhibition assay (routine newborn screening) or by measurement of phenylalanine levels in the blood. c. Pathology. There are nonspecific CNS changes, such as decreased brain weight, abnormal myelin, demyelination, and gliosis.

2. Galactosemia can result from two different enrqe deficiencies. a. Galactokinase deficiency is a benign disease. The main complication is cataract formation.

b. Galactose-l-phosphate uridyltransferase deficiency is a severe form of galactosemia. (

1) Clinical features. Only homozygotes have the classic syndrome. The defect causes elevated serum galactose and galactosuria. Impaired renal tubular resorption results in aminoaciduria. Early in the neonatal period, infants develop vomiting, diarrhea, failure to thrive, jaundice, hepatosplenomegaly, cataracts, bleeding diathesis, hypoglycemia, and mental retardation. Death occurs during infanry.

(2) Pathology shows neuronal

loss

in the CNS with edema and gliosis of the brain.

In the liver, there are fatty changes and, eventually, cirrhosis. 3. Albinism is caused by an enzymatic deficiency that prevents melanin synthesis from tyrosine. a. Types (

7s

ilitstical

1) Tyrosinase-negative type is caused by

a lack

of ryrosinase in melanocytes.

(2) Tyrosinase-positive type, in which tyrosinase is present, is caused by a defect in tyrosine uptake. b. Clinical features. The lack of melanin may be limited to the eye (ocular albinism) or may involve total body pigmentation (oculocutaneous albinism). In the latteS the skin is particularly sensitive to the sun, resulting in premature wrinkling and a tendency to develop solar keratosis, as well as basal cell, squamous cell, and melanocyte carcinomas. Eyes are very photosensitive; visual acuity is decreased.

4. Cystic fibrosis is caused by an abnormality in chloride channels. a. Diagnosis may be made by demonstrating elevated chloride and sodium in sweat.

b. Clinical features. Hlperviscous secretions lead to meconium ileus (small bowel obstruction) in 5-100/o of newborns. Patients suffer steatorrhea (from pancreatic

insufficiency), pulmonary obstruction, and pneumonia, leading to infection. Secondary cardiac complications follow Men may be sterile as a result of obstruction of the vas deferens. Cirrhosis of the liver is common. 5. Alpha,-antitrypsin deficiency a. Clinical features. The patient experiences progressive emphysema of the lower lobes of the lungs. This is in contrast to smoking-related emphysema, in which the upper lobes are affected first. cirrhosis of the liver is seen in some patients.

b. Incidence. The incidence of emphysema due to cr,1-anti-trypsin deficiency is less than 5% of that caused by smoking.

6' Sickle cell anemia and the thalassemias are discussed in Hematologic/Lymphoreticular Pathology in Organ Systems Book I (Volume III). Sex-linked diseases 1. Fabry disease is a lysosomal storage disease. a. Pathogenesis. A deficiency of cr-galactosidase leads to the accumulation of ceramide trihexoside. Affected cells include endothelial, reticuloendothelial, myocardial, ganglion, renal glomeruli and tubules, and connective tissue cells. Blood vessels throughout the body are thickened, leading to myocardial infarction and stroke as the most life-threatening results.

b. Clinical features

(1) Angiokeratoma corporis diftrsum (dermal cavernous hemangioma with overlying epidermal keratosis) appear as purplish dermal nodules over the entire bojy. (2) Proteinuria usually occurs by the second decade, leading to renal failure and hypertension by the fourth or fifth decade. c. Pathology. Intralysosomal laminated whorls give affected cells a foamy appearance. 2. Iesch-Nyhan disease a. Pathogenesis. Abnormal purine metabolism due to deficient hypoxanthine-guanine phosphoribosyltransferase (HGPRT) results in hlperuricemia. b. Clinical features include gout and CNS deterioration with mental retardation, selfmutilation, and spastic cerebral palsy.

c. Pathology. foints and kidneys exhibit gouty changes. CNS pathology is inconsistent.

iiiBhicat

79

Pathology

F. Disorders of chromosome number or structure

l.

Trisomic disorders are usually secondary to a meiotic defect. a. Down syndrome (trisomy (

2l)

1) Incidence. This defect increases with maternal age. It affects 1 in 2,000 live births if maternal age is less than 30 and I in 50 live births if maternal age is greater than 45. The incidence of having a second affected child is I in 60.

(2) Clinical features include severe mental retardation, characteristic facies (flat nasal bridge, epicanthal folds, oblique palpebral fissures), dysplastic ears, hlpotonia, a horizontal palmar crease, redundant neck skin, and a short trunk. There is also an increased incidence of ventricular septal defect (VSD), acute lymphoblastic leukemia (AIL), and neurologic changes similar to those of Alzheimer disease.

b. Edward syndrome (trisomy 18)

(1) Incidence is I in

5,000 births.

(2) Clinical features include

severe mental retardation, VSD, micrognathia (a small jaw), lower rocker-bottom feet, low-set ears, prominent occiput, and hypertonia. The average lifespan is 2-3 months.

c. Patau syndrome (trisomy 13) (

1) Incidence is

I in 6,000 births.

(2) Clinical features include microcephaly, severe mental retardation, arrhinencephalia, microphthalmia, cleft lip and palate, VSD, dextrocardia, and polydacryly. Death is usually in the neonatal period.

2. Chromosomal deletions a. Cri du chat syndrome (5p-)

(1) Pathogenesis. There is a deletion of the short arm of chromosome (2) Clinicd features. The patient exhibits a cat-like cry up to

I

5.

year of age, severe

mental retardation, microcephaly, and epicanthal folds; one in four patients has a VSD. Patients may live to adulthood. b. DiGeorge syndrome is caused by absence of the thymus and parathyroids, cardiovascular abnormalities, and low-set ears. It results from a deletion of chromosom e 22qll during development.

3. Disorders of sex chromosomes a. Klinefelter syndrome

(1) Karyotypes. The most common karyotype is 47,XXY, but other patterns may also be seen.

(2) Etiology. Nondisjunction during meiosis in either the maternal or paternal gamete may result in an extra X chromosome. (3) Incidence

increases

with maternal

age

or irradiation and affects

I in 800 male

births.

(4) Clinical features include testicular atrophy, sterilify, a small penis, failure of development of male secondary sexual characteristics, gynecomastia, and mild mental retardation. Mental deficiency is more marked with a greater number of X chromosomes.

Bo iliBhical

General Pathology

(5) Laboratory values show positive X chromatin, azospermia, low serum

testos-

terone, and elevated urinary excretion of FSH. b. Turner syndrome

(l)

Karyotype is typically 45,XO.

(2) Incidence is I in 3,000 female births. (3) Clinical features may

be subtle in mosaics. There is edema during infanry, a web neck, short stature, broad chest with wide-spaced nipples, low hairline, primary amenorrhea, infertiliry coarctation of the aorta, and streak ovaries.

c. SupernumeraryY chromosomes

(1) IGryotypes

are typically

(2) Incidence is

47,YW and 48,XYYY.

I in 1,000 male births. Affected

individuals are usually tall with

severe acne. The syndrome has been associated with antisocial aggressive behav-

iors in incarcerated individuals. d. Supernumerary X chromosomes

(1) Karyotypes

are typically 47,XXX and 48,XXXX.

(2) Incidence is I in

1.200 female births.

(3) Clinical features. Most patients

are phenotypically normal, although there is an increased incidence of mental retardation and menstrual irregularities.

e. Fragile-X syndrome

(l)

Karyotypes are typically 46,XY and 46,XX.

(2) Etiology. Cytogenetic abnormality of the long arm of the X chromosome

leads to

chromosome breakage in vitro.

(3) Clinical features are manifest in both males and females. In males. macroorchidism (enlarged testes) is observed bilaterally. Fragile-X syndrome is the second most important cause of hereditary mental retardation (Down syndrome is the most important).

iliii[ical

al

sEcTtoN

lv

Pharmacology

Pharmacodynamics and Pharmacokinetics

Pharmacology is the study of the action and disposition of chemicals that have a beneficial action in

the body. These chemicals or drugs are used by physicians to diagnose, prevent, or treat disease.

Ihis chapter covers pharmacodynamic and pharmacokinetic principles.

GENERAIPRINCIPIES A. Pharrnacodynamics characterizes the action of drugs on the biochemical and systems of the body and identifies the sites and modes of action.

haNubhetl

physiologic .

B. Pharmacokinetics characterizes quantitative aspects of drug absorption, distribution, metabolism, and excretion and describes the time course of drug ''---- metabolite --o and ----- concentrations at their site of action.

pharmacodvnamics: drug's effect on the body

'

Pharmacokinetia:

bod's effect on a drug

C. Therapeutics characterizes the clinical applications, contraindications, drug interactions, and adverse effects of drugs. All drugs have beneficial and unwanted, adverse, and toxic actions, which can be further categorized.

l.

Side effects are predictable effects seen in all individuals to a varying degree.

2. Idiosyncratic reactions are due to the individual, do not involve the immune system, are seen in a few patients, and are unpredictable. 3. Allergic reactions are due to the immune response of the individual, are seen in a few patients, and are unpredictable.

PHARMACODYNAMICS A. Drugs that act independently of receptors include: 1. Antacids. The base moiety of the compound neutralizes stomach acids.

2. Chelating drugs. These drugs bind metallic ions. 3. Osmotically active drugs include certain diuretics (e.9., mannitol) and cathartics (e.g., methylcellulose). 4. Volatile general anesthetics. These drugs cause reversible changes in synaptic function from within the cell membranes. Drug potency correlates with lipid solubility.

B. Drug-receptor interactions

l.

Receptors. Many drugs work by combining with specific target molecules on cells to initiate a biochemical "cascade" to oroduce their effect.

iliE[ical

85

Pharmacology

a. Receptors may be proteins, carbohydrates, nucleic acids, or lipids. b. Binding of drug to a receptor may involve ionic, covalent, hydrogen, or van der Waals bonds.

c. Four receptor families have been categorized

as:

(1) Cell membrane-embedded enzymes. Surface receptor binding activates

an

enzyme inside the cell to initiate a response.

(2) Ligand-gated ion channels. Receptor binding

opens a channel to facilitate trans-

membrane flow.

(3)

G protein-coupled receptor systems. Receptor binding activates then activates an effector (an enzyme or ion channel).

aG

protein that

(4) Transcription factors.

These are located in the nucleus on DNA rather than on the cell membrane. Receptor binding produces prolonged influence on tran-

scription. 2. Agonists are drugs that bind to receptors and stimulate them. 3. Antagonists are drugs that bind to receptors and decrease or block the effect of an agonist. They do not stimulate the receptors; they have zero efficacy.

In a Nutshell Competitive antagonists bind

a. Competitive antagonist. These drugs reversibly bind to the receptor and prevent binding of the agonist (i.e., the antagonist and agonist are lying for the same recep-

reversibly and can be

tor). High concentrations of the agonist can overcome the effect of a competitive antagonist. A competitive agonist produces a parallel right shift in the dose-response

overcome by a large amount

curve (Figure IV-1-1).

of agonist. Noncompetitive antagonists cannot be overcome, usually because

they bind ineversibly.

b. Noncompetitive antagonist. These drugs usually bind to the receptor in an irreversible way and prevent any agonist action. After administration of a noncompetitive antagonist, high concentrations of agonist cannot reverse the antagonist's effects. Duration of action depends largely on the turnover rate of the receptors. A noncompetitive antagonist decreases the height ofthe dose-response curve (Figure IV-l-l).

4. Partial agonists

are drugs that activate receptors at an intermediate level. These drugs bind to receptors to produce a submaximal response, but they also effectively act as antagonists because they compete with frrll agonists for access to the receptor binding site.

C. Graded dose-response curyes 1. These graphically depict the response ofa particular system to increasing concentrations of a drug (agonist). An agonist is a drug that binds to receptors and stimulates them. The effect of a drug is best analyzed by plotting the response versus the log of the drug concentration.

In a Nutshell A drug with high efficacy but

low potency reaches a high level of response with

a

greater dose; a potent drug reaches its maximum response at a lower dose.

06

iiiBiircal

a. EfEcacy. This is the maximum response that an agonist can produce. Efficary increases as you proceed up the 7-axis.

b. Potency. This is a measure of how much drug is required to produce a given effect. Potenry is typically expressed as the concentration that can elicit a 500/o response, the EC50. The less drug required to produce an effect, the more potent a drug is. Potency increases as the curve shifts to the left on the x-axis.

Pharmacodynamics and Pharmacokinetics

Agonist alone Agonist with noncompetitive antagonist

Agonist with competitive antagonist

Log (dose)

Figure lV-1-1. Graded dose-response curves for the same agonist alone, in the presence of a noncompetitive antagonist and a competitive agonist.

ln a Nutshell

D. Quantal dose-response curves 1. These curves show the minimum drug dose needed to produce a predetermined response in a population. The percent of the population responding is plotted against the log [dose] (Figure IV-l-2). a. ED50 (median effective dose) is the dose of drug that wi]l produce the effect in

50o/o

of the population.

Low therapeutic index indicates a relatively high incidence of side effects at usual doses (narrow range for therapeutic and toxic doses) High therapeutic index

b. TD50 is the minimum dose that produces a specific toxic effect in 500/o of the popu-

lation.

indicates a relatively low incidence of side effects at

c. LD50 is the minimum dose that kills 50% of individuals in the population. d. Therapeutic index (TI) is the ratio of the dose of drug required to produce a toxic or lethal effect to the dose needed for a therapeutic effect. The TI is used as an indication of drug safety and is expressed as: tt

=

LD5O TD5O ot

ED5o

usual doses. So, the higher the Tl, the safer the drug. Drug

companies shoot for a ratio of at least 4. Anything less than 2 requires close patient

monitoring (e.g., lithium).

ED5o

-oo, :tc

o_o

trn

ooo-(,

-o o! de

Figure lv-l-2. Quantal dose-response curves.

iiiEhical

87

Pharmacology

PHARMACOKINETICS The following concept map (Figure IV-l-3) presents the factors that determine the concentration of drug at its site of action or biophase.

Dose and route of administration

Site of action or "bioohase"

Figure IV-1-3. Concept map of factors that affect drug concentration at the site of action. n. Drug absorption

l.

Factors affecting absorption. These are factors that affect absorption from the site of administration and transoort. a. Permeability

(1) Lipid solubility. This correlates with the ability of a drug to cross cell membranes. Weak acids and bases are more lipid soluble in the nonionized state. (2) Aqueous solubility. Charged, water-soluble molecules are excluded from crossing many barriers (e.g., epithelial lining of the gastrointestinal tract and skin) unless they are very small.

(3) Facilitated transport. Membrane carriers transport the molecule into the cell. Note Fir$-pass metabolism = some drugs are metabolically inactivated by the liver or gut before reaching the systemic circulation.

b. Bioavailability. This is the fraction of administered drug that reaches the systemic circulation. Bioavailability is I (or 1000/o) when a drug is given intravenously. It is generally less than I when a drug is administered by other routes (e.g., oral) because of factors such as incomplete absorption and first-pass metabolism.

c. First-pass metabolism. This describes drugs that are absorbed from the gastrointestinal tract, enter the portal circulation, and are subject to inactivation by the liver before reaching the systemic circulation, thus decreasing bioavailability. 2. Routes of administration a. Oral (PO). Administration by mouth is the most common route. It is safe, economical, and convenient, but the drug must be lipid soluble and resistant to destruction by gastric acid, digestive enzymes, and gastrointestinal flora. The rate and degree of absorption can be variable.

sB ilitsiiical

Pharmacodynamics and Pharmacokinetics

b. Sublingual (buccal). Venous drainage from the mucosa under the tongue enters the systemic circulation (superior vena cava) and blaasses the portal circulation to the liver, where many drugs are metabolized. This route is useful for drugs that must be self-administered, require rapid onset of action (e.g., nitroglycerin in the treatment of angina pectoris), or are highly metabolized by the liver.

c. Rectal. Absorption from the rectal mucosa has less of a first-pass effect than from oral administration. This route is useful in vomiting or unconscious patients, although the absorption is irregular. d. Intravenous (IV) administration. The rapid and complete delivery of drugs to most target tissues is possible with intravenous administration. This route is useful in emergencies and for drugs that are highly metabolized by the liver or poorly absorbed from

the gastrointestinal tract.

e. Intramuscular (IM) administration. Aqueous solutions are absorbed rapidly, whereas oil solutions (depot forms) are absorbed slowly. This route is contraindicated for patients on anticoagulants.

f.

Subcutaneous (SC) administration. Only small volumes can be given by this route; drugs are relatively slowly absorbed.

g. Topical administration. Drugs

are applied locally to the skin, vagina, eyes, ear, nose, and throat. The transdermal route is for systemic administration of drugs applied to

the skin; absorption is slow (e.g., nicotine or nitroglycerin patch).

h. Intrathecd (IT) administration. Injection of drug into the subarachnoid space or ventricular system is by lumbar puncture or Ommaya reservoir, respectively. This route blpasses the blood-brain barrier and the blood-CSF barrier and therefore is usefi,rl for drugs with poor or slow CNS penetration or when high CNS concentrations are rapidly needed (e.g., severe meningitis, spinal anesthesia).

i.

Intra-arterial (IA) administration. This route allows delivery of high drug concentrations to selective organs. It is also used for x-ray contrast studies.

j.

Inhalation. The inhalation route is for gaseous and volatile drugs (e.g., anesthetics, bronchodilators).

B. Drug distribution. Once the drug reaches the circulatory system, several factors determine its disposition. 1. Plasma protein binding. The fraction of drug bound to plasma proteins is determined by the amount of protein, mostly albumin, and the binding constant for the drug. Binding is nonspecific, so several drugs may compete for the same binding sites. 2. Volume of distribution (Vd). distributes and is given by:

\

is the apparent or "virtual" volume into which a drug

Note Competition for plasma

protein binding explains some drug-drug interactions. For example, both

sulfonamides and coumarins are highly bound to plasma proteins. Therefore, the

total drus in bodv (e) plasma drug concentration (g/L)

administration of sulfonamides

to a patient chronically treated

a. Drugsthatarestoredmayhavea\greaterthantotalbodywater(e.g.,lipid-solubledrugs). b. Drugs that strongly bind to plasma proteins have

c. The greater the

\,

a

\

the slower the elimination rate.

that approaches plasma volume.

with warfarin can displace the drug from plasma proteins

and cause dangerously high free warfarin concentrations in the blood.

ifitstical

8e

Pharmacology

3. Unequal distribution. Factors that account for unequal drug distribution include the following: a. Tissue affinity. Binding to mucopolysaccharides, nucleoproteins, and phospholipids reduces the availability of drugs.

b. Bodyfat acts as a reservoir for lipid-soluble drugs. c. Blood-brain barrier is highly selective for lipid-soluble, nonionized compounds. d. Blood flow, if high, allows drugs to reach equilibrium faster (e.g., in brain).

C. Drug elimination. Pharmacologic effects of drugs are terminated by the biotransformation of the drug to an inactive metabolite before excretion or by the excretion of unchanged drug or active metabolite.

liver is the most important site of drug metabolism and biotransformation. Metabolic enzymes, the hepatic microsomal enzymes, are predominantly found in the smooth endoplasmic reticulum, e.g., the

1. Metabolism and biotransformation. The

cytochrome P-450 systems. Other enzymes are located in mitochondria (e.g., monoamine oxidase), the cytosol (e.g., alcohol dehydrogenase), and lysosomes.

I. Most metabolic reactions are oxidations, reductions, or hydrolyses (phase I reactions). Phase I reactions may be followed by phase II conjugations.

a. Phase

b. Phase II. Conjugation of drugs or metabolites involves the addition of an endogenous substance (e.g., carbohydrate or sulfate). This usually inactivates the drug or metabolite and facilitates excretion by making the drugs more hydrophilic.

(1) Conjugation may occur with glucuronic acid (most common), sulfate, and amino acids, or by acetylation.

(2) Enterohepatic circulation. Conjugated drugs

are actively secreted in the bile. In

the small intestine, the drugs are hydrolyzed, and most bile salts are reabsorbed in the terminal ileum. The drug may be excreted in the feces or reabsorbed and excreted in the urine. c. Factors that affect hepatic metabolism

(1) Age. Very young and elderly individuals may

In a Nutshell An important source of drug interaction is induction or

inhibition of metabolism by the liver.

lnducers

lnhibitors

Barbiturates

Cimetidine

Phenytoin Ketoconazole

Rifampin

have impaired metabolism or con-

jugation.

lsoniazid

Carbamazepine

(2) Genetics. The activiry of N-acetyltransferase is regulated by genetic factors and influences the metabolism of procainamide, dapsone, and isoniazid.

(3) Hepatic insufficiency may impair metabolism

(e.g., cimetidine).

(4) Drug interactions. Some drugs may competitively inhibit the metabolism of other drugs by the microsomal enzymes. Others may induce increased microsomal enzyme activiry thereby increasing the metabolism of other drugs.

(5) Hepatic blood flow. Congestive heart failure (CHF) and drugs that reduce cardiac output (e.g., propranolol) can impair hepatic metabolism by reducing hepatic blood flow.

2. Drug excretion a. Kidney. The kidney is the primary site of drug excretion.

(1) Glomerular filtration is a passive, nonsaturable process. Drugs that

are bound

to plasma proteins are not readily filtered.

(2) Tubular secretion is usually an active, saturable in the proximal convoluted tubule.

eo iiiE[rcal

process; this takes place mostly

Pharmacodynamio and Pharmacokinetia

(3)

Passive excretion. Charged particles cannot passively cross tubular membranes;

Clinical Correlate

neutral molecules can. This principle can be used to enhance the secretion of Alkalinization "traps" salicyclic

toxic charged particles. b. Lungs are important for the excretion of gaseous anesthetics and contribute to paraldehyde, alcohol, and garlic excretion.

acid in the renal tubule by increasing the ratio of charged

to uncharged molecules.

c. Gastrointestinal tract. Some drugs are secreted into the liver biliary tract and eliminated in the feces. d. Sweat, saliva, tears, and breast

milk contribute minimally to the excretion of drugs.

Lactating mothers should be under close medical supervision when breast feeding milk and can cause neonatal toxicity.

Because only the uncharged

molecules are in equilibrium across the tubular membrane,

excretion is enhanced.

because many drugs are excreted in breast

D. Drug decay curves. Fundamental pharmacokinetic principles are based upon the most elementary kinetic model, i.e., that the body is considered a single compartment (Figure fV-l-4). Drug decay curves describe the time course of drug in the compartment or body.

In a Nubhell

.

Zero-order kinetia-drug decreases at a constant rate

1. Zero-order kinetics. This occurs when the elimination process is saturated. A constant amount (not a fraction) of the drug is eliminated over a given time period (e.g., ethanol).

regardless of plasma drug

concentratron

.

First-order

kinetia-

elimination rate is

Plasma [drug]

proportional to plasma

Plasma Idrug]

drug concentration Fir$-order kinetia are

Time

characterized by the

Time First-order kinetics

Zero-order kinetics

concept of haltlife (t,7r) elimination.

Figure lv-l-4. Drug decay curves. 2. First-order kinetics. Most drugs at therapeutic doses follow fust-order kinetics, i.e., elimination is concentration dependent and follows exponential kinetics. In first-order kinetics: a. Processes necessary for absorption and excretion are not saturated. b. A constant fraction of the drug is eliminated per unit time.

c. The rate of drug removal is proportional to the plasma concentration, and the concentration of drug diminishes logarithmically with time. d. The rate of elimination may be described in two ways:

(1) Physiologic half-life (t,,r), which is the time required for

50olo

of the drug to be

eliminated, where 1,,, = 0.69/h

(2)

Rate constant of elimination

(\),

which is the percentage change per unit of time

\

3. Clearance (Cl) of drug from the body is equal to the product of the rate constant (h) and volume of distribution:

In a Nubhell Clearance is mathematically

equivalent to the volume of blood that can be completely

cr= (KX%)

=(#)

cleared of a drug per unit time.

ilits[ical el

Pharmacology

4. Drug accumulation. Repeated

doses may cause

accumulation of the drug (Figure IV-l-5).

Assuming fi rst-order kinetics: a.

If the rate of administration

exceeds the rate of elimination, accumulation occurs.

Metabolism and excretion

Dose of drug

Figure lV-l-5. The single-component pharmacokinetic model. Note With first-order kinetia, the. average drug concentration is

determined by the ratio of the dose to the dosing interval.

Therefore,agl4hwould produce the same average concentration that 8 g/8 h

would, except that the peaks and troughs would be more severe in the latter case.

b. Accumulation ceases when the rate of elimination is equal to the rate of administration; at that time, a steady state is established.

c. The time required for a drug to be eliminated is related to t,,r. Iust as it takes ,t-5 halflives for drug accumulation to reach steady state, it takes 4-5 half-lives for drugs to be almost completely eliminated.

Clinical implications 1. Half-life. The half-life desired level of drug. a. Drug

of a drug determines the dose interval

necessary

to obtain the

with short half-life. Giving twice the dose does not double the duration of

action of a drug with a short half-life. b. Drug with long half-life. A large loading dose followed by smaller maintenance doses (e.g., digitalis) are typical for drugs with a long half-life. c. Drug accumulation. Because approximately four half-lives are required for almost complete elimination of a drug, any dosage interval shorter than this leads to drug accumulation. 2. Prolongation of drugaction a. Frequent doses (e.g., sulfonamide every 4 hours) are necessary.

b. Coating tablet (time-release) or a "depot" form of the drug (e.g., crystalline insulin) allows slow absorption.

100

90

.80

Elimination rate constant ke = 0.693/tilz Half-life, tUz = 0.693/ke, where 0.693 = In(2)

Pzo Soo Euo 5+o

ogo

20

ln 0

1234

Time (half-life multiples)

Figure lv-l-6. A "drug decay curve" showing the time course of exponential elimination of a drug from the circulation over time.

s2

iliEhical

Pharmacodynamics and Pharmacokinetics

c. Slow excretion of drug (e.g., blocking secretion of penicillin G with probenecid) prolongs drug action.

of drug (e.g., blocking the metabolism of 6-mercaptopurine [6-MP] with allopurinol) also prolongs the drug action.

d. Inhibiting the metabolism

3. Loading dose. Certain drugs in clinical situations may require a loading dose to produce therapeutic levels without the delay of 4-5 half-lives (e.g., lidocaine in the setting of an acute myocardial infarction). 4. Disease states requiring adjustment of drug dose and dosing interval

€linical Correlate

a. Renal insufficiency (I

clearance correlates well with elimination of a drug by the kidney. Serum creatinine and blood urea nitrogen (BUN) correlate less well.

) Creatinine

(2) The initial or loading dose is usually the same, but the maintenance dose must be decreased or the interval between doses increased in proportion to the decreased creatinine clearance and the fraction of drug excreted unchanged in

A low creatinine clearance indicates renal insufficiency

and often necessitates decrease in dose or

a

a

decrease in dosing frequency

of renally excreted drugs.

the urine. b. Hepatic insufficiency. Although these patients may require adjustments in the dose and intervals of drugs that are metabolized bythe liver, accurate prediction of the adjustment is not possible based on liver function tests or other parameters. Serum drug concentration and clinical manifestations of toxicity must be followed closely.

ifitshical

eI

Autacoids

Autacoids are endogenously produced substances of intense pharmacologic activity that do not fit

into more specific classifications, such as hormones or neurotransmitters. They are also called paracrine secretions or "local hormones" and "autopharmacologic agents." The autacoids include hi$amine, serotonin, angiotensins, kinins, and the eicosanoids (prostaglandins).

HISTAMINE A.

Biosynthesis and physiologic properties 1. Histamine is synthesized by decarboxyiation

of the amino acid histidine (r-histidine

decarboxylase).

2. Histamine is found in varying concentrations in nearly all mammalian tissues. The highest concentrations are found in skin, lung, and especially the gastrointestinal mucosa. Large amounts are normally stored in the body, particularly in the circulating basophils and tissue mast cells.

3. Histamine release from mast cells is a secretory process triggered by the binding of specific antigen to two adjacent surface IgE molecules ("bridging"). Degranulation liberates histamine, which is responsible for many of the signs of immediate hnrersensitivity, allergy, and anaphylaxis. An increase in intracellular Ca2* results from the cross-linking of receptors, leading to increased Ca2* permeability and release to initiate degranulation. 4. Reduced cAMP or cGMP favors histamine release. Beta-adrenergic stimulation and glucocorticoids decrease release by increasing intracellular cAMP.

5. Other substances present in mast cell granules that contribute to allergy and anaphylaxis are: a. Kallikrein

b. Kinins c. Prostaglandins d. Slow-reacting substance of anaphylaxis (SRS-A)

B. Histamine receptors 1. H, receptors a. These receptors mediate constriction of smooth muscle in bronchi and the gastroin-

testinal tract. b. They mediate vasodilatation of small vessels and increase capillary permeability.

ifitstical

95

Pharmacology

ln a

NUtShell

Receptor

Action

Hr

Vasodi*-

H2

Diphen_ tation hydramrne Broncho- and others conenQon

d. They are coupled to phospholipase c. Activation leads to inositol 1,4,5-triphosphate

(IPr) and diacylglycerol (DAG), which activate protein kinase

c'

calmodulin-

dependent kinases, and phospholipase Ar, leading to response. e. H, blockade has no effect on gastric acid secretion.

Ca$ric acid Cimetidine

others CNS N/A clinically

secretion

H3

Blocker

c. They are blocked by pyrilamine and diphenhydramine; the classic agonist is 2-methylhistamine.

and

2. Hr receptors a. These receptors mediate gastric acid secretion and vasodilatation.

b. They are blocked by cimetidine, ranitidine, famotidine, and nizatidine. agonist is dimaprit; the classic agonist is 4-methylhistamine.

c. They are linked to the stimulation cAMP-dependent Protein kinases.

of

adenylate ryclase and, thus,

A

selective

to activation of

3. H, receptors a. These receptors were discovered

in the late

1980s.

b. They are found mainly in the CNS, where they inhibit the release of neurotransmitters. c. They may be involved in synthesis and release of histamine. d. They are selectively blocked by thioperamide; the selective agonist is cx-methylhistamine.

C. Organ system effects 1. Cardiovascular system a. Histamine produces a dilatory effect on vasculature, which causes flushing, lower peripheral resistance, hypotension, and increased capillary permeability (predomi-

.

nantly H,-mediated).

b. There is positive inotropic and chronotropic effects on the heart (Hr-mediated).

c. The classic "triple response" following intradermal injection (mainly H,) includes: (

1) Localized erythema due to vasodilatation

(2) Bright

red flare surrounding the local spot as a result of axon reflexes that produce

additional vasodilatation

(3) A wheal of edema secondary to increased permeability of postcapillary venules 2. Extravascular smooth muscle a.

cause contraction; bronchial smooth muscle is very histamine sensitive, and fatal bronchoconstriction can occur with excessive H,-receptor stimulation'

H, agonists

b. H, agonists cause relaxation. 3. Exocrine glands (gastric glands are the prototype) a. Histamine is the primary terminal common mediator of gastric acid secretion. Copious, higfiy acidic gastric juice is produced in response to histamine (H, receptor-mediated).

b. Histamine can also stimulate secretion from the pancreas, salivary glands, and bronchiolar glands.

4. Nerve endings cause sensations of pain (dermis) and itch (epidermis); classically, these effects are part ofthe triple response. 5. Histamine stimulates the adrenal medulla to release catechols.

e6

ilitshical

Autacoids

D. Metabolism

l. 2.

Histamine acts rapidly when given parenterally; oral histamine is, for the most part, inactivated by bowel flora.

Most histamine is metabolized by methylation (N-methyltransferase), yielding N-methylhistamine.

of the N-methylhistamine is then converted by monoamine oxidase (MAO) to N-methyl imidazole acetic acid and excreted by the kidney.

3. Most

4. Alternatively, some histamine is oxidatively deaminated by diamine oxidase (DAO) and then excreted as ribose conjugates.

E. Histamine-receptor agonism 1. Certain compounds release histamine directly without antigen-IgE interaction, e.g., cationic organic compounds (including a variety of drugs), amides, alkaloids, and certain antibiotics. 2. The action of some venoms and toxins may be mediated by histamine release. 3. Pathologic aggregations of mast cells and basophils may cause a variety of histaminic symptoms. Conditions such as urticaria pigmentosa (mastocytosis), systemic mastocytosis, carcinoid syndrome, and myelogenous leukemia are associated with urticaria, pruritus, headache, w-eakness, flushing, and gastric distress (including peptic ulcers).

F. Ctinical uses. Histamine has no current therapeutic

uses

but is used clinically in some

sys-

tem function tests. 1. Gastric function tests. Hyposecretion or hypoacidity of gastric juice in response to histamine is associated with pernicious anemia and atrophic gastritis; a hypersecretory response is found with Zollinger-Ellison syndrome.

2. Sensory nerve tests. Local flare after intradermal injection implies intact sensory nerves. 3. Bronchial reactivity. Inhalation of histamine is used to test the reactivity of bronchi. G. H, antagonists ("antihistamines") are used to control the symptoms of immediate hyper-

sensitivity.

Strategies for treating

hypersensitivity may also

1. Classes of drugs used for their H,-blocking activity

include physiologic

a. First-generation (nonselective)

(l)

Note

antagonists, such as

The ethanolamines include diphenhydramine, dimenhydrinate, and clemastine. Ethanolamines have strong sedative and anticholinergic effects; gastrointestinal disturbance is rare.

epinephrine or ephedrine.

(2) The ethylenediamines include pyrilamine and tripelennamine. Ethylenediamines are sedating and have local anesthetic actions; gastrointestinal disturbance is common.

(3) The alkylamines include chlorpheniramine, brompheniramine, and dexclorpheniramine. Alkylamines are less sedating than ethanolamines and ethylenediamines; they produce more CNS stimulation than other groups.

(a) The phenothiazines include promethazine. Phenothiazines

possess considerable

anticholinergic activity and moderate sedative effects. They are used primarily for their antiemetic effects.

ifiBhical

97

Pharmacology

(5) The piperazines include meclizine, hydroxyzine, and cyclizine. Piperazines have comparatively little sedative effects. CNS and anticholinergic effects are moderate and long acting. They are used for treating vertigo and motion sickness. Hydroxyzine has significant antipruritic action. b. Second-generation (peripherally selective)

(1) Cetirizine is in the piperazine

class.

It is a metabolite of hydroxyzine, but it does not

cross the blood-brain barrier. Thus, cetirizine is nonsedating.

(2) The piperidines include astemizole, fexofenadine, and loratadine. These are H, antagonists that do not cross the blood-brain barrier effectively and, thus, produce minimal CNS actions. Most piperidines are nonsedating.

2. Pharmacokinetics. All of the antihistamines are well-absorbed orally, metabolized by the liver, and excreted by the kidney.

3. Pharmacologic effects a.

H,

antagonists act by occupying the histamine

H,

receptor without initiating

a

response (i.e., they provide competitive inhibition).

Clinical Correlate

b. They have no effect on gastric secretion.

Physiologic antagonists,

c. They antagonize the bronchoconstrictor activity of histamine "triple response" to intradermal histamine.

such as epinephrine (which also exhibits antihistamine actrons to some extent), are

more effective for the

as

well

as

the cutaneous

d. They exert cough suppressive (antitussive) action via a presumed CNS effect. Other

CNS mechanisms include action

in the medullary chemoreceptive trigger zone

("vomiting center"), possibly by antagonism of acetylcholine.

management of acute asthma

e. They provide relief of the effects of motion sickness via a presumed CNS action.

and anaphylaxis than are

f. They are useful

the specific histaminereceptor antagonists.

as

nighttime sleep aids because of their sedative effects.

4. Indications for use a. Antihistamines are used for the palliation of syrnptoms of allergy, hay fever, and aller-

gic rhinitis and for the palliation of cutaneous allergic symptoms associated with chronic urticaria, atopic and contact dermatitis, and the urticaria of serum sickness and drug eruptions. b. They are not beneficial for treating bronchial asthma. c. They are mildly useful as secondary agents

in the treatment of

anaphylaxis and

angioedema. d. They are usefi.rl in the treatment of rhinitis associated with the common cold. e. They are used

to treat motion sickness and vestibular disturbances (e.g., M6nibre

disease).

5. Side effects and toxicity. The spectrum of side effects is frequently the basis for preference of specific agents.

a. Sedation is the most common side effect: except the piperidines.

it is common to all the antihistamines.

b. CNS effects include dizziness, Iack of coordination, tremors, and diplopia. c. Gastrointestinal effects include anorexia, nausea, vomiting, constipation, and diarrhea. d. Antimuscarinic effects include drlmess of mucous membranes and urinary retention.

eB iliBbicat

Autacoids

e. Cardiovascular effects include palpitations and hypotension. Serious cardiovascular side effects, including prolongation of the QT interval, have been associated with astemizole and terfenadine, especially with concomitant use of an azole derivative or

macrolide antiobiotic.

f. Peripheral

nervous system effects include paresthesias and weakness of the extremities.

Bridge to Pharmacology A USMLE favorite involves the interaction between the antifungal ketoconazole and astemizole. Ketoconazole

g. Teratogenicity may occur (especially with the piperazines).

inhibits liver metabolism of

h. Acute poisoning may occur, producing hallucinations, excitement, lack of coordination, seizures, fixed and dilated pupils, and fever.

to increased blood

H. H, antagonists ("H, blockers") act selectively on H, receptors with virtually no effect on H, receptors. They block gastric acid secretion.

the antihi$amines, leading concentrations that can result in lethal cardiac arrhvthmias.

1. Cimetidine a. Pharmacologic properties. Cimetidine is a histamine analog that contains the imidazole ring that is thought to convey receptor affinity. It acts as a competitive antagonist at H, receptors and greatly reduces both basal gastric acid secretion and mealstimulated acid secretion. It also reduces gastric juice secretion induced by histamine, gastrin, caffeine, and insulin. It is well absorbed orally and is mostly excreted unchanged in the urine. It inhibits hepatic microsomal enzlrnes.

for use. Cimetidine is used to treat duodenal and gastric ulcers, Zollinger-Ellison syndrome, and hypersecretion due to systemic mastocytosis and basophilic leukemia. It is also used to decrease gastric acidity in reflux esophagitis, stress gastritis, and the short bowel syndrome. It is of unproven benefit in active upper gastrointestinal bleeding and in the prophylaxis ofupper gastrointestinal bleeding in critically ili patients.

b. Indications

c. Side effects and toxicity

(l ) Side effects are minor, and their incidence is infrequent. Rash, fever, headache, dizziness, fatigue, and myalgias may occur; rarely, there may be confusion or coma (in elderly patients). Elevated creatinine may occur, probably as the result of competition between cimetidine and creatinine for excretion (i.e., it is not an indication of change in renal function).

(2) Antiandrogenic effects, including gynecomastia, loss of libido, galactorrhea, and reduction in sperm count, have been reported; there are no documented effects on fertility.

(3) Cimetidine reduces hepatic blood flow and can slow clearance of other drugs (e.g., lidocaine); it reduces the activity of cFtochrome P-450, thereby decreasing the metabolism of many other drugs (e.g., warfarin, theophylline, diazepam).

(a)

Rarely, leukopenia, thrombocytopenia, and hepatotoxicity may occur.

2. Ranitidine and famotidine

Note In addition to cimetidine,

another important drug that

inhibis the rytochrome P-450 is

the antifungal ketoconazole.

a. Pharmacologic properties

(1) They are much more potent than cimetidine (approximately six times more potent).

(2) These drugs effectively inhibit gastric acid secretion. They do not bind strongly to hepatic cytochrome P-450 enrymes.

(3) They produce less CNS penetration than cimetidine

and, therefore, may have less CNS toxicity. These drugs have no antiandrogenic effects.

iiitshical

ee

Pharmacology

b. Indications for use are similar to cimetidine; they are preferred in patients prone to CNS toxicity with cimetidine (e.g., elderly patients). They are used with patients taking drugs known to interact with cimetidine (e.9., warfarin and theophylline).

c. Side effects and toxicity have not been completely defined; rash, dizziness, headache, diarrhea, impotence, and confusion have all been reported.

SEROTON I N (5-HYDROXYTRYPTAMT N E) A. Biosynthesis and physiologic properties 1. Serotonin is endogenously synthesized by the hydroxylation and subsequent decarboxylation of the amino acid tryptophan. 2. Serotonin functions as a neurotransmitter in the CNS. It is present in enterochromaffin cells of the gastrointestinal tract, where it regulates smooth muscle function, and in platelets, where it serves to regulate platelet function. Approximately 90Vo is in the enterochromaffin cells.

3. Serotonin agonists are well known for producing hallucinogenic activity (e.g., lysergic acid diethylamide [LSD] and psilorybin). B. Organ system effects

l.

Respiratorysystem a. Serotonin produces a transient increase in respiratory rate. b.

It

also produces bronchoconstriction.

2. Cardiovascular system a. Serotonin usually produces vasoconstriction (especially of splanchnic and renal beds), but it produces vasodilatation of skeletal muscle vascular beds.

b. It produces both positive inotropic and chronotropic effects. c. It is responsible for the coronary chemoreflex, leading to hypotension and bradycardia (due to vagal potentiation and sympatholytic effects). d.

It has a triphasic pressor effect. The early depressor effect, followed by the pressor phase and then the late depressor effect, is a result of competing influences from the varied responses (constriction in splanchnic arterial beds and dilatation in muscle arterial beds).

e.

lt produces venous constriction.

f. It enhances platelet aggregation. 3. Smooth muscle. Through the action of muitiple receptors, serotonin usually inhibits, but may also enhance, gastric and large intestine motility while stimulating small intestine motility. +.

Exocrine glands. Serotonin reduces the volume and acidity of gastric juice.

5.

Nerve endings a. Serotonin is generally stimulatory, producing pain at the site of injection and stimulating autonomic efferents. b.

It alters ganglionic transmission variably at different

doses.

c. It depolarizes adrenal medullary chromafifin cells to induce catechol secretion.

roo iiiBbicar

Autacoids

6. CNS. Serotonin functions primarily as an inhibitory neurotransmitter. It is primarily localized in the raphe nuclei of the brain stem with axons projecting to the spinal cord, brain stem. and forebrain. 7. In the pineal gland, serotonin functions

as

precursor of melatonin.

8. In the platelets, serotonin potentiates aggregation. 9. There are pathologic accumulations of serotonin in carcinoid tumors; malignant tumor of enterochromaffin cells is associated with excess serotonin production, yielding symptoms of diarrhea, abdominal cramps, malabsorption, and flushing. C. Metabolism. The metabolism of serotonin begins with oxidative deamination by MAO to 5-hydroxyindoleacetaldehyde, which is further oxidized to 5-hydroxyindoleacetic acid (5-HIAA) by aldehyde dehydrogenase, and then renally excreted. D. Clinical uses. There are no current therapeutic uses for serotonin.

E. Serotonin receptors. Multiple serotonin receptor subtypes have been identified. At least seven 5-HT receptor families have been cloned, of which four, designated 5-HT1 through 5-HT, have been characterizrd.5-HT, and 5-HT+7 are G-protein--coupled receptors, whereas 5-HT. is a Na*/Kt ligand-gated ion channel receptor. The 5-HT, family has been characterized as five groups designated 5-HTrA through 5-HTrE. 5-HTrD has been the one most associated with migraine headaches.

F. Serotonin agonists 1. Sumatriptan, naratriptan, rizatriptan, and zolmitriptan a. Pharmacologic properties

(l)

These are indole derivatives structurally related to serotonin.

(2) They are selective agonists of 5-HT, receptors (more specifically, at

5-HT1D

receptors).

In addition, sumatriptan is administered intranasally and subcutaneously (but not intravenously because the latter route may cause coronary vasospasms.)

(3) These are administered orally.

(4) Sumatriptan is metabolized to an indole acid metabolite, which, along with the parent drug, is excreted in the urine. b. Indications for use. These are used in the acute treatment of migraine headaches. Agonist action at 5-HTrD receptors causes vasoconstriction, which blocks release of pro-inflammation neuropeptides to reduce the pain of a migraine attack. c. Side effects and toxicity

ln a Nutshell Sumatriptan is a 5-HT, receptor agonist used as treatment for migraine headaches.

(1) With sumatriptan, there maybe pain at the injection site, dizziness, chest discomfort, and transient elevation of blood pressure.

(2) They should be used with caution in patients with liver and renal dysfunction. (3)

Use is contraindicated in patients with ischemic heart disease, angina, or uncon-

trolled hlpertension. 2. Etgotalkaloids (selective, partial agonists with some antagonist action) a. Ergotamine (and dihydroergotamine)

(1) Pharmacologic properties. Ergotamine is administered orally, by inhalation, by the sublingual route, and in suppository form. It is often given along with caffeine,

iiitshical

rol

which enhances absorption and provides additional vasoconstriction. The ergot alkaloids are partial agonists and antagonists at 5-HT receptors. The mechanism of action for treating migraine is thought to be from agonist action like that of suma-

triptan.

(2) Indications for use. Acute migraine headaches and reduction in postpartum hemorrhage

(3) Side effects and toxicity. Adverse reactions include nausea and vomiting, diarrhea, paresthesia of limbs, and cramps. It is not indicated for long-term treatment because of its potential to cause gangrene. CliniCal

COnelate

b. Ergonovine and methylergonovine (

Ergonovine,

1) Pharmacologic properties. The uterine-stimulating action of these drugs

is

evi-

methyrergonovine,and

i:T,ll',:l:f,1:",:n;i1T:,,""*:n:.::ffi"1?:T:'ffllx:;,,:.T;:"":.?fi:

ergotamine cause

cies).

uterine

constriction and are therefore

(2) Indications foruse.

of postpartum bleeding. used in the control

These drugs are used to treat postpartum bleeding.

(3) Side effects and toxicity. Adverse reactions include nausea, vomiting, blurred vision, headache, hlpertension, convulsions, and abortion. G. Serotonin antagonists 1. Methysergide is a semisynthetic ergot derivative. a. Pharmacologic properties (I

) Methysergide inhibits

tlre vasoconstrictor effect of serotonin as well as its effect on extravascular smooth muscle.

(2) Its mechanism of action is evidently related to blockade of peripheral 5-HT receptors, but it may also act as an agonist at some central receptors. b. Indications for use (I

)

Methysergide is used in the prophylaxis of vascular headache syndromes.

(2) It is used in the treatment of postgastrectomy dumping syndrome. (3) It is used to treat intestinal hypermotility of the carcinoid syndrome. c. Side effects and toxicitF

(l)

Ergotism produces vasoconstrictive complications, including chest pain, pulselessness, weakness, myalgias, and paresthesias.

(2) Retroperitoneal fibrosis may develop with prolonged

use.

2. Cyproheptadine a. Pharmacologic properties (

I

) Cyproheptadine

is a phenothiazine derivative.

(2) It blocks both histamine (H,) and serotonin receptors. (3)

It

has weak anticholinergic effects, mild sedative effects, and calcium-channel activity.

b. Indications for use (

r02 ilitstical

I

) Cyproheptadine

is used in the treatment of pruritic dermatoses.

Autacoids

(2) It

is used as a prophylaxis ofvascular headache'

(3) It

is used to stimulate appetite and weight gain'

( ) It is used in the treatment

of intestinal hypermotility of the carcinoid tumor.

(5) It is used in the treatment of Cushing syndrome' c. Side effects and toxicitY

(1) Drowsiness, ataxia, and confusion may occur' (2) Hlpotension and tachycardia may develop' (3) Blood

dyscrasias maY develoP.

(4) Weight gain and increased growth in children (via distortion of insulin and growth hormone secretion) may occur.

ANGIOTENSINS The vasoconstrictive polypeptides angiotensin

II and angiotensin III

are products

ofthe renin-

angiotensin system.

A. Biosynthesis and physiologic properties 1. Renin a. Renin is an acid protease enzyme synthesized and secreted by cells

of the kidney

juxtaglomerular apparatus; stimuli include:

(1) Lowering of renal perfusion pressure (e.g., decreased cardiac output or blood volume, hemo.rhage, lowered total peripheral resistance, renal artery stenosis)

(2) Reduction in sodium load to the kidney (3) Sympathetic B,-receptor stimulation (juxtaglomerular

cells have B' receptors)

b. Renin is metabolized by the liver and kidney. 2. Angiotensinogen a. Angiotensinogen is an ctr-macroglobulin, produced primarily by the liver.

b. It serves as a substrate for renin to produce angiotensin

I'

c. There is increased slmthesis with glucocorticoids and thyroid hormone. d. Angiotensin-specific cell surface receptors are believed to mediate effects on cells. They are invofved in the constriction of arterioles and the stimulation of synthesis and

secretion of aldosterone.

3. Angiotensin I and angiotensin-converting enzyme (ACE) a. Angiotensin I is converted to angiotensin endotheliurn, especially in the lung.

II byACE; 2040o/o of ACE

is

in the vascular

b. ACE is a zinc-binding exopeptidase.

c. ACE also participates in degradation ofbradykinin and enkephalins. 4. Angiotensin

II

a. Angiotensin

II is a vasoconstrictive octapeptide'

b. It stimulates the production and release of aldosterone'

ifitstical

r05

Pharmacology

c.

Bridge to Physiology JCA perfusion { -Decreased Renin pressure

hormone of the renin-angiotensin system because

it

d. Angiotensin II is hydrolyzed by aminopeptidase to a heptapeptide, angiotensin which is also active (but less so than angiotensin II).

+

Angiotensinogen Angiotensin

It is the most important

is

responsible for the conservation of sodium and the maintenance of blood volume through its control ofaldosterone release.

I

III,

5. Renin-angiotensin system in hnrertension

I

I

a. Elevated plasma renin activity (PRA) is associated with hypertension, resulting from renal artery stenosis and malignant hypertension.

ACF

V

-t

Ansiotensin ll Y

b. Normal or low PRA is found in most patients with essential hypertension.

Vasoconstrictron

and aldosterone

c. Antagonists of the renin-angiotensin system are potent antihypertensives even in cases where PRA is not elevated.

release

d. Prostaglandins and ryclic nucleotides have been implicated as intracellular mediators.

B. Organ system effects ofvasoconstrictive angiotensins (angiotensin II and angiotensin III) 1. Cardiovascular system a. The active angiotensins produce vasoconstriction ofprecapillary arterioles and postcapillary venules. Angiotensin II is one of the most potent pressor agents known (it is 40 times stronger than norepinephrine). b. The vasoconstriction is most striking in skin and in renal and splanchnic beds.

c. They produce increased inward calcium current in cardiac muscle; there is a positive

inotropic effect. d. They increase extravascular fluid as a result of the separation of endothelial cells. e. They increase lymph flow.

2. Central neryous system a. They increase sympathetic

outflow contributing to

a rise in blood pressure.

b. They stimulate drinking behavior (dipsogenic).

c. They stimulate ADH release.

3. In the peripheral nervous system, they increase release of and response to catechols. 4. In the adrenal cortex, they stimulate aldosterone synthesis and secretion. 5. Kidney a. There are complex effects of the angiotensins because of vasoconstriction, aldosterone, and ADH action; the net result is usually antidiuresis and antinatriuresis.

b. The angiotensins may cause opposite effects in the presence of hepatic cirrhosis. C. Angiotensin antagonists

l.

Antagonists ofangiotensin

II

(the prototype is saralasin)

a. Pharmacologic properties (

1) These antagonists competitively block angiotensin II receptors.

(2) There is lower blood pressure in high-renin and normal-renin states, reflecting the contribution of the renin-angiotensin system to the maintenance of blood Dressure.

r04 iliBbicat

Autacoids

b. Indications for use. In the past, angiotensin antagonists were used mainly diagnos-

tically. They are currently not in clinical use. c. Side effects and toxicity. They may cause dangerous hypotension stenosis or malignant hypertension.

2.

ACE

inhibitors

in renal artery

(e.g., captopril, enalapril)

a. Pharmacologic properties (

I

) These

drugs block the conversion of angiotensin I to angiotensin II.

(2) They cause

decreased vascular resistance and a drop in blood pressure in hypertensive patients. Little reflex tachycardia has been noted.

(3) They exert their most profound

effects in high-renin hypertension; they are also

efficacious in normal-renin hpertension. The latter effects may be due in part to decreased inactivation ofendogenous hypotensive peptides, such as bradykinin.

b. Indications for use

(l)

ACE inhibitors are diagnostically important in identi$ring patients with surgically reversible renovascular hypertension.

In a Nutshell ACE Inhibitors

.

(2) These drugs are used in the treatment of mild-to-severe essential hpertension, elevated-renin hlpertension, cHF (they reduce afterload and preload), and hypertension in chronic renal failure patients. c. Side effects and toxicity

(l)

Severe hypotension may occur after the initial dose in patients taking diuretics; patients may be sodium depleted.

(2)

Rash, loss of sense of taste, and cough may occur.

(3) Leukopenia and proteinuria rarely occur.

Block angiotensin |

-+

angiotensin ll (decrease

hlnn/

.

nrpqcrrrp\

Inhibit bradykinin degradation (can cause side

cffpcic p o cnroh\

.

Are used in the treatmenr

of hypeltension and congestive heart failure

PTASMA KtNtNS (BRADYKIN|N, KAIUKRE|N, KALHDIN,

AND RETATED

PEPTTDES)

A. Biosynthesis and physiologic properties

I

Kinins are produced and cleaved by a group of enrymes called kininogenases; the most interest has been in a group of enzymes called the kallikreins.

2. Prekallikrein is converted to kallikrein by the Hageman factor (factor XII). Kallikrein catalyzes the conversion of high-molecular weight kininogen (HMWK) into bradykinin and the conversion of both HMWK and low-molecular-weight kininogen (LM\4rK) into kallidin. 3. The formation of bradykinin and kallidin is extensively interwoven with the activation of the clotting and fibrinolytic cascades as well as with the complement system.

4. Kinins have half-lives of 10-20 seconds; most are inactivated in the pulmonary bed by kinase II.

5. Kininase I converts some bradykinin and kallidin to their respective des-Arg metabolites, which are agonists of Bl receptors.

ilitsbical

r05

Pharmacology

B. Organ system effects 1. Cardiovascular system. Kinins have a potent vasodilatory and flushing effect. They also increase microcirculatory permeability and edema formation.

2. Kidney. Kinins regulate urine volume and composition. 3. Extravascular smooth muscle. The most important efFect plasma kinins have on smooth muscle is constriction of the tracheobronchial muscle.

4. Nerve endings. Plasma kinins are powerful pain stimulators. 5. Inflammation. Injected kinins mimic inflammation. 6. Adrenal gland. Plasma kinins are powerful stimuli for catechol discharge. C. Mechanism of action. The mechanism of action of kinins is not completely understood.

l. Two kinin receptors, B, and a.

Br, have been characterized.

The B, receptor, previously studied as the bradykinin receptor, mediates most of the actions of bradykinin and kallidin in the absence of inflammation. B, receptors are coupled via G-proteins, producing increases of IP. and DAG.

b. The B, receptor is selective for the des-Arg metabolites of bradykinin and kallidin. B, receptors are increased during inflammation and may predominate during episodes of tissue damage or inflammation.

2. Prostaglandins and phospholipase A, are involved; ryclic nucleotides may be involved in some tissues.

3. Hereditary angioedema is a result of a deficienry of C, esterase inhibitor; episodes of edema are caused in part by excess bradykinin. 4. Septic and anaphylactic shock are partly becaused by bradykinin release. D. Clinical uses. There are no current clinical uses for the kinins; however, a kallikrein inhibitor, aprotinin, has had some success in the treatment of acute pancreatitis and carci-

noid syndrome. E. Other kinins 1. Substance P is a

probable neurotransmitter.

a. Its effects include vasodilatation, stimulation of smooth muscle, salivation, diuresis, and natriuresis.

b. It is present in enterochromaffin cells. c. It contributes to symptoms of the carcinoid syndrome. d. It is involved as a mediator of pain in sensory pain neurons.

2. Vasoactive intestinal peptide (VIP) is a potent vasodilator and pancreatic secretagogue. a. It is found in the nervous system and pancreas. b. It may be responsible for the watery diarrhea syndrome (Verner-Morrison or pancre-

atic cholera).

r06 ilitsbicat

Autacoids

EICOSANOI DS: PROSTAGLAN Dl NS, PROSTACYCH N,

THROMBOXANES, AND TEUKOTRIENES A. Biosynthesis and physiologic properties (Figure IV-2-1)

(membranes)

Phospholipids

Cyclooxygenase

Prostacyclin Leukotriene 44

PGlz (Prostacyclin)

(LTA4)

Figure lV-2-1 . Biosynthesis of prostaglandins (PGD2, PGE2, PGF2, PGG2, PGH2), prostacyclin (PGlt, thromboxane (TXA2), and leukotrienes (LTA4, LTB4, LTC4, LTDa, LTEa, LTFa). (5-HPETE = 5-hydroperoxyeicosatetraenoic acid; and 5-HETE = S-hydroxyeicosatetraenoic acid)

t. Generally, prostaglandins are derived from 2O-carbon fatty acids; they contain three to five double bonds and a central cyclopentane ring.

Arachidonic acid is the chief precursor in humans; it is derived from dietary linoleic acid (an essential fatty acid) or as a component of meat. Body arachidonate is stored by esterification to the phospholipids of cell membranes. Phospholipase A, acts on these esterified lipids to release arachidonate; it is believed to be rate limiting in the formation of free arachidonate. Arachidonate, once released, is acted upon by either of two enzymes: cyclooxygenase or lipoxygenase. a. Cyclooxygenase produces prostaglandins.

(1) There are two isozymes of rycloorygenase (COX-I and COX-2)

i.

COX- I is norma\ present in most cells. It has been associated with protection of stomach lining, reduction of fever, and promotion of platelet aggregation.

lfiBhical

r07

Pharmacology

ii.

COX-2 is induced by the presence of certain cytokines and growth factors. has been associated with the production of pain and inflammation.

It

(2) Oxidation and cyclization of arachidonate forms endoperoxides. (3) Prostaglandin G and H (4) PGG, and PGH,

(PGG2, PGH2) are the first two products.

are unstable; they isomerize to form PGD2, PGE2, or PGFr.

(5) PGH, is broken into thromboxane A, (TX4), which is likewise unstable and breals down to TXBr.

(6) PGH, may alternatively be converted to prostaryclin (PGIr) by prostaryclin synthetase.

(7) Certain

tissues synthesize relatively more or less of certain prostaglandins; lung and spleen syntiesize all types, whereas endothelia synthesize PGI, and platelets synthesize TXA".

b. Lipoxygenase produces

leukotrienes.

(1) It is present in lung, platelets, and leukocftes. (2) It converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (S-HPETE), which is then converted to S-hydroxyeicosatetraenoic acid (5-HETE) or leukotriene

4

(LTA4).

(3) LIA4 can be converted to LIB* or LIC*. (4) LID4, LTE., and LIF,

are produced in successive steps from LTC'.

(5) Slow-reacting substance of anaphylaxis (SRS-A)

is a mixture of LTC, and

LID'.

B. Organ system effects 1. Cardiovascular system a. Most prostaglandins are potent vasodilators, but in some sites and species, they can

induce vasoconstriction.

b. In response to peripheral vasodilatation induced by prostaglandins, cardiac output and rate increase. c. TXA, contracts vascular smooth muscle. d. PGI, causes vasodilatation and hypotension. e. Leukotrienes cause an initial increase in blood pressure, then prolonged hypotension. The latter effect is probably due to leukotriene-induced reduction in coronary blood flow, which leads to reduced cardiac output.

2. Blood a. Platelets

In a .

Nutshell

Vascular

(l)

endothelium

produces PCl2

-+

platelet

inhibition '

Platelets produce TXA2

platelet aggregation

ro8 iiiBf,ical

-+

Prostaglandins inhibit platelet aggregation; PGI, is the most potent.

(2) TXA, promotes platelet aggregation. b. Prostaglandins promote erythropoietin release from the kidney.

c' LTB' is a polymorphonuclear leukocyte chemoattractant'

Autacoids

3. Kidney a. PGI, and PGE, can increase renal blood flow to produce diuresis with sodium and

potassium excretion. b. TXA, decreases renal blood flow.

c. Prostaglandins can stimulate renin release. d. In animals, PGE, inhibits ADH release.

4. Smooth muscle a. Bronchial

(1) PGF, induces bronchoconstriction. (2) PGE, dilates bronchial muscle. (3)

LTC4 and

LID,

are potent bronchoconstrictors.

b. Uterus (

1) PGE, PGA, and PGD cause uterine relaxation.

(2) PGF causes uterine contractions. c. Gastrointestinal muscle. The effects of different prostaglandins on different gastrointestinal muscles are variable. Oral PGE produces decreased gastrointestinal transit time, diarrhea, and cramps. 5. Gastrointestinal system. Gastric acid secretion is inhibited by PGE, and PGI,. Small bowel secretion is increased by PGE, and PGF,.

6. CNS. Intraventricular injections of PGEs cause sedation, stupor or catatonia, and fever. 7. Afferent nerves a. PGEs cause pain when injected intradermally.

b. PGEs and PGI, sensitize afferents to incoming chemical or mechanical stimuli. 8. Endocrine system a. PGE, stimulates release of ACTH, growth hormone, prolactin, and gonadotropins.

b. PGE, facilitates release

of leutinizing hormone and t\roid-stimulating hormone,

insulin, and steroids. c. PGF, reduces progesterone secretion from the corpus luteum (luteolysis) in certain mammals; however, this efFect is not observed in humans.

9. Metabolic effects. PGEs inhibit lipolysis. 10. Autonomic nervous system a. PGEs depress catechol release and end-organ responsiveness. b. PGFs stimulate catechol release and end-organ sensitivity.

C. Mechanism of action 1. Receptors for prostaglandins have been identified. They are classified into five groups (DR ER FR iR and TP) according to the prostaglandin for which they are most selective (PGD, PGE, PGF, PGI2, and TXA, respectively). Prostaglandin receptor activities are associated with adenylate ryclase activation, adenylate cyclase inhibition, and phospholipase C stimulation.

iiitsticar

roe

Pharmacology

L. 3.

Receptors for leukotrienes that activate phospholipase C have been described.

cAMP also stimulates prostaglandin synthesis; this may represent a positive feedback loop.

4.

PGI' PGE' and PGD,

5.

TXA, reduces cAMP levels, which

increase platelet cAMP and causes

inhibit platelet aggregability.

platelet clumping and may also act as a calcium

ronopnore. D. Metabolism

l.

Prostaglandins are rapidly and efficiently catabolized by enzymes widely distributed

throughout the body. 2. The initial step in their breakdown is accomplished by prostaglandin-specific enzymes. 3. The second, slower degradation is accomplished by the general beta and omega oxidation systems for fatty acids. E.

Prostaglandins in physiologic and pathologic processes 1. PGI, and TXA. have opposite actions in modulating platelet-endothelial interactions and the formation of hemostatic platelet plugs and thrombi.

Clinical Correlate Prostaglandins may play

2. There is high concentration of prostaglandins in human semen (role unknown). a

causal role in dvsmenorrhea

3. Increased prostaglandin synthesis may play a role in the genesis of dysmenorrhea; this is proposed mechanism for how ryclooxygenase inhibitors relieve dysmenorrhoeic pain.

a

4. Prostaglandins are elevated during labor; cyclooxygenase inhibitors delay parturition and arrest premature labor.

5. Increased prostaglandins are associated with Bartter syndrome of high PRA, hyperaldosteronism, potassium loss, normal blood pressure, and insensitivity to angiotensin; chronic administration of ryclooxygenase inhibitors normalizes airgiotensin response, PRA, and aldosterone level, although potassium wasting persists.

6. Local generation of PGE, and PGI, may maintain patency of the ductus arteriosus; aspirin-like agents induce closure of a patent ductus.

7. PGE, can dilate bronchial smooth muscle. PGF, and TXA, cause bronchoconstriction. Leukotrienes (e.g., LTCr) are probably the major autacoids responsible for allergic bronchoconstriction of asthma. In a Nutshell

.

In the congenital heart

8. Certain tumors are associated with elevated circulating prostaglandin levels; these include medullary carcinoma of the thyroid and breast carcinoma.

defect, transposition of the

9. PGEs are

great arteiles, which is prostaglandins are given to maintain a patent ductus arteriosus. This can allow an is

mature enough to undergo corrective surgery.

.

and PGI, increase blood flow to areas of inflammation. Leukotrienes increase vascular permeability and are leukocyte chemoattractants.

10. PGE,

incompatible with life,

infant to survive until it

potent osteolytic agents and may contribute to hypercalcemia of malignancy.

11. PGEs can inhibit neutrophil and macrophage hydrolase release, killer T-cell function, and release of lymphokines by activated T cells. PGEs suppress mast cell degranulation and inhibit lymphocyte participation in delayed hypersensitivity.

F. Clinical

uses

1. PGI, can be used in place of heparin in renal hemodialysis.

Indomethacin is the drug of .Choice

for closing a patent

ductus arteriosus.

2. PGEr and PGI, can dilate a patent ductus arteriosus and thereby improve blood orygenation in infants with certain congenital heart defects. 3. PGEr and PGI, are used in clinical trials in severe peripheral vascular disease.

Autacoids

4. PGI, has been used experimentally to protect against platelet loss during dialysis or extracorporeal circulation.

5. PGEI improves harvest and storage of platelets for transfusion. 6. Dinoprostone

is a PGE,

preparation available in vaginal suppository form to induce abor-

tion, to evacuate a missed abortion, or to treat benign hydatidiform mole; side include nausea, vomiting, and

diarrhea.

effects

ln a Nffbhell

G. Inhibitors of prostaglandin synthesis

l.

cylcoorygenase

inhibitors

a. Aspirin and related anti-inflammatory agents block production of prostaglandins by permanently inhibiting both COX-l and COX-2. This appears to be a major mecha-

NSAIDs act

to inhibit

cyclooxygenase, thereby decreasing pro$aglandin Droduction.

nism of their action because their efficary as anti-inflammatory agents is proportional to their potency as cyclooxygenase inhibitors. The inhibition of COX-2 accounts for their analgesic and anti-inflammatory effects. The inhibition of COX-l accounts for their GI bleeding and irritation side effects. b. COX-2 inhibitors celecoxib and rofecoxib do not have the above GI side effects because they do not interface with COX-I activity.

2. Imidazole inhibits thromboxane synthetase but does not yet have clear clinical relevance.

iliBkcal rr#

Lead Toxicity and Chelating Agents

Lead toxicity is the most frequent cause of heavy metal poisoning and is usually the result of

industrial or environmental exposure. Chelating agents are used in the treatment of heavy metal toxicity to bind to the metal and prevent it from binding competitively with other essential elements.

LEAD POISONING Lead poisoning in the home environment produces devastating neurologic damage to the CNS

in children (encephalopathy) that is characterized by edema, convulsion, and coma. Lead poisoning in adults results largely from occupational exposure, producing clinical or subclinical signs of peripheral neuropathy, usually without CNS involvement.

A. Pharmacologic properties

l. Absorption. Lead is absorbed

by ingestion or by inhalation. Although inorganic lead is

poorly absorbed through the skin, organic compounds like tetraethyl lead are wellabsorbed. a. Gastrointestinal absorption varies with age. Although the average lead absorption is 107o, children absorb lead to a much greater degree than adults.

b. Dietary calcium, iron, and phosphorus alter lead absorption. Enhanced gastrointestinal absorption occurs with iron, calcium, and zinc deficiency.

2. Distribution. Lead is bound to red blood cells and is widely distributed throughout the

It concentrates first in the kidneys and liver, but most retained lead is eventually deposited in bone and hair. It can also cross the placenta and is a hazard to the fetus.

body.

3. Excretion. Approximately 90o/o of lead is eliminated by the fecal excretion of unabsorbed lead or by the kidneys'excretion of intestinally absorbed lead.

B. Mechanism of toxicity. Lead has an affinity for suI{hydryl, carboxyl, and phosphoryl groups, forming complexes that impair enzFme activity. Enzymes Ieading to the synthesis of porphobilinogen are most sensitive to lead; inhibition leads to the accumulation of its precursor (i.e., 8-aminolevulinic acid tAfA]) in urine. The amount found serves as a diagnostic indicator of lead poisoning.

C. Major forms of lead intoxication 1. Acute lead poisoning is less common today. Industrially, it may result from ingestion of Iead oxide. In small children, it may result from ingestion of lead oxide paints. Removal of lead from paints and organic lead from gasoline has significantly reduced the incidence

of poisoning, but it still exists.

iiiiifical

I 15

Pharmacology

a. Household ingestion by children of lead-based paint flakes (pica) from old painted structures remains a significant problem.

Clinical Corelate Lead ingestion from paint is a

b. Urine samples collected for 24 hours and analyzed for lead is the usual method of screening.

frequent cause of

anemia in children.

c. X-rays show deposition of lead along bone metaphyses, called "lead lines."

of acute lead poisoning include a local astringent effect in the mouth, thirst, metallic taste, nausea, vomiting, abdominal pain, paresthesias, pain, weakness,

d. Symptoms

and hemolytic anemia.

2. Chronic lead poisoning is more common than acute poisoning. Symptoms include the following: a. Abdominal syndrome involves anorexia, constipation, metallic taste, nausea, vomit-

ing, and abdominal pain. b. Neuromuscular syndrome includes weakness, fatigue, myalgia, and wrist- and footdrop (so-called "lead palsy").

c. CNS syndrome includes vertigo, ataxia, headache, irritability, confusion, seizures, coma, vomiting (projectile), meningismus, and visual disturbances. The most serious effect is lead encephalopathy. d. Renal tubular necrosis occurs after years of exposure to lead. Renal hypertension may also occur.

on blood include basophilic stippling of RBCs (not pathognomonic but highly indicative) and microcytic anemia (with iron deficienry).

e. Effects

f. Coproporphyrinuria

due to inhibition of the enzfme ferrochelatase can also occur.

D. Treatment of lead poisoning

l.

Removal of the patient from exposure and decontamination of the skin are the first steps. Supportive measures are then applied, and anticonyulsant drugs to treat seizures are used

judicially.

2. Chelation a. For severe poisoning, dimercaprol plus calcium-sodium ethylenediaminetetraacetic acid (EDTA) is the first line of treatment. To avoid decreased available calcium, the calcium salt is used.

b. Succimer (2,3-dimercaptosuccinic acid) is approved for treating lead Porsomng rn children. c. Penicillamine can be used for less severe cases and for long-term therapy, although succimer is preferred.

3. Fluids are used to prevent shock and to increase lead elimination.

CHELATING AGENTS Chelating agents are compounds that form complexes with metals in competition with reactive Sroups essential for enzyme or other activity. The stability of the complex varies with the metal. Lead and mercury have greater affinity for sulfur and nitrogen than for oxygen, whereas calcium has a greater affinity for orygen.

n4 iliEtrcal

Lead Toxicity and Chelating Agents l\"i

*$:

A. Dimercaprol was developed for its affinity and treatment of the arsenical compound, lewisite, which is a vesicant. It is sometimes referred to as British antilewisite (BAf). 1. Pharmacologic properties a. Dimercaprol chelates lead, arsenic, mercury, and antimony. b.

It is a rapid source of sulfhydryl groups that bind metal ions and reactivate enzymes inactivated by heavy metals.

2. Infications for use include arsenic poisoning, mercury poisoning, and lead poisoning (with calcium-sodium EDTA). 3. Side effects and toxicity of this drug include increased blood pressure, tachycardia, nausea, vomiting, and headache. B. EDTA-edetate calcium disodium (CaNa, EDTA) 1. Pharmacologic properties

of divalent and trivalent ions. It is available as calcium-sodium (usual preparation to avoid calcium loss) and sodium EDTA (used in hypercalEDTA cemia).

a. EDTA is a chelator

b. EDTA enhances the excretion of zinc, copper, iron, cadmium, lead, and manganese.

c. EDTA is poorly absorbed from the gastrointestinal tract, so

it is usually given intra-

venously. d. EDTA is cleared by glomerular filtration; therefore, normal renal function is required for effective therapy.

2. Indications for use. CaNa EDTA is indicated principally in lead poisoning. 3. Side effects and toxicity include fatigue, malaise, chills, fever, and anorexia; renal damage; and hlpocalcemic tetany (if sodium EDTA is used intravenously).

C. Succimer 1. Pharmacologic properties a. Succimer (2,3-dimercaptosuccinic acid) is an analog of dimercaprol. b. It is an orally active heavy metal chelator.

c. It only minimally mobilizes essential metals, e.g., zinc, copper, or iron.

2. Indications for use a. Succimer is approved for treating all children with blood lead levels about 45 ILC|dL.

b. It is used for treating symptomatic lead intoxication without encephalopathy. c. It may also effectively chelate arsenic and mercury. 3. Side effects and toxicity a. Toxicity is iess than enzymes.

with dimercaprol and includes transient elevations of hepatic

b. Common adverse effects include nausea, vomiting, diarrhea, a metallic taste in the mouth, and loss of appetite. c. Rashes have been reported and may be limiting.

ifitshical

I 15

Pharmacology

d. There may be CNS effects including drowsiness, dizziness, and sensorimotor neuropathy. e.

It

may cause cloudy increased proteinuria.

film in the

eyes, plugged ears,

difiiculty of urination, and

D. Penicillamine

l.

Pharmacologic properties a. Penicillamine is a product of penicillin degradation. b. Unlike other chelators, penicillamine has good gastrointestinal absorption and can be given orally. c. This compound chelates copper, mercury, zinc, and lead. d. It inhibits pyridoxal-dependent enzymes. e. Penicillamine is metabolized by the liver and is excreted in urine.

2. Indications for use a. Wilson disease and primary biliary cirrhosis

b. Copper and mercury poisoning soning

as

well

as

secondary treatment of lead and arsenic poi-

c. Cystinuria d. Rheumatoid arthritis

3. Side effects and toxicity include hypersensitivity rashes, fever; hematologic abnormalities, including leukopenia, agranulocytosis, and aplastic anemia; and renal toxicity. E. Deferoxamine

l.

Pharmacologic properties a. Deferoxamine chelates free iron and removes iron from hemosiderin and ferritin. does not effect hemoglobin or cytochrome iron.

It

b. Oral absorption is poor, so it is administered parenterally.

In a

NUtShell

ueleroxamrne ts useo I0

c. Deferoxamine is excreted rapidly in the urine.

2. Indications for use

patients with transfusion-dependent reduce iron toxicity in

a. Acute iron poisoning and iron storage disease

b. Tiansfusion-dependent thalassemia (iron overload occurs due to repeated transfusions)

thalassemia.

3. Side effects and toxicity include hlpersensitivity, abdominal pain, cataracts, and neurotoxicity with chronic administration.

I

16 ilitstical

Antineoplastic Agents

Neoplasm can be defined as uncontrolled new growth, and when neoplasms are invasive or able to meta$asize, they are classified as malignant. In view of these properties, treatment of malignant neoplasms is difficult because it requires elimination of all malignant cells. The three main approaches

for removing malignancies are surgery, irradiation, and chemotherapy. Antineopla$ic chemotherapy usually targets key $ages of the general or differentiated cell cycle and, therefore, also produces damage to other actively growing or similarly differentiated cells. Categories of antineopla$ic agents include alkylating agents that primari[ disrupt replication of DNA, antimetabolites that block processes essential for DNA synthesis and cell division, plant derivatives that affect the mammalian cell cycle,

antibiotia that affect the mammalian cell cycle, hormones that normally regulate growth of specific differentiated cells, and a few miscellaneous agents (Figure M-a-t).

GENERAT PRINCIPLES A. Cell cycle

l.

G, phase is the presynthetic phase. This is the most variable phase and involves protein synthesis.

2.

S

phase is the synthetic phase.

a. Biosynthesis and replication of DNA occur. b. Many of the chemotherapeutic agents act on cells during this phase.

3. G, phase is the postsynthetic phase. a. RNA and protein synthesis occur.

b. Cells contain double the amount of DNA.

4. M phase involves mitosis. B. Fate of cells after mitosis

l.

Cells can re-enter the cell rycle (rycling cells).

2. Cells continue to differentiate without further cellular division. 3. Cells next enter a dormant state and are referred to as Go cells. a. These cells can re-enter the cell cycle at a later time.

b. They are often not affected by chemotherapeutic agents.

iiiBliical

r17

! A|

O

3 ol o o oa

Il>

-o;

c. IT o !, I

Nitrogen Mustards Mechlorethamine Cyclophospham ide lfosfamide Melphalan (r-phenylalanine mustard; L-PAM) Chlorambucil

Other Triazene Derivative Dacarbazine

Ethyleneimine Derivative Thiotepa (triethylene thiophosphoramide)

Methylmelamine Derivative Altretamine (hexamethylmelamine)

Platinum Coordination Compounds

Vincristine Vinblastine Vinorelbine

Podophyllotoxins Etoposide (VP-16) Teniposide (VP-26)

Taxanes

Antibiotics Dactinomycin (actinomycin-D)

Anthracycline Antibiotics Daunorubicin Doxorubicin (adliamycin) ldarubicin Mitoxantrone Plicamycin (mithramycin) Mitomycin

Paclitaxel (Taxol) Docetaxel

Cell-Cycle

Nonspecilic Alkylating agents Antibiotics (except bleomycin)

Specific Antimetabolites Vinca alkaloids Bleomycin Hydroxyurea

Hormonal Agents Glucocorticoid Prednisone Progestins

Bicalutamide GnRH Inhibitors Leuprolide Goserelin

Hydroxyprogesterone Estrogens Medroxyprogesterone Ethinyl estradiol

Megestrol Androgens Fluoxymesterone Testosterone Antiandrogens Flutamide

Effects Common

Side

Pyrimidine Analogs

6-Mercaptopurine (6-MP) 6-Thioguanine (6-TG) Pentostatin (deoxycoformycin) Fludarabine Cladribine

5-Fluorouracil (5-FU) Floxuridine (fluorodeoxyuridine,

Agents Related to Purine Analogs

FudR)

Cytarabine (cytosine arabinoside, Ara-C) Gemcitabine

Azathioprine Allopurinol

Cisplatin Carboplatin Procarbazine

Plant Derivatives Vinca Alkaloids

Purine Analogs

Diethylstilbestrol (DES) Estramustine

Biologic Response Modif iers

Miscellaneous Agents

lnterferons (recombinant nterf e rons alt a-za. alt a-2b. alfa-n1, alfa-n3) Aldesleukin (recombinant Interleukin-2 [L-2])

r-Asparaginase Hydroxyurea Mitotane

i

Antiestrogens Tamoxi{en Anastrozole Aminoglutethimide

Unique

Cyclophosphamide-hemorrhagic * Bone marrow suppression cystitis Oral and gastrointestinal Vincristine-neurotoxicity ulcers/stomatitis Cisplatin-nephrotoxicity Nauseaandvomiting Daunorubicin-cardiotoxicity * Exceotions: Doxorubicin-cardiotoxicity Bleomycin-pulmonary toxicity r-Asparaginase Plicamycin-hemorrhagic diathesis Bleomycin Vincristine Hormonal agents

Figure lV-4-1. Summary of the antineoplastic agents.

Topoisomerase Topotecan lrinotecan

I

Inhibitors

Antineoplastic Agents

C. Tumor doubling time. The doubling time of a tumor is related to several factors.

l.

Length of cell rycle

2. Growth fraction (proportion of cells undergoing cell division) 3. Cell loss

ATKYTATING AGENTS A. Overview 1. Mechanism of action a.

A$ating

agents form highly reactive intermediate compounds that are able to transfer a reactive allgl group to DNA, RNA, and proteins. Alkylation of DNA is the primary mode of antitumor activity.

b. The 7-nitrogen atom of guanine appears most sensitive to alkylation. c. Alkylation can result in: (

1) Miscoding of DNA strands secondary to mispairing of bases. This is most likely to occur with monofunctional alkylator agents because these can each transfer only a single alkyl group.

(2) Incomplete repair of an alkylated segment, leading to strand breaks or depurina-

agents (3) Excessive cross-linking of DNA and an inability for strand separation at mitosis, resulting in cell death, which occurs with polyfunctional alkylators because these can each transfer multiple alkyl groups tion, which is also most likely to occur with monofunctional alkylator

In a Nubhell Alkvlation results in

the crosslinking of DNA, which reads to ceil deatn.

(a) Akylating agents are not cell-cycle phase-specific but are dependent on proliferation. They most often affect cells as the cells enter the

S

phase.

In a NUtShell

2. Side effects and toxicity a. In general, toxicity involves sites of rapid cell turnover, such as bone marrow, (spermatogenesisj, gastrointestinal tract, and hair follicles (alopecia). b. Acute toxicity can cause nausea, vomiting, and

testicles :|^d::ff-tt:,:::lfftlt 0n cells wtn a raplc turnover'

phlebitis.

i.e., cells continuously involved

in cell divsion.

c. Delayed toxicity is seen as bone marrow suppression and late secondary neoplasia,

including leukemia. B. Nitrogen mustards (mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil) 1. Mechlorethamine a. Indications for use

(1) Mechlorethamine is used

as a

chemotherapeutic agent. It is administered intra-

venously only.

(2)

It is used to treat Hodgkin disease as part of the MOPP regimen (i.e., mechlorethamine, vincristine, procarbazine, and prednisone), lymphosarcoma, chronic lymphoblastic leukemia (CLL), chronic myeloblastic leukemia (CML), mycosis fungoides, and polycythemia vera. Intracavitary infections are used to control pleural, peritoneal, or pericardial effirsions.

(3) It is directly cytotoxic and does not require metabolic conversion.

ilitsticat

ne

Pharmacology

b. Side effects and toxicity include gastrointestinal disturbances (e.g., nausea, vomiting), hematologic disorders (e.g., leukopenia, thrombocytopenia), and extravasation wiih tissue damage.

2. Cyclophosphamide a. Drug actions

(1) Cyclophosphamide, a derivative of mechlorethamine, is a cyclic phosphamide.

It is a prodrug that

(2)

requires metabolic activation by the cytochrome P-450 oxidation system in the livet which forms phosphoramide mustard.

b. Routes of administration. It is well absorbed orally and is administered orally. intravenously, or intramuscularly.

c. Indications for use

(1) cyclophosphamide

is used for lymphomas (Hodgkin and non-Hodgkin), multiple myeloma, Burkitt lymphoma, cLL, acute lymphoblastic leukemia (AlL), carcinomas (e.g., breast, lungs, cervix, ovary, small cell), mycosis fungoides, and

neuroblastoma. It is one of the most commonly used chemotherapeutic agents.

(2) It is used

as an

immunosuppressive agent for Wegener granulomatosis, rheuma-

toid arthritis, organ transplantation, and lupus. d. Side effects and toxicity include alopecia (common), nausea and vomiting, hemorrhagic cystitis, and interstitial pulmonary fibrosis.

3. Ifosfamide a. Mechanism of action. Ifosfamide is an analog of ryclophosphamide. Like cyclophosphamide, it is a prodrug that is metabolically activated in the liver. b. Routes of administration. Ifosfamide is usually infused intravenously over 30 minutes.

c' Indications for use. Ifosfamide is approved for cer.

It

use

with other drugs for testicular can-

is used to treat pediatric and adult sarcomas, carcinomas of the cervix and lung,

and lymphomas.

Clinical Correlate Cyclophosphamide can cause

hemonhagic rystitis.

d. Side effects and toxicity

(1) Ifosfamide

it is coadministered with

MESNA and adequate hydration to avoid

severe urinary tract toxicity. MESNA is a sulfhydryl-releasing agent (2-mercap-

toethanesulfonate) that conjugates toxic metabolites at acid pH in the urine to detoxify metabolites of ifosfamide that cause rystitis.

(2) Ifosfamide may

neurologic toxicity from its metabolite chloracetaldecauses nausea, vomiting, anorexia, leukopenia, nephrotoxicity, and CNS disturbances. hyde.

cause severe

In addition to hemorrhagic cystitis, ifosfamide

4. Melphalan (r-phenylalanine mustard: r-pAM) a. r-phenylalanine mustard is a derivative of mechlorethamine. b. Routes of administration are intravenous or oral.

c. Indications for use include multiple myeloma, ovarian carcinoma, malignant melanoma, and polycythemia vera. d. Side effects and toxicity include bone marrow suppressiop, especially of the platelets. Nausea, vomiting, and alopecia are rare.

r20 iliB&ical

Antineoplastic Agents

5. Chlorambucil a. Pharmacokinetics. Chlorambucil is the slowest acting nitrogen mustard. b. Route of administration is oral. c. Indications for use include CLL, Waldenstro macroglobulinemia, cold agglutinin disease, vasculitis associated with rheumatoid arthritis, and polycythemia vera. d. Side effects and toxicity. There is less myelosuppression than mustards.

with other nitrogen

C. Alkyl sulfonate derivative (busulfan) 1. Route of administration is oral.

2. Indications for use include selective bone marrow suppression, principally of granulocytes.

It is used to treat CML, polyrythemia vera, and myeloid metaplasia.

3. Side effects and toxicity include diarrhea, hyperpigmentation, pulmonary fibrosis, and gynecomastia.

D. Nitrosoureas (carmustine, lomustine, semustine,

1' Drug

streptozocin)

In a NuBhgll

actions

Side effects of busulfan

a. Nitrosoureas are bifunctional allcylators, which require in vivo

activation.

b. carmustine and lomustine can cross the blood-brain barrier and can therefore used for CNS tumors.

include hyperpigmentation

be

and pulmonary fibrosis'

c. Streptozocin has a sugar moiety attached to the nitrosourea. It is a naturally occurring antibiotic with an afiinity for beta cells of the pancreatic islets.

2. Routes of administration. Carmustine is administered intravenously. Lomustine and semustine are given orally.

3. Indications for use a. Carmustine is used

for meningeal leukemia, primary brain tumors, and Hodgkin

disease.

b. Lomustine is used

for Hodgkin

disease,

primary skin tumors, multiple myeloma,

hpernephroma, and carcinoma of the breast. c. Streptozocin is used for pancreatic islet cell tumors (e.g., insulinomas, \llP-producing tumors, gastrinomas), malignant carcinoid, and Hodgkin disease.

4. Side effects and toxicity a. Carmustine, lomustine, and semustine can cause delayed onset of leukopenia and thrombocytopenia, nausea and vomiting, and pulmonary fibrosis; CNS, renal, and hepatic toxicity have been noted.

b. Streptozocin can cause nausea and vomiting, renal toxiciry and hepatic toxicity. E. Tiiazine derivative (dacarbazine) 1. Drug actions a. Dacarbazine requires activation by the P-450 system of the liver to an alkylating agent.

b.

It

acts as an alkylato6 inhibiting DNA, RNA, and protein synthesis.

In addition,

a

metabolite inhibits purine incorporation into DNA.

2. Indications for use include malignant Hodgkin disease and sarcoma.

iiits[ical

r2l

Pharmacology

3. Side effects and toxicity.

Severe nausea and

vomiting

are very

common, and there is mod-

erate myelosuppression.

F. The ethylenimine derivative thiotepa (triethylene thiophosphoramide) is given by bladder installation for recurrent bladder carcinoma. G. The methylmelamine derivative altretamine (formerly known as hexamethylmelamine) is used to treat advanced ovarian cancer after the failure offirst-line approaches.

H. Cisplatin and carboplatin are platinum coordination compounds. 1. Mechanism of action. These cause inter- and intrastrand DNA cross-linking. They disrupt the DNA double helix and interfere with DNA synthesis.

2. Pharmacokinetics. There is no cell-cycle specificity and no CSF penetration. 3. Route of administration. It is administered intravenouslv.

4. Indications for use a. Cisplatin is used for testicular carcinoma (in combination with bleomycin and vinblastine) and for carcinomas of the ovaries and bladder.

b. Cisplatin is used for bronchogenic carcinoma of the lung, especially small cell carcinoma. c. Carboplatin is less reactive than cisplatin, but they are similar for treating specific cancers. Carboplatin is an alternative for patients unable to tolerate cisplatin. It is also used in high-dose therapy with bone marrow or peripheral stem cell rescue. 5. Side effects and toxicity a. Acute side effects include intense nausea, vomiting, and anaphylactic reaction.

b.

Delayed side effects

(1) There is a cumulative dose-related renal tubular damage, which can be minimized by the use of large volumes of intravenous fluids and diuresis.

(2) Ototoxiciry mild-to-moderate bone marrow depression, peripheral neuropathy, renal potassium, and magnesium wasting are other possible side effects.

c. Carboplatin is relatively well tolerated with less nausea, neurotoxicity, ototoxiciry and nephrotoxicity than with cisplatin. The dose-limiting toxicity of carboplatin is myelosuppression.

[. Procarbazine 1. Drug actions a. Procarbazine is a methylhydrazine derivative. b.

It auto-oxidizes and produces hydrogen peroxide, which can lead to denaturation of DNA.

c. Broken chromatids are observed after its use.

It inhibits DNA, RNA,

and protein

synthesis. d. It functions as an MAO inhibitor and can cross the blood-brain barrier.

2. Indications for use a. It is most usefirl in Hodgkin disease (as a component of the MOPP regimen).

b. It is useful in primary brain tumors and small cell carcinoma of the lung.

tzz ilitstical

Antineoplastic Agents

3. Side effects and toxicity a. Acute side effects include a disulfiram-like effect

with tricyclics, sympathomimetics,

and alcohol. It causes hypertension with tyramine-containing foods (MAO inhibitor).

b. Delayed side effects include bone marrow suppression, CNS depression, neuropathy, pneumonitis, stomatitis, and induction of second malignancies.

ANTIMETABOTITES Antimetabolites resemble normal metabolites. They interfere with normal metabolic pathways by competing for enzymatic active sites. The antimetabolites are cell-rycle specific.

A. Methotrexate (MTX)

l

Drug actions

It inhibits dihydrofolate reductase, thereby blocking the conversion of folic acid to tetrahydrofolate (the active cofactor). The result is an inability of the cell to convert deoxnrridylate to thymidylate. It blocks DNA, RNA, and protein synthesis and kills cells during the S phase.

a. MTX is a folic acid analog.

b. Leucovorin (formyltetrahydrofolic acid) bypasses the metabolic block by MTX. used to rescue normal cells from MTX toxiciry

It

is

h a N,bhell Leucovorin is used to

,,rescue,,

normal cells from MTX.

c. MTX is approxima tely 3lo/oprotein bound and is displaced by salirylates, sulfa drugs, and phenytoin. d. It is excreted in urine; higher doses can precipitate in renal tubules.

2. Routes of administration a. It can be administered orally, intravenously, intramuscularly, and intrathecally. b.

It

has poor CNS penetration and, for central action, may require intrathecal use or high-dose intravenous administration (with leucovorin rescue).

3. Indications for

use

Note MTX is being inve$igated

a. It is used for maintenance therapy of childhood

AIL.

b. MTX is used for choriocarcinoma and other trophoblastic tumors, lymphomas, mycosis fungoides, carcinomas (breast, ovary, bladder, head, neck), and osteogenic sarcoma

as a treatment for

ecoplc pregnancy'

in high doses. c. The non-neoplastic conditions for which arthritis, and Wegener granulomatosis.

it

is used include psoriasis, rheumatoid

4. Side effects and toxicity a. Acute side effects include nausea, vomiting, and diarrhea. There is also bone marrow

suppression and gastrointestinal ulceration of the mucosa. Renal toxicity occurs with high doses, and it is contraindicated in patients with compromised renal function. b. Delayed side effects. Hepatotoxicity occurs with long-term administration and can lead to cirrhosis.

B. 5-Fluorouracil (5-FU) and floxuridine (fluorodeonyuridine, FUdR)

L Drug

actions

a. 5-FU is a pyrimidine analog.

iliBlical t2t

Pharmacology

b. FUdR is the deoxyribonudeoside of 5-FU.

c. 5-FU is enzymatically converted to FUdR and then converted to the active form, 5fluoro-2'-deoxyuridine-5'-phosphate (F-dUMP), which forms a complex with tetrahydrofolate to inhibit thymidylate synthetase. d. F-dUMP blocks conversion of deoxnrridylate to thymidylate, which limiting step in DNA synthesis. It also affects RNA synthesis.

is the rate-

e. Resistance develops by decreased activation of the drug and by increased inactivation.

2. Route of administration. They are administered parenterally and metabolized in the liver. Administration may be preceded by leucovorin to enhance F-dUMP formation. 3. Indications for use a. 5-FU is used for carcinoma of the breast (usually in combination with other agents).

b. 5-FU is less usefrrl for carcinoma of the ovary, cervix, bladder, prostate, pancreas, and gastrointestinal tract.

c.5-FU has topical uses against superficial basal cell carcinoma, actinic keratosis, and psoriasis. d. FUdR is primarily used for metastatic carcinoma of the colon.

4. Side effects and toxicity include gastrointestinal disturbances (e.g., anorexia, nausea, stomatitis, diarrhea), myelosuppression, alopecia, dermatitis, and cerebellar ataxia. Its use

with leucovorin increases gastrointestinal toxicity. C. Cytarabine (cytosine arabinoside, Ara-C) 1. Drugactions a. Ara-C is a pyrimidine nucleoside analog (ribose replaced by arabinose) and is con-

verted to nucleotide triphosphate by deoxycytidine kinase. b. Ara-C interrupts DNA synthesis and functions by inhibiting DNA polymerase and incorporating into the DNA or RNA of the cell.

c. It is cell-rycle specific for the

S phase.

d. Resistance results from insufficient activation or from increased inactivation.

2. Routes of administration. It can be administered intravenously, intramuscularly, subcutaneously, or intrathecally. CNS disease.

It cannot be administered orally. It is given intrathecally for

3. Indications for use a. Induction therapy AML with daunorubicin is successfi.rl in up to 75o/o of cases.

b. It is less usefrrl for induction therapy of AIL. c. It is used in combination with other drugs for treatment of lymphomas.

4. Side effects and toxicity a. Acute side effects include nausea, vomiting, and diarrhea.

b. Delayed side effects include bone marrow suppression with megaloblastic changes, gastrointestinal upset, stomatitis, alopecia, and hepatotoxicity.

t24 ilitshical

Antineoplastic Agents

D. Gemcitabine 1. Gemcitabine is a pyrimidine analog which, when converted to its nucleotide diphosphate, inhibits DNA synthetic enzymes. The triphosphate form is incorporated into DNA to cause misreading during DNA replication.

2. Route of administration. It must be administered by intravenous infusion. 3. Indications for use. It is used primarily for palliative therapy of pancreatic carcinoma.

4. Side effects and toxicity a. Acute side effects include gastrointestinal effects and flu-like symptoms.

b. It can cause shortness of breath, hypertension, stroke, cardiac arrhythmias, and hemorrhage.

c. Delayed side effects include bone marrow suppression, which is generally the doselimiting toxicity.

E. 6-Mercaptopurine (6-MP) 1. Drug actions a. It is a purine analog (sulfhydryl-substituted analog ofhypoxanthine). b.

It is converted

by hpoxanthine-guanine phosphoribosyltransferase (HGPRT) to

6-thioinosine-5'-phosphate (T-IMP). c. The formed T-IMP results in:

(l)

Blocked conversion of IMP to AMP

(2) Blocked oxidation of IMP to xanthosine monophosphate (XMP), subsequently to GMP

(3) Pseudofeedback inhibition on the first committed step of purine biosynthesis (4) Incorporation into nucleic acids as a false

base

(5) Inhibition of purine nucleotide synthesis and metabolism and altered synthesis and function of RNA and DNA d. 6-MP is metabolized by xanthine oxidase to 6-thiouric acid. The action of xanthine oxidase is blocked by allopurinol; thus, the dose of 6-MP must be decreased if given

with allopurinol. 2. Route of administration. It may be administered orally. 3. Indications for use include maintenance of remission in childhood AlL, often used with MTX. It is less usefrrl in AML and CML and is not usefr.rl in CLL, lvmphomas, or carcinomas.

4. Side effects and toxicity a. Acute side effects include infrequent nausea, vomiting, and diarrhea.

b. Delayed side effects involve gradual bone marrow suppression and cholestatic jaundice in one-third of patients.

F. 6-thioguanine (6-TG; amino analog of mercaptopurine) 1. Drug actions a. This purine analog is a sulfhydryl-substituted analog of guanine.

b. It is converted by HGPRT to 6-thioguanosine-5-monophosphate (6-thio GMP).

iiiB[ical

r25

Pharmacology

c. 6-thio GMP is converted by guanylate kinase to a triphosphate nucleotide. It is then gradually incorporated as a false base into nucleic acids.

(1) 6-thio GMP inhibits inosinate dehydrogenase, which converts IMP to XMp and then to GMP.

(2) There is a pseudofeedback inhibition on the first committed step of the purine biosynthesis. d. 6-TG affects purine nucleotide synthesis and metabolism. It alters RNA and DNA synthesis and function.

2. Route of administration. It is administered orally. The metabolism depends little on xanthine oxidase, and there is no dose reduction needed if it is given with allopurinol. 3. Indications for use. It is usefi.rl in induction therapy of AML (with Ara-c). 4. Side effects and toxicity are similar to 6-MR but it causes less gastrointestinal upset. Bone marrow suppression, hepatotoxiciry and stomatitis occur. G. Pentostatin (2'-deoxycoformycin)

l.

Drug actions a. Pentostatin is an adenosine analog that inhibits adenosine deaminase. The inhibition results in the accumulation of deoxy-ATP, which inhibits ribonucleotide reductase via feedback inhibition. b. Reduced reductase activity leads to a decrease of other deoxlnucleotides; thus, DNA synthesis and repair are diminished.

c. Pentostatin inhibits methylation in RNA transcription; therefore, it is active in dividing and nondividing cells.

2. Indications for use include hairy cell leukemia, indolent non-Hodgkin iymphomas, and CLL.

3. Side effects and toxicity. Pentostatin is highly immunosuppressive. a. Moderate-dose side effects include fever,

mild

nausea, and rashes.

b' High-dose side effects include renal failure, hepatic enzyme elevation, confusion, and coma.

H. Fludarabine

l.

An analog of adenine, fludarabine resists inactivation by adenosine deaminase and requires phosphorylation for activation.

2. Indications for use include hairy cell leukemia. 3. Side effects and toxicity include diarrhea, nausea, vomiting, pain, pneumonia, skin rash, and excessive tiredness. It also causes anemia, leukopenia, and thrombocytopenia.

I.

Cladribine 1. Cladribine is an adenosine analog that is incorporated into DNA and impairs DNA repair. Unlike most antimetabolites, it is not cell-rycle specific, i.e., it does not require active cell division to be cytotoxic.

2. Indications for use include hairy cell leukemia 3. Side effects and toxicity include skin rashes, fever, anorexia, nausea, vomiting, headache, and excessive tiredness.

uric acid levels.

t26 ilitstical

It

also causes anemia, neutropenia, and cytopenia and elevates

Antineoplastic Agents

j.

Agents related to purine analogs 1. Azathioprine is a precursor of mercaptopurine.

It is used as an immunosuppressive agent in organ transplants, Wegener granulomatosis, and related vasculitides. It is used in the treatment of autoimmune diseases (e.g., SLE and ITP). It is not usefi.rl as an antineoplastic agent.

a. Indications for use.

b. Side effects and toxicity. Leukopenia occurs decreased

with its use. The dosage must

be

if it is used with alloourinol.

2. Allopurinol a. Allopurinol is a hypoxanthine analog and an inhibitor of xanthine oxidase, which con-

verts hypoxanthine to xanthine and then to uric acid. b. Indications for use

(l) It is used in the treatment

Note of hyperuricemia and gout, but it is not used in an

acute gouty attack.

Allopurinol is useful in

"tumor lysis syndrome."

(2) It is used during leukemia induction therapy or treatment of other malignancies with high tumor burdens where rapid cell lysis is expected to release large quantities of intracellular purines, which would otherwise be converted to uric acid and cause renal stones or failure.

PLANT DERIVATIVES A. Vinca alkaloids (vincristine, vinblastine, and vinorelbine) 1. Drugactions a. The structures of the vinca alkaloids are similar. The methyl group in vinblastine is replaced by the aldehyde group in vincristine. They are both derived from the peri-

winkle plant. b. They bind to tubulin, a component of cellular microtubules. This leads to disruption of the mitotic spindle apparatus and prevents segregation of chromosomes lined up in metaphase, producing metaphase arrest.

c. It is cell-cycle specific for the M phase. d. Vinca alkaloids are eliminated via the liver. There is increased toxicity in the presence of obstructive jaundice. Dosages should be decreased in patients with hepatic insufficiency.

2. Indications for use a. Vincristine (Oncovin) is used

for Hodgkin disease (as part of the MOPP regimen), induction of childhood AIL (with prednisone, the remission rate is 900/o), lymphoma, sarcoma, CNS tumors, and Wilms tumor.

b. Vinblastine is used for metastatic testicular tumors (with bleomycin and cisplatin), Hodgkin disease, lymphomas, Kaposi sarcoma, and Letterer-Siwe disease (histiocytosis X). c. Vinorelbine is used to treat non-small-cell lung carcinoma.

3. Side effects and toxicity a.

Vincristine (1) Acute side effects involve local reaction ifextravasated.

ifits[ical

r27

Pharmacology

(2) Delayed side effects include the following: There may be dose-limiting neurologic toxicity. It may produce slowly progressive sensorimotor peripheral neu-'"fl

lf '#J.*::l:::ffi \T.i."::"T,f"A[':fi frLii:Tf il:ffiT;

secondary

Nutshell . Vincristine -+ neurotoxicity, low bone marrow toxicity . Vinblastine -+ bone

vincristine.

In a

to the autonomic neuropathy) and alopecia are also caused by It has a minimal effect on bone marrow, which is unusual for a

.hemotherapeutic agent. b. Vinblastine

(l)

marrowtoxicitv

Acute side effects include mild nausea, vomiting, and phlebitis.

"' 3,$7:l;*;["i:'.:il:]:* *:iffii:li*H;trilx

espe-

#:.::'ssion'

c. Vinorelbine

(1) Acute side effects include anorexia,

nausea' and vomiting.

(2) Delayed side effects include bone marrow suppression, leading to granulocytopenia, anemia, or leukopenia.

B. Podophyllotoxins: etoposide (VP-f6) and teniposide (VM-26) 1. Drugactions a. Podophyllotoxins are semisynthetic glycosides that block cells at the S-G, interface. At high doses, this can cause G, arrest. b. The proposed mechanism

of action is that it stimulates topoisomerase II to

cause

DNA cleavage. 2. Indications for use

for refractory testicular tumors (with cisplatin and bleomycin); small cell (oat cell) lung carcinoma (with cisplatin); and breast carcinoma, lym-

a. Etoposide is used

phomas, and Kaposi sarcoma. b. Teniposide is used for refractory ALL in children.

3. Side effects and toxicity include leukopenia (dose-limiting), nausea, vomiting, alopecia, and hlryersensitivity.

C. Taxanes: paclitaxel (TaxoD and docetaxel

l.

Drug actions a. Paclitaxel is derived from the bark ofthe Pacific yew tree.

b. Docetaxel is a more potent analog of paclitaxel produced through side chain modification. c. Thxanes stabilize the mitotic apparatus by promoting microtubule assembly and preventing microtubule depolymerization.

2. Indications for use a. They are active against cisplatin-resistant ovarian cancer, metastatic breast canceg

malignant melanoma, and AML. b. They are used alone for breast cancer, and the activity approaches that of doxorubicin.

3. Side effects and toxicity a. Primary toxicity involves dose-dependent neutropenia after about 1 week.

r28 iliBtical

Antineoplastic Agents

b. Hypersensitivity reactions include urticaria, bronchospasm, and hlpotension. c. Mild sensory neuropathy, myalgias, and arthralgias may also occur'

ANTIBIOTIC ANTINEOPTASTIC AGENTS These antineoplastic antibiotics are all products of Streptomyces fungi. Their cytotoxic effect is secondary to their disruption of DNA functions. With the exception of bleomycin, these agents are not cell-rycle specific.

A. Dactinomycin (actinomycin D) 1. Drug actions a. Dactinomycin was the first antibiotic used in cancer chemotherapy.

b.

It

binds with double-stranded DNA and blocks the action of RNA polymerase,

thereby inhibiting DNA transcription. c. It inhibits rapidly proliferating cells but has no cell-cycle specificity. d. Resistance results from decreased cellular uptakes.

2. Route of administration is intravenous.

3. Indications for use a.

It is used for

childhood tumors such as Wilms tumor domyosarcoma, Ewing sarcoma, and Kaposi sarcoma.

(with vinblastine), rhab-

b. Other indications include MTX-resistant choriocarcinoma and testicular carcinoma.

4. Side effects and toxicity a. Acute side effects include nausea, vomiting, and phlebitis.

b. Delayed side effects include bone marrow suppression, alopecia, stomatitis, proctitis, and skin changes in areas exposed to radiation therapy. B. Anthracycline antibiotics: daunorubicin, doxorubicin (adriamycin), idarubicin, and

mitoxantrone 1. Drug actions a. The structure of anthracycline antibiotics is characterized by tetracycline ring structures attached by glycoside linkage to daunosamine (sugar). These intercalate and bind to DNA between base pairs on adjacent strands, which results in uncoiling of the DNA helix. This destroys the DNA template and inhibits DNA-directed RNA and

DNA polymerases. b. The maximum effect occurs during the

S phase,

but it is not cell-cycle specific.

c. The chemical structure of the two agents differs by a single hydroxyl group. 2. Route of administration. the CNS.

It

is usually administered intravenously, but

it

does not enter

3. Indications for use a. Daunorubicin is used in AIL and for the acute phase of CML. It is the treatment choice with Ara-C for AML, but it is not useful for solid tumors in adults.

of

iiitsbrcal ns

Pharmacology

utiliry including lymphoma, AlL, Hodgkin, sarcoma, breast carcinoma, bladder carcinoma, small-cell carcinoma of lung, gastric and pancreatic

b. Doxorubicin has a wide

carcinomas, as well as ovarian and bronchogenic carcinomas. c. Idarubicin is similar to daunorubicin and doxorubicin: it is used to treat AML.

4. Side effects and toxicity a. Acute side effects (both agents) include nausea, vomiting, red urine (not hematuria),

tissue necrosis with extravasation, transient EKG changes (ST-T wave changes), and

arrhythmias.

ln a Nutshell

b. Delayed side effects include bone marrow depression, alopecia, stomatitis, gastrointestinal upset, and cardiotoxicity. Cardiotoxicity is characterized by the following:

Cardiotoxicity is an important side effect of the "rubicins."

(1) It is dose related and unresponsive to digitalis. (2) The effect can be delayed for months after treatment is complete. (3) The risk factors include previous radiation to the mediastinum and previous

use

of other anthraryclines or ryclophosphamide.

(4) There are decreased incidences with lower weekly

dosages, rather than larger

dosages every 3 weeks.

(5) The mechanism of action involves binding to cardiac DNA (structural similarity to glycosides), which also may damage myocardiai membranes by release of free radicals.

(6) Pathology includes nonspecific

decrease in fibrils and mitochondrial changes.

5. Mitoxantrone is a synthetic anthracenedione analog of doxorubicin. It is effective for the

treatment

in

breast cancer, non-Hodgkin lymphoma, and acute nonlymphocytic

leukemias. It produces less cardiotoxicity than daunorubicin and doxorubicin.

C. Bleomycin

l.

Drug actions a. Bleomycin is a mixture of polypeptides; some contain sulftr, and others are glycoproteins. b.

It introduces DNA chain-breaks and fragmentation (possibly mediated via chelation with ferrous ion). it may inhibit enzymes involved in DNA repair.

c.

It

causes in vitro accumulation of cells in the G, phase. It is cell-cycle specific with major effects at the G, and M phases of the cell cycle, and it may cause synchronization of tumor cells into the same phase of the cycle.

2. Indications for use a. Bleomycin is used in combination with other agents. It is very effective against testicular tumors. There is approximately 75olo complete remission rate when given with

vinblastine and cisplatin. b. It is usefi.rl for squamous-cell carcinoma of the head and neck, esophageal and genitourinary carcinomas, Hodgkin disease, and lymphoma. 3. Side effects and toxicity a. Acute side effects include nausea, vomiting, fever, and allergic reactions (including

anaphylaxis).

b. Delayed side effects include the following:

(1) Mucocutaneous reactions, including alopecia, stomatitis, hyperpigmentation,

rro ilitsfical

skin ulceration, and Raynaud phenomenon

Antineoplastic Agents

(2) Minimal bone marrow toxicity (3) Pulmonary toxicity

is the most serious side effect and is dose limiting. It begins as

nonspecific pneumonitis and can progress to pulmonary fibrosis. Risk factors include age over 70 years, underlying lung disease, higher doses, high inspired concentrations of oxygen, and prior concomitant radiation therapy to the thorax. D. Plicamycin

(

mithramycin)

1. Drug actions a. Plicamycin affects DNA-dependent RNA synthesis through a mechanism similar to

that of dactinomycin. b. A specific effect is to inhibit osteoclasts, thereby lowering Ca2* concentration.

2. Indications for use include embryonal cell testicular carcinoma, hypercalcemia of malignancy, and possibly Paget disease ofbone.

3. Side effects and toxicity. a. Acute side effects include nausea, vomiting, and phlebitis.

b. Delayed side effects include marked bone marrow suppression (especially platelets), hepatic and renal damage, and hemorrhagic diathesis (possibly as a result of impaired synthesis of clotting factors). E.

Mitomycin 1. Drug actions a. Mitomycin contains a quinone group that undergoes enzymatic reduction and results

in a bifunctional alkylating b.

agent.

It cross-links DNA and inhibits DNA synthesis

(acts as alkylating agent).

It is most

active during the G, and S Phases.

for use include palliative therapy of gastric carcinoma (with 5-FU doxorubicin). It is used occasionally to treat carcinoma of the cervix, colon, rectum,

2. Indications

and and

bladder.

3. Side effects and toxicity a. Acute side effects include nausea and vomiting.

b. Delayed side effects involve bone marrow suppression, alopecia, pulmonary fibrosis, and infiltrates. Renal and hepatic damage may occur at high doses.

4. Drug interaction. It increases doxorubicin's cardiotoxic effects.

HORMONAT THERAPY A. Glucocorticoid: prednisone 1. Physiologic effects (relative to antitumor effects) are to supPress mitosis in lymphocytes. 2. Indications for use

AlL, for Hodgkin disease (as one component of the MOPP combination), lymphoma, CLL, myeloma, and breast carcinoma (works by suppressing adrenal estrogen production).

a. Prednisone is used in remission induction in

ilits[ical

r5l

b.

It reduces edema associated with brain or spinal cord metastases, primary CNS tumors, and tumors causing bronchial or ureteral obstruction.

c. It is used before the initiation of radiation therapy to areas where initial edema would be harmful (e.g., CNS). It can aid in symptomatic improvement (e.g., increase appetite, suppress fever).

3. Side effects and toxicity a. Acute side effects. Psychiatric disturbances, peptic ulceration, glucose intolerance

hypokalemia, sodium retention, hypertension, edema, and increased susceptibility to infection may occur early in treatment. b. Delayed side effects. Osteoporosis, cataracts, myopathy, and avascular necrosis are more likely to occur after long-term use.

B. Progestins: hydroxnrrogesterone, medroxyprogesterone, and megestrol 1. Physiologic effects. Some tumors are thought to have growth enhanced by certain hormonal agents. The goal of therapy is to block the action of these hormones and suppress tumor growth.

2. Indications for use include metastatic endometrial carcinoma, prostate, breast, renal cell, and ovarian carcinomas.

3. Side effects and toxicity a. Hydroxyprogesterone. Side effects include hypercalcemia and cholestatic jaundice.

b. Medroxyprogesterone. Side effects include fluid retention and hypercalcemia.

c. Megestrol. Side effects include fluid retention and thromboembolism. C. Androgens: fluo>
b. The effect is delayed for several weeks.

2. Side effects and toxicity include masculinization, hypercalcemia, and fluid retention. D. Antiandrogens 1. Flutamide and bicalutamide a. Flutamide and bicalutamide are nonsteroidal antiandrogens that bind to androgen recePtors and inhibit the translocation of the androgen receptor to the nucleus. b. Indications for use (

I

) The principal

use of these agents is for advanced and metastatic prostate cancer, usually with GnRH blockade or an estrogen.

(2) An antiandrogen combined with

a GnRH agonist, such as leuprolide, facilitates androgen blockade by also blocking the action of androgens produced in the

adrenals.

c. Side effects and toxicity

(l)

Side effects and toxiciry include diarrhea, nausea, vomiting, and reversible liver

function abnormalities.

ttz ili$bicat

Antineoplastic Agents

(2) These drugs can produce loss of sexual function,

decreased libido,

hot

flashes,

gynecomastia, and mastodynia.

2. Leuprolide and goserelin a. Leuprolide and goserelin are synthetic analogs of LH-RH. They suppress secretion gonadotropin-releasing hormone, which in turn reduces the synthesis and release testosterone.

of of

b. Indications for use. They are used primarily for treating prostatic carcinoma. The LH-RH analogs are usually combined with flutamide (or bicalutamide), thereby providing two different mechanisms for eliminating androgens. c. Side effects and toxicity

(1)

These agents produce side effects associated with low testosterone levels.

(2) They

cause anorexia, breast tenderness, edema, nausea, and vomiting.

(3) They may produce various cardiovascular

effects.

(4) Goserelin can cause an initial flare of the disease due to an initial transient increase of testosterone caused by the agent.

(5) Leuprolide may produce blurred vision, ness

dizziness, headache, insomnia, and numb-

of the hands and feet.

E. Estrogens: ethinyl estradiol, diethylstilbestrol (DES), and estramustine 1. Indications for use a. Estrogens are useful in the palliation of advanced prostate carcinoma. Orchiectomy,

removal of the androgen stimulation of the tumor, is sometimes done. They compete

with androgens for their receptors. b. They may be useful in postmenopausal women but are contraindicated in patients

with estrogen-receptor-positive breast carcinoma. 2. Specific agents include: a. Ethinyl estradiol and diethylstilbestrol (DES)

b. Estramustine combines estradiol with a nitrogen mustard. It concentrates in estrogensensitive tissue. Toxicity is mainly that of the estrogen component because blood concentrations of the nitrogen mustard are minimal. 3. Side effects and toxicity a. Side effects include hypertension, which is secondary to fluid retention and increased

production of renin substrate by the liver. b. Accelerated cardiovascular disease (dose dependent) and gynecomastia may occur.

F. Antiestrogens

l.

Thmoxifen binds to estrogen receptors and blocks estrogen's growth effects on estrogendependent tumors. It is also translocated into the nucleus where it binds to nuclear chro-

matin in an atypical manner. It may take weeks to become effective, but the genome refractory to estrogen stimulation for a period of time.

is

left

ilitstical

r55

a. Indications for use (

1) For breast carcinomas, response

(2) It may

is usually best

in estrogen-receptor-positive patients.

have an effect on prostatic and endometrial carcinomas.

b. Side effects and toxicity

(l)

Side effects and toxicity include nausea, vomiting (usually mild), and hot flashes.

(2) Pain at tumor

sites or local flare of the disease is associated with a good response

to tamoxifen.

(3) Infrequently, hypercalcemia,

edema, headache, and mild decrease in platelets and

leukocytes occur.

2. Anasttomle inhibits aromatase to produce lower circulating estrogen a. Indications

levels.

for use. Anastrozole is used for treating breast carcinoma in

post-

menopausal women, generally after it has not responded to tamoxifen. b. Side effects and toxicity include:

(l ) Nausea, chest pain, edema, shortness of breath

(2) Gastrointestinal tract and nervous (3

G.

system efilects

) Possibilitv of thromboembolism

Aminoglutethimide 1. Drug actions a. Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone, which results in a medical adrenalectomy caused by blockage of adrenal steroid production.

b. Corticosteroid replacement therapy must be given concomitantly.

2. Indications for use include female patients with estrogen-receptor-positive breast carcinoma. It is also used in the treatment of Cushing syndrome and adrenocortical carcinoma. 3. Side effects and toxicity a. Acute side effects include lethargy, visual disturbances, and ataxia.

b. Delayed side effects include hypothyroidism, bone marrow suppression, and mas-

culinization.

BIOLOGIC RESPONSE MODIFIERS A. Interferons (recombinant interferon a-2a,a-2b,cx,-nl, cr,-n3). Interferons are proteins are part of the body's defense system and generally impede cell proliferation.

tiat

1. Route of administration. Intramuscularly or subcutaneously

2. Indications for use. Interferons are used for treating hairy cell leukemia, genital warts, and Karposi sarcoma in patients with acquired immunodeficiency syndrome. 3. Side effects and toxicity a. Side effects include a flu-like syndrome, CNS and peripheral neurotoxicity, loss of appetite, diarrhea, nausea, vomiting, skin rash, and tiredness.

rr4 iliEtical

Antineoplastic Agents

b. At higher doses, toxicities include neurotoxicity, gastrointestinal toxiciry and cardiovascular toxicity.

B. Aldesleukin is recombinant interleukin-2 (IL-2).Interleukins are regulatory glycoproteins produced by lymphocytes. IL-2 binds to specific receptors to induce proliferation and differentiation of T helper cells and T cytotoxic cells. 1. Route of administration. Intravenous infusion or subcutaneous injection

2. Indications for use. IL-2 is used for treating metastatic melanoma and renal-cell carcinoma.

3. Side effects and toxicity include: a. Severe hlpotension with life-threatening cardiovascular toxicity

b. Pulmonary edema secondary to capillary leak syndrome c. Renal toxicity, hematologic toxicity, central nervous system toxiciry and skin toxicity with local inflammation

MISCETTANEOUS AGENTS A. r-Asparaginase Note

1. Drug actions a. This enzyme is produced by Escherichia coli and catalyzes the hydrolysis of asparagine.

b. It deprives neoplastic cells of exogenously supplied r-asparagine and thereby interferes with their protein synthesis. Some neoplastic tissues, such as ALL cells, require an exogenous supply of this amino acid.

L-Asparaginase takes advantage

of the dependence of ALL cells on exogenous asparagine.

2. Route of administration. It is administered parenterally. 3. Indications for use include induction therapy of ALL with prednisone and vincristine. It spares bone marrow and gastrointestinal mucosa, which is rare for an antineoplastic agent.

4. Side effects and toxicity a. Acute side effects include nausea,

vomiting, abdominal pain, and hypersensitivity

reactions.

b. Delayed side effects involve hepatic and renal toxiciry pancreatitis, CNS effects (e.g., depression to coma), and alterations in the clotting mechanism, which results in thrombosis and, later, hemorrhage.

B. Hydroxnrrea 1. Drug actions a. Hydroxyrrrea is a hydroxylated urea compound.

b. It interferes with ribonucleoside diphosphate reductase, which is responsible for the generation of the deoxyribonucleotides needed for DNA synthesis. c. It is S-phase specific.

2. Indications for use a. It is an alternative to busulfan in the treatment of CML. It is used in polyrythemia vera and essential thrombocytosis. b. There is a reduction of dangerously high WBC counts in AML or CML (blast crisis).

iiiBbical

r15

Pharmacology

3. Side effects and toxicity a. Acute side effects include gastrointestinal upset.

b. Delayed side effects include bone marrow suppression (reversible), alopecia, and hyperpigmentation. C. Mitotane 1. Mitotane, an analog of the insecticides DDT and DDD, causes a selective destruction of normal and neoplastic adrenal cortical cells.

2. Indications for use include palliation of adrenal cortical tumors (i.e., tumor) and relief of symptoms of excess corticosteroids.

it

shrinks the

3. Side effects and toxicity a. Acute side effects include nausea and anorexia.

b. Delayed side effects involve somnolence, dermatitis, adrenal insufficiency, and hemorrhagic rystitis. D. Topoisomerase I inhibitors: topotecan and irinotecan

l.

These agents

inhibit topoisomerase I to produce DNA strand breaks.

2. Indications for use a. Topotecan is primarily used to treat ovarian carcinoma after first-line therapy fails. b. Irinotecan is primarily used to treat colorectal carcinoma after first-line drug failure.

3. Side effects and toxicity a. These drugs can produce gastrointestinal effects, loss of hair, neutropenia, and weakness.

may cause tingling of the hands Neutropenia may be dose limiting.

b. Topotecan

or feet and sores in the

c. Irinotecan frequently produces anemia, leukopenia, and breathing difficulty.

r16 llitsiiieal

mouth.

sEciloN v

Behavioral Sciences

The Basics of Behavioral Sciences

Before discussing the many

topia that constitute the Behavioral

Sciences, we must first address the

importance of the subject for the field of medicine and review some of the terms, definitions, and foundations upon which the specialty is based. This introductory chapter reviews basic topics and axioms and discusses the issues of medical interviewing and patient education.

RATIONALE FOR THE BEHAVIORAT SCIENCES [n1997,7 of the 10 leadingcausesof deathinindividualsof allageswereeitherdirectlycaused or significantly compounded by self-destructive and controllable behavior. In children between I and 4 years of age, the leading cause of death is accidents, and the third is homicide. In youth between 5 and 14 years of age, accidents are the leading cause of death, homicide is the third leading cause, and suicide is the fifth. In individuals 15-24 years of age, accidents are first, homicide is second, and suicide is third. These age-related causes of death have not changed significantly for at least a decade. Many people approach human behavior as if it is isolated from the study of the human body. This derives from the concept of the Mind-Body dichotomy that grew out of religious history. It held that the mind was the seat of the soul, and because the soul could not be sick, the mind could not be sick. The "Mind-Body" split is not a medical reality. Today we recognize that mind functioning has its base in brain activity. Much of the study of the behavior of humans has proceeded on the basis of observational data and therefore is based in statistical correlation. Although it is very tempting to view a correlation as a "cause-effect" statistic, it is not. A correlation must always be interpreted in three ways. If a and b are the two variables that are covarying, they must be interpreted as l) a causes b; 2) b causes a; or 3) both a and b are related through a third variable c. For example, for many years it was noted that mothers of autistic children (now called pervasive developmental disorder) were cold, aloof, and very protective of their offspring. This was interpreted as a cause-effect relationship, where the mother's behavior caused the child to be autistic. However, further research has clearly demonstrated that the mother's behavior actually develops after the child's autism becomes apparent. Her alooi emotionally cold approach to the child is all the emotion the child can tolerate; the overprotectiveness develops after the child's inability to care for himself becomes evident. Many of the issues in behavioral health are associated with the concept of prevention. However, you must keep in mind that there are different types of prevention: l) preventing the negative event from ever occurring;2) if it does occur it should be prevented from becoming a permanent condition, and the person should be returned to the predisturbance state; and 3) ifneither the first nor second option is available, then the disturbance should be prevented from deteriorating any further.

ifiBhical

rre

Behavioral Sciences

BEHAVIORAT SCIENCES GENERATIZATIONS A.

Past behavior is the best predictor of future behavior. If a person has done something once, he is very likely to do the same thing again unless there has been significant intervention into

their behavior pattern. B. Most human behavior is multiply determined. It is a product of biology, genetics, learning, environment, etc. The contribution of each varies for each individual. C. Most human behavior is familial (not necessarily genetic). Behavior tends to run in families, but it is not necessarily genetically determined. For example, all members of a given family usually speak the same basic language. That is an example of a learned familial behavior; however, the fact that virtually all humans can learn to speak any language is an example of a species' genetically determined behavior. D. Being poor is hazardous to your health. Poverty places significant limitations on access to health information and health care. The overall health of individuals with limited financial resources is negatively affected; their children may be compromised by that limitation. These children may be equally restricted in earning power by the compromise transmitted by the family. They, in turn, are further limited in their health care, and the downward spiral continues.

E. Changing human behavior. Human beings have the ability to learn new information very rapidly. This learning can modifr basic genetically programmed behavior (e.g., sexual drive). There are two basic principles of changing human behavior: J.

If you want the behavior to reoccur, reward it. For example, if you want

an obscene telephone caller to continue to bother you, then yell, blow a whistle into the telephone receiver, slam the phone down, etc. You are giving the caller what is wanted-attention and recognition.

2. If you want the behavior to stop, do not reward it. Using the same example: quietly hang up, turn on the answering machine, or unplug the telephone.

DEFINITIONS AND CONCEPTS There are some basic terms and definitions that need to be reviewed.

A. Prefixes

l a--:

When the letter "a" appears as a prefix to a behavioral word, the "a" means the person is without the behavior. For example, the Greek word "lexia" means to read; the word alexia means without the ability to read.

2.

dys--: When "dys" appears as a prefix to a behavioral word, the "dys" means the person is partially without the behavior. For example, dyslexia refers to a person who can read somewhat but is not up to the expected level for his/her age, intelligence, and developmental achievement.

3.

hyper--:

4.

hypo--:

When "hyper" appears as a prefix to a behavior, it means the person has more than normal. For example, hyperactivity means the person is more active than normal. When "hypo"appears as a prefix to a behavior, it means the p-erson has less than normal. For example, hypoactivity means the person is less active than normal.

B. Behavior. We generally think of behavior

as something that can be seen by others (i.e., it is objective). However, behavior can also be totally inside the person and known to others only

r40 iliilhical

The Basia of Behavioral Sciences

ifthe person chooses to share that private experience (i.e., it ior can be motoric, a thought, feeling, emotion, or belief'

is subjective). Therefore, behav-

C. Normal versus abnormal. In studying human behavior you will often encounter the words normal and abnormal. Abnormal should be interpreted to mean that the behavior is away from the norm. It does not imply any pejorative judgement and should not be interpreted as bad, evil, or wrong.

ln a Nubhell Behavior can be observable psychomotor acts or

a

thought, a feeling, an emotion, or a belief.

INTERVIEWING When gathering subjective information from patients, the style of the interaction between the doctor and the patient can facilitate or inhibit the free flow ofrelevant data. Although there are many variations, there are ttvo basic types of medical interviews that health care providers use.

A. Interrogative or "laundry list" interview. In this tlpe of intervie$ the health care provider asks detailed questions that require the patient to give a one- or two-word response' For example: "Do you have a fever?" "Do you have a sore throat?'] etc. The underlying message from the physician is: "I know what is important to ask and all you should do is answer my questions."

1

Often, when this type of interview is employed, the patient may know details that would be helpful or even essential to the provider but about which the provider does not ask. As a result, the patient does not volunteer the information under the assumption that if it were important, the doctor would ask.

2. If this type interview

is to be useful,

it should be used under very special conditions. Some

of those include situations where: a. The patient is providing too much detail.

b. The patient has pressured speech and is having difficulty narrowing his focus to provide useful information.

c. An associative interview has been done and, there is specific data that the health care

provider still needs. B. Associative interview. In an associative interview the interviewer directs the interview as little as possible. At most, the opening statement to the patient might be "What brings you to see me today?" Other associative interviewers may start the interview with a simple nod of the head or a question of "Yes?" The point of this minimal input is to get the maximal information from the patient without imposing the interviewer's own agenda or preconceptions on the patient's reality. To do this, the interviewer associates his responses and inquiries to the information provided by the patient, not to the interviewer's preset agenda. Associative interviews are facilitated by the behavior of the interviewer. 1. The interviewer must take the time to establish a therapeutic relationship with the patient and to assure the patient that the interviewer is on his side. To establish such rapport, the interviewer must gain an understanding of the patient's world. Empathy (feeling along with the patient) helps build rapport and can be demonstrated by statements such as, "I can understand that must have been upsetting to you." The nondescript word "upsetting"

it

does not imply a specific feeling; i.e., upset may mean angry, sad, scared, disgusted, etc., and it would be inappropriate for the interviewer to assume a given specific feeling if the patient had not identified it as such.

is used because

ln a Nubhell An asjociative interview encourages the patient to tell his own unbiased history.

2. During an associative interview the interviewer must remain as silent as possible because silence conveys that the patient is important and should continue with the narration. However, depending on the nonverbal behavior of the interviewer, silence can also convey disinterest in the patient's information.

ifiBbical

r4l

Behavioral Sciences

3. Rapport can also be facilitated by the interviewer taking the time to reflect on what the patient has said, communicating the interviewer's understanding, and asking for confirmation of that understanding. This reflection is often coupled with a summary statement such as, "Let me see if I understand what you have been telling me." The summary may help the patient crystallize diverse thoughts in his mind and give him the opportunity to agree or disagree.

4.

If

the patient disagrees with the summary, the interviewer may need to confront the patient with the data used to establish the summary conclusion. Sometimes the confrontation needs to include a rationaLle for how the interviewer arrived at the given conclusion. Confrontation does not imply an aggressive, combative stance.

5. Interpretation is helpful for the patient, particularly if the interpretation is coupled with reassurance that it is okay for the patient to behave as he did. Support does not necessarily mean the interviewer approves of the patient's behavior; it implies that the interviewer supports the patient's decision to behave in a given manner. 6. At the end of an associative interview, if there are still specific details the interviewer needs, an interrogative mode can be used. The interviewer might say, "I think I understand what the problem is. Now I just need to ask a few specific questionsJ' 7. Most authorities in the field of medical interviewing agree that the associative interview is the most efficient and productive manner in which to gather behavioral-psychoiogical

information.

PATIENT EDUCATION In all patient care, information transfer is a part of the treatment process. Eliciting the patient's cooperation in his/her own health care is central to prevention and intervention. It is unrealistic for the physician to assume that everything said will be recalled and followed by the patient. The physician should take into consideration the relative differences between the physician's specialized education and that of the patient; i.e., the physician must translate highly technical data into language the patient can understand.

Tlpically, the patient feels ill, is preoccupied with what the illness means (e.g., "Is it terminal?", "Is it going to result in loss of work?'l "Is it going to be embarrassing?", etc.), and has limited concentration ability. Implied in these considerations is the distinction between anxiety and fear. Fear is being afraid of something that is threatening (whether it is real or imagined) and knowing what the threat is. Anxiety is experiencing the same fear-rype reaction without knowing what the threat is. When delivering infbrmation, the physician must take care to decrease the anxiety and, fear responses in the patient. Physicians can best do this by monitoring their own behaviot and while conveying concern, making sure not to convey panic. The first information to be conveyed should be a summary-this is usually the diagnosis. The next information to be conveyed is what the physician deems to be the most important thing for the patient to hear because little else wili be absorbed by the patient after the summary diagnosis and first steps.

Note The simple faci that the

information is available gives the patient the awareness that it is permissible to discuss the topic with the physician.

t42 iiiBtiical

it is essential that the p\sician appreciate that education begins by telling the patient the diagnosis. In American medicine, it is the physician's responsibility to tell the Above all,

patient about his condition. Once the patient has a name for what he is experiencing, he can more readily deal with it. The patient no longer has to be anxious about the unknown; he can begin to process information about the diagnosis. Even then, if the patient's feaf response is too intense, the processing of information is compromised. To decrease the fear response, the physician can provide the patient with a plan of how, together, they are going to deal with what the diagnosis implies.

The Basia of Behavioral Sciences

In all of these educational efforts, some basic ground rules about learning can be followed.

A. First, learning is best if it is multimodal. That is, the data should be presented verbally and should be reinforced with written and/or pictorial material that the patient can take home and examine at a later time.

B. Information is best retained if it is repeated multiple times in multiple settings. C. Information that is actively recalled has the best chance of being remembered. The physician can ask the patient to repeat what has been said. Simply reading over the same information repeatedly does not insure retention; active recall does. D. Printed information should be available without the patient having to ask or pay for it. Patients often feel embarrassed by certain medical issues and are reluctant to address them with the physician. If the physician's waiting room has free literature readily available with appropriate (e.g., nonthreatening) illustrations about given conditions, the patient can take the information and examine it at his leisure-

In a Nubhell Information that is actively recalled and reDeated many times is best retained.

iliBtical

t45

Brain-Behavior Correlations

All behavior is based in the functioning of the brain. This chapter examines the relationships between behaviors and their psychophysiologic and neuroanatomic correlates. lt also focuses on large integrated semi-autonomous behavioral complexes, their biologic associations, and their implications for medical practice.

NEUROPHYSIOTOGIC AND NEUROANATOMIC CORRETATIONS OF BEHAVIOR The human brain mediates and regulates behavior. The brain s functioning is called "mind". Homeostasis is primarily subserved by the brain stem and midbrain. The primary function of the rest of the brain (forebrain, cerebral hemispheres, cerebellar neocortex) is to interact with the environment through behavior.

A. Subcortical areas important in behavior 1. The reticular activating system (RAS) has two main functions: activation and inhibition

(or filtration).

a. Connections between the RAS and other CNS structures are diffrrse and extensive. Reciprocal connections with the cerebral cortex pass through thalamic nuclei. Many symptoms of anxiety and fear may be due to RAS response to cortical signals (i.e., we can scare ourselves with thoughts).

b. The RAS mediates arousal, particularly in response to abrupt changes in the environment such as unexpected noises or silences. The "orienting response" to novel stimuli is controlled here. c. Disorders involving arousal problems (e.g., stupor) or problems with filtering out extraneous stimuli (e.g., attention deficit) probably involve this area. 2. The limbic system includes: a. The cingulate and parahippocampal gyri of the limbic cortex b. The dentate gyrus, subicular complex, and hippocampus of the hippocampal gyrus c. The basolateral complex and the centromedial complex of the amygdala d. The nucleus accumbens and the mammillary bodies of the hypothalamus e. The anterior nucleus and dorsomedial nucleus of the thalamus

f.

Selected cerebral cortical regions (orbitofrontal, temporal pole, and the insula) Behaviors involved in instinctual expression (e.g., aggression, sexuality) and memory (e.g., amnestic disorders, Korsakoff syndrome) probably arise from the limbic system.

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Clinical Correlate Sleep disorders (especially

narcolepsy) are thought to be caused in part by brain $em

3. The brain stem regulates the basic biologic functions of the body: respiration, cardiovascular activiry consciousness, and sleep.

B. Cerebral cortex. The cerebral cortex can be functionally divided into five zones: limbic cortex, paralimbic cortex, primary sensory/motor cortex, unimodal association areas, and heteromodal association areas.

(pons) dysregulation.

1. The limbic cortex mediates the functions of the limbic system by regulating homeostasis, providing emotional coloring to experience, modulating drives and instincts, and participating in memory and learning.

2. The paralimbic cortex forms a rough link between the limbic system and the heteromodal association areas. It includes the orbitofrontal cortex, insula, temporal pole, parahippocampal gyrus, and cingulate gyrus.

3. The primary sensory cortex receives incoming (afferent) information from the external environment. a. The primary auditory cortex is in the temporal lobes.

b. The primary visual cortex is in the occipital lobes.

c. The primary somatosensory cortex is in the first postcentral gyrus. d. The primary olfactory cortex is in the olfactory bulb at the tip of the temporal lobe. e. The thalamus and a special heteromodal cortical area in the temporal lobes help integrate the various pieces of information (e.g., touch, sound, vision) so that the sensory experience is not a kaleidoscope, but an integrated experience.

4. The primarymotor cortex in the frontal lobes recruits motor neurons to perform movements. It contributes to the internal capsule, the corticospinal tract, and the corticobulbar tract, which convey motor impulses to the skeletal musculature for movement via the spinal cord and brain stem, respectively. 5. Unimodal association cortex a. Each primary sensory and motor area is connected to a unimodal association area that organizes sensory information into recognizable patterns (i.e., perceptions).

b. Unimodal motor association areas contain motor programs for particular complex movements (e.g., typing, writing, speaking, performing surgery, playing golf). These programs guide the primary motor cortex in selecting the correct pools of motor neurons to do the task. c. The unimodal motor association areas in turn are guided by sensory information. Sensory information about what each part of the body is doing and where it is located in space at each moment in time is necessary to guide motor sequencing.

6. Heterornodal association areas are in the inferior parietal lobule and the prefrontal cortex. These areas synthesize sensory information from different unimodal sensory association areas and, along with the limbic system, produce an integrated language-relevant perception so that, for example, identifring names are attached to visualized objects. C. Cerebral lateralization

l.

The two cerebral hemispheres differ in function.

"dominant" hemisphere (i.e., dominant for speech), the left hemisphere in a majority of the population, is organized to process information sequentially and in detail. It is more adept at processing language-related input and output.

a. The

146

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Brain-Behavior Correlations

b. The nondominant hemisphere is organized to process information for general patterns and in a parallel fashion, i.e., processing multiple inputs simultaneously. It is more adept at processing visual-spatial information.

2. Because the left hemisphere is usually dominant for language, even in left-handed people, dysfunction often results in aphasia and other language-related syndromes. Dysfunction in the right hemisphere in right-handed persons often results in dysregulation of mood

ln a Nutshell The dominant cerebral hemisphere (left for most people) is responsible for language. The nondominant

(e.g., expiosiveness, shifting overly intense moods), problems with recognition (e.g., faces,

is responsible for

places), and in poor visual-spatial function.

visual-spatial functioning.

3. The twcl cerebral hemispheres communicate with each other via a large white fiber bundle called the corpus callosum. Disruption to this structure results in the left hand not knowing what the right hand is doing; it makes tasks such as tying shoes impossible if the person is not looking directly at the shoe laces. D. Functional regions. Although the brain functions in systems that cross many traditional arlatomic boundaries, many cognitive functions can be correlated with identifiable cortical regions and their related subcortical structures. 1. Frontal lobe functions. The prefrontal heteromodal cortex, basal ganglia, and thalamus form a series of parallel loops, each of which is a functional unit. Together they perform the executive functions of planning, initiating the planned action (e.g., thought, movement, speech), monitoring and self-correcting the action, and terminating the action when completed. Persons with frontal lobe lesions or dysfunction often have difficulty with executive function. They make mistakes and are less efficient because they cannot plan well or self-correct. They sometimes become inactive because no plans, even for daily activities of living, come to mind. They perseverate (i.e., repeat the same ideas and actions) because they are unable to terminate action when it is completed. Their judgment and problem-solving abilities are also impaired because they cannot plan how to solve the problem and cannot judge ifany solution they devise is correct.

Clinical Correlate Broca aphasia is caused by a

frontal lobe dvsfunction.

2. The fiontal lobe loops are also involved in abstract thinking, sustained attention, shortterm memory, expressive language and speech, and voluntary movements. Evaluation of motor function and tests of speech, thinking, concentration, and memory are used to assess frontal lobe function. 3. The nondominant frontal lobe is also involved in the expression of emotion and in the intonation and musicality of speech. Lesions in this region can result in a loss of emotional expression, producing monotonous speech and an expressionless face. This is termed motor aphasia and is documented by observation during history taking or by asking the patient to mimic specific emotions. 4. Temporal lobe functions. The temporal lobes are involved in memory, new learning, providing emotional tone to perceptions, facial recognition, and language. a. Facial recognition is tested by either showing pictures of famous people or by asking the patient to identif' relatives or staff members. Inability to recognize faces, despite adequate vision, is termed prosopagnosia. b. Emotion is tested by observing whether the patient recognizes and responds to the spontaneous or mimicked emotions of the examiner. Inability to recognize the emotional expression of others is termed receptive aphasia.

Clinical Correlate Wernicke aphasia is caused a temporal lobe dysfunction.

5. Parietal lobe functions. The parietal lobes are involved in recognizing concurrent sensory signals as a single perception, being aware of three-dimensional space and the relationship of the self to that space, the integration of visr.ral and tactile information with ianguage, linking perception to motor performance and the guidance of movement in space, and organizing theoretical space.

ilitsbical

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Behavioral Sciences

a. Lesions in the parietal lobes have a debilitating effect on IQ scores, intellectual life, and the understanding of abstract concepts.

b. Patients with astereognosis cannot identifr objects by touch in the extremity contralateral to the parietal lobe dysfunction. c. Patients with agraphesthesia cannot identifr numbers or letters traced on the palms of the hand contralateral to the parietal lobe dysfunction. d. Patients who cannot perform simple motor tasks or praxic functions, such as using scissors or a hammer, even though primary motor skills are intact, are said to have dyspraxia or apraxia depending upon the extent of impairment. E.

Neurotransmitters and behavioral correlates 1. Biogenic amines. There are five biogenic amines that have known relationships with behavior. a. Dopamine (DA). There are two significant behavioral states that are correlated with DA.

(1) The first is DAs role in substance abuse, particularly stimuiants. Dopamine is central to the subjective experience of pleasure or reward. When certain

ofDA in the synaptic cleft that produces a subjectively rewarding response. However, if repeated use of the substance occurs, DA stores can be depleted, and regardless ofhow much ofthe drug is used, no pleasurable experience will occur. substances ofabuse are used, there is an increase

(2) DA is significantly involved in schizophrenia. The available data suggest that schizophrenics have too much DA available. All medications used to treat schizophrenia block DA receptors. b. Norepinepherine (NE). NE has an activating effect on behavior. Because of this property, NE is involved in both stimulant substance abuse and mood disorders.

(1) Stimulant substance abuse makes more NE available in the synaptic cleft; the result is energizing. In large quantities, this energizing effect can produce aggressive and violent behavior; individuals who are abusing stimulants can be quite dangerous to those around them.

(2) NE also has significant pain control properties. If individuals have an excess of NE in the synaptic cleft, they will not experience pain to the degree they would without the augmentation.

(3) Many of the heterocyclic antidepressant medications

increase the amount of NE

in the synaptic cleft. c. Serotonin (5-HT). 5-HT regulates a number of different behavioral states, including mood, aggression and violence, sleep, and pain. 5-HT is important for impulse control and may act in conjunction with other neurotransmitters to produce behavioral effects. Low levels of 5-HT may allow pathogenic effects of other neurotransmitters to be expressed. For example, people who commit suicide have low levels of 5-HT, and

those who use violent means

to commit

suicide have extremely low levels.

Hallucinogens affect 5-HT receptors. d. Histamine. Because histamine-producing neurons are found primarily in the hypothalamus, this neurotransmitter is primarily correlated with vegetative functions such as sedation, weight control, and cardiovascular effects. e. Acerylcholine. The most important correlate of acetylcholine is memory. It is involved in the dementias of the Alzheimer Wpe.

r48 ifitshical

Brain-Behavior Correlations

2. Amino acids. These neurotransmitters are the most numerous of any in the brain. a. Gamma-aminobutyric acid (GABA). GABA has an inhibitory function on many neurons of the CNS, with its major correlate being anxiety states. Benzodiazepines are

anti-anxiety medications that potentiate the effect of GABA. GABA also has inhibitory action on other systems in the CNS and has been used for its anticonvulsant properties. b. Glutamate is an excitatory neurotransmitter and has been implicated in schizophrenia. This hypothesis stems from the observation that one of the glutamate receptors is the efflective site of action of the abused substance phenryclidine (PCP). Individuals under the influence of PCP have psychotic-like behaviors that are similar to some symptoms of schizophrenia.

3. Peptides. These neurotransmitters are short proteins. Their major functions are the control of stress and pain. They have also been implicated in mood disorders, schizophrenia, eating disorders, and some dementias (Alzheimer and Huntington types).

BEHAVIORAT COMPTEXES AND BIOTOGIC CORREIATES A. Eating patterns 1. Normal. Normally, people eat at given times of day, and they eat enough to satisfr their hunger. The hypothalamus has feeding (perifornical region of the lateral hypothalamus) and satiety (paraventricular nucleus of the medial hypothalamus) centers that are influenced by many neurotransmitters, including cholecystokinin (CCK), NE, DA, and 5-HT. Normal eaters stay within a given caloric intake for their body size, age, and sex. For women the range is 1,600-2,200 calories per day, and for men it is 2,300-3,000 per day. With increasing age, caloric need decreases. As activity level goes up, caloric need increases.

2. Obesity. Obesity is defined as being son's age, gender, and build.

20o/o

or more over the ideal body weight for the per-

a. Approximately 3lo/o of males and 35o/o of females in the United States are obese.

b. Twin studies and adoption studies have documented a very strong genetic contribution for truly obese individuals.

Cliniol Correlate Obese persons are less responsive to internal cues of satiety and more responsive to external cues like the sight or smell of food.

c. Recent data suggest that a specific substance that signals the individual to stop eating

(leptin) is absent or nonfunctional in obese mice. d. Other studies have documented that individuals with childhood-onset obesity have fat-cell hyperplasia (too many), whereas those with adult onset obesity have fat-cell hypertrophy. Thuly obese people have both types of fat cells. e. Excessive abdominal weight (more characteristic of males than females) has been correlated with high blood pressure, diabetes, early heart disease, and some types of cancer.

3. Weight-reduction strategies. The most successfi.rl programs are medically directed behavior modification programs. They involve stimulus control (e.g., eating in one room only, eating only at certain times, not eating during pleasurable activities, not buying fattening or "junk" foods, not shopping for food when hungry, removing food from the table after eating, no snack trays, storing food in opaque containers). Most weight reduction strategies work; however, the weight is soon regained if there has been no change in the individual's behavior patterns. 4. Anorexia and bulimia. These are psychiatric eating disorders related to the body image perception ofthe individual. They are covered later in the Psychopathology chapter.

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Behavioral Sciences

B. Pain. The experience of pain involves the interplay among neurologic, emotional, and psychological variables. 1. Infants and children may be more sensitive to pain due Distraction is the best management for children in pain.

to CNS maturation

issues.

2. Chronic pain has four major correlates: a true physiologic substrate, a psychological component ("I'm weak"), social control of self and others, or the pain may represent holding onto a lost loved one by developing similar symptoms to those that led up to the death ofthe loved one.

C. Sensory deprivation. When all of the senses get into a steady state with minimal variation or simulation of the sensory receptors, a very predictable situation develops. Initially, the person enters into a light "hlpnotic-like" condition in which he does not seem to be processing available information. As the deprivation continues, profound anxiety develops, depression and/or hostility appear, auditory and visual hallucinations occur, depressed level of consciousness and attentive behavior are present, and extreme stimulus hunger and suggestibility develop.

In a Nutshell Sleep is an active, not passNe, pr0cess.

D. Sleep 1. Neurophysiologic systems regulate the sleep cycle: a. The ascending RAS modulates level of arousal and wakefi.rlness. b. The non-REM sleep system, whose neurochemical basis remains unclear

c. The REM sleep system, which is based in nuclei in the pons d. Serotonin is the neurotransmitter that apparently regulates the sleep process.

2. Polysomnography. The stages of sleep and wakefulness are characterized by distinctive patterns of EEG waves, eye movements, and muscle tone. Standard EEG recordings are augmented by electro-ocular and electromyographic recording to detect eye movement, nose and mouth thermistors to detect airflo$ intercostal electrodes to measure respiratory effort; monitors of blood oxygen saturation, electronic pupillography to assess the level of arousal and penile tumescence to help differentiate secondary impotence from primary impotence. 3. Normal EEG and sleep architecture. When a person does mental work, the EEG pattern is high-frequenry beta waves (15-18 Hz). In a relaxed but alert state, a person exhibits predominantly alpha waves (8-12 Hz). Lower-frequency and higher-voltage waves characterize increasingly deeper ievels ofsleep. 4. Non-REM (NREM), or synchronized, sleep consists of four stages. a. In Stage

l,

theta waves (4-7 Hz) appear accompanied by slow rolling eye movements.

b. In Stage 2, (which constitutes approximately 45-50o/o of total sleep), there is continued slowing of the EEG with slower theta waves and the appearance of sleep spindles (12- to 14-Hz series of waves increasing and then decreasing in amplitude).

c. In Stage 3, there is the appearance of delta waves (high amplitude, slow waves of less than 4 Hz). d. Stage 4 is characterized by the presence of approximately 50o/o delta waves. e. Stages 3 and 4 are called slowwave or delta sleep, during which breathing and heart rates are slower than waking rates and muscle tone is maintained. Stages 3 and 4 usually occur only during the first two rycles of the night.

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Brain-Behavior Correlations

5. REM (rapid eye movement) sleep (also called paradoxical or desynchronized sleep). REM periods occupy approximately 20-25o/o of a normal young adult's sleep. a. Delta waves and spindles disappear.

Clinical Correlate During REM sleep, memories are consolidated and

b. Low-voltage random frequenry waves with bursts of sawtooth waves (4-7 Hz) appear and are accompanied by occipital alpha waves (8-l2Hz).

extraneous cognitive material

c. The eyes make rapid alternating left and right lateral movements under the closed eyelids.

to which the oerson has

d. People are least responsive to external stimuli during REM sleep. e. There is generalized muscle atonia except for ocular and middle ear muscles, and deep tendon reflexes disappear.

f.

is dropped out of material

been recently exposed. For

good retention of learned material, adequate REM sleeo is essential.

There is great variation in heart rate, blood pressure, and respiration.

g. There is vascular engorgement of the genitalia.

6. The sleep cycle. A typical sleep cycle progresses through all four stages of NREM sleep, with slow-wave sleep predominating in the first hour. The first REM period occurs approximately 90 minutes after sleep onset. This period may be briei but as the 90-minute rycle reoccurs through the night, REM periods become progressively longer. The average REM duration is 20 minutes, although in the last third of the night RXM periods may last 40 minutes or longer. Because of REM atonia, tossing and turning as well as sleepwalking, sleeptalking, and "night terrors" are phenomena most likely to be observed during NREM sleep, whereas vivid visual dreaming is associated most closely with REM sleep.

7. Developmental aspects of sleep. Slow-wave sleep is not established frrlly until several months after birth. It comprises a large proportion of sleep time in children and young adults. Its presence decreases with age, sometimes disappearing altogether in the elderly. Because of this decrease in slow-wave deep sleep, the elderly are more susceptible to envi-

ronmental stimuli, resulting in multiple awakenings throughout the night. REM sleep may occupy up to 500/o of total sleep time in infants and children, steadily decreasing to 20-25o/o in young adults and less than 20o/o in the elderly. Clinical Correlate

8. Sleep disorders a. Excessive daytime sleepiness is common in the elderly. When onset occurs in younger people, the disorder may result from intense exertion at work or sports, environmental stress that causes poor or little night-time sleep, the abuse of recreational drugs (including alcohol), and CNS or respiratory dysfunction.

b. Sleep apnea. Apnea is the cessation of air flow for l0 seconds or more. The key symptom is loud, rasping snoring. Sleep apnea is the most frequently encountered complaint in sleep disorder clinics.

Many psychiatric disorders (e.g., depression, mania, anxiety disorders) and general medical conditions (e.9., chronic pulmonary disease,

arthriti$ have sleep di$urbances as a symptom.

(1) Obstructive apnea, the most common type of

sleep apnea, is caused by muscle atonia in the oropharynx, obstruction by the tongue or tonsils, or nasal obstruc-

tion. Contributing factors include obesiry use of alcohol or sedatives, and hypothyroidism. During sleep apnea, pulmonary and systemic arterial pressure rise, taxing the right heart, sometimes resulting in asystole and heart failure. Bradycardia and hlpoxemia can cause arrhythmias. It may also lead to increased risk for hypertension, ischemic heart disease, arrhythmias, and stroke. Adults may have reduced libido, and children may have early morning cyanosis. Sleep apnea usually results

in daytime sleepiness and impaired concentration

that may lead to traffic accidents and reduced work performance.

Excessively sleepy patients should be warned against operating automobiles and dangerous

machinery.

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Behavioral Sciences

Tieatment includes the avoidance of alcohol and other sedatives, weight control, sleep position training, placement of a positive pressure nasal mask to prevent airway collapse (CPAP), and surgical interventions (e.g., tonsilectomy) to correct

obstructions.

(2) Central sleep apnea occurs when the medulla

does not respond to the accumu-

lation of CO, in the blood. Central sleep apnea almost always occurs in children and is considered to be one of the causes of SIDS (sudden infant death syndrome). Typically, the child is cyanotic upon waking in the morning.

Treatments include repositioning the child's characteristic sleep posture, installing abuzzer warning system that wakes the parents when chest movements cease, and administering theophylline to lighten sleep. When the theophylline takes effect, the buzzer warning system can be discontinued. Children with central sleep apnea usually"grow out of it" by age 2-3 years.

Clinical Correlate The most common causes of insomnia are situational problems, such as a new

environment encountered in travel or hospitalization, excessive noise, bright lights,

uncomfortable beds (particularly problematic for

the elderly), and dreamrelated disturbances, such as nightmares.

c. Insomnia is an individual's subjective perception of not sleeping enough during the night. Approximately 107o of insomniacs have no demonstrable pathology. They often report having dreams that they are awake when in fact they were asleep. Tiue insomnia associated with atypical polysomnographic features is characterized by frequent awakenings primarily out of NREM periods; 5olo of persons with insomnia have REM sleep interruption. Insomnia is generally more common in women and increases

with (

age.

1) Psychogenic problems such as fear of sleep or not being able to fall asleep, sexual arousal, or rumination over problems can also be etiologic. Insomnia may be associated with nocturnal myoclonus (muscle twitching) and restless leg syndrome (leg movements throughout sleep) and may accompany illnesses that cause pain or hypoxia and neurologic disorders such as head trauma and epilepsy.

(2) Tleatment of insomnia. Nonpharmacologic treatment is used most often. Relaxation techniques (e.g., biofeedback) and systematic desensitization may be used. The elimination of recreational drug use, including alcohol, is axiomatic in the treatment of all sleep disorders. Other patient education guidelines include: use the bed for sleeping and sex only; no daytime naps; eat a light snack at bedtime; establish a regular time for morning wfing regardless of the amount of sleep the previous night; exercise daily; and maintain a quiet and comfortable sleep environment. Pharmacologic treatment of insomnia should be restricted to

"last resort" efforts. Barbiturates and other nonbenzodiazepine sedativehypnotics are very addictive, suppress REM sleep and should be avoided. Benzodiazepines reduce the period of slow-wave sleep and higher doses reduce the duration of REM sleep. Nevertheless, the short-acting benzodiazepines are the drugs of choice to treat underlying anxiety. However, they should not be given for longer than l-2 months because the likelihood of addiction after this period of regular use is virtually 1000/0. d. Narcolepsy is a chronic disorder in which there is sudden onset REM sleep during the day, forcing the person to sleep. This may occur during conditions in which sleep onset is embarrassing or dangerous. In most cases the etiology is unknown, although it may be associated with head trauma, encephalitis, or other brain dySfunction. Some cases have been linked to the short arm of chromosome 6l others have been linked to

histocompatibility antigen HLA-DR2. The disorder often follows

a

famiiial pattern.

e. Cataplexy, which often accompanies narcolepsy, is the sudden loss of voluntary muscle tone after strong emotions (e.g., laughter, joy, surprise, or rage) or abrupt

movements (e.g., coughing, sneezing, or orgasm), causing the person to collapse. Attacks usually last less than 2 minutes and usually end suddenly with full recovery.

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Brain-Behavior Correlations

f. Sleep paralysis

is similar to cataplexybut occurs when falling asleep (hypnagogic sleep paralysis) or when waking up (hypnopompic sleep paralysis). It represents an inappropriate activation of the normal REM motor pattern. It usually lasts between one and ten minutes, although patients may perceive it as lasting longer. Symptoms may be terminated by external stimuli.

g. Hypnagogic and hypnopompic hallucinations are considered "normal" hallucinations because they are not accompanied by any other "abnormal" behavior. They are halluci-

nations that occur during transitions into (hypnagogic) and out of (hypnopompic) sleep. Patients characterize them as dream-like states with visual, auditory and, occasionally, somesthetic hallucinations. The level of consciousness may be fairly high, but more often it is clouded and the patient is unable to recognize the experience as unreal. Hypnagogic hallucinations are often accompanied by sleep paralysis. h. Disorders of the sleep-wake schedule (may be transient or persistent)

(l)

In delayed sleep phase syndrome,

a 24-hour periodicity is maintained, but the onset of the sleep period is delayed, resulting in difficulty arising in time to meet morning schedules. This is common in people who travel across time zones ("jet lag") and those who change time shifts at work (e.g., nurses).

(2) In advanced sleep phase syndrome, wakefulness cannot be maintained in the early evening, resulting in early morning awakenings. This disorder is seen more commonly in the elderly.

i.

Parasomnias. These occur more frequently in children and often spontaneously remit

after childhood.

In a NuBhell As a general rule, sleep

problems that require active

(1) Somnambulism (sleepwalking) occurs during the first few hours of deep sleep in children and in other NREM sleep stages in adults. The disorder is familial. Episodes of clumsy walking last for several minutes. The sleepwalker can avoid some, but not all, obstacles and usually returns to bed with no memory of the el-ent. The syndrome usually abates by puberty. Tieatment includes protecting the patient from falls and harmfi.rl objects, education of the family, identifring waking time anxieties and the administration of long-acting benzodiazepines (stage 4 sleep suppressants).

muscle involvement cannot arise from REM sleep because muscles are totally relaxed during REM.

(2) Pavor nocturnus (night terrors) occurs during deep or other NREM sleep stages. It is familial and can occur simultaneously with sleepwalking. Patients suddenly sit up in bed looking terrified, scream, are inconsolable, unable to conwill run from the room. Episodes typically last for a few minutes, after which the patient returns to sleep with no memory of the event upon wakening. The treatment is the same as for sleepwalking.

verse, and, occasionally,

(3) Sleep-related enuresis (bed wetting) occurs mainly during slow-wave sleep in children, in the first third of the night's sleep. Tieatment is discussed in the Psychopathology chapter.

(4) Bruxism, or teeth grinding, occurs predominantly in NREM stage 2. (5) Head bangrng occurs in early childhood during E.

sleep onset.

Language problems associated with brain dysfunction. The evaluation of language requires the assessment of the spontaneity, emotional tone, fluency, and articulation of speech; the ability to repeat speech; auditory comprehension; word usage and syntax and naming, reading, and writing. Syndromes related to abnormalities in these characteristics are termed aphasias.

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Behavioral Sciences

In a Nutshell Broca Aphasia

. . .

Frontal lobe dysfunction Comprehension unimpaired Speech production telegraphic and ungrammatical

.

Patients have trouble

repeating statements

1. Broca and transcortical motor aphasias. Broca aphasia results from dysfunction in the "watershed" area in the posterior inferior region of the dominant frontal lobe. Watershed areas are brain areas that are poorly supplied by blood vessels; therefore they are particularly lrrlnerable to hypoxia.

is characterized by nonfluent, agrammatic, telegraphic speech in which only common nouns, verbs, and the occasional adjective are used. Repetition is also impaired. Speech is slow and labored, but comprehension is relativelypreserved. Other forms of expressive language, such as writing, are similarly affected.

a. Broca aphasia

b. Common "neighborhood" signs (i.e., due to damage in the tissue surrounding Broca's area) include contralateral hemiparesis, impaired conjugate gaze, and buccolingual dyspraxia. In the latter, the patient is unable to demonstrate how to blow out an imaginary candle or sip from an imaginary straw; however, if provided the real objects he can perform the task. An ipsilateral hand dyspraxia can also occur, in which the patient is unable to demonstrate the use of imagined simple objects such as keys, scissors, or a hammer. c. Transcortical motor aphasia. This sprdrome results from a lesion close to Broca's area. The symptoms are the same as in Broca aphasia, except that repetition is preserved.

2. Wernicke and transcortical sensory aphasias a. Wernicke aphasia is also associated with dysfunction in a watershed region in the posterior aspect of the superior temporal gyrus of the dominant temporal lobe. Wernicke

In a Nutshell Wernicke Aphasia

.

Temporal lobe dysfunction

.

Comprehension impaired

.

Verbal paraphasias (word

.

Trouble repeating

substitution)

statements

aphasia is characterized by fluent speech with normal prosody (the emotional and gestural component of language) and spontaneity that is severely paraphasic. Paraphasias include neologisms (made-up words) and word approximations (e.g.,

"writer" for pen).

Speech may be totally agrammatical and sound like double talk or foreign language. Auditory and reading comprehension are poor; repetition is poor.

a

b. Tianscortical sensory aphasia results from lesions close to Wernicke area. The symptoms are the same as for Wernicke aphasia, except that repetition is intact.

3. Global and conduction aphasias

of Broca and Wernicke aphasia. Speech is slow, labored, dysarthric, and telegraphic as in Broca aphasia but is also paraphasic as in Wernicke aphasia. Repetition and auditory and reading comprehension are poor. Dysfunction involves both Broca and Wernicke areas.

a. Global aphasia is a combination

b. Conduction aphasia results from a lesion in the arcuate fasciculus, the fiber bundle that connects Wernicke with Broca area, thus limiting posterior to anterior communication. Repetition is severely impaired, but language output and comprehension are only mildly affected.

4. Subcortical aphasia. Lesions in the left thalamus or left caudate nucleus can result in aphasia. After an initial loss of fluency and spontaneiry speech becomes fluent. Paraphasic errors are common, but repetition is relatively preserved. Of all the aphasias, this type most resembles the speech problems observed in schizophrenics.

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Brain-Behavior Correlations

GENETICS AND BEHAVIOR Some authors estimate that as many as 50o/o of personality traits and behaviors are controlled

by genetics. To date, there is a long list of affected behaviors, including aging, alcoholism, Alzheimer disease, cognition, intelligence, Huntington chorea, mental retardation, mood disorders, normal personality traits (e.g., introversion and extroversion, shyness, risk taking, need for rewards), some personality disorders, schizophrenia, and sexual object preference. Genetic contributions to human behavior are studied by the following designs:

A. Family studies focus on first-degree relatives and the prevalence of illness in these relatives compared with controls or the population prevalence. B. Twin studies. Monozygotic (MZ) twins share l00o/o of their genes. Dizygotic (DZ) twins share up to 50o/o of their genes. Twin studies examine coincidence rates (e.9., if one twin has

twin also have it?) between MZ,DZ, and nontwin siblings. Twins reared apart versus twins reared together are also studied to assess the effect of the environment on the disorder or characteristic. Unequal uterine blood profusion of MZ twins modifies the effects of genetic determination of behavior. a disorder, does his

C. Adoption studies. Adopted children are studied to see parents or their adopted parents.

if they

are more like their biologic

D. Cross-fostering studies are studies of children within one household, some of whom are adopted and some of whom are the biologic children. Because both sets are reared in the same household, the effects of environment and genes can be assessed.

E. Linkage studies examine pedigrees to find genetic markers linked to the characteristic of interest. This can be used to map the characteristic or to predict with greater accuracy the probability of inheriting the characteristic.

F. Genetic counseling. With techniques for screening for more than 450 genetic conditions, genetic counseling issues arise that are more ethical than technical. Should the person get-

ting the counseling be told the probability of the event occurring? Should the results be allowed to be used for insurance screening purposes to exclude high risk individuals from being insured? Should at-risk individuals be advised to get tested? There is concern that if persons are advised they are positive for a given condition, they may overinterpret normal errors, e.9., normal forgetting interpreted as the onset of dementia in a person who is positive for a specific dementing disease, or they may take their lives if they find they are positive for a deteriorating or potentially fatal disorder.

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r55

Defining the Mind

Because "the

mind" is a hypothetical construct, it must be defined in terms of behaviors that are

observable and can characterize the concept. This chapter reviews those divisions of mental activity that are the primary dimensions of the functioning r"rrind. ln addition, a discussion of psychological assessment is included because psychological tests are used to operationalize the mind.

CONSCIOUS N ESS, ORI ENTATION, MEMORY, ATTENTION,

AND CONCENTRATION A. Consciousness is the state of physiologic arousal. During the waking time of day, a normal individual is alert, and his/her level of consciousness does not fluctuate. This is not true of pathologic conditions; it is particularly not true of those conditions associated with general medicai disorders, such as delirium. B. Orientation is the person's awareness of the here and now. Does the person know who they are, where they are, what the date/time is? This is sometimes referred to as being oriented "times three," meaning the person is oriented to person (e.g., name, address, date of birth), place (e.g., where the patient is at the present time), and time (e.g., the date, day of the week, year, morning or night). If orientation to the present situation is included (e.g., "What are we doing at this time?"), it is called being oriented"times four." You need to be very clear in your questions to a patient who may be disoriented because the patient can often answer the question correctly without being totally correct. For instance if you ask, "Where are you?" the patient may answer correctly, "The hospital." However, she may not know what city or what hospitai she is in. C. Memory, as opposed to orientation, is concerned with the past and whether the patient has access to that past. For clinical purposes, memory is usually divided into three types. 1. Immediate memory is what has happened in the last 10-15 minutes. Usually, this is tested by asking the individual to repeat three unrelated things and a few minutes later asking the patient to recall those three items.

2. Recent memory refers to the previous 2 weeks. It is usually assessed by asking the patient about significant news events that may have transpired in the last 2 weeks. Asking about the patient's activities during the last 2 weeks is helpfi.rl only if the interviewer can verif| the data.

3. Remote memory refers to information that is more than 2 years old. Again, this should be verifiable data and information that the interviewer has had the opportunity to learn.

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4. As a general rule, normal memory loss proceeds tiom losing immediate memory process first and remote memories last. As people age, that normal pattern is apparent. If someone loses remote memory for given selected events, but immediate and recent are intact, the examiner should suspect a more psychological basis for the memory impairment. D. Attention and concentration 1. Attention refers to the process of bringing one's cognitive processes to focus on a given item. It requires the RAS to be intact and functioning so the individual can activate his cortical processes and inhibit extraneous material from the attention process. Clinicians assess this function by noting if the patient is able to listen to questions and respond without the clinician needing to repeat the question.

2. Concentration is defined

as the ability to attend to a problem and solve the issue at hand. This is usually tested by asking the patient to do mental arithmetic, e.9., serial subtraction of the number 7 from a given starting point of 100 or reporting events to which the interviewer has directed the patient (e.g., tap every time the interviewer says the letter "a").

E. Mnemonic COMA. If a patient demonstrates problems in Consciousness, Orientation, Memory, and/or Attention and concentration, the physician should assume a physiologic cause

until proven otherwise.

SENSATION, PERCEPTION, AND THINKING

In a Nutshell

.

Consciousness, orientation,

memory, attention, and concentration are basic defining factors of the mind

.

Sensation, perception, and

thinking are higher level functions of the mind.

A major portion of the functioning of the mind is to relate to and interpret the environment in which the person lives. This is accomplished by sensing and perceiving the world and by bringing logical thought process to bear on the task.

A. Sensation is the process by which stimuli are brought into the awareness of the individual. For this to occur, the sensory end organs and the primary sensory projection aleas of the brain must be intact. For these to be normal, there should be a stimulus of some sort that triggers the sensation. Pure sensations are very rare. Usually, sensations are integrated into a frame of reference or understanding that is termed "perception". If pure sensation occurs and the individual cannot understand the sensation, the individual expericnces strong anxiety. If sensations occur in the absence of external stimuli, abnormality of the brain should be considered.

B. Perception is the understanding of sensation. Normally, perception occurs almost immediately upon sensation, and this understanding reduces anxiety levels. However, there are two forms of perceptions that are considered abnormal and regularly occur with psychopathology. 1. Illusions are the misperception of a real stimulus. For example, while walking at night, a stump of a tree may be misperceived as an animal that is a threat to the person. People who have some types of psychopathology, usually secondary to general medical illness, may misperceive an intravenous line as a snake attacking their arm.

2. Hallucinations are the perception of something when there is no appropriate stimulus. For example, the individual may hear voices when no one is there, see things that are not present in the environment, or smell things that are not truly there. Integrated hallucinations that "have a message" for the patient and occur in the auditory and sometimes visual modalities are characteristic of more psychopathologic etiologies. On ihe other hand, as a general rule, l) if hallucinations are of reasonably primary sensations and 2) if they are tactile, olfactory, or visual, they are usually secondary to some pri-mary general medical condition such as an infection, toxin, or brain tumor. For example, seeing bright sparkling lights or dark scotoma in a visual field often happens with migraine heaclaches.

r58 ilitsticar

Defining the Mind

C. Thinking is the regimented efficient mental process by which people come to solutions, invent new things, plan for the future, etc. Normally, people think in a very logical manner and reach valid conclusions. The result of normal thinking is a conclusion that is reasonable and can be followed by others. Abnormal thinking is characterized by some fairly consistent aberrations.

1. Some people demonstrate circumstantialiry in which they give excessive detail of the situation at hand. This is not efficient and often does not allow the individual to reach a valid conclusion,

2. Others may become tangential and instead of addressing the issue at hand, become involved with somewhat related issues that are not on target relative to the problem or question they are trying to address. For example, they may be asked their home address but give the examiner a description of where they live or the address of their parents. 3. Some patients who are exhibiting abnormal thought processes develop very loose associations between concepts, and, consequently, their conclusions are erroneous. For example, "God was a man"; "I am a man"; "I am God." This looseness can be so tenuous as to have association only on the basis ofthe sounds ofthe words ("clang associations"). 4. Delusions are false, fixed-belief systems that are not shared with the maiority of other persons.

5. Sometimes the person's thought processes are so fragmented that he cannot make associations between ideas; rather, he simply talks in unrelated whole concepts. For example, "It's a nice day. The puppies are with their mother. Fresh strawberries really taste good in the summer. I'm going to the movies today'' 6. Thinking can also be disrupted in terms of the rate at which the person thinks. That rate can be accelerated, retarded, or totally blocked, in which case the person cannot recall what he was thinkine about.

PSYCHOTOGICAT ASSESSMENT Because "the mind" is a hypothetical construct,

it is important to be able to operationalize it to relative normative functioning. Psychological assessment involves techniques such as "paper and pencil tests," interviews, direct observation, and psychophysiologic measurement. The purpose of psychological assessment is fourfold: l) to identifr the current level of functioning, 2) to determine if there are deviations from "normal", 3) to determine possible bases for the deviations ifthey exist, and 4) to develop intervention strategies ifpossible. assess

Psychological tests are standardized in administration and scoring to assure the tests have reliability (i.e., two administrations of the same test to the same person yield the same results) as well as validity (i.e., the test measures what the tester intends for it to measure).

A. Intelligence tests

l.

Scores

on intelligence tests or Intelligence Quotient (IQ) are most successfrrl in predicting

academic achievement; i.e., individuals who achieve high IQs are likely to be good students. However, IQs are poor predictors of occupational success and show little relationship to abilities required outside of academic settings. The overall or Full Scale IQ (FSIO is an average ofscores achieved on verbal and nonverbal subtests. Verbal IQ (\aIQ) and Performance IQ (PIO are usually reporred in addition to the FSIQ. Comparison of these ovo sub-IQ scores can allow inferences relative to the intact functioning of the brain. For example, if VIQ is less than PIQ by more than 15 points, it suggests the dominant (usually left) hemisphere is dysfunctional.

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2. Approxirnately two thirds of the population have IQ scores between 85 and 115 (standard deviation). Scores below 70 are consistent with mental retardation, and scores above about 130 are considered to be very superior. Test-retest reliability is fairly high, and IQ scores begin to become relatively stable by 3 or 4 years of age. However, IQ scores taken at a later age are more indicative of the overall functioning of the person than those taken at an earlier age.

3. Use of intelligence tests across cultures is one of the most controversial issues in psychological assessment. At issue is whether tests statistically developed and standardized primarily on white, American, middle-class persons can be validly applied to members of other ethnic and socioeconomic (SES) groups. The major issues are: a. Language. Intelligence tests, which are highly dependent upon oral and written middle and upper SES English grammar, may not be fair to individuals for whom English is a second language, preverbal children, individuals raised in a lower SES community with little access to verbal enrichment, individuals with a sensory-motor disability (e.g., deaf and aphasic persons), etc. Tests have been constructed so that neither the instructions nor the responses require the use of oral or written language. For instance, examinees may be required to choose one of several alternatives in complete an abstract pattern (e.g., the Raven Progressive Matrices).

b. Time limit. Some cultures place little value on rapid performance, and some people may be naturally slow because of peripheral problems in motor skill (e.g., arthritis). Therefore, tests that require responses to be executed quickly may penalize individuals from these groups. Many instruments used for cross-cultural testing either offer extended time limits or do not reward rapid responses.

c. Item content. Many traditional tests for intelligence require examinees to identifr or understand the functions of particular objects that may be unfamfiar to individuals from some cultural groups. Also, general information items are dependent upon exposure to educational systems that may not be available in certain SES and ethnic groups.

4. Commonly used measures of intelligence a.

For children under 2 years of age, developmental scales such as the Denver Developmental Scale may be used.

b. The Stanford-Binet Test is best for younger children not rely exclusively on language.

(24

years old) because

it

does

c. The Wechsler Preschool and Primary Scale of Intelligence (WPPSI) is used for children 4-6 years of age. d. The Wechsler Intelligence Scale age 16 years.

e. The Wechsler and older.

f. The Wechsler

for Children (WISC III) is used from

age 6 years

to

Adult Intelligence Scale (WAIS-R) is used for those age 17 years

scales have the advantage

of reporting VIQ, PIQ' and FSIQ.

g. Instruments specifically constructed for cross-cultural use include the Leiter International Performance Scale, Raven Progressive Matrices, and the Culture Fair

Intelligence Test.

B. Personalitytests can be divided into two categories: objective and subjective. 1. Objective tests are designed to quantifr characteristics and behaviors and yield scores that compare the individual's responses to a standard. These tests are "atheoretical". The

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Defining the Mind

standard is based on measurement of a relatively large sample that is presumed to be representative of the population of interest.

(MMPI) is the most popular objective personality test. The MMPI contains 10 clinical scales as well as scales designed to indicate whether individuals are responding to the test honestly or are faking their answers to appear either less or more disturbed than they actually are.

a. The Minnesota Multiphasic Personality Inventory

This inventory is "objective" because scores on its various scales are determined by comparing an individual's responses with those of patients with known diagnoses. The person's score is expressed in standard score deviations away from "statistical normal" performance. However, the scales reflect pathology and say little about other dimensions of performance. b. There are numerous personality tests that assess dimensions of "normal" personality. Most of these are based on some theoretical position. For example, the Myers-Briggs Personality Inventory is based in |ungian theory and assesses basic dimensions of personality (e.g., extroversion). It has been used extensively in occupational counseling.

c. There are special tests of behavior patterns that may be correlated with given pathologic states. The Type A and B Behavior Patterns Test assesses the amount of "driven quality" a person has to their life. Type A people are "always running out of time." Although the research on this pattern has failed to demonstrate a correlation between a type A Behavior Pattern and the onset of cardiovascular problems, type A individuals who experience a cardiovascular event are less likely to have a good course of recovery. 2. Subjective (projective) tests do not yield scores that can be compared to statistical norms. a. These tests often employ ambiguous stimuli such as inkblots in the Rorschach Test or

vague pictures depicting ambiguous interpersonal situations

in the Thematic

Apperception Test. b. Because the stimuli are ambiguous, the basis of these tests is that persons "project" their own thoughts, feelings, and conflicts into their responses. The examiner interprets these responses and categorizes them by their theme and form. c.

In projective

tests, the pattern

Note Note the similarity between projective tests and the unstructured, associative-type interview

of an individual's responses, rather than any single

response, is of greatest importance. The responses are typically compared against lists of established responses to determine whether they are significantly different from the responses of the average person and how they may differ. This process allows the inter-

pretation of projective techniques to have more than a simply subjective basis. The interpretations of most of these projective tests are based in psychodynamic theory. 3. Behavioral assessment. Behavioral approaches tend to focus on symptoms, so behavioral assessment attempts to sample the way in which people respond to important life situations. It is assumed their responses are not due to underlying personality traits. Instead, a person's behavior is believed to be a function of the situation in which the person is found. For example, if a patient reports anxiety in interviews, it is thought that the anxiety is related to some aspect of the interview situation and not to the person's personality structure. The goal of behavioral assessment is to discover the arxiety-producing element in the situation

and devise a therapeutic strategy that addresses the anxiety in the interview situation rather than a presumed personality defect.

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C. Neuropsychological assessment 1. Neuropsychological assessment is helpful in determining whether or not brain dysfunction is present and, if so, which locations and skills are affected. They may also be useful in predicting the outcome of rehabilitation efforts for the brain-dysfunctioned patient. Predictions may be made by charting gains on neuropsychological measures within the first months or year of treatment and extrapolating to future status.

2. Neuropsychological assessment includes the administration and interpretation of a battery of tests, including intelligence tests, the Halstead-Reitan test battery, and the Luria-Nebraska test battery. Each test measures more than one skill, although a given test may emphasize one tfpe of function. It is necessary to analyze the pattern of scores to evaluate cognitive impairment. Dysfunction in a particular area of the brain is likely to result in a characteristic profile of scores that can be differentiated from the profile associated with dysfunction in another area.

t62 iiiBbical

Human Development and Sociocultural lssues

To help the reader

to understand how human behavior develops throughout life, this chapter

discusses theoretical and observed developmental milestones as well as hazards. Then, the chapter

reviews the developing individual's interactions with the environment and other people, focusing on

normal development and sociocultural issues.

THEORIES OF HUMAN DEVELOPMENT: GENERAT ISSUES A. Personality theories. Personality researchers describe behavioral, cognitive, and emotional variables that define normal differences among people and within an individual over time. These differences include internal processes (e.g., perceptions, thoughts, and attitudes) and observable actions. Although there are numerous factors thought to influence the development of personality, most researchers agree they are studying habitual behavioral patterns of interactions with the environment that are unique to the individual. These habitual patterns develop early in life and are fully formed by early adulthood. How much they can change after that depends on the theory, but most studies suggest that personality behaviors are stable over one's life span. Most theories agree that personality development proceeds from a

In a Nutshell

combination of:

1. Biologic factors. Some authors estimate that as much as 500/o of the contribution to individual differences in personaliry traits is due to genetic influence. Many genes seem to be involved (polygenic determinants), and their additive effects combined with unicuely experienced environmental factors determines personality.

2. Conditioning and learning factors. Aversive conditioning (e.g., punishment or evocation

offear) can lead to avoidant behavior; reward can lead to strengthening and repetition of behaviors. Nonreward leads to a disappearance of a behavior. This is called extinction. These relative repetition/avoidance patterns within any individual are significant determinants of personality characteristics.

Most theories agree that personality development proceeds from a combination

of biologic factors, conditioning and learning factors, and social factors. Experiences with parents in

early childhood have

a

very powerful ability to motivate and modify

3. Social factors. Social psychology studies the ways people learn various attitudes, such as altruism or hostility. The concepts of modeling (i.e., learning by imitation) and vicarious reinforcement (performance of a behavior after observing another individual being rewarded for it) are relevant to social learning approaches to personality. The influence of experiences with significant others can help shape an individual's identiry behavior patterns, and personality from an early age. Most importantly experiences with parents or parenting figures in early childhood have a very powerful ability to motivate and modifr

subsequent behavior.

subsequent behavior.

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4. There are two general categories into which theories ofpersonality can be divided. a.

Trait theories emphasize the existence of various characteristics or traits in relative proportion to one another. Many trait theories concentrate on a major characteristic that can be placed on a continuum between extremes. For example, extroversion versus introversion, warm versus cold, anxious versus calm, etc.

b. Character theories emphasize interactions among theoretical parts of the mind or between the individual and social influences. The most widely known and influential character theory is Freud's psychoanalytic theory, which is concerned with internal processes (largely unconscious) and how the interaction of various theoretical divisions of the mind determine personality. This theory has formed the basis of psychodynamic formulations of normal personality, psychopathology, and nonpharmacologic interventions for disordered behavior.

SPECIFIC THEORIES OF DEVETOPMENT A. Psychodynamic formulations. All

are based

in Freud's psychoanalltic formulations.

1. Stages of development. There are five stages in Freud's model of development. "Sexual" (libidinal) drives motivate behavior; at each stage libidinal energy is focused on a

particular part of the body. Freud's psychosexual model posits that early childhood psychosexual-emotional experiences during the different stages profoundly affect later personality development. a. Oral stage

(0*l year). During this

stage, infants use their mouths to satis$r not only aggressive impulses as well. If the

their nutritional hunger, but their libidinal and

infant is not satisfied or is overindulged during the first year of life, there will be an unsuccessftil resolution of this stage.

(1) The theory links "oral" disorders with difficulty in this stage. Such disorders include drug addiction, excessive eating (obesity), smoking, and traits such

as

sarcasm and cynicism.

(2) A disturbance in the oral

stage is also sometimes invoked to explain primitive personalities with low frustration tolerance, impulsiviry and affective instability.

b. Anal stage (2-3 years). During this stage, retention and elimination of feces are sources of gratification. However, they are also supposed to form a battleground upon which struggles over obedience and defiance are fought. The classic obsessional character demonstrates traits that are thought to be related to unsuccessful resolution of this stage: procrastination, indecision, isolation of affect, and obsession with maintaining control. These individuals may be either excessively prim and orderly, excessively sloppy and wasteful, or a mix of both.

c. Oedipal stage (3-6 years). In this stage, there is competition with the same-sexed parent for their role with the opposite-sexed parent. This is successfully resolved by

identification with the same-sexed parent. Hysteria, sexual inhibitions, and fear of success reflect unresolved

oedipal conflicts.

d. Latency stage (age 7 to puberty). Libidinal energy is submerged (nonlocalized), so there are fewer potential developmental problems. The child's attention can be redirected toward learning and mastering skills. e. Genital stage (puberty through adulthood). If the child has successfully navigated the previous four stages, sexual gratification, productive work, and stable family life are negotiated in the genital stage.

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2. Mental structures. Freud's model of development also includes three intrapsychic struc-

In a Nubhell

tures: the id, the ego, and the superego.

id is completely unconscious and is the seat of human drives and instincts. Freud thought these drives were primarily sexual and aggressive and termed the sexual energy libido. Id drives are said to demand constant and immediate gratification. They also are said to be associated with a type of symbolic, convoluted thought termed primary process thinking. Dreams, according to Freud, are examples of pri-

unc0nsct0uS

a. The

drives and instincts keeps id in

Ego

check and

mary process thinking.

mediates

b. The ego is said to mediate the conflict between the id and superego. The ego is the interface between the id and the real world. It limits and censors the id with defense mechanisms (see below), which transform the id's drives into more acceptable behaviors and relieves the tension of those drives. Secondary thought process refers to the thought processes ofthe ego. They are conscious, logical, and sequential.

c. The superego is the conscience, governing constructs of right and wong. It can be absent or weak, resulting in an antisocial person, or it can be overly harsh and punitive, resulting in an obsessive, rigid person. The superego also contains the individ-

between

rd

an0 superego;

it is conscious 0r aware

Superego

-

c0nscience;

right versus

wrong

uait "ego-ideal." 3. Freud's theory also addressed how individuals use defense mechanisms to deal with anxiety caused by internal conflicts between the id and superego. In the normal person, these defense mechanisms are unconscious, shared by most people, and are variously applied in different situations. Emotionally disturbed individuals have only a few immature defense mechanism that they apply rigidly in all situations. Those defense mechanisms that are viewed as being more healthy are those that include some element of understanding and conscious awareness. The major defense mechanisms follow arranged in alphabetic order: a. Conversion is the automatic turning of conflict into physical disabiliry i.e., loss of function of the dominant hand before a written examination. It is always a pathologic defense mechanism because it compromises free functioning.

b. Denial is the automatic distortion of reality to exclude material that evokes conflict; for example, by saying something does not eist when in reality it does. This is the central defense mechanism in substance abuse disorders. c. Displacement is the automatic transferring of a wish or an affect from one object to a substitute. For example, a man who is angry at his boss releases his hostility by yelling at his wife or kicking the dog. d. Humor is a very mature defense mechanism, where the individual relieves the threat of the moment by making the difticult situation comical. For example, the "black" humor that AIDS patients, recovering drug abusers, and/or cancer patients manifest. e. Projection. Attributing one's own traits, feelings, and attitudes to someone else is called projecting. This is seen in the angry person who thinks others are hostile.

In a Nutshell Mature defense mechanisms

don't distort reality excessively; they produce

constructive behavior.

f. Rationalization is the automatic

development of superficial insight that allows the individual to remain unaware of painful thoughts and feelings.

g. Reaction

formation automatically involves turning a repressed impulse or uncon-

scious wish to its opposite. This is often the defense mechanism behind prejudice. For

example, a person who has homosexual impulses that are unacceptable to that person's Superego becomes a person who criticizes and physically attacks homosexuals.

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h. Regression is the automatic retreat to a less mature level of behavior with stress. This defense mechanism is viewed as being the expected behavior pattern when one is ill or is hospitalized.

i.

Rqrression occurs when the conflicting thought or feeling is automatically hidden from the persont awareness. Conflicts are still present, but the person does not have direct access to them. Forgetting an emotionally charged event is an example of repression.

j.

Splitting refers to the unconscious inability to see an important person as having both good and bad characteristics. These are "split," and the person is perceived as either wonderfirl or terrible. For example, the physician successfirlly removes a small wart from a woman's arm, and she says the physician is the best surgeon she has ever had. However, when the same surgeon tells her 2 months later that she doesn't need a rhinoplasty, she yells at him and calls him totally incompetent.

k. Sublimation, a very mature defense mechanism, involves consciously turning socially unacceptable impulses into acceptable or more benign forms to allow their expression. For example, a person with impulses to commit violent acts becomes a grocery store butcher.

l.

Suppression is the conscious removing of a stressfirl event from awareness. For example, consciously ignoring the fact that you just accidentally spit on a person while you were talking to him at a party.

m. Undoing involves automatically performing actions that symbolically counteract

an

unacceptable wish or act. For example, the parent who fears her anger toward her child will hug and comfort the child after disciplinary actions have been taken.

4. Primary and secondary gain a. Primary gain. In psychoanalytic thought, primary gain is the maintenance of internal homeostasis. That is, all instinctual drives are under control (Note: control means regulation, not total inhibition), and the interchange between the internal and external

world is not conflicted. Clinical Conelative Transference and countertransference are significant issues in

controlling malpractice.

b. Secondary gain is when the ego tries to gain advantages or reinforcements from the external world. This secondary gain may be in the form of attention, sympathy, money, position, power, etc.

5. The psychoanalytic literature also includes two concepts that have been applied to the doctor-patient relationship. a. Transference is experiencing toward one's doctor the feelings that one had originally

for important people in one's childhood. For example, a patient had a harsh father who always found fault with him. The patient now attributes this characteristic to his surgeon even though the surgeon is not like that. b. Countertransference occurs when the doctor experiences toward the patient the same feelings the doctor had originally for important people in her childhood.

B. Psychosocial development. Erikson placed his emphasis on social relationships and cultural factors that influence human development. His eight-stage theory spans life from infancy through old age. Each of Erilaon's eight stages is organized around a "psychosocial crisis" that must be resolved to move to the next stage. Difficulties in a particular stage may create a vuinerability that does not prevent moving into the next stage; however, this unresolved stage will flavor the person's adult life. The eight stages follow (ages listed in parentheses are approximate):

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l.

Trust versus mistrust (0-1 year). The infant develops trust in his social environment that his needs will be met. The mother's sensitivity to the infant's signals and her ability to respond promptly, appropriately, and consistently are crucial to the infant's well being and sense

oftrust.

2. Autonomyversus shame and doubt (1-3 years). The child develops autonomy, i.e., selfcontrol and independence. This stage parallels Freud's anal stage: the development of controi over elimination is an important part of the child's sense of autonomy. The "terrible two's" of the obstinate child who is trying to establish autonomy from mother is based

ln a Nutshell Erikon's stages focus on the interchange between the individual and the environment:

. .

here.

. .

4. Industryversus inferiority (age 6-1 1). The child develops a sense of competence (industry) or mastery of the immediate environment, principally through the experience of schooling and peer relationships. The "small for age," handicapped, or otherwise disadvantaged child may have problems of inferiority emanating from this stage.

.

5. Identityversusrolediffrrsion(ll-20).Adolescenceisatimeof confusionaboutidentity. The major task for the child is to separate from the family as the sole emotional support system and to begin to gain support from peers. Adolescents develop a sense oftheir own uniqueness while learning to sustain loyalties to peers. This step is preparatory to

.

(l-3)

Initiative versus guilt (3-6) lndustry versus inferiority

(6-ll

)

ldentity versus role

diffusion

.

(0-1)

Autonomy versus shame and doubt

3. Initiative versus guilt (3-6 years). The child develops a sense of initiative in undertaking activities himself. Excessive fear of punishment by the parent may interfere and the child develops a sense of guilt or an overly harsh superego.

mating.

Trust versus mistrust

(ll-20)

lntimacy versus isolation (20-40) Cenerativity versus stagnation (40-65)

.

Ego integrity versus

despair (6s)

6. Intimacy versus isolation (2040). Early adulthood is marked by the development of the ability to sustain intimary in a love relationship with another human being. Avoidance of commitments and subsequent isolation follow if the individual is unsuccessftrl in this stage. 7. Generativityversus stagnation (40-65). This stage is characterized by the development of the ability to care for others, share acquired experiences and knowledge, and assist the upcoming generation. Unsuccessful resolution results in people being stingy, self-centered, and pessimistic about the future.

8. Ego integrityversus despair (65+). The ability to maintain one's identity while accepting impending death is the central issue in old age. Looking back at one's life and accepting that given all contingencies, it was the only way the life could have been lived is the healthy resolution of this stage. Fear of death and wishing one could relive their life differently is the unhealthy resolution of this stage. C. Piaget's stages of intellectual development. Piaget highlighted the cognitive or intellectual development of the child. His model of development comprises four stages that cover the years from birth to adulthood. Mature forms of cognition emanate from and are dependent on earlier development. 1. Sensorimotor period (0-2 years). During this first stage, the infant begins to develop his senses, including proprioception, as well as his motor behavior, such as sucking' grasping, kicking, and looking. Throughout the first 2 yearc, the infant becomes increasingly sophisticated in the use of sensorimotor skills. He slowly builds up more differentiated, complex, and integrated sensorimotor behavior patterns. For example, simple hand movements present from birth (the grasp reflex) give rise to the ability to coordinate the thumb and forefinger in a precise pincer movement at 1 year. These early sensorimotor patterns enable more sophisticated body and limb movements in the later years of childhood. This includes progressive coordination of lips, teeth, tongue, palate, etc., to enable fluent speech to develop. The child lacks object constanry-the capacity to know that a hidden object still exists. Toward the end of this period, activity is internalized symbolically. The child is

ln a Nutshell Piaget focused only on the

cognitive or intellectual development of the child, not

the personality development.

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able to substitute language for motor discharge, or form mental imagery to lessen reliance

on sensory input.

2. Preoperational thought (2-7 years). During this second stage, the child becomes increasingly sophisticated in the use of symbols, principally language. However, the child has not yet developed the ability to take the perspective of others, and thus the child's thinking tends to remain egocentric or self-oriented. Thought at this stage is called "preoperational" because the child can conceive of static states but cannot fully comprehend transformations between states. For instance, a 3-year-old child will insist that a tall thin In a Nutshell

if he sees the identical volume of water poured from one to the other. Induction and deduction are unknown at this stage. glass contains more water than a short squat one, even

Piaget Stages

. . . .

Sensorimotor (0-2) Preoperational thought (2-7) Concrete operational (z-11)

Formal operational (11+)

3. Concreteoperationalperiod(7-llyears).Duringthisthirdstage,thechildisabletoreason in a logical way but is still tied to the concrete physical world. For example, a l0year-old child is able to understand that volume is conserved when the same liquid is poured from one container to another by reasoning inductively from everyday experience. He is unable, however, to understand abstract concepts.

4. Formal operational period (age 1l years to adulthood). During this stage, the adolescent is no longer tied to the concrete physical world but can reason deductively, i.e., reason from an abstract general rule to an anticipated experience. Abstract concepts such as moraliry justice, love, and existence become more fully comprehensible. D. Behaviorism and learning theories. The concepts of generalization and habit hierarchies are important in learning theories of personality. Generalization refers to the transfer of behavior learned in one context to similar contexts. The degree to which generalization occurs is proportional to the degree of similarity between contexts. Habit hierarchies are ordered statements about the probability of occurrence ofbehaviors. Those behaviors that have been reinforced more strongly will be more likely to occur and will therefore be explained as higher in the response hierarchy. Deviant behavior is viewed as the result of inappropriate or inadequate responses that are high in the hierarchy. The expression of personality is a function of behaviors that are high in the individual's habit hierarchy. Behaviorism is based upon learning theory. It states that most behavior is acquired through associative learning processes, including classical conditioning and operant conditioning, and through nonassociative learning processes, including observational learning, habituation, and sensitization. Psychopathology is therefore seen as the product of faulty learning: it may be due to aversive conditioning, to inappropriate reinforcement, or to a failure to learn responses that are adequate to cope with environmental demands.

l.

In a Nutshell

a.

Classical conditioning

substitutes one stimulus for

another one, the latter of which predictably elicits

a

gMen resp0nse.

ln a Nutshell lf you encounter the words "classical conditioning,"

If a novel stimulus (conditioned stimulus-CS), is repeatedly paired with

a standard

stimulus (unconditioned stimulus-UCS) that elicits a standard response (unconditioned response-UCR), the novel stimulus will come to elicit a highly similar or identical response (conditioned response-CR). In this manner, new stimulus-response connections become established. Pavlov demonstrated this theory by pairing a ringing bell with a dog's food; after time, the dog would salivate in anticipation of the food when he heard the ringing of the bell alone. b. Classical conditioning is believed to play an especially important role in the development of emotional reactions to given situations and in the origin of common medical phenomena such as office-produced hypertension.

thinr

Pavlov's dog (and vice versa)

r6s iliBfrcal

Classical conditioning

c. Many behavioral theorists believe that phobias develop through classical conditioning. For example, if an individual had a frightening experience on an airplane, the fear might generalize so that any stimulus associated with flying, such as the sight or sound

Human Development and Sociocultural lssues

ofan airplane, comes to provoke severe anxiety. The phobic avoids re-exposure to flying even though additional experience with airplanes might alleviate the anxiety. Avoidance of the feared object perpetuates the phobia.

2. Operant conditioning is based on the relationship between a response and the consequences that follow that response. New behaviors can be acquired through shaping, a process in which successive approximations of a desired response are positively reinforced. Reinforcement is central to operant conditioning. There are primary and secondary reinforcers and reinforcement can be positive, negative, or aversive. a. Primary reinforcer is something that is normally rewarding food, water, sex, absence of pain, etc.

to the person, such as

b. Secondary reinforcer is something that the person has learned is important, such

as

grades, money, etc.

c. Positive reinforcer is something that the person will work to get. For example, students may study to get an "ll'for a course. Negative reinforcer is something that the person wants to get rid of. For example, a teenager may finally take out the garbage to stop his mother from nagging him. More importantly negative reinforcement in the form of removing pain is the basis of all successfi.rl medical practices. If a physician is not good at this form of behavior modification, they will not have a successful practice. d. Aversive reinforcement. Aversive punishment behavior is often confused

with

nega-

tive reinforcement. Aversive punishment is the use of something unpleasant (e.g., pain, nausea, hostile criticism) to suppress a given behavior. It is important to note tiat aversive punishment does not stop behavior; it only inhibits the behavior in the presence of the person who is delivering the punishment.

e. Extinction.

f.

If a behavior is no longer reinforced, it will

disappear.

Reinforcement schedules

(1) If a person is rewarded every time they emit a given behavior, they will soon become satiated and stop the behavior. To avoid this, reinforcement can occur on a partial basis. Note: Behaviors established under partial reinforcement are the most resistant to extinction. Partial reinforcement can be viewed as consistenry of child disciplinary approaches by parents. That is, if a child can sometimes "get away with something they like to do," they will continue to do it.

(2) Partial schedules can be

based on the ratio of the number of times a person has to do something before they are rewarded or based on the amount of time that

must go by before the reward appears. They can also be fixed events or variable events. For example, fixed interval means equal amounts of time must go by before the reward can be attained (e.g., narcotics administered every 4 hours); variable interval means sometimes only t hour must go by, sometimes 3 hours, and so forth before the narcotic is available. Fixed ratio means a given number of behaviors must be done before the reward is available (e.g., the child must ask the mother three times before she'll give him a cookie). Variable ratio means sometimes a behavior is rewarded the first time, sometimes the third, etc.-very characteristic of gambling behavior. 3. Behavior and personality. Behavioral theory differs from other approaches to personality in its emphasis on overt behavior. Whereas other theories use behavior to make assumptions about the underlying personality structure, behavior theory focuses on the behavior itself as an indication of the person's personality. The theory states that a person's behavior is determined by the social and physical environment and by the individual's learning history. If a person behaves in the same way in two situations, it is

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because the situations are perceived as similar. then a different response would occur.

If two situations

are viewed as different,

4. Behavioral theory and psychopathology. Behavioral theory holds that psychopathological behavior is learned by the same processes as normal behavior. That is, abnormal behavior is controlled by environmental stimuli, reinforcements, and punishments. Abnormal behavior is therefore not viewed as qualitatively different fiom normal behavior but as a response to an improperly learned behavior.

E. Cognitive theory differs from behavioral theory in postulating the existence of mediating factors that occur between stimulus and response. The cognitive model posits that our thoughts lead us to react to environmental stimuli in particular ways. In other words, thoughts control feel ings.

F. Observational learning. Observational or social learning theory posits that behavior observed in another (e.g., parent, sibling, or peer) is imitated. This is the concept of modeling and encompasses the entire area of how parents and peers have influence on a child's developmental behaviors.

ln a Nutshell Modeling or imitation is a major factor in the learning of social behaviors.

1. The behavior may be performed by the observer due to anticipation of reinforcement, often from observing someone else being reinforced for it (vicarious reinforcement). Or, the behavior may be acquired in the identification process with or wanting to be like or accepted by significant emotionally reinforcing people in the child's life.

2. In this theory, learning is achieved by watching others, although the observer may or may not immediately exhibit the behavior seen. Thus, there is a distinction between the acquisition of a given response (i.e., the observer knows how to carry out the behavior) and its performance (i.e., the observer actually carries out the behavior). Performance may be inhibited, for example, if the observer believes he will be punished for displaying the behavior. This may be the underlying principle behind child abuse, spouse abuse, and elder abuse. That is, the abuser was abused as a child; however, physical retaliation at that time was not possible due to the relative physical prowess of the abuser. As the child matures physically, having learned earlier by observation that "big or strong people" physically abuse "smaller or weaker people," the grown up child begins to abuse others. G. Moral development. Kohlberg divided moral development into a stage-wise progression. It is important to note: (l) that individuals can become fixated at a given level and not develop further; and (Z) because morals derive from a collective set of data that a group of people agree upon, different groups of people may in fact have different morals that can be in conflict with each other. These moral differences enter into the practice of medicine and are discussed in the Medical Ethics chapter. 1. Preconventional level

l. The orientation is simply toward punishment and deferring to power. The child is simply avoiding some punishing consequences of given behaviors.

a. Stage

b. Stage 2. The person is focused on satisfiing his own needs and, occasionally, those of others. For example, in early adolescence when sexual exploration begins, it is not unusual for the individual to be focused on the issue of feeling good and bragging about what they did with whom, without thinking of the consequences to the person about whom they are bragging.

2. Conventionallevel

3. Kohlberg refers to this as the "good boy-good girl" stage, where the individual is adapting his/her behavior to get approval from his significant others. Obviously, if the person's significant other network encourages socially appropriate

a. Stage

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Human Development and Sociocultural lssues

in an overall socially acceptable manner. However, if the approval is for antisocial behavior, then overall social deviance results.

behavior, moral development proceeds

b. Stage 4. In this stage the orientation is toward authority and maintenance of the social order. Obeying all the rules set forth by the important group is the central theme. Again, the relevant issue here is what set of rules is deemed important. If it is the rules of the overall society, then no problems develop. However, if the rules are of a subculture that is at odds with the overall society (e.g., gangs, organized crime, militia movements), then adaptive problems develop. 3. Postconventional level a. Stage 5. Social-contract orientation means the individual enters into and honors binding agreements and general laws/rules of the overall society (e.g., don't steal, don't lie, don't kill, etc.).

b. Stage 6. This stage deals with issues that are over and above social rules noted in Stage 5. These are universal principles of justice, reciprociry and equality of human rights. These principles may require that overall rules important in Stage 5 be broken. For example, if one person hides another from danger, and the person representing the danger asks where this individual is, it is necessary to lie in order to preserve this individual's life.

NORMAT HUMAN DEVETOPMENT: BIRTH TO SCHOOT AGE A. Emotional development 1. Facial expressions. Low-intensity, spontaneous smiling begins within several days after birth and disappears by 3 months. Smiling at any face occurs by 2 months, followed quickly by smiling only at familiar faces and when pleased. By 3 months, infants can imitate facial expressions; they laugh by 4 months.

2. Crytng occurs from birth. It expresses pain, hunger, wetness, cold, and fatigue. Parents can often associate the type of cry with the cause. Crying peaks at 6 weeks and is most frequent from 4-6 prr.r. "colic" is crying more than 3 hours/day, more than 3 days per week. The cause is unknown, but air trapped in the gastrointestinal tract is suspected. Colic usually spontaneously resolves by 4 months. Treatments include holding, avoiding overstimulation, and antispasmodics. 3. Normal anxiety a. Stranger anxiety is normal between 5 and 9 months. It is triggered by confrontation with unfamiliar people. Adults are more likely to produce this reaction than are children.

b. Separation anxiety is also normal during 10-18 months of life. It occurs when the infant is separated from "mother." It also is normal for the first day of entering school or starting a new school. c. Having a favorite object that is comforting (e.g., a teddy bear) is seen in over 600/o of US children from 2 months to 2 years of age. This "transitional object" is usually discarded by age 4, when the transition from dependence on the mother to independence is more complete.

4. Differentiation of emotion. The newborn expresses undifferentiated excitement during active periods. By 2 or 3 weeks, this has been differentiated into two specific emotions: distress and delight. By 2 or 3 months, distress has differentiated into fear and anger, whereas delight has differentiated into joy and affection.

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Note Fear knows what

it is scared

of; anxiety does not.

Note Anger results from getting goal-directed behavior blocked or frustrated.

Note Sadness results

from loss.

a

a. Fear and anxiety are intimately related. Fear is the physiologic reaction that is experienced when there is threat of injury, regardless of whether the threat is real or imagined. Anxiety is the same physiologic reaction, but the person does not know what the threat is. Anxiety conditions are associated with three neurotransmitter systems: NE 5-HT' and GABA. This distinction between fear and anxiety is very important to understand because anxiety underlies many of the psychopathologies that are treated by mental health professionals. In many instances, converting anxiety to fear is part of the therapeutic process ("making the unknown known") because once the threat is recognized, the person can address it appropriately. b. Anger or aggression is an important emotion because it is the result of basic drives being blocked. The aim of the anger or aggression is to remove the agent that is blocking the attainment of the object of the drive.

c. Sadness is the emotional accompaniment of loss. There are losses in life, and sadness is a normal expectation of such losses. Sadness is self-limiting, and the person usually accommodates to the loss. One of the biggest challenges in medical practice, as well as in everyday life, is distinguishing sadness from depression. Depression is a psychiatric disorder that has a syndrome-level diagnosis. Depression and sadness are not synonymous. d. There is continued differentiation of emotions throughout infancy. Until by the third year, anger, envy, jealousy, and disappointment are clearly represented. Emotional

development follows a U-shaped curve of development such that many complex emotions in adulthood have their roots in infantile emotional experience. e. Stress. Stress is not a true primary emotion. It is best defined as felt pressure or tension that is indicative of homeostatic disequilibrium. When a person is experiencing stress, they characteristically release adrenaline. Note that when pregnant women are experiencing stress, their blood levels of adrenaline are increased, and, consequently, the embryo or fetus is bathed in these increased levels. It is believed that these increases set a biologic level of activation for the fetus that is carried into neonatal and postnatal life. (

1) Psychosocial stress has a tendency to result in compromised and compromising behaviors. Examples include depression, gastrointestinal disorders, and maladaptive self-medication such as smoking, drinking, and recreational drug use.

(2) There

is a curvilinear relationship between amounts of stress and human performance. Small-to-moderate amounts seem to be motivating and have an efficacious effect. Higher amounts tend to interfere with efficienry, and the quality and quantity of results are compromised.

(3) Stress management. Life is stressful and gets more so as the demand for more and more efficient production increases. Managing stress requires a lifestyle that recognizes the effects of stress and tries to minimize them. This lifestyle includes

the following:

(a) (b) (c)

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iliBticat

Self-care. Regular diet, exercise, recreation, minimizing recreational drug use.

Situation management. When confronted with a stressful situation, study the circumstances, plan how to deal with the situation (e.g., behavior and appearance), and plan rewards for successful completion of the tasks. People who deal well with stress are mature people who don't indulge in a great deal of immature defense mechanisms (denial, repression, etc.).

Human Development and Sociocultural lssues

B. Social development 1. Social milestones in infancy include the social smile and the attachment bond between the mother and the infant. It is believed that the bonding begins at birth and is firmly estabiished by the sixth month. Mother-child bonding promotes survival by keeping the infant close to the mother. Behavioral indices of attachment inciude the infantt foiiowing the mother with his eyes and limbs, clinging to the mother, smiling at the mother, or signaling fright and the need for maternal comfort. The attachment bond profoundly aft'ects emntional growth and emotional patterns in adulthood. If this bonding does not occur in the lirst years of life, there is serious potential for the child not to be able to bond to others as an adult. 2.

At 18-22 months, the infant

gains sufficient mobility and hopefully enough sense of autonomy to be able to stray from the mother. During the second year of life the child enters the "terrible twos," during which the child asserts her independence from the mothering figure(s) by refusing to comply with directives. By the middle of the third year, the child plays alongside others while ignoring them in what is known as parallel play. It is not until the beginning of the fourth year that children begin to play cooperatively.

C. Motordevelopment

l.

Early development. T'he grasp reflex is present at birth and disappears by 2 months. The use of the arrns foliows a proximal-to-distal progression, so that the voluntary grasp at 4 months occurs after voluntary reach. There is also an ulnar-to-radial progression: the infant picks up objects on the little finger side at 4-5 months and with the thumb and index finger at 6-7 months. Pronation precedes supination, and grasp precedes release (seen at 9-10 months). Hand preference emerges between I and 3 years.

2. Motor development milestones. Infants can roll over by 2-4 months, sit without support by 5-7 months, pull themselves to a standing position by 6-10 months, walk forward with assistance by 12 rnonths, and walk alone by 13 months. Toilet training is not possible before the age of 18 months because the long nerve fibers have not myelinated, and sphincter control is not possible. Although toilet training is gradually accomplished, it is usually completed by about age 4. D. Language development 1. Linguistic milestones. Milestones include the categorical perception of speech sounds at I month. Thus, infants, like adults, are able to divide the sound spectrum of language into phonemes, the smallest units of sound in language. Categorical perception is essential for language comprehension and production. At 34 months, babbling appears, but it drops out when the first words appear at 10-15 months.

2. When children first talk, they echo the last few words that are said to them. This echolalia may persist until age 2. If the child grows up in an environment in which little attention is given to her, or if the environment is devoid of stimulation, talking may be seriously delayed or impaired. By 24 months, infants are able to pair words together into phrases. At this point, the average child has a vocabulary of approximately 200 words. Their multiword utterances herald the beginning of sentence formation. Words are now learned rapidly in one or two exposures. By age 3 they can assemble three-word sentences, by age 4 they can assemble 4-word sentences, and by age 5, the child has almost fully mastered adult syntax. 3. Associated milestones. Along with language, other symbolic activities develop, such as mental imagery (e.g., daydreaming) and symbolic play (e.g., representing a horse by using a broom handle). By age 2, the infant is able to internalize physical activity as mental activity.

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E. Environmental influences. There are many environmental factors that can directly or indirectly affect the deveioping embryo or fetus.

l.

Maternal diet is important to the development of the fetal nervous system. A deficiency of folic acid has been implicated in increased risk of neural tube defects.

2. Smoking while pregnant can lead to infants with lower-than-average birth weights and birth defects. Children may demonstrate difficulty in school and may be hyperactive. 3. Alcohol can have a wide variety of effects depending on the trimester and amount of exposure. The most extreme form of disability is fetal alcohol syndrome (FAS), which can result in mental retardation and physical abnormalities of the face, heart, lungs, extremities, etc.

4. Cocaine use during pregnanry can result

in mental retardation and small-for-birth-

weight children. 5. Recreational drugs can produce addiction in the newborn. Newborns may show signs of a general withdrawal syndrome, such as irritabiliry trembling, and vomiting, regardless of the drug to which they are addicted. Long-term f
6. Radiation exposure can cause chromosomal abnormalities or spontaneous abortion. 7. Rubella virus can pass from the mother through the placenta to the developing embryo, causing deafness, cataracts, heart defects, autism, and mental retardation.

8. Sexually transmitt€d diseases such as syphilis may produce spontaneous abortion or physical and mental abnormalities in the child. 9. Maternal age. Women over 35 years of age are at greater risk of bearing a child with chromosomal abnormalities such as Down syndrome. Mothers under 15 years of age have a greater risk of stillbirth, spontaneous abortion, and premature birth. Premature birth children are at great risk to develop alarge number of both acute and chronic physical and emotional problems. 10. Emotional stress. Women who are overly tense during the course of the pregnancy tend to have more difficult labors and deliveries. Their newborn infants tend to cry more and

show more irritability.

F. Child-rearing 1. Divorce. Approximately 40-50o/o of all children born in the United States will live for at least 6 years in a single-parent household. a. Emotional effects (

I

) Children

are aiways affected by the leaving of one parent, regardless of the emo-

tional conflict caused by the divorce process. Children under age i I tend to blame themselves for the divorce and mourn the lost parent.

(2) The effects of divorce are worse if the parents speak ill of each other and try to turn the child against the other parent. Children emotionally adfust better if parents refrain from accusations and remain in contact with their children. However, a conflict-ridden intact family may be more deleterious to children than is a stable home in which parents are divorced.

(3) Likewise,

a rejecting or inaccessible parent within the family can be more detrimental to the child's development than the absence of a parent because the child can mourn the loss of an absent parent and get on with life. A continuously rejecting or inaccessible parent continues to have the rejecting effect on the child.

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Human Development and Sociocultural lssues

In both

cases, divorce can be a positive solution to a destructive family relationship. Nevertheless, once the divorce occurs, only a small percentage of children

feel relieved.

(4) Boys show

a greater increase in the incidence ofbehavioral disorders and problems in interpersonal relations after divorce. This may reflect the fact that 90o/o of all children of divorced parents live with their mother. The loss of the father is more stressful for boys perhaps because boys need an appropriate role model.

b. Common behavioral responses to divorce

(1) Children 2t/2-5years of

age often exhibit sleep disturbances, enuresis, moodiness, and anxiety, and frequently crave physical contact.

(2) Children 5-8

years of age experience bereavement and feeling rejected. They often fantasize about reconciliation and show a decline in school work. They may harbor a fear of being thrown out of the house, especially boys whose fathers have left the house.

(3) Children 9-l2years ofage show feigned nonchalance or a decline

anger. They often have

in school performance and experience peer problems, such

as develop-

ing close relationships.

(4) Adolescents tend to be depressed and may attempt suicide or

use

illicit drugs or

alcohol. They may exhibit changes in their sexual activities.

2. Children born outside of marriage and raised in a single parent home. These children have three times more behavioral and emotional problems than the average child. They also exhibit triple the level of teenage sexual activity. Young women in this category have

twice the probability of having a child out of wedlock, and young men have twice the probability of becoming a threat to society, engaging in criminal activities, and eventually ending up in jail. 3. Adoption. TWo to three percent of infants are adopted, 50% of them by relatives. Multiple foster home placements before adoption or adoption after age 6 months increases the risk of behavioral problems after adoption. Adopted children should be told about the adop-

tion

as early as possible.

4. Hospitalization. Nearly 30o/o of children are hospitalized at least once. Separation from parents, contact with strangers, the discomfort of medical procedures and of being ill, and medications may all affect behavior. Distress at hospitalization is greatest between 6 months and 4 years. School-age children often make friends with staffmembers and other child patients. Age-appropriate education before the hospitalization has been shown to minimize adverse behavioral responses. Flexible visiting hours, rooming-in by parents, and parental participation in care also help minimize behavioral problems. 5. Television. The effect of television on children may be related to the amount of violence that parents permit children to watch. Nearly all American children watch TV, with the average viewing time between 2-6 hours per day. By graduation from high school, it is estimated that the average American child has seen 18,000 televised murders. There is a stronger correlation with younger children than with older children between the amount of viewing time and subsequent aggressive activity. Positive role models on TV may exert beneficial effects on children. For example, preschool children who regularly view educational Programs on public television, such as Sesame Street, have shown gains in

IQ scores.

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6. Effect of parental behavior a. Observational learning. Children learn a great deal from parents and older peers simply by observing and then imitating their behaviors. Children are not necessarily reinforced for imitating the correct behaviors by parents; rather, they copy adult behavior because the adult model seems to be regarded by them or because the child receives

reinforcement through alignment with a parental figure.

Note The abused child usually defends the parent and views the abuse as a form of "love" and caring.

b. Child abuse. The largest number of cases fall in the neglect category, followed in order by physical abuse, sexual abuse, and emotional abuse. Prevalence in female children is slightly higher than for male children, and roughly 600/o are under the age of l0 years.

(1) The abused child is usually perceived as temperamentally and behaviorally different. The abused child is often in foster care. The child often defends the parental abuse and views the abuse as some sort of "caring" from the parent. They view the parent as having no choice. Abused children are more likely to be arrested between the ages of 9 and 12. Abuse also predisposes children to later develop serious mental disorders like post-traumatic stress disorder (PTSD).

(2) Abusing parents were often victims of child abuse. However, it is important to know that all abused children do not grow up to be child abusers. Often, the parents view the abuse as their "right" because the child "belongs to them," or they get into competition with the child for the other parent's affection. Many parents do not know any other way to discipline their children because the abuse was what they learned from their parents. Although abuse occurs in all socioeconomic groups, poverty, unemployment, parental antisocial personality disorder, alcohol use, and family discord and isolation are frequently seen as contributors.

(3) Physicians are legally required to report suspected abuse held liable if they comply with the law.

cases and cannot be

ADOTESCENCE Adolescence begins with puberty and ends in adulthood. Puberty usually begins earlier in girls than in boys and is beginning at younger and younger ages. This maturational disparity creates some interactional friction and discomfort between boys and girls. Teenage boys who physically mature earlier tend to be more self-assured and poised; earlier-maturing teenage girls tend to be less self-assured and more awkward. Adolescents undergo substantial development in cognitive ability, skilled motor abiliry social behavior, and sexuality.

A. Self-image. Adolescence is a time of great emotional turbulence. There are three main factors at work: 1. The emergence of secondary sex characteristics (pubic hair, development of the breasts in women, etc.) and issues of sex role identification

2. The task for adolescents is to attain autonomy from the family and replace it with peer group support. Expressions of autonomy include experimentation with sex, drugs, music, and clothes. 3. The adolescent is occupied with forging a personal identity or sense of self. Although in some ways the adolescent is seen as conforming to the peer group, often indulging in social and intellectual fads, in other ways the adolescent is very much concerned with establishing a personal and unique identity.

B. Suicide. Adolescents who encounter this tumultuous period lacking the coping resources of an adult are especially prone to suicide. Ln2002, suicide was the third leading cause of death in adolescents (accidents was the fust, and homicide was second). Girls are more likely to make

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suicidal attempts than are boys, but are more likely to be successfrrl in their attempts. Suicide can be prevented if suicidal tendencies are recognized early and especially if underlying psychiatric diagnoses are uncovered and treated. The family, the school, and the physician can each help by being alert to the needs of the adolescent who shows social withdrawal, poor school performance, depression, and despair. Thctfi.rl but direct questioning about suicidal thoughts is often in itselfa reliefto the suicidal adolescent. There is no evidence that questioning about or mentioning suicide increases the risk for suicide; most data suggest the opposite.

C. Drug abuse

l.

Many youths experiment with drugs of different types; however, a relative few develop regular use or abuse. Most adults who abuse drugs began their drug abuse as adolescents. The etiology of drug abuse is very complicated and differs from person to person. However, genetics, observational learning from parents and peers, media encouragement (e.g., advertising and marketing), social problems, environmental living conditions that foster drug use, and family living circumstances that are unbearable (e.g., child abuse), all coalesce to create etiologic and maintenance variables that result in chronic drug use.

2. Of particular concern are the effects of alcohol

use and smoking marijuana. Large numbers

of high school graduates report alcohol use and marijuana use (the estimates vary between l0 and 30olo). Alcohol has been implicated in a constellation of debilitating physical effects, including contributing to automobile and other vehicular accidents and suicide. Marijuana use has been associated with poorer performance, including slowed reflexes, apathy, dulled senses, and reduced driving ability. The affinity of the THC molecule for receptors in the hippocampus clearly establishes this recreational drug's ability to negatively affect memory.

ADUTTHOOD The major tasks of adulthood are finding a mate and establishing a family; selecting an occupation is an integral part of this. Financial security is paramount, and guiding the children in the family to self-esteem and accomplishment is a central goal.

A. Currently, people are experiencing rather significant changes in career paths and opportunities. With the increase in technocracy, increased educational and electronic skills are required, resulting in more people frequently changing jobs and many people taking parttime positions or temporary employment. Frequent job changing affects one's eligibility for medical and other benefits. This contributes to the fact that over 45 million Americans do not have health care benefit coverage.

B. Divorce is a key issue in adulthood. About 50% of first-time marriages end in divorce. C. Issues of spouse abuse are clearly an important part of the physician's health care experience with adults. Spouse abuse has been described as a phasic phenomenon in which a clear pattern develops over time.

l. In the first

stage, the abuser gives prodromal warnings of loss of control. The abuser becomes hostile, argumentative, accusing, and demanding of compliance with wishes. This can be equated with emotional abuse.

2. In the next

phase, the actual abuse event occurs in which the abuser erupts into uncontrolled punching, hitting, kicking, and sometimes cutting and shooting behavior. If the abuser enters this phase, there is little if anything the abused person can do to get the abuser's attention to terminate the event. The abuser is totally out of control. The abuser, however, reports that this behavior is an attempt on their part to communicate with the abused person.

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3.

In the last

phase, the abuser is apologetic and remorseful,

with behavior that

suggests

sincerity in the remorse.

4. If the abused person does not intervene forcefirlly with authority on the first episode of abuse, the abuse usually continues until it extends to the children. At that time the abused individual usually takes decisive action. Note Like abused children, some abused spouses view the abuse as a

form of "love" and caring.

5. Spouse abusers have the same characteristics as child abusers. They have often been victims directly or observed spouse abuse, have a restricted repertoire of communication (disciplinary) skills, and rigidly believe themselves justified in the abuse. Abused people have often grown up in a family of spouse abuse, so they do not see the behavior as aberrant. Note: The abuser can be either the husband or the wife, although abuse of the wife is more likely to be reported.

AGING America is becoming an elderly nation. Population pyramids in the 1950s had a large base of young people with a small percentage of the population at the top of the pyramid. Now the base is nnrrower, and the top is broader. This population distribution is problematic for public health and social welfare programs because it is taxation of the younger people that provides the funding mechanism for programs for the elderly such as Medicare, Social Securiry etc. This means that as the population ages, fewer young people are providing the fiscal resources for more elderly people.

Note Verbal intelligence does

not decrease with aging.

A. Intellectual correlates of aging. Cross-sectional studies comparing groups of people of different ages have shown steady declines in intelligence scores from 30 years on. Verbal scores decline less than performance scores on the Wechsler Adult Intelligence Scales (WAIS). However, longitudinal studies following the same group of people over a period of time have indicated that intelligence scores decline little if any up to about age 60 and then drop only slightly after that. It seems that response speed, memory span, and nonverbal reasoning are more dependent upon efficient CNS functioning than on education or experience and show some decline over adulthood. Crystallized intelligence scores, such as reading comprehension and vocabulary which are less dependent upon rapid CNS functions and are more dependent upon education and experience, remain steady or even increase, at least up to the age of 60.

B. Chronic illness and aging. Eighty percent of the elderly population have one or more chronic illnesses. Although people over the age of 65 represent abott I2o/o of the U.S. population, they consume

30olo

of the health care services.

C. Elder abuse. The abuse of elderly by persons their care takers, whether a family member or an employee of a care faciliry is an established fact. Virtually all the points made about child abuse and spouse abuse are true for elder abuse as well.

SOCPCUTTURAT ISSUES A. Sexuality

l.

Sexandgender a. Gender is defined as the biologic variables of a person. At conception, all embryos are female, and with the addition of selected factors, some female embryos develop into males. In general, the resultant chromosomal sex, fetal hormonal environment, and subsequent development of internal and external organs are all characteristically male or female. Such normal development is called "concordant." In a minority of individuals, however, development is "discordant," resulting in an intersexed individual.

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sodo.ulfu

Androgenital syndromes (a) Congenital adrenal hyperplasia in a chromosomal female leads to a fetal environment in which there is increased exposure to adrenal androgens. This results in the development of ambiguous external genitalia. The term

"pseudohermaphrodism" is used to distinguish it from "true hermaphrodism," in which gonads of both sexes are present. True hermaphrodism is rare. Androgenital syndrome females raised as girls exhibit "masculine" behaviors and frequently have little interest in traditional "feminine" behaviors such as playing with dolls. The prenatal exposure to increased androgens exerts a modifring effect on brain systems responsible for gender role behavior.

(b) Testicular feminization syndrome. A chromosomal male possesses testes, but his peripheral tissues lack androgen sensitivity. Normal levels of androgen do not produce a virilizing response, and development occurs along female lines, with the formation of normal-appearing female external genitalia and a blind-pouch vagina. The condition generally goes undiagnosed until puberry when menstruation fails to occur.

2. Psychological variables a. Gender identity. One's sense of oneself as male or female is a combination of genetic,

biologic, and environmental variables. Gender identity is difficult to alter after l8 months of age, and by 3-4 years it is completely consolidated.

Clinical Correlate Discordant gender identity is also called gender

identity disorder.

b. Gender identification or role behavior. Gender role behavior is influenced by environmental, biologic, and sexual factors. Most sex role behavior is learned from appropriate role models in the environment. That is, children learn how to walk, talk, sit, stand, etc. by modeling their behavior after their role models-usually the same-sexed parent. However, for some people there is no same-sex role model and they pattern their public behavior after the model available (an opposite-sexed parent); the result is cross-sexed behavior.

c. Sexual object choice. Same-sex arousal and emotional attachment may be seen in men and women whose biologic sex, gender identiry and gender role behavior are concordant. Homosexuality is not considered a mental disorder because for most homosexual people there is no attendant functional impairment. The etiology is not totally clear at this time; however, recent genetic studies on twins suggests a very strong heritability factor for both males and females. Homosexual behavior and homosexuality are different. In restricted same-sex environments (prisons, military, single-sex schools, etc.), homosexual behavior predictably occurs. However, when a heterosexual object choice is available, the homosexual behavior is discontinued.

of sexual response. Vasocongestion and myotonia characterize the sexual response in both men and women. Vasocongestion is involuntary, whereas myotonia may be either voluntary or involuntary. The entire physiologic sexual response, from the start of the cycle to orgasm, is approximately 3 minutes for men and 12-15 minutes for

3. Phases

women. a. Appetitive phase is the initial phase of desire influenced by personal preferences about

partner, situation, and method. b. Excitement phase consists of pleaswable feelings, flushed skin, and increased respiration, heart rate, and blood pressure.

(1) In men, the corpora

cavernosa and corpus spongiosum in the penis distend with blood due to parasympathetic nervous system input, resulting in an erection.

Note The late$ $udies sugge$ that

male homosexuality

is twice

as prevalent as female

homosexuality (6 versus 3Vo).

Behavioral Sciences

(2) In women, the

Note

may become erect, the inner two thirds of the vagina begins to elongate, the

cervix elevates, and the vaginal barrel enlarges and extends. Vasocongestion results in vaginal lubrication within 15-30 seconds of stimulation, and the labia minora and majora enlarge with blood.

Continuous genital epithelial

stimulation is necessary and sufficient for the

completion of the human sexual response cycle.

breasts increase in size, and the nipples become erect. The clitoris

c. Plateau phase is characterized by the intensification of the changes seen during the excitement phase. (

is reached, and fluid that originates from Cowper's gland may before ejaculation. This fluid contains sperm as well as infectious be discharged HlV. agents such as

1) In men, firll erection

(2) In women, the outer third of the vagina

enlarges, the breasts continue to enlarge,

and the area surrounding the nipple enlarges. The clitoris retracts under the hood just prior to orgasm. There is marked myotonia at this point. d. Orgasm/ejaculation. There is a difference between orgasm and ejaculation, although in most people they are simultaneous. Orgasm is the psychological experience of the feeling of emotional well being associated with this stage of the human sexual response cycle. Ejaculation is the physiologic tension relcase and reduction. The importance of the distinction is apparent for those people who have cord lesions that do not allow them to experience both simultaneousl.v. In the cord lesion patient, there may be excitement and ejaculation of which the person is unaware unless they see it. Often, however, they classically condition themselves to experience an orgasm by an alternate stimulation route (e.g., visual, tactile, etc). (

1) In men, a further increase in heart rate and blood pressure occurs. The inevitability of ejaculation is experienced as the vas deferens, seminal vesicles, ejaculatory duct, and prostate contract. During actual ejaculation, the periurethral muscles, ischiocavernosus, and bulbospongiosus muscles contract rhythmically. Seminal

fluid is expelled explosively from the urethra; slow nonexplosive contractions follow immediately. A refractory period during which erection cannot occur folIows the contractions.

(2) In women, the uterine muscles and muscles in the outer third of the vagina contract simultaneously; these are experienced as the intense pleasure of orgasm and may be followed by slow irregular contractions. There is no refiactory period, hence, women can experience multiple orgasms. e. Resolution phase is characterized by a return of the heart rate, blood pressure, and respiration rate to normal.

(1) In men, the penis immediately

decreases

to one half erect size and to baseline

within t hour. (2) In women, the breasts return to normal

size

in 5-10 minutes and the clitoris in

10 seconds. Vasocongestion gradually wanes. As the vagina returns to normal size, semen collects in the cervical os; the cervix dips into the pool as it descends to its resting position, maximizing chances of fertilization.

4. Common issues in sexuality a.

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Menstruation. Other than religious taboos or personai preference, there are no specific contraindications to intercourse during menstruation. There is some unproven concern, however, that the risk for endometriosis is higher amottg those couples who regularly engage in intercourse during menstruation.

Human Development and Sociocultural lssues

b. Pregnancy. There is no risk to the mother or fetus from intercourse with one orgasm during the first two trimesters. Intercourse with no orgasm until the 34th week of an uncomplicated pregnancy is also safe. After the 34th week, intercourse may be uncomfortable, and orgasm may slightly increase the risk of premature labor. Sex should be avoided if the pregnancy is associated with vaginal bleeding. After delivery, intercourse can be safely resumed, usually after 6 weeks. Resumption depends on the female's

comfort. 5. Age spectrum and sexual response a. Normal development. By age 5, the majority of children have developed the physiologic capacity for orgasm. Puberty occurs earlier in girls than in boys and is beginning earlier today than 20 years ago. Almost all teenage boys, and the majority of teenage girls, masturbate. After age 50, excitement occurs more slowly, the imperative toward orgasm is decreased, orgasm is shorter, and resolution is more rapid. b. Elderly (

Note

1) In men, the erection may not be as firm, and the plateau phase lasts longer. They may not experience a sense of inevitability of ejaculation and force of expulsion, the amount of seminal fluid released is less, and the refractory period is longer. In men, vascular erectile impotence (e.g., atherosclerosis), neuropathic impotence (e.g., diabetes), and chronic painfirl conditions (e.g., arthritis) are common sources of decreased sexual activity.

The be$ predictor of whether an elderly person will continue to have sexual relations as they age is the presence of a partner.

(2) In women, lubrication occurs more slowly, and the vagina loses much of its elasticity. The labia swell less, and there are fewer uterine contractions during orgasm. In women, sexual inactivity over an extended period of time may lead to changes in the vagina, which occur to a lesser degree in sexually active older

women. Sexually active older women have thicker vaginal mucosa with more rugae than do inactive older women. Masturbation may also reduce the rate of change in women who are otherwise sexually inactive.

(3) Sexual problems. The most common

reasons for decreased sexual activity in the elderly are no available partners and illness. Past sexual activity is the best predictor of sexual activity in old age. Some common medical problems can lead to decreased sexual activity in elderly persons.

6. Sexual dysfunction a. overview. Sexual dysfunction may be primary (as when orgasm has never been achieved), situational (when the problem occurs in specific circumstances or with a specific partner), or random (as when achievement of orgasm is infrequent and unpredictable). Alcoholism, or even minimal alcohol and other recreational drug use, may cause impotence. Many diseases that lead to fatigue, including anemia, cancer, and improper diet, may present as sexual dysfunction. Depression also reduces libido in all age groups. Many medications cause impotence, including antihypertensives (e.g., beta-adrenergic blockers), antidepressants, neuroleptics, digitalis, anticonvulsants, histamine, Hr-receptor blockers (e.g., cimetidine), and cholesterol-lowering

drugs (e.g., clofibrate). b. Problems in the appetitive phase

(1) Notably reduced or absent interest in sex (hyposexuality) as well as problems in other phases of the human sexual response rycle often result from the "key psychological triad": problems in the relationship, performance anxiety (e.g., confusion of enjoyment with evaluation), or fear of the consequences of sexual intercourse (e.g., an unwanted pregnancy, anticipated pain

or

dyspareunia,

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acquiring a sexually transmitted disease, etc.). Hyposexuality may also result from depression, psychotic disorders (particularly schizophrenia), various medications, epilepsy, and chronic bipolar mood disorder. Acute mania can lead to hypersexualiry as can some frontal lobe medial orbital lesions.

(2) The paraphilias

are also disorders

ofthe appetitive phase.

These are described

in

the Psychopathology chapter. c. Problems in the excitement phase

(1) Male dysfunction includes the inability Approximately

40o/o

to attain or maintain an erection.

of all men experience this at some point in their lives.

(2) Female dysfunction includes inability to attain or maintain vaginal lubrication, difficulty relaxing the muscles of the vaginal barrel, etc. Approximately 600/o of all women experience this at some point in their lives.

(3) Causes of excitement phase disorders for both males and females include the "key triad": comorbid psychopathology, recreational drug use, fatigue, and certain medications. Excessive alcohol consumption is a common cause. Other causes include diabetes mellitus (Note: the effectiveness of the control of the diabetes is important), peripheral vascular disease, perineal surgery or radiation, renal failure, aortic occlusion at the iliac bifurcation (Leriche syndrome), peripheral neuropathy, multiple sclerosis, and spinal cord transection.

(4) Tfeatment includes correcting the

cause if possible, relaxation training, educahormone injections, penile injections, prostheses, or vacuum pump if neurologic or general medical conditions cannot be corrected.

tion,

sensate focus exercises,

d. Problems in the plateau phase

(1) Some people are able to become interested in sexual activity,

are able to excite,

but are unable to involve themselves in the pleasurable activity of sexuality. While this may be psychologically based (belief that one should not enjoy sexual behavior), these problems are often based in more physiologic issues.

(2) Primary sexual pain disorder (a) Dyspareunia is characterized by pain during coitus. It may be secondary to infection or endometriosis, tissue trauma, insufficient vaginal lubrication, hymenal tags, phemosis, or medications (e.g., some psychotropics). It occurs in both males and females. (b) Vaginismus is characterized by involuntary muscle spasms of the vaginal barrel that occur before or during coitus and make penetration impossible. They may accompany and be secondary to dyspareunia, but they may also occur independently and may not be experienced subjectively as anything other than an inability to achieve penetration. A pelvic examination is necessary to exclude pathology. Vaginismus can sometimes be treated successfrrlly by mechanical dilatation. e. Problems in the orgasmic/ejaculatory phase

(1) Premature ejaculation is when ejaculation occurs before the couple desires it. Primary premature ejaculation can be due to the "key psychological triad"; secondary premature ejaculation is often due to prescribed or recreational drugs. In many instances, the etiology is the failure of the man to learn mental control of the excitement and ejaculatory phases of the sexual response. The most effective treatment is the "squeeze technique" in which the head of the penis is squeezed when the man experiences ejaculatory inevitability. This stops the

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Human Development and Sociocultural lssues

ejaculation, can be repeated often without damage, and "backward conditions" the psychological control of the ejaculatory response. Note that there is no counterpart to this disorder in females.

(2) Female orgasmic disorder is delayed or absent female orgasm. Primary disorder is most likely due to how well the female feels she can trust her partner. Secondary disorder is most likely due to local genital pathology, endocrinopathy, medications, alcohol, or recreational drugs.

f.

Psychologic response to sexual dysfunction. Sexually dysfunctional couples usually present with avoidance of sexual behavior, including less physical intimary in addition to less intercourse, avoidance of discussion of sex, and, often, a general decrease in communication. Both partners may become removed observers during sex. The nondysfunctional partner may be disappointed and, finally, angry (although he or she may deny these feelings). Often, the anger is expressed in nonsexual situations such as fights about work, children, or trivial disagreements. The nondysfunctional partner may also feel personally responsible, inadequate, and unloved. The dysfunctional partner may feel shame and a sense of hopelessness that might prevent him or her from seeking help. Both partners may fantasize or actually engage in extramarital relationships, and guilt, as well as a further decrease in communication, may result. Masturbation may be employed and kept secret, causing additional self-degradation and anger. All of these things combined produce unhappiness, emotional isolation, and the eventual failure of the relationship.

7. Sex

therapy

a. Diagnostic evaluation. Twice as many sexual difficulties are identified if physicians ask directly rather than if they wait for the patient to initiate the subject. Questions the

physician should explore include: (

1) Current problem-onset, duration, and previous problems

(2)

Possible general medical causes, neurologic causes, medications, and alcohol and drug use

(3) Strength ofsexual desire (particularly as an expression ofdepression or relationship problem)

(4) Degree of partner's sexual functioning (5)

Sexual preferences: object and behaviors

(6) Quality of the relationship (7) Patient's view of the cause, although his or her account may not

be fi.rlly accurate

b. General approaches

(1)

in nonphysical physical but nongenital intimacy, followed by orgasm reached through means other than intercourse, and then, finally, to have intercourse. Along with this gradual exposure, the couple is encouraged to communicate with each other regarding their desires and pleasures. Sensate focus. Couples are encouraged to enjoy each other first

ways, then

in

(2) Psychotherapy. As the sensate focus treatment progresses, related issues may require treatment. c. Premature ejaculation. Specific techniques that have been successful in the treatment of premature ejaculation include the "stop-and-go techniquej' involving repeated arousal that stops just short of ejaculatory inevitability in order to build up control over ejaculation. The "squeeze technique" was described earlier.

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B. Death and dying

l.

Kubler-Ross stages of dying. It is generally agreed that the process of mourning or detachment has definable elements. In the Kubler-Ross model there are five stages in the dying process, although not all five stages are necessarily apparent in all dying patients. Note: The same process can be identified when a person is informed that they have a serious but not necessarily terminal disease. In this case, unless the person completes the stages, they often sabotage treatrnent. a. Denial. In the first stage, the individual refuses to believe the data. b. Anger. In the second stage, the person feels treated unfairly. There is consequent rage and anger over impending death, often displaced on the physician.

c. Bargaining. In the third stage, the individual accepts the inevitability of his death but bargains for more time, e.g., to postpone death to complete unfinished business. d. Sadness/depression. In the fourth stage, the individual mourns his pending death but becomes quiet and prepares himself for eventuality. e. Acceptance. In the fifth stage, there is acceptance of the impending end, without great unhappiness or undue joy.

2. Health care system and dying a.

A great deal of denial also exists in the health care delivery system. Often, the care givers do not tell the dying person that they are terminal and provide no platform from which a discussion of the issue can proceed.

b. End-stage illness requires specialized considerations.

(l)

Minimizing suffering with self-administered narcotic

systems. Physicians

typi-

cally undertreat patients who need narcotics.

(2) Hospice care is a team effort, usually involving

a nurse, social worker, psychia-

trist, primary care physician, or specialist. This care is often beneficial in

cases

of

prolonged illnesses, such as AIDS. Note: The term "hospice" means a number of different things. A hospice can be a physical place (e.g., ward in a hospital, a freestanding hospice facility), education (e.g., of caretakers, books, pamphlets), or a group of people who make periodic house calls, etc.

(3) When interfacing with people who

are chronically ill, it is not uncommon for the family, friends, and health care professionals to "wish the person would just go on and die." This thought causes guilt in these individuals, and when the chronically ill person does in fact die, their guilt increases over wishing the death (fantasied omnipotent murder).

(4) Advanced directives,

e.g., "living wills," are often ignored by physicians. Limited power of attorney given to a trusted relative or friend carries more legal weight.

C. Grief and bereavement

l.

Like death and dying, adjusting to the loss of

a

loved one, divorce, or object such as a job

has a step-wise progression. The stages are: a. Acute disbelief (similar to denial

in death and dying)

b. Grief work-Saying good-bye and re-establishing the present life without the lost person or object in the life c. Resoiution-Assuming

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a

guilt-{iee relationship with others that is rewarding and caring.

Human Development and Sociocultural lssues

2. Survivors can often accept the reality of the death by expressing their feelings and adjusting openly to the new environment without the deceased. Support groups and community and religious organizations are common sources of help to survivors. 3. Grief is different given the

age

and understanding of the person left behind.

a. It is common for infants who lose their mothering figure to withdraw and run the risk of dying if the mothering figure is not replaced.

Note Children under age 5 do not understand what death is. They

don't under$and that death is permanent until age B.

b. Young children who are only at Piaget's level of concrete thinking may try to joke about the loss or respond concretely, e.g., "The nice thing about someone dying is that everyone brings in all this really great food." They also tend to work out their distress by motor activity. That is, they become hyperactive and distractible. c. Adolescents often turn to maladaptive pleasurable activities such as recreational drug abuse, hypersexualiry and antisocial-type behavior (e.g., speeding vehicles, shoplift-

ing, fighting). d. Adults frequently develop psychophysiologic stress reactions (e.g., gastritis, angina).

e.

older adults, particularly the elderly, often withdraw and die within the year after their loss.

4. Abnormal grieving conditions include such acts as preserving the world as it was when the loss occurred (e.g., never changing the room of the person who is gone), constantly talking about the lost person years after the loss, etc. After a prescribed mourning period is finishei (6 months to 1 year for the loss of an adult; years if it is the loss of a child), this rumination about the loss tends to alienate other people, subsequently causing the grieving individual to withdraw from social contact. This isolation tends to heighten feelings of sadness, which may

turn into depression. D. Mental sets: beliefs, attitudes, stereotFpes, and prejudices. These issues are important because they set the groundwork for adherence and compliance to therapeuti. p.o..rr. 1. Beliefs are what a person accepts as true about a given situation. It has nothing to do with what the reality of the situation is. For example, if the patient believes a physician is competent, they are more likely to follow the physician's recommendations. However, if the patient believes the physician is incompetent, he will not foliow the therapeutic plan. Recall that delusions are fixed belief systems.

2. Attitudes are beliefs that have an emotional component added to them. Because of the added emotional component, attitudes tend to have more influence than do beliefs.

3. Stereotypes are attitudes that individuals have about an entire group of people. For instance, if the patient thinks all physicians are in medicine to get rich, they will evaluate the physician's recommendations from the standpoint of the secondary gain the physician may make from a given treatment recommendation. Likewise, if the patient believes the stereotype that all physicians are good, well educated, and know what they are doing, they are likely to go along with all recommendations and may not see a problem when lt exists.

4. Prejudice is a harmfril attitude toward a person or group of people. For example, some health care professionals have a prejudice against treating certain patients, be they elderly, young, a given ethnic group, homosexual, etc.

E' Adherence and compliance. Patients' adherence to the directives of the physician is usually less than what the physician believes. Basically, one third of patients will do everything the physician recommends, one third will partially comply, and one third will not comply at all.

l.

The doctor-patient relationship. Age, gender, socioeconomic status, ethnic group, and other demographics per se are not associated with adherence. It is important that the

In a Nutshell The doctor-patient relationship is the most

important factor in good adherence and compliance

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physician show respect, e.g., using titles (Mr., Mrs., Ms., etc.); talking with the patient, not at them; being on time, friendly and being sensitive to the patient's background.

2. Communication issues a. Regarding the diagnosis and treatment plan, the physician shoulo:

(l ) Solicit the patient's view of the illness.

(2)

Be sensitive to the patient's concerns.

(3) Give

a suitable explanation of the diagnosis and treatment plans.

(4) Solicit the patient's feedback about problems with the treatment plan. (5) Remember what he is told by the patient. (6) Tell the patient the most important things first. (7) Combine written and verbal information about the diagnosis and treatment. (8)

Tell the patient exactly how long to continue the treatment.

b. Throughout the diagnostic and treatment process, the patient's anxiety/fear levels must be maintained at an optimum level. With too little, there is no motivation to comply, and with too much, the patient goes into denial. Moderate amounts are motivating and helpful.

3. There are treatment issues that influence compliance. a. The treatment must have few side effects and minimaliy alter the patient's lifestyle. b. The regimen must be simple, with the patient having to take an action no more than four times per day that can be correlated with meals and bedtime.

c. The course of treatment should be as brief as possible (which underscores the reality that chronic conditions such as preventive cardiovascular treatment and intervention into chronic mental problems have poor compliance).

If the patient has limited means, the physician should arrange some mechanism to pay for the interventiorr.

d. Above all, the treatment must be affordable.

4. The increasing prevalence of HMOs has brought into national focus issues such as continuity of care with the patient's regular physician and the means by which a patient is referred to a specialist. F.

Subculture parameters 1. Definition. A subculture is a group of people who share a common language, similar dress, appearance (whether genetic or acquired), characteristic identifying behaviors, shared beliefs, attitudes, stereotypes and prejudices, living arrangement, etc. There are many different traits that make the subgroup identifiable.

€linical Correlate

2. Sick role. Persons who are ill tend to form a subculture or subgroup of individuals that

psychiatric disorder called

has specific attributes. These issues are significant not only because of tbe enormous economic impact through health care delivery and lost work, but also because attempts to enter the sick role subgroup may actually get expressed as psychopathology in the forms

factitious disorder.

of malingering and factitious illness. The most important elements of the sick role are:

The sick role is central to the

a. The rights of the sick person. When a person enters the sick role, they are not held accountable for their responsibilities (e.g., going to work, taking care of the household, etc.). On a chronic illness basis, they are excused from responsibilities that could exacerbate their illness.

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b. Obligations. The sick person must be motivated to get well. To do this they must seek technically competent care, and they must comply with the directives that are given to them. Also, they must not transmit their illness to others. c. The sick role does not lend itself well to stigmatic illnesses such as a sexually transmitted disease (e.g., AIDS), any trpe of mental illness (e.g., being depressed is not an acceptable excuse from going to work), chronic illnesses (e.g., most people with a chronic illness will be approached by their employer relative to continued employment), and mild illnesses where the person is expected to continue to work even though their production is not up to their usual performance. 3. Networks. Much of the health care that is provided to the sick comes from networks that are not in the traditional health care system. Family and friends actually provide the majority of care to people who are ill; this increases as the illness becomes chronic. Being in a network brings obligations. a. Family networks. In these systems, the members are closely tied to one another. This is particularly true if the family is nuclear (family of procreation) but remains true of extended famfies (more than one family of procreation linked by blood relations).

(1) The advantage of the family network

is that assistance is usually available. Living together or being related by blood seems to allow people to be more responsive to the needs of family members.

(2) The major disadvantage is that families tend to share information about certain conditions, and family-shared information is more likely to be believed than information conveyed by an "outsider" (e.g., the physician). If the information that is shared is misinformation, tlere will be difficulty countering the misinformation effectively. b. Friend networks. The major advantage of friend networks over family networks is that more independent sources of information are available to the person. However, there is also less assistance available because friends (compared with family) are more likely to place their own interests and needs before those of a sick friend.

4. Subcultureeffects

in a subculture predisposes the members to behave in a given manner. This includes having certain health care conditions and access to, use of, and compliance with health care.

a. Membership

b. In the United States, one of the major health care subculture issues is socioeconomic status (SES) and, most specifically, poverty or low SES (LSES).

5. Social mobility a. One of the issues of poverty is how one can move from a LSES to one that is higher or not impoverished. Upward mobility is dependent upon getting more education. To do so requires that the person defer gratification. Because of some of the issues facing LSES individuals, that may not be possible because of the presence of family responsibilities at a young age. b. An additional issue in social mobility is the reality of downward rnobility. The greatest risk for an individual drifting downward in the social hierarchy is for that person

to become physically disabled. If the individual cannot work and does not have a significant savings, the likelihood is that they will sink below the poverty level. The next greatest risk is for the individual to develop a mental condition that will affect his cognitive abilities or will make him appear to be "strange". In fact, the mentally ill form a subculture about which many people have stereotypes and prejudices. The

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chronically and seriously mentally ill are often found in LSES sections of metropolitan areas and represent the majority of the homeless population. This has often been mistakenly believed to be etiologic in the mental illness (i.e., LSES causes mental illness). However, the rnentally ill'drift" to LSES occurs because the demands for performance and conformance are less, the tolerance of unique behaviors is highea and there are social welfare systems (e.g., missions and shelters) that are not found in other parts of cities. 6. LSES effects and social factors. The following is a list of the realities of being in

a LSES

group.

of LSES usually marry at a younger age, which significantly compromises their ability to continue education and be upwardly mobile. The compromised educational status usually resu-lts in the individual being less communicative, relying instead on nonverbal behaviors and cues. Spouse, child, and elder abuse tends to be seen as a form of communication.

a. Persons

b. There is greater sex role differentiation in LSES groups, with males as financial providers and females responsible for child-rearing and home maintenance.

c. There is more parental death and a higher prevalence ofseparation and divorce. d. Persons of LSES usually have higher-risk occupations. These occupations have higher job-related accidents and death.

in turn

ofmaternal household heads than in the general population. This, in turn, limits the parental supervision outside the home, causing attendant problems of behavioral dyscontrol in the children.

e. As a consequence of the above, there is a higher rate

7. LSES and primary prevention of illness a. Because of the compromised educational achievement noted above, people of LSES have less formal knowledge about physiology, anatomy, and their bodies. b. As a result of the compromised education and poverry it is unlikely that LSES individuals eat a balanced diet. This is of particular importance for pregnant women.

c. Because of their limited financial resources, LSES individuals are less likely to obtain health checkups that cost money. Even when preventive health visits are provided at no cost, LSES individuals have fewer preventive health visits and less chance of receiving free vaccines. This may be a function of educational level. d. LSES individuals have inadequate dental care. They typically ignore their oral hygiene and wait until pain develops, at which time the tooth is extracted and not usually replaced. Replacement is seen as an unnecessary expense.

8. Illness prevalence and LSES a. LSES individuals tend to have more premature births and at younger ages than the general population. These premature births are at higher risk to develop different

types of psychopathology later on. There is also a higher-than-average infant mortality rate. Young children develop more speech problems, and LSES is also correlated with low self-esteem in children. b. Psychiatric conditions. There tends to be a higher prevalence of mental disorders in LSES individuals. This is a correlational statement. The following occur with higher frequenry: mental retardation, psychosis, antisocial personality disorder, schizophrenia, and somatic presentation of mental illness.

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c. General health conditions. LSES individuals experience a greater incidence of chronic illness, blindness, obesiry iung disease, tuberculosis, and sexually transmitted diseases. They are also victims of more accidents, homicide, rape, and robbery. As a consequence, they have a shorter life expectancy. 9. LSES and health care delivery. Persons of LSES have less access to good health care. Most of their health care is provided by government facilities. 10. LSES and illness behavior a. LSES individuals are more responsive to crisis than theyare to prevention. They wait until they are in discornfort before they seek care. When they are ill they are less likely to refer themselves to physicians, and they are more likely to attempt selfmedication or seek assistance from a "folk healer." As a consequence of these behaviors, the individual tends to be more ill when they finally arrive at physician-based health care facilities, and if thcy are hospitalized, they have longer stays.

b. LSES individuals as a group are less likelyto adhere to schedules. Therefore, they are often late for or do not keep appointrnents. Once they begin a treatment regimen, they are less likely to follou, the prescribed scheclule of medications and other recommendations. 11. Positive correlates ofLSIIS

to be more generous with their possessions and are more likely to share what they have with others. Their expression of gratitude to those who have assisted them is higher. LSES individuals are aiso more likely to report child abuse than are people ofhigher SES.

a. LSES individuals tend

b. Overali, people fiom LSES groups tend to handle adversity better than do those from higher SES groups. Suicide is not as prevalent in LSES groups. When temporary problems occur, LSES individuals are more experienced in dealing with the difficulties, viewing them as short-term instead of permanent. 12. Community organization and mental health a. Community clrganization includes such entities as public transportation, programs for the indigent, recreational facilities, support programs for people at risk (e.g., handicapped, elderly, chronically iil), fbrmal educationai opportunities, etc. As a commu-

nity begins to become disorganized, symptoms of dysfunctional behavior increase. Without strong comtnunity organization and npportunities that provide structures and organizations to assist people with life's difficulties, stress levels mount, and people who have been vulnerable become more dysfunctional. Increased rates of mental illness and substance abuse are common findings in such situations. b.

If environmental extremes

are encountered, one observes increased levels

of

stress.

These increased levels are cumulative and the people rvho have had more recent (within the past year) stresses are more likely to develop significant problems with such

behavior complexes as GI problems, mood disorders-particularly depression, infections, acting out (e.g., drugs, alcohol, antisocial activity), and anxiety reactions. 13. Occupational hazards. There is a long below.

list of high-risk occupations. A few are listed

a. Boxers and high-risk athletes: brain injury

b. Miners, construction workers, ktggers, farmers: accidentai death c. Restaurant workers, car mechanics: burns d. Coal miners: anthracosis

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Behavioral Sciences

e. Sandblasters: silicosis

f. Writers

and other high SES individuals: alcoholism

g. Policemen and firemen: suicide h. Nurses, warehouse employees: back injuries G. Violence. Violence is a very common phenomenon in the United States. Violence may be the result of I ) prolonged frustration of a person or group of people, causing the normal aggression to magnifr and explode; 2) alearned response from observing others perform violent acts be rewarded; 3) an entirely different phenomenon that has genetic, neurotransmitter and/or brain structure foundations; 4) personality variables that are acquired or inherited; or 5) other heretofore undocumented variables. Violence may be self-directed (suicide), other-directed (homicide and rape), familial (child, spouse, and elder abuse), or large-scale of natural or manmade design.

1. Suicide. Suicide is the ninth leading cause of death among adults and is the third leading cause of death among teenagers in the United States. It is also the second most preventable cause of death in the United States (lung cancer is the first). Although suicide as a relative cause of death is high in teenagers and young adults, it is much more likely to occur in people who are over 50. It is a permanent solution to a temporary problem. a. Biologic origin. Suicide, especially violent suicide, has been associated with low levels

of 5-HIAA, a serotonin metabolite. b. Demographics. There are over 30,000 completed suicides yearly in the Llnited States, with ten times as many attempts yearly. Of the total unsuccessful attempts, 100/o will eventually be successful. (

I

) Males are three times try more frequently.

(2) Whites

as

likely

are twice as likely to

as females

to commit suicide, although females

kill themselves than

Blacks.

kill themselves than are people who are

single,

(4) Suicide is more common among creative writers, artists, musicians,

poets,

(3) Married people

are less likely to

widowed, separated, or divorced. policemen, firemen, and female professionals.

(5) Suicide rates are higher in

U.S. Western Mountain states and in cities.

(6) Worldwide, suicide is more frequent in the spring, even though depression more common in the winter'

is

(7) Among depressed patients, suicide risk is highest in the year after the worst depression. genders, gunshot is the most common fatal method. When medications are used, antidepressants are the most common fatal ingestion'

(8) For both

(9) Suicide is a familial condition. That is, it tends to run in families, which may reflect the genetic contributions to mood disorders and alcoholism. c. The major risk factors for suicide are the presence of the depressive s;'ndrome and alcohol abuse. A third group at risk are those people who have disabling or painful chronic general medical or neurologic illness. d. Most important: The clinician's judgment that a person is suicidal takes precedent over any demographics.

reo ilitsbicat

Human Development and Sociocultural lssues

Homicide

In 2002, there were 16,204 (6/100,000) murders, down from the all-time high of 24,500 in 1993. Seventy-one percent of homicides involve firearms.

a. Demographics.

(

1) Males are more likely to act violently than are femaies, although violence by women is increasing.

(2) Males (3)

are more often murder victims than are fbmales.

Persons between 15 and 34 years of age have the highest likelihood of

killing or

maiming someone.

(a) The majority of homicides

are intraracial.

(5) Although random killing is increasing,

45o/o of killers know their viaims. The most corrunon situation leading to homicide is an argument over money or sexual partners.

(6) The likelihood of committing

a murder increases if the person has antisocial personality disordet is a substance abuser, and has a weapon (e.g., a gun) available.

(7) The likelihood of being killed or maimed

increases if the victim has antisocial personality disorder, is a substance abuser, has a weapon (e.g.,a gun) available, or is a police officer or mental health worker (2040o/o of mental health professionals have been assaulted by a patient).

b. Clinical assessment of violence. The best clinical predictors of violence are recent violent behavior; past violent behavior; the expression of anger, irritation, and agitation during a physical examination; as well as shouting, making verbal threats or threatening gestures, and having persecutory delusions (particularly ofbeing poisoned).

Note Alcohol is involved in over 500/o of all murders (either victim or perpetrator)

Violent death by accident is the fifth leading

cause of death in the United States, killing over 85,000 people per year. The rate has steadily decreased as automobile safety has improved. After motor vehicle deaths, violent deaths in the United States most frequently result from falls, poisoning, drowning, fires, and burns. a. Accidents are the leading cause ofdeath in individuals from l-37 years ofage, but the overall peak is in individuals over 74. Among children, the peak age is less than I year.

b. Males are twice as likely to suffer a fatal accident than are females, but males are only slightly more likely to suffer a nonfatal accident than are females.

Note

c. Fifty percent of fatal accidents are associated with drug and alcohol use. 4.

In

1995, aggravated assaults, exclusive of other forms of violence such as rape, totaled over a million cases. Methods included blunt obfects, hands, fists, feet, firearms, and

knives or cutting instruments.

Alcohol use is positively correlated with violence and, particularly, death by accidents.

violence expressed in a sexual act. In 1995 there were 97,464 rapes reported. One of four women report being raped at some time in their lives. Male rapists are usually young, naive, sexually immature, and poorly educated. The trauma of the experience is Iikely to have effects for some time after the actual event. Fear is often the initial response of a rape victim, as are guilt and shame. Due to the orientation of the culture, it is difficult for a woman to initially experience and express anger about the event. Often, the raping event is a psychosocial stressor that results in a psychiatric diagnosis of post-traumat-

5. Rape is

ic

stress disorder (PTSD), which is discussed Psychotherapy for the rape victim is recommended.

in the

Psychopathology chapter.

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I

Medical Ethics

All medical decisions are governed by ethical considerations. Ethical decisions involve two essential features. First, there must be a real choice among two or more possible courses of action. Second,

the decision cannot be made solely on the basis of empirical grounds because the individuals involved may attribute different values to each possible action. In certain medical situations, ethical guidelines are specific, as in what constitutes informed consent or when is a patient dead. 0ther situations are guided by ethics that are not codified but which are nevertheless widely accepted by

the medical profession. This chapter reviews the mo$ important ethical principles governing the oractice of medicine.

MEDICAT ETHICAI PRINCIPTES A. Utilitarianism or consequentialist position. The greatest good for the greatest number; the end justifies the means, etc. (e.g., triage of a large number of accident victims). There are two specific issues of ethical behavior regarding doing the greatest good for the greatest number:

l.

Benefiicence is the physiciant obligation to help the patient based on medical knowledge.

2. Nonmaleficence is the obligation to not do something that is harmfirl.

B. Deontologist position. Some actions and behaviors are simply wrong and should not be done. Autonomy of the patient is based in this position. This means that the physician is obligated to tell the patient the truth about the nature of his illness, even in the case of a terminal or potentially fatal illness. The patient therefore has the "autonomous" right to decide his treatment course.

CONFIDENTIATITY. PATIENT RIGHTS, AND INFORMED CONSENT A. Confidentiality. The physician must keep information contained in the patient's record confidential. In theory, only those individuals directly treating the patient have the right to read the record without the patient's expressed permission. In practice, however, others can and often do read it. 1. Patient access to his own records. Medical records belong to the service provider, i.e., the physician or hospital from whom the patient is receiving medical care. The patient has a legal right to access his own medical records.

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2. Physicians can be subpoenaed into court when testimony is relevant but should not reveal patient information unless he/she has the patient's permission or the patient is a danger to himself or others. 3. Physicians can provide limited information to insurance companies to justify treatment and payment (patient must have signed a consent).

4. Peer reviews are required.

5' Physicians must inform public health agencies about a communicable

disease.

B. "Patient rights" is a term that covers issues such as the right to treatment, the right to refuse experimental treatment, and the right to see medical records. Legal precedents have expanded the patient's right to participate in making treatment-related decisions; the physician who excludes the patient from the decision-making process may be in violation of the law. The issue of informed consent derives from this autonomy of the patient.

C. Informed consent

I' Steps required to obtain informed

consent. Informed consent is necessary when a proposed treatment is intrusive, has significant risk for the patient, or is of questionable benefit. Informed consent is also required in securing patient participation in research. The process of obtaining informed consent consists of two parts:

patient is provided with information concerning the risks and benefits of a proposed treatment and information about alternative treatments, including no treatment. The information must be presented in a manner that is comprehensible to

a. The

the patient.

In A Nutshell For informed consent. patient must be told:

. . . .

a

What is proposed Purpose or rationale Benefits and risks

b. The patient must make a voluntary choice to accept or reject the proposed treatment. Informed consent can be withdrawn at any time before the implementation of the treatment. The patient may also waive the right to informed consent, for example, by asking the physician to make the decision.

2. Conditions necessary for informed consent to be valid a. The patient must be legally competent. The patient cannot be a minor, cannot be declared mentally incompetent, and cannot be temporarily incapacitated, e.g., due to

alcohol use or emotional stress. Availability of alternatives

b. The patient must be able to understand his rights. Temporary incapacitation may interfere with the patient's ability to understand the informed consent process. c. The patient must give consent voluntarily. He cannot be coerced in any way, including being threatened with the discontinuation of treatment if consent is not given.

3. Exceptions to the informed consent process. There are two conditions under which the informed consent can be overridden: a. An emergency exists in which the patient is unconscious, not legally competent, or otherwise unable to give consent, and the withholding of treatment would be poten-

tially life threatening. The physician must seek out close relatives of the patient who can supply consent, but in such an emergency the physician treats assuming the patient would want the treatment if he understood the situation. This is termed

"implied consent." b. The physician has clear-cut evidence to support a belief that full disclosure regarding the proposed treatment would result in severe emotional distress or would cause the patient to become more ill.

re4 iliBtiical

Medical Ethia

4. Difficulties with the informed consent process. There are several areas in which difficulty n-ray be encountered in the process of obtaining informed consent. a. Disclosure of information. First, the patient is told about the benefits and risks of the proposed treatment. The physician has a duty to report any possible danger to the patient, but the amount of information that needs to be revealed to the patient is unspecified. b. Voluntary consent. Emotional upset due to illness may affect a patient's judgment so that consent is not truly voluntary.

5. Patients who are not legally competent to give informed consent

Note

a. Minor children. The parent or legal guardian of a minor child must give informed consent for treatment. Ethical conduct requires that the child's informed consent be sought as well because it is the child who is the actual patient. b. When the patient is incompetent, the spouse or close relatives can speak for him. If the physician has reason to doubt that these individuals are acting in the patient's best interests, he may seek another representative for the patient, such as the court or another relative. As a last resort, the physician may make the decision himself. If the physician is unsure about the patientt capaciry for example, when an elderly patient appears confused and forgetful, he should seek the consent of the patient's close relatives as well as the patient's consent.

"Emancipated Minor" Exception Children over age 13 living on

their own are given adult rights. Anyone married or in

the armed services is an emancipated minor. Having children does not make someone emancipated.

c. Note: Neither mental retardation, mental illness, nor emotional stress precludes obtaining informed consent. Patients in these categories may be legally competent, able to understand the informed consent process, and capable of making a decision.

6. Special considerations relative to informed consent a. Spousal consent is not necessary prior to sterilization or abortion. b. When a person's religious belief precludes all or some types of medical interventions, the courts have allowed adults to refuse treatment. In contrast, courts usually require children of parents with such religious beliefs to undergo treatment.

c. Sometimes, physicians do not inform patients because it is believed that to do so is not in the best interest of the patient. This is termed "therapeutic privilege." However, the general rule is to tell the patient everything. 7. Use of consent forms. Consent forms should provide specific information and be written in a simple language that the patient can understand. "Blanket" consent forms commonly used by hospitals have little or no legal effect.

DUTY TO WARN, COMPETENCE, CAPACITY, AND TERMINAT CARE A. The duty to warn and duty to protect 1. The physician must inform authorities about threats to third parties.

2. If a patient is considered a threat to kill himself or others, and if the physician cannot have the patient restrained or hospitalized, then he must warn the victim(s) and call the police.

3. TarasoffI and II decisions a. Thrasoff I. A physician must warn the potential victim his patient will harm the potential victim.

if the physician truly

believes

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Behavioral Sciences

b. Thrasoff II. Even though a physician must warn a potentiai victim, he must also protect his patient from harm from the potential victim.

B. Competence and capacity: the physician's role

1

Competence is a legal term, not a medical term. Only a court can declare competence.

2. Competence has different standards in different situations a. A person must understand the nature and consequences of an agreement to be con-

sidered competent to sign the agreement.

b. A person must understand the indications, alternatives, benefits, and risks of a treatment to be considered competent to authorize the treatment and be able to make valid decisions on the basis ofthat understanding. c. A person must be capable of not mismanaging funds to be considered competent to manage funds. d.

A person must understand the charges and be able to participate intelligently and cooperatively in his own defense to be considered competent to stand trial.

e. To be considered competent to be executed, a person must understand the nature of his crime and that the punishment for his crime is death.

3. Capacity is the ability to perfonn

a function. Testamentary capacity refers to the ability of a person to write a will. The person must understand that he's writing a will, know the extent

of his possessions, and know who is legaily entitled to inherit his

possessions. Being

mentally ill does not necessarily preclude the person from having the capacity to write a will.

C. Terminal care. Competent indivicluals have the right to refuse treatment even if such refusal results in death. Physicians must be able to comply with the patient's wishes. 1. Brain death. Patients are legally dead if certain clinical indications of an irreversible loss of function in the entire brain are present. a. A patient is generally considered brain dead if there is no cerebral function, i.e., no behavioral or reflex response involving structures above the cervical spinal cord. b. A patient is considered brain dead ifthere are no brain stem reflexes, including fixed pupils, no corneal reflex, no response to ice-water caloric, and no spontaneous respi-

ration during l0 minutes of apneic oxygenation. Circulation must be intact; spinal reflexes are allowed.

c. Additional criteria include a flatline EEG, absent brain stem-evoked responses, and absent cerebral circulation on angiographic exam.

2. Chronic vegetative state is preserlt when the patient is not brain dead but remains with no purposeful cerebral activity, with no chance of recovering consciousness. The issue is to continue or discontinue life-support measures. Physicians must honor any promises made to the patient when the patient was conscious and must also honor "living wills" that detail the patient's wishes regarding care. In the absence of promises or instructions, decision-making involves input from the patient's tamily, other physicians, and hospital representatives. "Living wills" are often ignored; the best chance for a patient's instructions to be carried out is to have a living will plus a designated healthcare prory with a limited power of attorney for medical decisrons. 3. Patientswhoarenotlegallycompetent.

Ifaterminallyill patientisnotcompetent,some-

one representing the patient's interests must evaluate the situation and decide whether to continue treatment. A judicial hearing may be held in such cases.

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Medical Ethics

4. Ordinary versus extraordinary me.rns of preserving life is a distinction adopted by the AMA code of ethics to determine when to continue treatment in terminal cases. Physicians commonly set up categories of treatment and label each as ordinary or extraordinary. Although this approach leads to more objective decisions, it fails to account for factors that may influence the decision, such as the patient's age or overall health. 5. Euthanasia refers to death that is hastened for the patient's own benefit, e.g., when the patient is in great pain. Euthanasia may include active interventions that lead directly to the patient's death or the withholding or withdrawal of life-sustaining measures. Some forms of passive euthanasia are not considered homicide under the law; e.g., failure to start a patient on a respirator would not be deemed homicide, but turning off a respirator may be considered as such. Passive euthanasia may be acceptable when the patient's terminal status is clear and the family gives consent.

6. Physician-assisted suicide is illegal in every state in the United States except Oregon. Many states have proposed legislation that would make physician-assisted suicide legal under certain circumstances: the patient is not depressed, multiple independent evaluations have been sought, the patient most likely has less than 6 months to live, and the patient has repeatedly requested assistance. Even if the legislation is passed, the physician-

Note Surrogates make decisions for patients based on one of three rules:

1. Subjective standard: What did the patient say he/she wanted?

2. Substituted judgment: What do we believe the patient would say if he/she

assisted suicide is always considered unethical.

COUId?

7. Do not resuscitate (DNR) orders. The patient asks that their life not be prolonged by artificial means. Such directives must be documented in the patient's chart.

3.

Best interest standard:

What would most people want?

MEDICAL-LEGAT ISSUES A. Documentation.

If it is not in the patient's

chart, it did not happen. The chart is the legal

record and must be maintained as such. at the scene of an accident to render care is not requiredphysicians are free agents. If the physician does stop, he must practice within his scope of confidence and he may not abandon the patient.

B. Good Samaritan issues. Stopping

C. Insanity defense. Physicians are sometimes asked to make a judgment relative to the legal concept of"insanity"; that is, was the person not responsible for his behavior secondary to mental illness.

L MacNaughton rule. The person couldn't know the nature and

consequences

of

his

actions secondary to mental illness. For example, a woman with schizophrenia drowns her child in a toilet at the bus station because auditory hallucinations told her to do it.

If a policeman

was standing at the person's side, could the person have controlled their behavior and not executed the act? This is the concept of uncontrollable passion.

2. Irresistible impulse.

3. American Law Institute guidelines supports the use of both of the above but adds that the individual cannot be a habitual offender. D. Respondeat superior. We are responsible for our trainees. The entire chain of command of a facility in which trainees are present is legally responsible for the actions of the trainees.

E. Rights and obligations of trainees

l.

Tiainees have the right to learn by supervised care ofpatients.

2. The quality of the care under supervision must be the same as quality provided by skillful practitioners. A trainee status is no excuse for poor quality care. 3. Patients must be informed of the trainee's status; the patient can refuse care by a trainee.

iliBhical tsl

Psychopathology

Previous chapters have focused on normal human behavior and how it develops. This chapter concentrates on the different types of abnormal behaviors as conceptualized by the Dlagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Indicated treatment approaches are

integrated into each of the diagnostic categories where appropriate. Note that a given type of treatment, which is described in detail the first time it is presented, is usually appropriate for many

different diagnoses. For example, the group therapies are appropriate in many diagnostic Sroups; however. thev are described onlv under schizophrenia,

BACKGROUND CONSIDERATIONS A. Definition: A given behavioral condition is only considered to be psychopathologic when that condition interferes with the individual's ability to function. Sometimes that inability to function is due to the person's gross distortion of reality (e.g., psychoses); sometimes it is because they are so dreadfi.rlly unhappy (e.g., neuroses); and sometimes it is because their behavior is so disruptive to others around them that society limits their freedom (e.g., personality disorders), etc. B. Many general medical conditions can present as a psychopathologic condition or can have emotional symptoms as a natural sequela. A few of the general medical emotional cclrrelates are:

1. CNS infections. Viral or bacterial infections (e.g., encephalitis, meningitis, and neurosyphilis) may affect cogr-ritive processes and emotions. The effects of encephalitis and meningitis are often only temporary but in some cases there is a permanent decline in intellectual skills as well as paralysis, tremors, seizures, deafiness, and speech disturbances,

2.Head, trauma. Both closed-head and open-head injuries may disrupt brain function. Concussion or contusion may lead to memory loss and disorientation. 3. Prescribed medications that commonly produce cognitive disturbance include L-dopa, digitalis, propranolol, cimetidine, indomethacin, reserpine, corticosteroids, and opiates. The list is endless, and the very young and old are most susceptible. 4. Toxins, such

as lead

and mercury, and recreational drugs may produce a variety of psy-

chiatric syndromes. 5. Nutritional deficiencies. Niacin, thiamine, and vitamin B,, deficiencies have been noted to cause intellectual deterioration.

6. Acute intermittent porphyria may present with frank delirium. 7. Acquired metabolic disturbances

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Behavioral Sciences

a. Uremic and hepatic encephalopathies can both cause delirium. In milder forms, cognitive impairment may be subtle and may mimic depression. b. Hyperglycemia can affect arousal, leading to stupor or coma.

c. Hypoglycemia may result in irritabiliry confusion, and stupor. d. Hlper- and hlponatremia can cause stupor or delirium. e. Hypercalcemia can cause depression and intellectual impairment.

f. Hypomagnesemia

may result in depression, irritability, and psychosis. It is common

in alcoholics. 8. Endocrine disorders a. Hypothalamic lesions characteristically cause profound changes in drive behaviors (i.e., hunger, thirst, sex) as well as disordered arousal and aggressiveness.

b. Pituitary tumors. Excessive prolactin secretion by a chromophobe adenoma may cause apathy, anhedonia, and a blunting ofpersonality. c. Hlpothyroidism may mimic depression or dementia. Hyperthyroidism may cause

irritabiJity and anxiety. d. Addison disease may cause depression. Cushing disease may cause a spectrum

of

mood disorders, occasionally with hallucinations and delusions. e. PheochromocFtoma may cause panic symptoms.

9. Stroke. Dementia, delirium, depression, and persona-lity changes are well recognized complications of strokes. These conditions are particularly likely if the stroke is in the frontal lobe, basal ganglia, or temporal lobe. 10. Brain tumors usually present with headache. Some slow-growing anterior tumors can cause depression, memory loss, and emotional lability. Frontal lobe tumors particularly may present with personality changes before the onset of focal neurologic findings. Temporal lobe tumors may present with behavioral changes attributable to temporal lobe epilepsy, or they may be expressed as primary integrated hallucinations (e.9., "uncinate fits" typical of tumors of the uncus often first appear as hallucinations of foul smells like feces, burning rubber, etc.). I

l.

Multiple sclerosis may produce

a

variety of mood symptoms and intellectual deterioration.

12. CNS vasculitides, most notably those secondary to systemic lupus erythematosus, may produce mood disorders or may produce an acute psychosis. 13. Cancer or chronic infection may produce a secondary depression. Although psychological reactions to illness play a part, the depression frequently precedes the patient's awareness of the illness. Pancreatic carcinoma commonly presents with depression. 14. Any serious general medical illness involving the compromise of vital functions may produce a delirium through such mechanisms as hypoxia, cerebral hypoperfusion, altered pH, and fever. In addition, the critical care setting often involves sensory deprivation and absence of normal diurnal cueing signals. This may precipitate or worsen delirium in the already compromised patient. The entity of "ICU psychosis" is well recognized.

C. Common phenomena in different psychopathologies

l. Hallucinations

are perceptions without external stimuli occurring

modalitv. a. Auditory hallucinations are most common.

2oo lfitstiical

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Psychopathology

b. Sustained, vivid, or frequent hallucinations indicate serious illness. c. Hallucinations occurring in multiple sensory modalities or vivid visual hallucinations suggests identifiable or "coarse" neurologic disease or brain dysfunction. d. The more fantastic the content of the hallucination (e.g., demons or alien invaders), the more likely the patient has a drug-related disorder.

2. Illusions are distortions or misinterpretations of a real stimulus, such as mistaking tree's shadow for a lurking figure. Illusions can occur when a person is fatigued, in strong emotional state, or mentally ill.

a a

3. Psychosensory features are sensory distortions associated most commonly with limbic system disease, particularly temporal lobe epilepsy. a. Dysmegalopsia is seeing objects change in size. b. Dysmorphopsia is seeing objects change in shape.

c. Derealization

is

when the world suddenly seems unreal, as if the person were in a dream.

d. Depersonalization is suddenly becoming "detached" from oneself, as if floating outside of one's body. It is often experienced by people with anxiety disorders. e. D6ja vu and jamais vu. D6ja lu is the sudden, intense feeling that the event, place, and people involved have all been experienced before. famais vu is the opposite experience in which familiar places and people suddenly seem unfamiliar.

4. Delusions are fixed, false beliefs not in keeping with one's education or background, not shared with a large number of others, and that are based on arbitrary thinking (e.g., "The FBI is spying on me because the mailman rings the doorbell and doesn't drop the mail through the mail slot."), based on no logic whatsoever (e.g., "The FBI is spying on me because a yellow car drove by my house."), or based on other psychopathology (e.g., "The FBI is spying on me because the voices told me so.").

5. Ideas of reference are delusional interpretations of the actions of others in which the delusion is always referred to the self. For example, "Everyone always stares at me when I walk down the street as if they know what I'm thinking."

6. Psychosis is defined as the presence of hallucinations, delusions, and unusual behavior that adversely affects one's daily function. 7. Realityperception and testing. Reality perception refers to the ability to accurately perceive the real world. Reality testing refers to the ability to determine if one's perceptions are accurate. If one hallucinates and knows he's hallucinating, his reality perception is poor, but his reality testing is good. 8. Motor disturbances a.

is increased motor activity (restlessness, fidgeting, pacing) usually reflecting an intense mood. Agitation is a nonspecific sign commonly seen in delirium, mood disorders, anxiety states, and intoxications.

Agitation

b. Hyperactivity is increased activity beyond normal. It is commonly seen with mania and stimulant drug intoxication. c. Hn>oactivity is decreased activiry usually to the point where the person performs no activity at all. Eating, drinking, and defecating may be reduced. It is seen in depression, frontal lobe s1'ndromes, schizophrenia, and CNS depressant substance use.

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Behavioral Sciences

9. Flight of ideas and circumstantiality a. Flight of ideas usually occurs in the context of rapid, hlperverbal speech. The person

jumps from topic to topic, without completing ically seen in mania.

a

single thought. This speech is typ-

b. Circumstantiality is speech that is filled with unnecessary detail or parenthetical remarks. This type of speech is observed in mania and hypomania, as well as in alco-

holics, in patients with chronic temporolimbic disease, chronic stirr,ulant drug users, and in some elderly people. 10. Formal thought disorder is characterized by fluent, aphasic-like speech (paraphasias and occasional strings of meaningless speech) with adequate repetition. This type of speech is tlpical of schizophrenia but can be seen in chronic psychosis associated with hallucinogenic drug use. 11. Emotional blunting is the loss of emotional expression (similar to that seen in motor aprosody) and the loss ofvolition for any action. The term "flat affect" has been used to describe the loss of emotional expression. Emotional blunting also reflects the loss of volition (the loss of drive and motivation and increased apathy and indifference). Emotional blunting is typical of schizophrenia and some frontal lobe lesions. D. The Diagnostic and Statistical Manual, Fourth edition (DSM IV) 1. The DSM is the official diagnostic system for psychiatric disorders in the United States It is "axis-based" in that each disorder is classified into five distinct categories: a. A state of illness from which the patient "recovers," at least until the next acute episode

(Axis I) b. A long-lasting unchanging pattern of maladaptive behavior that may not be due to

underlying pathology (Axis II) c. A psychiatric disorder due to an underlying general medical condition (Axis

III)

d. A scale ofseverity ofpsychosocial stressors over the past year (Axis IV)

e. A scale assessing the patient's overall level of functioning (Axis V)

2. The DSM is also "criteria based" in that the patient must fulfill a specific set of criteria (i.e., a syndrome) in order to be diagnosed with a particular disorder. The purpose of the criteria system is to achieve high reliability of diagnosis and consistency of diagnosis among different clinicians. 3. The DSM is "hierarchical based" in that some categories of illness take diagnostic precedence over others for the purposes of triaging multiple disorders that must be treated. Axis I disorders take precedence over Axis II disorders. Among the Axis I disorders, the most severe, chronic disorders (e.g., the psychoses) take precedence over the less severe forms (e.g., anxiety disorders). For example, an alcoholic patient with major depression who has an antisocial personality disorder would be classified as "major depression, alcohol abuse, antisocial personality." 4. The DSM diagnostic procedure. The DSM requires the clinician to approach diagnosis systematically. a. Step one is the determination of the behavioral syndrome.

b. Step two is to decide if the syndrome is primary (i.e., idiopathic) or secondary to some specific neurologic (e.g., head injury, epilepsy) or general medical disorder (e.g., hyperthyroidism, hypertension).

202 lfiBbical

c. Step three is to identifr additional conditions that the patient might have. These are referred to as comorbidities. The decisions regarding these three steps will then determine treatment and management choices.

E. Prevalence of mental illness in the United States 1. The most comprehensive and well designed prevalence study of mental illness in the United States, the NlMH-Epidemiologic CatchmentArea (NIMH-ECA), was published

in

1988.

2. Representative areas across the United States were surveyed using the DSM systern. That study found the point prevalence (percentage of ill people in the population at the time of the study) for at least one DSM Axis I or II diagnosis was about 20%o, representing 47 million people. The lifetime prevalence (individuals who have ever been :/.l) was 32o/o. 3. The most common conditions (lifetime prevalence) in the United States were alcohol and drug abuse disorders (16.40/o), anxiety disorders (14.60/o), and mood disorders (8.30lo). 4. As a general rule, psychopathology increases as one moves from the suburbs of the city to the inner city areas (e.g., the homeless are not typically found in suburbs and the majority of the homeless are mentally ill). Also as a general rule, the more severe the mental illness, the lower the socioeconomic status (SES) of the person. Exception: bipolar illness tends to occur more often in higher SES individuals. 5. Emotional disorders that cause other illnesses. Some types of psychopathology can lead to other disorders-

will have sleep disturbances, will try to self-medicate with recreational drugs, and will have decreased appetite, which if prolonged, can result in

a. A person who is depressed

malnutrition. b. A person who has anorexia nervosa and induces vomiting will have erosion of the teeth from the acid in the mouth and all of the complications of malnutrition.

c. Individuals with antisocial personality fisorder have accidents with injuries, substance abuse, neglect of hygiene, have fight-related injuries, and have unprotected sexual activity with multiple partners, resulting in high rates of sexually transmitted disease.

F. Effects of mental illness on the family 1. The family tends to sociallywithdraw from others.

2. Family members become protective of the patient. 3. Other family members do not receive

as

much attention and are often resentful.

4. As with any chronic disease, over time, the family can grow resentful of the patient. Family members can experience psychological burnout. G. Genetic considerations. Genetics play a strong role in a number of mental disorders. These

include the following: 1. Schizophrenias

2. Mood disorders 3. Substance abuse 4. Mental retardation; for example, Down syndrome (#l cause of mental retardation), fragile-X syndrome (#2 cause of mental retardation), and phenylketonuria 5. Personality disorders; for example, antisocial, schizoid, and schizoqpal 6. Selected dementias; for example, Alzheimer disease (early onset type) and Huntington disease

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PSYCHOTIC DISORDERS A. Sctrizophrenia Schizophrenia is a chronic, psychotic thought disorder with high heritability thatiesults in deficits in emotional expression, volition, speech, and language. Seventy-five percent of patients develop their first psychotic episode between the ages of 15 and 25, although, rarely, an episode can occur as early as 7 or 8 years old. First psychoses after age 40 are unlikely to be schizophrenia. Males and females are equally affected, but males generally exhibit more chronic symptoms. Lifetime prevalence is approximately lo/o. 1. Diagnosis: deterioration of most major mental functions and a chronic course of disease. There is substantial loss of functioning that lasts for at least 6 months.

2. Characteristic findings a. Positive and negative symptoms. Positive symptoms include hallucinations, firstrank symptoms, and speech and language disturbances. Negative symptoms include loss of emotional expression, social withdrawal, lack of motivation, inability to plan and carry out tasks, and poverty of speech. b. First-rank symptoms. One or more of the following symptoms are experienced by approximately 7 5o/o of schizophrenics.

(1) Complete auditory hallucinations.

Clear, sustained voices may be experienced.

(2) Experiences of control. The individual believes an outside force is controlling thoughts or actions. Associated delusions include thoughts being read or taken away (thought withdrawal), the person being made into a puppet or robot, and persecution (spied upon, poisoned).

(3) Experiences ofalienation. The individual experiences an external force putting thoughts in his mind.

(4) Delusional perceptions. The individual personalizes and gives important meaning to real but usually trivial perceptions (e.g., a chipped plate in a restaurant "told" a patient that he was being poisoned). (5) Thought broadcasting. Experience that

one's thoughts are being transmitted so

that others can hear them' c. Speech and language disturbances

(l)

Paucity of speech. Many lose their spontaneity of speech, and when they do speak, utterances are brief.

(2) Poverty of content. Even if the amount of speech is adequate, speech is vague, repetitive, and full of "stock phrases" or paraphasias. Strings of totally disorganized speech ("loose associations") can occur.

(3) Neologisms. Words that are coined by the patient and that are meaningless to others are frequentlY uttered.

(4) Disturbances of affecL Emotional expression is reduced in intensity; there is very little difference in the way the patient expresses widely differing emotions. The patient may stare blankly at the environment, showing no interest in external events. When emotions are expressed, they tend to be inappropriate to the situation.

(5) Disturbed relationships with others. Social skills deteriorate. The social relationships are often impaired even before the onset of overt symptoms. They may be interested in the outside world but have difficulty maintaining a steady work life or anything more than formal, distant social relations.

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iliB[icat

(6) Loss of volition. Apathy may prevent the patient from working or participating in self-care activities. The attention to tasks is reduced. They are indifferent to their situations and have no plans for the future. 3. Schizophrenia-like psychoses. There are many conditions that can present with schizophrenia-like psychosis. In addition to those issues listed previously, recreational drug intoxication should always be suspected, particularly hallucinogens and stimulants. 4. Subtypes of schizophrenia are not necessarily stable over time. a. Disorganized schizophrenia. Emotional blunting, silly or inappropriate moods, and disorganized speech. Systematized delusions are not present. There may be disorganized thoughts and ideas of persecution. Degree of impairment is usually severe. Premorbid adjustment is generally poor, the course of the illness is chronic deterioration and severe impairment, and the prognosis is poor'

b. Catatonic schizophrenia. A motor disturbance that includes rigidiry odd postures, great resistance to being moved, and refusal to obey verbal instructions. Some patients will also be mute. Sometimes, the withdrawal erupts into excitement; this can be dangerous to the patient secondary to dehydration. c. Paranoid schizophrenia. Delusions of persecution and grandeur. fealousy is often present. Ideas of reference frequently occur. The patient may be anxious, quarrelsome, and/or aggressive. However, paranoid schizophrenics are less disorganized and have the best prognosis. d. Undifferentiated schizophrenia. Mixture of psychotic symptoms (e.g., delusions and hallucinations) found in all the other subtypes e. Residual schizophrenia. After a schizophrenic episode is in remission, patients lack prominent psychotic symptoms but continue to exhibit subtle cognitive impairment, eccentric behavior, or negative symptoms'

5. Biologic etiologies in schizophrenia a. A strong genetic component is shown in Thble V-6-1' Table V-6-f . Genetic component of schizophrenia.

Lifetime Risk

Population

lo/o

General population Parents of schizophrenic patient Siblings of schizophrenic patient

4o/o 8o/o

Children of schizophrenic patient Dizygotic twin of schizophrenic patient Monozygotic twin of schiz-ophrenic patientx

l0-l2o/o l0-l2o/o 40-600/o

,Risk for monozygotic.twins is.unchanged if the twins are raised in separate families. This impli€s that the transmlsslon ts prrmarlly genetrc.

b. Numerous neurologic abnormalities have been demonstrated in schizophrenia. (

1) Increased lateral ventricle size on CT scans of certain chronic patients

(2) Reduced blood flow to the frontal lobes during tasks requiring frontal lobe activity

(3) Abnormal smooth-pursuit

eye movements

(4) Abnormal nonspecific EEG and sensory-evoked potential records

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(5) Difftrse nonspecific deficits on neuropsychological

tests

(6) Soft neurologic signs. These include minor incoordination and

decreased right-

left discrimination. c. Current research into the etiology of schizophrenia centers on the dopamine excess hypothesis. The fact that antipsychotic medications are dopamine antagonists and that their ability to relieve psvchotic symptoms can be correlated with their ability to block dopamine receptors (in particular D2 receptors) provides support for this theory.

6. Developmental disorder hyryothesis a. The mothers of schizophrenics experience a greater incidence of gestational, labor, and

delivery problems. Second-trimester exposure to influenza virus has been linked to schizophrenia. b. Children who bec
7. Psychosocial theories of schizophrenia. The view that family interactions are responsible for the development of schizophrenia was once widely heid but has now been rejected by almost all researchers.

8. Social class theory. Research has shown a strong relationship between social class and schizophrenia; this is the "dorvnward drift" noted previously. B.

Other disorders share common features with schizophrenia 1. Brief reactive psychosis. Hallucinations and delusions of less than 1 month duration with no loss of emotional expression. Mood symptoms are oflen present. There is usually a signifi cant psychosocial stressor.

2. Schizophreniform disorder. Psychotic symptoms are present for more than 2 weeks but less than 6 months. There may be no loss of function; otherwise, symptoms are similar to schizophrenia.

3. Schizoaffective disorder. The status of this diagnostic category is unclear. It is used when the clinical picture includes symptoms of both schizophrenia and a psychotic level mood disorder. C.

Treatment of schizophrenia 1. Token economy systems. A formal system of reinforcements is often incorporated into controlled psychiatric settings, particularly with psychotic and mentally retarded patients. For example, a schizophrenic patient may be reinforced with a snack for straightening his room. The reinforcement in this case is immediate and tangible. In a "token economy," patients are awarded a specific number of "points" or "tokens" for appropriate perfcrrmance of specified behaviors. Patients accumulate these tokens and later trade them in for reinforcers such as favorite snacks, permission to visit the hospital store where they can purchase items, or attending a movie shown on the ward. Patients participating in a token economy must be able to toierate some delay of gratification. Some token economies include a system in which inappropriate behaviors have an aversive consequence through a loss of a specified number of earned tokens.

2. Typical antipsychotic medications are effective in controlling psychotic agitation and most positive symptoms. They have also been shown to decrease the rate of relapse for

206 iiiBbical

Psychopathology

acute psychotic episodes. Newer atypical antipsychotic agents are useful in treating both the positive and negative symptoms of schizophrenia.

3. The use of antipsychotic medications is associated with a high incidence of movement

disorder side effects. a. Dystonia. The tonic, unopposed contraction of a muscle group, typically in the head or neck. These usually occur within the first 72 hours of treatment.

Clinical Note Antipsychotic medications are effective in controlling psychiatric agitation and most positive symptoms; they also decrease the rate of relapse.

b. Akathisia a subjective sense of motor restlessness that results in restless behavior.

c. Parkinsonian syndrome resembles idiopathic parkinsonism: rigidiry postural instability, bradykinesia, and resting tremor. d. Thrdive dyskinesia. Choreiform or athetoid movements that may involve any part of the body, but most often the oral and lingual muscles. It appears late in treatment and may persist for years or may be permanent, even after treatment is discontinued.

4. Nonpharmacologic treatments. Skilled social and cognitive rehabilitation is essential if loss of function and repeat episodes are to be minimized. After an acute episode, patients

Bridge to Nervous System The antipsychotic medications are discussed in detail in the Psychoactive Drugs chapter of

Organ Systems Book

I

flolume lll).

may attend: a. Partial hospitalization, where the patient has structured therapeutic time (group and individual) for an extended part ofthe day. There are nurses and physicians attending

to these facilities. b. Day hospital programs, where the focus is to get the patient involved with productive activities (sheltered workshop situations) under minimal supervision. c. Halfway houses, where patients have protected living for part of the day and work or attend to other activities for the rest ofthe day. d. Group homes are sheltered supervised living environments for patients who are not yet able to live independently.

5. Group therapy is often useful for schizophrenics patients and for patients with a wide variety of other emotional disorders. The therapeutic factors in group therapy are:

Clinical Correlate Reducing high levels of expressed emotions in

the patient's family and living circumstances may reduce relapse rates by as much as

500/0.

a. Universality. Many individuals believe they are the only one with a particular difficulty. Discovering that others have similar problems can be helpful. b. Hope. Patients learn that others have managed to cope with similar problems.

c. Cohesiveness. In a successful group, the group provides an atmosphere of cooperation, closeness, trust, and safety. The closeness engenders feelings of comfort in sharing feelings and experiences with the group, taking risks, and accepting feedback. d. Sharing

of information. Members receive feedback, suggestions, and advice from

patients and therapist. e. Catharsis. It allows open expression of emotion.

f.

Role-modeling. The patients can learn from the behavior of other members as well as of the therapist. Because patients are more likely to perceive other patients as being similar to themselves, other patients can be more effective role models than can therapists.

g. Corrective recapitulation of the primary family. The group offers an opportunity to re-examine family relationships and explore patterns that developed in the primary

family and continue to interfere with current relationships. h. Altruism. Patients learn that they can be of assistance to others, which boosts their self-esteem.

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Shared learning. The group provides an opportunity for learning about interpersonal relationships, social skills, and conflict resolution.

It

is assumed that new healthier behavior learned in the group will generalize to outside the group.

Table V-6-2. Depressive syndrome versus manic syndrome. Depressive syndrome

Manic syndrome

Sleep disturbances

Decreased need for sleep Self-destructive pleasurable activities (e.g., sex, drugs, and

Appetite changes Weight changes Sexual disinterest Psychomotor changes Energy changes Fatigue

Concentration diffi culties Worthlessness Suicide

spending to excess)

Agitation Flight of ideas Talkative with pressured speech Inflated self-esteem or grandiosity Distractible, but increase in goaldirected activities

D. Psychotic mood disorders. There are two general mood syndromes that are used to establish a diagnosis of a mood disorder (Table V-6-2). 1. Major depressive disorder. The lifetime prevalence of major depressive disorder is 5.8ol0. Roughly speaking, the female to male ratio is 2:1. a. The risk is highest in the unmarried, widowed, and divorced people over 60, in urban settings, and in people of low socioeconomic status. Onset usually peaks between ages J) ano 4).

b.

It is familial, but less so than bipolar disorder. The risk among relatives is l0% for recurrent depressive illness and 2o/o for bipolar illness. The concordance rates for monozygotic and dizygotic twins are less than those for bipolar disorder, at approximately 40 and 107o, respectively.

c. Individuals with recurrent episodes have a high mortality rate (4-5 times that of the general population) due to suicide, cardiovascular disease, and infection. Patients with cardiovascular disease or a major infection are much more likely to die from these conditions if they are depressed as well. d. The dominant clinical features are a sustained, autonomous, depressive syndrome with anhedonia (a loss of interest or pleasure in one's usual activities).

(1) The person feels listless with little interest in goal-directed behaviors, like hobbies, social relationships, or sexual activity.

(2) Appetite is often disturbed, with reduced appetite (anorexia) and weight loss. Some individuals eat more than usual and gain weight when depressed.

(3) Sleep is also disrupted. Typically, the patient experiences insomnia with early morning awakening or difificulty falling asleep. Some individuals, though, sleep excessively.

(4) There may be psychomotor agitation, with pacing, hand wringing, pulling or rubbing of hair, skin, or clothes, and outbursts of shouting. When psychomotor retardation is present, speech is slow and often monotonous and may be reduced in quantity or even absent. Movements are also slow.

2os

iliiitical

Psychopathology

(5) The patient may report that thought processes seem slowed. The

depressed

patient feels tired and lacks energy. The slightest task seems to require too much effort. e. There may be feelings of guilt and worthlessness, sometimes of delusional proportion. There may be somatic delusions of serious illness or bodily decay. The patient may feel anxious or experience panic attacks. In some cases, the patient has recurrent thoughts of death or suicide and may attempt suicide.

2. Major depressive disorder with melancholic features

is a severe form of depression. It is characterized by a profound, unremitting, sad, dysphoric, or apprehensive mood with vegetative signs reflecting hypothalamic/biologic clock dysfunctions, such as anorexia with a 5olo body weight loss in 3 weeks, early morning awakening, a diurnal mood swing (worse in the morning), and a loss of libido. There is often agitation with floor pacing and hand wring-

a. Melancholia

ing behavior. b. Persons with melancholia are more likely than individuals with other depressions to be delusional (usually delusions of guilt and worthlessness) and to commit suicide. They tend to show evidence of brain dysfunction (e.g., nonsuppression of cortisol to a dexamethasone challenge test, high and diurnally abnormal cortisol levels, a phaseshifted diurnal body temperature, and frontal hypometabolism). 3. Bipolar affective disorder is defined by the presence of a manic episode. a. The lifetime prevalence of bipolar disorder is 1.0%. Women are slightly more at risk than are men. All social classes and ethnic groups are affected. The disease is somewhat more prevalent in upper socioeconomic groups and among creative writers, musicians, painters, and performing artists. It is strongly familial, with concordance rates in monozygotic and dizygotic twins of approximately 60 and 20o/o, respectively. The incidence ofbipolar disorder peaks between the ages of25 and 30. b. The clinical presentation of a manic episode is characterized by an altered, intense

mood, with rapid/pressured speech and hyperactivity. (

1) Persons in

a manic episode often have an excessively elevate
(2) Speech is rapid and loud, often filled with puns, jokes, or clang associations. There is typically a nonstop flow of conversation (pressure of speech) with frequent changes in topic (flight of ideas). In its severe form, the speech of manics may be incoherent.

c. They may express grandiose ideas about their capabilities and become involved in impractical projects. At times, their excessive self-confidence may reach delusional proportions, e.g., they may feel they have been selected for some special mission. The delusions are consistent with the prevailing emotion. Bipolar patients can also have persecutory delusions, hallucinations, and exhibit first-rank symptoms. d. In a manic episode, the individual is easily distractible and hyperactive. There may be participation in numerous activities, with frequent inappropriate and extreme sociabil-

ity. Judgment deteriorates, and there may be

excessive spending, unwise business

investments, and flamboyant dress. There is little need for sleep; the manic individual may not sleep for days. Symptoms are similar but milder in hypomanic episodes, but the hlpomanic patient does not require hospitalization, and his level of functioning is not markedly reduced.

ilits&ical

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Behavioral Sciences

e. There are two forms of bipolar affective disorder: bipolar I and bipolar II. (

1) Bipolar I. Although the term "bipolar" implies the presence of both a depressive syndrome episode, a depressive episode is

a manic and not necessary to establish

the diagnosis of bipolar I.

(2) Bipolar II. This condition is characterized by a hypomanic episode; however,

Clinical Note Pseudodementia is a major depressive disorder in the elderly, which is often misdiagnosed as dementia.

there must be a history of a depressive episode.

4. Pseudodementia. Elderly patients with major depression may have intellectual impairment manifested by memory loss and poor concentrating abfity. This is referred to as i'pseudodementia" because it is often misdiagnosed as dementia and because the primary pathophysiology is depression, from which these patients can fi.rlly recover if properly tieated. A number of features can help distinguish pseudodementia from Alzheimer disease.

a. There are more depressive features in pseudodementia than in Alzheimer disease, particularly features of melancholia, hallucinations, and delusions. b. There is a greater likelihood of a personal and family history of mood disorders in patients with pseudodementia.

c. Pseudodementia patients maximize their complaints; Alzheimer patients minimize

their deficits. 5. Theories of mood disorders a. Biochemical theories. There are two major biochemical theories of mood disorder. One suggests that lowlevels of serotonin cause depression. The relationship between

serotonin and mania is less clear. The other theory suggests that low levels of norepinephrine yield depression, whereas excessively high levels cause mania.

(1) Serotonin theory. Both individuals with mania and with depression show significantly lower CSF levels of 5-HIAA than do controls subjects. These low concentra-

tions persist even after symptoms of mania or depression have

disappeared.

Urinary excretion of 5-HIAA appears to drop during depressive episodes but rise during manic phases. Postmortem studies of depressed individuals who have committed suicide suggest that brain levels of both serotonin and 5-HIAA are lower in these individuals than in controls subjects. The effectiveness of spccific serotonin re-uptake blockers (e.g., fluoxetine) in treating depression supports this serotonin hypothesis.

(2) Norepinephrine theory. Support for this theory derives from a variety of sources, the most significant of which is the effectiveness of cyclic antideoressants in treating depression.

b. Genetic theories. Family, twin, and adoption studies are all consistent with a genetically related disorder.

c. Cognitive theories. These suggest that for depression, there are learned automatic negative thoughts that, in turn, cause negative emotions to appear. That is, thoughts

control feelings. 6. Treatment of mood disorders a. Antidepressants include several classes transmitters and brain enzymes. (

2ro ilitstitcal

of drugs that have varying effects on neuro-

1) Nonselective monoamine reuptake inhibitors, or triryclic antidepressants, have substantial side ef[ects, including cardiac conduction abnormalities. They are not well tolerated by elderly patients because oftheir anticholinergic properties (dry

Psychopathology

mouth, blurred vision, decreased GI motility) and because their tendenry to produce orthostatic hypotension can resuit in injury-producing talls.

(2) Serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine)

are used

to treat all types clf depression and some anxiety disorders.

(3) Monoamine oxidase (MAO) inhibitors

(e.g., phenelzine) are second-line drugs anxiety disorders. used to treat depression and some

is effective in the treatment of the manic episode and in the prevention of the recurrence of both manic and depressive episodes in bipolar disorder. Because lithium is highly toxic at greater than therapeutic concentrations, blood levels of lithium are regularly monitored.

(4) Lithium carbonate

Bridge to Nervous System The antidepressants are reviewed in greater detail in

the Psychoactive Drugs chapter of Organ Systems

Book

I (/olume

lll).

(e.g., carbamazepine and valproic acid) are used to treat bipoiar affective disorder. Most patients not responding to lithium are treated either with an anticonvulsant alone or in combination with lithium.

(5) Anticonvulsants

b. Electroconvulsive therapy (ECT) is most indicated for melancholic depression. are placed on one or both sides ofthe head, and an eiectric current is passed through the brain, inducing a tonic clonic seizure.

(1) Electrodes

receives a general anesthetic before and a strong depolarizing muscle relaxant during the procedure to prevent bone fracture from occurring dur-

(2) The patient

ing the seizures.

(3) The patient is also ventilated, and EKG and EEG are monitored. (a) In typical

Clinical €orrelate

depressive episodes, 5-7 treatments are needed.

loss, generally lasting only a few days or weeks, often occurs with ETC. Serious complications are rare.

(5) Memory

After ECl, 900/o of patienb show immediate imDrovement

(6) The only true contraindication is increased intracranial pressure' c. Cognitive therapy. Cognitive theorists relate ps,vchopathology to inappropriate thought patterns, such as expectations of failure, negative thoughts about oneself, and unrealistic beliefs. According to the cognitive viewpoint, maladaptive thinking patterns can be unlearned so that new, more appropriate thoughts can be substituted. Cognitive factors are seen as very reievant to the development of depression and anxiety.

(l)

Cognitive relabeling. If an individual's emotional reaction depends upon how he labels or interprets a given situation, anxiety or depression results from holding an unrealistically negative view about a situation, its likely outcome, and one's own capabilities. If a person believes a situation to be threatening, he is likely to feel apprehensive about facing it. Il on the other hand, he perceives the situation in a more positive way, he is likely to feei relaxed and eager to enter the situation. Cognitive relabeling focuses on teaching patients to evaluate situations more realistically and thereby control their anxiety and or depression. For example, a person may be anxious about public speaking because he fears performing ineffectively and thinks that such a failure would be catastrophic. Through cognitive relabeling, the patient might learn to accept failure, if it occurs, and to realize that poor performance would not be so terrible.

(2) Thought-stopping can be helpful when the patient is troubled by a recurring thought. The patient is told to preoccupy himself with the thought. After briefly allowing the patient to focus on the thought, the therapist loudly says "Stop!" thus interrupting the thought. The verbal prompt is gradually f'aded, and the patient eventually learns to block the thought on his own.

iliBtical

2r I

Behavioral Sciences

(3) Covert assertion. Once thought-stopping has succeeded in eliminating the troubling thought, it may be necessary to teach the patient to substitute positive, assertive thoughts that run contrary to established patterns ofnegative thinking. For example, if thought-stopping wipes out the thought that the patient is a "bad

person," the patient may be told to mentally assert, "I'm a good person." In this manner, a repertoire of positive self-statements can be built up to counteract the negative ones.

(4) Cognitive rehearsal. The patient is asked to imagine behaving appropriately instead of actually acting out the behavior. The patient is typically asked to "think out loud" so that the therapist can provide coaching. d. Supportive psychotherapy (supporting the ego defense system). As with most psychiatric disorders, supportive psychotherapy as an adjunct to bipolar treatment is almost always recommended. Supportive psychotherapy includes empathic listening, reassurance, and education, with limited advice giving.

E. Psychotic conditions associated with general medical conditions 1. Delirium

Clinical Note

a. Clinical features. Delirium is characterized by an altered state of consciousness, i.e., there are arousal and attention problems with difftrse cognitive impairment. (

Delirium has a fluctuating

1) Perception is often disturbed; the person may hallucinate or misinterpret stimuli.

course of symptoms;

(2)

particularly, the level of

(3) Patients

consciousness the sensorium is clouded.

( ) The sleep-wake

Dementia is a downhill course

(5) The person may be disoriented and

in a normal state of arousal.

Speech is rambling at times, and agitation is common. are usually anxious, and,

if hallucinating or delusional, terror stricken.

cycle is disturbed; the patient may have difficulty sleeping at

night or be drowsy during the day. have memory difficulties.

b. The onset of symptoms is generally rapid, occurring over a period of hours or days. The symptoms fluctuate. With few exceptions, the clinical features are nonspecific and do not reveal the cause.

(1) Approximately 10-15o/o of acute medical/surgical inpatients are delirious. Most of the symptoms go unrecognized, which adversely affects care.

(2) Most cases of delirium in hospitalized patients are caused by medication, metabolic, or fluid and electrolyte problems revealed by standard hospital laboratory tests.

(3) Except for delirium tremens, where the EEG is characterized by low-voltage

fast

activity, the classic EEG in delirium is high-voltage slow waves. c. Delirium requires rapid recognition and resolution because several of its possible causes may be fatal if untreated. These include hypoglycemia, hlperpyrexia, hypoxia, uremia, encephalitis, and drug intoxication.

2. Dementia a. Clinical features. The major distinguishing factor between delirium and dementia is that dementia occurs in the presence of a normal state of arousal. The sensorium of the person is clear. c. The major intellectual problem is

difficulty with memory functioning. In

severe

cases, the demented person cannot remember his personal history and forgets the names of close friends and relatives.

2tz ilitsbicat

Psyrhopathology

(1) Dementias involving mostly cortical tissue

(e.g., Pick disease, Alzheimer disease)

are characterizedby aphasia, apraxia, agnosia, and amnesia.

(2) Dementias involving mostly subcortical tissue

are characterized by motor slowing and other disorders of movement, disturbances of mood (apathy or depression), and sluggish cognition.

(3) Cognitive functions:

Loss of abstract reasoning ability and difficulty performing

perceptual-motor tasks. Language may be vague, or there may be difficulty naming objects (dysnomia).

(4) Personaliry change is almost always present. The individual with mild dementia who is aware of his impairment is likely to become anxious or depressed. There is a tendenry to withdraw from interaction with others. There may be irritability. Judgment may deteriorate, and, often, the individual begins to make inappropriate sexual advances to others. There is increased risk of suicide, especially in individuals in whom social isolation has ensued. d. Alzheimer disease (dementia

of the Alzheimer type) is the most common type of

dementia.

(l)

Clinical findings. Typical onset is in the mid-70s, with the incidence rising with each successive 5 years. In the early stages of the illness, patients experience difficulty with new learning, word finding and naming, and visual-spatial and visual-motor coordination.

(2) The disease is sometimes familial; approximately 50o/o of first-degree relatives of the patient will develop the disease. The nucleus basalis of Meynert and its acetylcholine enervation to the cortex are affected. The locus ceruleus and its norepinephrine projections are also involved. One subtype of the disease is associated with a chromosome 2l mutation and a family history of myeloproliferative disorders and Down syndrome. In some cases, Alzheimer appears linked to a particular apolipoprotein E mutation on chromosome 19.

(3) Pathologically, the brain shows marked atrophy with ventricular enlargement and microscopic deposits called neuritic plaques. Thick fibrous strands of unclear significance called neurofibrillary tangles are found in the neuronal cytoplasm. e. Vascular dementia or

multi-infarct dementia

is linked to cerebrovascular disease and

is accompanied by focal neurologic signs, such as weakness in the extremities and dysarthria. Early on, some skills may appear unaffected. The disease tends to progress

in a step-wise fashion.

f. Parkinson

disease. Twenty to forty percent of patients develop a subcortical dementia. Classic features include a slow and shuffl.ing gait, expressionless face, resting hand

tremor and pill-rolling finger movements, sweating, drooling, rigidiry and micrographia (i.e., small and choppy writing). Degeneration of dopaminergic neurons in the substantia nigra of the basal ganglia is the most common underlying lesion. Tieatments include t-dopa, anticholinergics, amantadine, and fetal tissue transplants. g. Huntington disease is caused by a dominant mutation on chromosome 4. The mutation can be detected by amniocentesis or blood sample. The disease begins in the midthirties or forties and can cause depression, impulsiveness, and personality changes. In the early stages, suicide is a risk. In the later stages, subcortical dementia occurs. The classic choreiform motor movements can occur after the behavioral changes.

iiiElicat 2t,

Behavioral Sciences

h. Wilson disease is caused by a genetic defect resulting in reduced ceruloplasmin, a serum protein that binds copper. Copper excretion is reduced, and copper builds up in several organs including the liver, causing cirrhosis, and in the eyes, resulting in Kayser-Fleischer rings around the iris. A build-up of copper in the basal ganglia causes wing-beating arm

movements, tremor, mental retardation in children, and dementia in adults. Patients are placed on a low-copper diet, and chelating agents are administered. Early detection is key.

i. Normal pressure

hydrocephalus is caused by blockage of the foramen of Monro. Spinal pressure remains normal, but ventricular pressure builds up, destroying tissue and producing hugely dilated ventricles. Dementia, ataxia, and urinaryincontinence are classic features. Common causes include alcoholism, subarachnoid hemorrhage, vitamin deficiencies, and syphilis. T[eatment is the placement of a shunt to drain the fluid and relieve the pressure.

j.

Pick disease is a rare dementia, progressive\ affecting the frontal lobes and then the temporal lobes. A schizophrenia-like psychosis and frontal lobe behavioral syndromes can precede the dementia. There is no treatment.

3. Amnestic disorders. These conditions may have a psychotic level of disturbance. They have a singular symptom of disturbance in short-term and long-term memory. Immediate memory, which retains information for a few seconds, is not affected by the amnestic syndrome. Other cognitive functioning is intact. a. Etiology. There are general medical conditions that underly these problems. These can include avitaminosis, head trauma, CNS infections, recreational substance abuse,

hypoxia, etc. b. The intervention is to address the underlying pathologic condition. Conditions may be reversible (i.e., acute), partially reversible, or irreversible (chronic).

NEUROTIC CONDITIONS The term "neurosis" has been removed from the DSM-IV classification scheme. However, it has been retained in the International Classification of Diseases, and many authors still find the category to be useful. It will be retained for this book, and relevant disorders classified by DSMIV will be organized under this heading. The definition of neurosis is the symptoms displayed by the patient bother the patient. The patient's functioning is compromised because of the unpleasant nature of the symptoms. That is, the symptoms are ego-dystonic.

Note Somatoform disorders focus the symptoms on

body experiences. They use the somatization

defense mechanism.

Note Be sure

to learn the

differential diagnosis among

somatoform disorders, factitious disorders, and malingering.

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A. Somatoform disorders 1. Somatization disorder. The patient has multiple medically unexplained symptoms (described dramatically or vaguely) in multiple body systems, causing work limitation, increased visits to the physician, needless surgery, or unnecessary medical treatments. a. Begins before age 30, usually by the teens. It is far more common in women than men and affects approximately I-2o/o of women. It is familial, with high risk of the disorder in female relatives and high incidence of antisocial personality disorder and alcoholism in male relatives. b. Diagnosis. Must exhibit at least the following: four pain symptoms (e.g., back and joint, headaches), two gastrointestinal symptoms (e.g., nausea, abdominal pain), one sexual symptom (e.g., dyspareunia, sexual indifference), and one pseudoneurologic symptom (e.g., muscle weakness, sensory loss).

Psychopathology

2. Conversion disorder. Neurologic-like complaints that do not easily mesh with presentday knowledge about the nervous system, e.g., anesthesia not running along a nerve distribution. The symptoms Qpically involve organs of special sense and voluntary muscles. Paralysis, blindness, tunnel vision, aphonia, insensitivity to pain, seizures, impaired coordination, and paresthesia are the most frequently reported. It is more common in women than in men, in individuals with dramatic-emotional personaliry in less educated individuals, and in individuals from LSES backgrounds.

Note Conversion disorders use the conversion

defense mechanism.

a. Unlike factitious disorder and malingering, the condition is not faked; the person actually experiences the symptoms. "La belle indifference," a relative lack of concern about the symptoms, is sometimes present. b. Psychodynamic theory proposes the conversion symptom enables the person to achieve "primary gain" (i.e., to keep conflict from awareness) and affords "secondary gain" by enabling the person to avoid anxiety-provoking activities or ensuring attention or sympathy that the person might not otherwise receive.

3. Psychogenic pain (chronic idiopathic pain) disorder is chronic pain without medical explanation presumably resulting from psychological stress or conflict. Peak onset is between ages 30 and 40, with women more at risk than men. It is familial with comorbid conditions such as nonmelancholic depression, anxiety disorder, substance abuse, and antisocial personality disorder. All these conditions are also more common in the families of chronic pain patients. The psychodynamic theory behind this condition is the same as for conversion disorder.

4. Hypochondriasis. Patients interpret body signs or sensations as pathologic and are preoccupied with the fear of being seriously ill. Despite physical examination demonstrating no pathophysiologic process and reassurance that all is well, the person persists in believing he is ill. The preoccupation interferes with functioning on the job or in social interactions. a. It mayoccur at anyage but is most common in the fourth and fifth decades. Its occurrence is equal between males and females. It is seen in patients with major depression, OCD, anxiety disorder, somatization disordet and anxious-fearful personalities.

b. Psychodynamic theory proposes that individuals with hypochondriacal disorder substitute a physical symptom for an emotional one because they are unable to express their yearnings for personal contact. The symptom, therefore, is a distorted attempt to form a relationship with the doctor and overcome the patient's emotional isolation.

5. Body dysmorphic disorder. The person is preoccupied with the belief that some part of their body is marred in looks. The body part may have a slight irregularity or none at all. This disorder usually begins in adolescence and occurs with equal frequency in males and females. Most adolescents have some concerns about their appearance; however, with this neurotic condition the person is severely impaired in their ability to function. B. Nonpsychotic level mood disorders a form of bipolar disorder in which the mood state gradually shifts from hypomania to mild depression. The shift may occur over weeks or months. These patients rarely have episodes of illness or severe symptoms but seem to always be either moody or full of energy.

1. Cyclothymia is

Between 30o/o and 50o/o of all bipolar patients become chronically ill, usually with many or prolonged episodes annually or with substantial loss of social and job functioning between episodes. Fifteen percent commit suicide, usually during a depressive episode.

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2. Dysthymia is a low-grade depression that lasts longer than 2 years. Dysthymics do not have vegetative signs, are rarely psychotic, and have a sad or dysphoric mood that can

lift

under some circumstances. Unlike melanchoiics, who are rarely tearful, dysthymics cry frequently. C. Dissociative disorders. Dissociative disorders involve a gradual or abrupt, temporary change in consciousness, identiry or motor behavior. When consciousness is disturbed, the person is unable to recall important personal events. With a disruption in identiry the person either forgets his own self and assumes a new identity or his sense of identity is replaced by a feeling of unreality. The change in motor behavior in these disorders refers to wandering from place to place. Most documented cases of dissociative disorder have been associ-ated with an underlying condition. These include epilepsy, multiple sclerosis, frontal lobe lesions, anxiety disorders, and dramatic-emotional personality disorders. Many cases have been associated with malingering.

l.

Dissociative amnesia is the most common of the dissociative disorders, although its prevalence is low in absolute terms. The incidence of the disorder is high during wartime and natural disasters but is actually highest in females aged 15-30. a. The disorder is characterizedby a loss of memory for personal events while basic facts and language are still recalled. The loss is too extensive to be explained by ordinary forgetfi.rlness. Threats ofphysical harm or death or other stressfirl events (e.g., divorce or abandonment by a spouse) may precipitate the disorder. Both the onset and termination of symptoms is sudden, and there is only a temporary loss of memory functions. b. The type and severity of memory loss differs across patients. Amnesia may be localized in time, selective of some events at certain times, generalized for major periods of one's life, or continuous from a specific period onward.

2. Dissociative fugue. The person suddenly travels away from his customary place of daily activities. Reports of individuals assuming a new name, new job, and new lifestyle with a new, often more outgoing personality are unproven. Activities during the fugue are rarely so elaborate. Usually, the fugue is brief and limited to unexpected travel. The person may appear to be without other psychopathology during the travels; however, in most cases the fugue is associated with some alteration in consciousness.

3. Dissociative identity disorder (formerly "multiple personality disorder") is an extremely rare disorder that has been popularized in the movies "The Three Faces of Eve" and "Sybil." a.

Most such cases are actually malingering, or a suggestible, immature, dependent person unduly influenced by a therapist (inexperienced or exploitive) who "suggests" the various personalities. Experienced therapists doubt the validity of this diagnosis.

b. Frequently, a person who truly has a borderline personality disorder is misdiagnosed as having dissociative identity disorder. c. The disorder is not to be confused with schizophrenia, which is often thought by patients to mean "split personalityJ'The "split" in schizophrenia refers to differential deficits in various mental functions, i.e., some are intact, whereas others are severely disturbed. d. Defined as two or more distinct personalities that alternate in control of the person. These personalities are said to each have separate names, ages, complex behavior patterns, memories, and so on. They may describe themselves as being of different genders, races, and ages. The individual personalities are almost always different in temperament, often seem to be opposites, and, when well documented, are limited to two.

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Psychopathology

e.

In most

cases, the original personality is not aware of the other personalities (called "subpersonalities") but may become cognizant of their existence through "lost

time," i.e., time for which the individual has no memory. The patient may

be

informed by others of activities that were carried out during these times that might be quite uncharacteristic ofhis usual behavior. Alcoholic "blackouts" shouid be ruled out. 4. Depersonalization disorder is a sudden feeling of being outside one's self. a. The patient may feel as if he is observing himself from afar and. is not in complete control of his speech and behavior. He may have a "mechanical" feeling, i.e., that he is behaving automatically, or may feel as though he is in a dream. Limbs may appear changed in size. b. In addition to changes in the way the self is experienced, there may be an alteration in the perception of external realiry a phenomenon called derealization. For example, objects may appear flat, and other people may seem dead or mechanical.

5. Etiologic theories of dissociative disorders a. Psychoanalytic theory relates dissociative disorders to massive repression stemming from unacceptable sexual impulses in the Oedipal phase. In adulthood, these Oedipal

desires become stronger and may be finally expressed as an impulsive sexual act; repression can't remove the act or impulse from consciousness. The person responds by splitting an entire aspect ofpersonality from awareness and gives a new identity to the dissociated part. b. Behavioral theory sees dissociative disorders as serving to protect the person from some highly stressful life event.

c. Biologic causes may include excessive cortical arousal (induced by stress, drugs, or disease) that triggers inhibition of synapses in sensory motor pathways. D. Anxiety disorders. Symptoms of anxiety are among the most common patient complaints in general practice. Women are affected more than men, and the age of onset is usually between 15 and 35. Unless the condition is in response to extreme stress (e.g., PTSD and acute anxiety reactions), onset after age 35 is suggestive of a general medical condition (e.g., thyrotoxicosis). Approxim ately 4o/o of the population will suffer at some point from the more severe anxiety disorders. These are familial; concordance rates in monorygotic and dizygotic twins are 60 and 30olo, respectively. 1. The first group of anxiety disorders are the phobias. a. Specificphobias are characterized by great anxiety or distress out ofproportion to any real danger upon exposure to some feared object or situation and a strong desire to avoid the object or situation. Specific phobias generally do not extend beyond the particular object or situation. Phobias may have their onset at any age, although they commonly originate in childhood, adolescence, or the early twenties. Approximately l2o/o of the population experiences a phobia during their lifetime. Fear of harmless objects, such as insects, are tairly common but rarely become disabling. It is only when the fear is a persistent source of distress or causes dysfunctional avoidance that significantly interferes with social or job functioning that the diagnosis of specific phobia is made. b. Agoraphobia is the fear of being in a public place from which escape might be difficult and where one is likely to panic and lose control and embarrass oneself.

(1) Individuals with agoraphobia are especially fearfrrl of being incapacitated in places where no one would be able or willing to help them, such as on a bridge or in a crowded shopping mall. They restrict their range of activities and, in severe cases, become home bound.

iiitshical 2tl

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(2) This disorder is more frequent among women. (3) Panic attacks often precede the onset of agoraphobia, which may be a response to the repeated experience of panic attacks.

(4) Common comorbid conditions include panic disorder,

social phobia, an anxious-

fearful personality disorders nonmelancholic depression late in the course, and mitral valve prolapse (approximately 20o/o of patients compared with 5-10o/o in the general population). Note that these are not etiologically linked. c. Social phobia is the fear of being scrutinized by others or behaving in a way that will cause embarrassment. Common fears are of public speaking, dating, using public bathrooms, and talking on the telephone. Men and women are equally affected.

2. The next group of anxiety disorders are those that are in response to a stressing event. a. Post-traumatic stress disorder (PTSD)

(1) PTSD

is a response to stress ofunusual strength that would cause great distress in almost anyone. The stressful event may involve natural or man-made disasters (e.g., earthquake, fire, airplane crash) maybe experienced alone (e.9., rape) or

Note Distinguish between PTSD and acute stress disorder on the basis of the

lengh of time

symproms are presenr.

with

others (e.g., combat). Events that induce PTSD are typically outside the normal range of hurnan experience. Symptoms include re-experiencing the trauma through recurrent recollections or dreams, reduced responsiveness to the external world, a phenomenon known as "psychic numbing," feelings of detachment from others, and a loss ofinterest in activities. Patients will experience hyperalertness, sleep disturbances, dilliculty concentrating, and memory impairment. They may feel survivor's guilt and will avoid activities related to the traumatic scene. S1'rnptoms often worsen when the individual is exposed to conditions that physically or symbolically resemble the trauma. Most PTSD patients have comorbid conditions, including nonmelancholic depression, anxiety disorder, obsessivecompulsive disorder, substance abuse, or antisocial personality disorder.

(2) The syndrome may be acute (onset within a few

days

or 1 month of the trauma

and symptoms lasting 6 months or less) or chronic.

(3) For acute PTSD, treatment includes counseling, support groups, short-acting benzodiazepines for sleep (during the first 3 monihs only), and returning to job and personal responsibilities as quickly as possible. For chronic conditions, the comorbid conditions are treated. b. Acute stress disorder is similar to PTSD but lasts less than 4 weeks. longer, the diagnosis is changed to PTSD.

If symptoms last

3. The last group of anxiety disorders are those that have unpredictable onsets of anxiety that are not precipitated by environmental events. Note Panic disorder usually does

not have environmental stressors as the etiologic event

a. Panic disorder is defined as frequent, sudden, spontaneous episodes of intense anx-

iety. Attacks iast approximately 20-30 minutes and are characterized by agitation; sweating; pounding heart; shortness of breath; vertigo; coldness; "butterflies in the stomach"; fear; worry; hyperventilation resulting in paresthesias (tingling in the hands or feet) and dizziness; feeiings ofunreality; or fears ofdying, going insane, or ofdoing something uncontrolled during the attack. Panic attacks are short in duration and are often misdiagnosed as a cardiovascular event. However, the patient's "background" anxiety level is usually elevated between attacks. Common comorbidities include agoraphobia, nonmelancholic depression, mitral valve prolapse, and an anxious-fearful personality disorder. Attacks can be triggered chemically by sodium lactate infusion.

2rB ifiBbical

b. Generalized anxiety disorder (GAD) is characterized by a lower level of anxiety than

that in panic disorder, but the anxiety is present almost daily. The anxiety is not associated with particular situations but is experienced continuously. In most cases, anxiety is evident through motor tension, autonomic hyperactiviry apprehension, and hypervigilance.

c. Obsessive-compulsive disorder (OCD)

(1) OCDaffectsapproximately2Voofthegeneralpopulation;boysmorethangirls, men and women equally. Average age of onset is 20; if onset is in childhood, a mood disorder should be suspected. If the onset is after age 35, OCD secondary to specific disease (e.g., basal ganglia lesions, epilepsy) should be considered.

(2) Obsessions are recurrent, persistent, and intrusive thoughts that the person initially knows to be illogical, improbable, or silly. Common obsessions include doing something outlandish (often associated with sex or violence), being destructive, needing order and symmetry being contaminated by dirt or g.rtttr, or thinking about religion or philosophy.

(3) Compulsions are rqretitive, stereotnred behaviors that are performed in a ritualistic fashion usually driven by the obsessions. Compulsive acts are usually experienced as senseless or pleasureless but necessary if anxiety is to be avoided, contained, or reduced. The urge to perform the act is perceived to be irresistible, and, if the person is prevented from performing the compulsion, anxiety invariably increases until the act is carried out. Acting on the compulsion, however, does not result in a reduction of anxiety already present in the patient. Approximately 75-95o/o of OCD patients have both obsessions and compulsions; the most common tfpes are washing and checking. Treatment consists of relaxation, in vivo exposure, and specific serotonin re-uptake inhibitors.

4. Tieatment of anxiety disorders a. Antidepressant medications (SSRIs) are the drugs of choice for long-term treatment

of anxiety disorders. (

1) These drugs are often combined with in vivo exposure and relaxation techniques. These are sometimes augmented with benzodiazepines.

(2) Sedative-hlpnotics such as barbiturates and related medications (meprobamate, chloral hydrate, and glutethimide) had been widely prescribed in the past for generalized anxiety. Because oftheir overdose potential, synergistic interaction with alcohol, and addictive qualities, they should not be used. b. Behavior therapy is the nonpharmacologic treatment of choice for specific phobias. Some of the best results in dealing with the anxiety-type disorders have been obt"in.a from application of learning theory-based behavior modification the address, symptoms and does not attempt to alter personality. One or more of the treatment techniques listed below are used to treat anxiety disorders and other behaviorally based pathologies. (

1) Reinforcement. Changing the consequences of a response can lead to a modification in the frequenry of the response. There are two basic rules in these type of

If a behavior is desired, reward it whin it if a behavior is unwanted, withdraw reinforcement of the behavior.

behavior modification programs: occurs; and

(2) An aversive technique often found in behavioral programs is "time-out" from reinforcement. When maladaptive behavior occurs, the individual is briefly removed from his normal environment and is isolated in a location where it is impossible to receive any reinforcement. This is often used when children are having a temper tantrum.

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2ts

Behavioral Sciences

(3) Biofeedback is a process by which psychophysiologic states that are antithetical to anxietF or tension are brought under the patient's control by allowing the patient to become aware of when they are in that psychophysiologic state (e.g., a light bulb goes on when the state is entered, and all the patient must do is keep the light bulb on).

(4) Relaxation training focuses on teaching the patient to relax muscles and thereby reduce anxiety. When this technique is successfi,rlly used, the patient learns to discern tension, to relax instead ofbeing tense, and to use the skill when necessary. New behaviors can be shaped by reinforcing responses that are increasingly close to the desired behavior.

(5) Sensitization refers to the increased responsiveness to a stimulus due to the repeated presentation of the stimulus. For example, a daily obscene phone call results in the victim showing a marked startle response every time the telephone rings. Or, in sex therapy, a patient having problems with the appetitive or excitement phase may be involved in "sensate focus" exercises in which their interest in sexual issues is increased.

(6) Habituation is

decreased responsiveness to a stimulus resulting from repeated presentations of the stimulus. For example, a medical student eventually habituates to the smells and sights of the anatomy lab that are at first so offensive. This is the principle behind desensitization and flooding techniques.

(a) Flooding is usefrrl when a specific object or situation is feared. Flooding requires the patient to imagine the most anxiety-arousing situation possible and to hold the image for an extended period of time. By forcing patients to confront their worst fears, the patient learns that no harm is likely to result from an encounter with the feared object or situation. (b) In desensitization, the person is placed in the feared situation and required to interact with what is frightening them, e.g., fear of public speaking.

(c) Systematic desensitization relies on mental imagery of a feared situation while the patient is relaxed to systematically expose the patient to increasingly anxiety-provoking elements of the situation. In vivo or actual exposure to the stimulus is sometimes added during treatment.

ADIUSTMENT DISORDERS Adjustment disorders are clinically significant emotional or behavioral symptoms in response to identifiable stress. Symptoms must develop within 3 months after the onset of the stress, go beyond what one would normally expect, and result in job or social impairment. Types -of adiustment disorder include those in which the reaction is one of depression, anxiery conduct disturbance, or combinations of these reactions. It is assumed that the symptoms will disappear when the stress ceases or when the person adapts to living with the stress. Adjustment di;der cannot be a grief response.

PERSONATITY DISORDERS Personality traits are enduring patterns of interacting with one's environment and thinking about oneself. They are consistent in a wide variety of situations and over time. The sami groups of personality traits are observed in people across the world, in all cultural settings. Human personality has a basic "floor plan," with the various combinations of inherited and acquired traits accounting for individual differences in personality. Many personality traits are

z2o iliBliieal

Psychopathology

independently and highly heritabie. In personality disorders (PDs), the traits are deviant, leading to personal or interpersonarl difficulties, distress, or other maladjustment at home, school, or work. PDs do not derive from a psychosocial stressor. They are life-long patterns of behavior that tend to bother other people, not the person who exhibits them. That is, PDs are egosyntonic. To meet criteria for a PD, a person must have inflexible, maladaptive, long-standing behaviors beginning in childhood or adolescence that lead to interpersonal distress and that affect several areas of life. These may include impaired social or job function, poor impulse control, and distress in others over behavior that deviates markedly from cuitural expectations. Note: These disorders are diagnosed only in the adult (18 years old or older). The only and rare exception is if there have been persistent and pervasive symptoms that have been present for at least I year and are not characteristic of a given developmental stage. The DSM divides the PDs into three clusters: A, B, and C.

A. Cluster A-Odd-eccentric PDs. Some are clearly heritable.

I. ParanoidPD a. Persons with paranoid PD have traits of suspiciousness, excessive vigilance toward

the environment, mistrust of others, and a concern with hidden meanings or motivations. They are extremely sensitive to criticism and have great difficulty relaxing. They tend to be "cold" and exceptionally serious. 'Ihey iack a sense of humor and c'rften bear grudges. They have particular difficulty dealing with colleagues or supervisors at work and are often members of {iinge social groups. b. These individuals rarely reach the attention of clinicians because they are generally unwilling to seek help. There is no proven treatment.

2. Schizoid PD. These are "loners" who have few close relationships with either family members or friends. They are indifferent to the f'eelings of other people and appear detached and are considered cold, alooi or uninteresting by others; however, they are not

characterized by either eccentricities of behavior or disordered thought. They usually choose jobs and hobbies that enable them to avoid contact with others. They rarely come to treatment.

3. SchizotypalPD a. These patients are emotionally cold and aloof like schizoid patients, and they also display odd "magical thinking" (e.g., beliefs that others can sense their thoughts or feelings). They may have ideas of reference, recurrent perceptual illusions, depersonalization, or suspiciousness. They have few close friends, appear distant even in

one-to-one interactions, and are prone to becoming involved with unconventional social or political organizations, where they find other schizotypal individuals who share their delusional belief systems. They rarely seek treatment but may respond to low-dose neuroleptics. b. Schizoid and schizotypal personality disorders are thought to be low-grade illnesses related to schizophrenia. They are familial and occur with greater frequency in relatives of schizophrenics, but they are not prodromes to schizophrenia. They may represent mild forms of the disease because individuals with schizoid and schizotypal PDs also have many of the biologic abnormalities (EEG, MRI) seen in schizophrenics.

B. Cluster B-Dramatic-emotional PDs. This ciuster is highly heritable.

l.

Histrionic PD is more common among wornen (2a/o).lt is described by shallowness, dramatic behavior, and exaggerated affect. Patients demand continuous attention and

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reassurance from others. They tend to be vain, self-centered, and dependent. They crave novelty and excitement. They often initially appear charming and behave seductively; however, once a relationship is established, they quickly become controlling or dependent, which causes disruptions in interpersonal relationships.

2. Narcissistic PD is personified by the word entitlement. These individuals have a grandiose but unstable sense of self-importance that often alternates with feelings of unworthiness. Patients are preoccupied with unrealistic goals, e.g., unlimited wealth and power. Interpersonal relations are invariably disturbed because they seek constant attention and admiration from others, expect others to perform special favors for them, and take advantage of others. However, there is a pronounced lack of empathy for the feelings of others. When ignored or criticized, patients become enraged or feel excessively bad

about themselves. 3. Antisocial PD a.

It is estimated that antisocial PD occurs in approximately

3o/o

of American men and

lolo of American women. These individuals have disregard for and violate the rights of others. Persons with this disorder are deceitfirl, impulsive, reckless, irresponsible,

and remorseless. Delinquency, lying, substance abuse, promiscuiry poor school performance or work record, and fighting may occur at an early age; however, this disorder cannot be diagnosed unless the person is

I8

years of age or older. Individuals colleagues.

with antisocial personality disorder tend to be poor parents, workers, and

b. Antisocial PD is associated with the childhood triad of fire setting, cruelty to animals, and enuresis. Many children with childhood conduct disorders grow up to have

antisocial PD. c. Antisocial PD is rarely seen after age 55, even in those who have exhibited the disorder in earlier years. Many people with the disorder do not survive to age 55, and those who do survive tend to "mellow" with age and become less aggressive.

in the same famiwith male relatives being antisocial and substance abusers and female relatives being histrionic and narcissistic. Persons with these personality disorders are also more likely to have somatization disorders. In families where the male has an anti-

d. Antisocial, histrionic, and narcissistic PDs are familial and appear

lies,

social PD and is alcoholic, the first-degree female relatives are often depressed.

4. Borderline PD

with identity (e.g., gender identiry values), anger, and impulse control. Self-destructive behavior, e.g., gambling or overspending, may be present. They are emotionally labile, expressing intense feelings inappropriately.

a. These individuals have major problems

b. The individuals are often prone to "micropsychotic" episodes, where they have ego disintegration with hallucinations, etc., for a short period of time (e.g., sometimes for a few minutes). c. They may be very manipulative and aggressive. d. They have difficulty being alone and may become self-abusive with mutilation and

suicidal gestures. e. Their interpersonal relations are tragic due to their desperate desire for a close reiationship; however, they do not know how to handle the interdependency and closeness to maintain it, and they uitimately sabotage it.

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Psychopathology

f. Many of these patients also meet diagnostic criteria for mood disorders, particularly bipolar II and ryclothymia. They can exhibit the same biologic deviations seen in the mood disorders. They often have a family history of mood disorders and many respond to treatments for mood disorders. C. Cluster C--Anxious-fearfrrl PDs. This cluster demonstrates some heritable tendencies. 1. Avoidant PD patients have a fear of rejection in interpersonal relationships. They are hlpersensitive and show excessive concern about being completely accepted without criticism. Self-esteem is usually low. Unlike individuals with schizoid PDs, avoidant personalities intensely want to establish relationships with others but are terrified unless they are guaranteed acceptance. These patients may benefit from individual or group therapy and assertiveness t ra in ing.

Clinical Correlate Persons

with PDs rarely

present for treatment because they perceive

themselves as normal.

2. Dependent PD. These individuais allow others to assume responsibility for important areas in their lives. There is a lack of self-confidence, and the priorities of others are given the most attention. This disorder is more frequently found among women. Assertiveness training is particularly useful. 3. Obsessive-compulsive PD (OCPD) must be distinguished from OCD. It is characterized by a rigid, conformist, and perfectionistic style of behavior. These people have a tight, restrictive range of affective expression. Compulsive personalities are "workaholic" types who are unable to relax. They may waste time ruminating over things rather than accomplishing real work. Either individual or group therapy may be helpful. Most OCPD individuals perceive their own behavior as "okay" and believe that individuals who object to it "have a problem." D. PD not otherwise specified: passive-aggressive PD. These patients have a great deal of difficulty asserting themselves and expressing anger appropriately. They may act out their anger indirectly, presenting a resistant stance in situations involving social or occupational functioning. A person with passive-aggressive PD may "unconsciously" forget to do what is asked of him, thereby sabotaging tasks in demanding situations, for example, when working

Note Passive-aggressive PD is

no longer part of the main PD clusters in the DSMIV

and therefore is less likely

to appear on the exam.

with bosses. Psychotherapy may be useful.

OTHER DISORDERS OF IMPUTSE CONTROT In these disorders, there is a failure to control actions or urges, and the behavior that results is harmful to the patient or others. Affected individuals often feel the impulse consciously or sense an increase in tension before the act. Carrying out the impulse leads to an immediate reduction in tension and even pleasure. Guilt may follow after the action has occurred but is not inevitable. With the exception of kleptomania, all of these disorders are more common in men than in women.

A. Intermittent explosive disorder. The patient becomes enraged from time to time over trivial matters, resulting in assaults to others or destruction of property. B. Kleptomania. The patient experiences an unpremeditated urge to steal and does so with little consideration of the consequences. The objects are not stolen because they are useful or valuable. The person almost always has the money to pay for the items. C. Pathologic gambling is gambling that interferes with social or occupational functioning. The patient may gamble away money that should be used for household expenses and may engage in forgery, embezzlement, or other illegal but nonviolent acts to obtain money for gambling. There may be associated marital stress, job loss, and legal difficulties.

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D. Pyromania. The patient experiences an unpremeditated urge to set fires and greatly enjoys watching them. E. Trichotillomania is the compulsive pulling of one's hair, resulting in noticeable hair loss.

SUBSTANCE-INDUCED DISORDERS Eleven percent of the U.S. population abuses alcohol, and an additional 5-6%o abuses illegal drugs. However, in the clinical picture, alcohol and other drugs are usually combined in their recreational use and abuse. In approximately 50o/o of people with a substance a.buse diagnosis, there is another comorbid psychiatric disorder.

A. Alcohol-related syndromes 1. Alcohol intoxication results from recent use or the continued presence the body.

of alcohol in

a. It is characterized by slurred speech, unsteady gait, a flushed face, and nystagmus. If the individual's tolerance level is exceeded, poor judgment and decreased visual motor function always occur.

b. Because alcohol initially has stimulant effects, talkativeness and loss of inhibitions may occur. In the pharmacologic "long runi'however, alcohol is a sedative. c. Breath odor alone is not

a reliable

diagnostic test; alcohol blood levels above 0.1 g/100 mL

are diagnostic.

d. Treatment includes rest and supportive conversation. If the patient becomes comatose, maintain a patent airway and administer normal saline, thiamine, and fructose.

2. Alcohol withdrawal follows the cessation or reduction of heavy, prolonged drinking. a. Severe withdrawal occurs in 5olo of patients and is characterized by tremors in the hands, tongue, or eyelids and delirium tremens (DTs) by the second or third day. b. The DTs are often associated with persecutory delusions, visual and tactile hallucinations, severe agitation, and autonomic arousal (tachycardia, sweating, elevated blood pressure). Life-threatening seizures may occur.

c. Treatment includes long-acting benzodiazepines, carbamazepine, thiamine, and

multivitamins. 3. Alcohol hallucinosis. This disorder is rare and is unrelated to other psychoses. Hallucinations (classically, frightening voices) and anxiety or irritability are the hallmarks of this condition. In approximately 90o/o of all cases, symptoms disappear in less than I week after alcohol is discontinued. 4. Alcohol amnestic disorder is a memory impairment due alcohol abusers. a.

If

acute,

a delirium

develops, marked

to thiamine deficiency in

by ataxia, ophthalmoplegia (particularly

abducens nerve palsy), reduced level ofconsciousness, agitation, and diffrrse cognitive

impairment. The acute syndrome (Wernicke encephalopathy) may be rapidly reversed by intramuscular thiamine administration.

b. Frequently, there remains a residual defect in recent and long-term memory and in learning (Korsakoff psychosis).

(1) These patients are alert and have no aphasia but suffer from retrograde amnesia (an inability to recall past events) and anterograde memory impairment (the

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Psychopathology

inability to lay down new memory traces, another definition of learning). They may fill in memory gaps with highly improbable information from the present, called confabulation. Confabulation, however, is not specific for Korsakoff psychosis.

(2) Patients with Korsakoff psychosis also have cognitive deficits in other domains and may be delusional and hallucinate.

(3) Peripheral neuropathy is common in

these patients.

(4) Treatment of Korsakoff psychosis is nonspecific. 5. Dementia from the direct toxic effects of alcohol on the brain is distinguished from alcohol intoxication or withdrawal. In the dementia, cognitive deficits must be present for at least 3 weeks after alcohol is discontinued. This disorder develops only after many years of heavy drinking. 6. Chronic alcohol abuse can also cause gastritis, pancreatitis, esophageal varices, cirrhosis, cardiomegaly, peripheral neuropathy, and cerebellar atrophy.

B. Barbiturate or sirnilarly acting sedative-hypnotic related disorders include disorders arising from the abuse ofbarbiturates, benzodiazepines, and other hypnotics. 1. Barbiturate intoxication. Symptoms are nearly identical to alcohol intoxication. As a barbiturate dependence develops, the margin between an intoxicating dose and a lethal dose narrows; it becomes easily possible to accidentally ingest a lethal dose. The treatment for acute intoxication is gastric lavage followed by a charcoal load to absorb the drugs that are not accessible by lavage.

2. Barbiturate withdrawal symptoms are virtually identical to those of alcohol withdrawal except that tremor is not always present. As with alcohol withdrawal, life-threatening seizures may be the first sign of withdrawal

3. Barbiturate withdrawal delirium include, a rebound increase in the amount of REM sleep, nightmares, disturbed sleep, and seizures similar to those of alcohol withdrawal delirium. Tieatment is with titrated doses of a long-acting barbiturate (e.g., phenobarbital). Abrupt withdrawal from these drugs should be avoided. 4. Barbiturate amnestic disorder is similar to that of alcohol amnestic syndrome. C. Opiate and opioid-related disorders are disorders caused by to the use of natural opiates (e.g., heroin and morphine) and synthetic opioids (e.g., meperidine and methadone). 1. Opiate/opioid intoxication a. Pupillary constriction is always present, except when there is profound tolerance or if the overdose has caused severe anoxia. In the anoxic cases, pupils may be dilated.

b. Body temperature drops and respiratory depression can occur. c. Mood changes are common, either euphoria or depression, along with indifference and psychomotor retardation. The person is sleepy with slurred speech and impaired attention and memory. Combativeness does not occur. d. For severe intoxications, naloxone can be life saving.

2. Opiate/opioid withdrawal follows stopping the drug after physical addiction has occurred. Even I week of continuous use can result in withdrawal symptoms if the drug is stopped abruptly. a. The clinical signs (called "cold turkey" or "kicking") closely resemble influenza, with low-grade fever, teary eyes, runny nose, sweating, diarrhea, insomnia, joint and abdominal pain, and piloerection. The time course of the symptoms varies with the

particular drug.

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b. Opiate/opioid withdrawal is uncomfortable and temporarily incapacitating

but

is

generally not life threatening. However, fetal death can occur during a pregnant woman's withdrawal. c. opiate/opioid withdrawal is treated with

a

long-acting opioid, methadone.

d. Chronic opiate/opioid injection use can lead to AIDS, subacute bacterial endocarditis, pulmonary edema, hepatitis, tetanus, and thrombophlebitis.

D. Cocaine-related disorders 1. Cocaine intoxication results in agitation, elation, talkativeness, grandiose ideas, tachycardia, high blood pressure, pupillary dilation, increased sweating, chills, nausea, vomiting, and hlperthermia. a. Hallucinations (e.g., bugs crawling under the skin [formication], geometric shapes), delusions ofpersecution, or seizures can occur ifcocaine is taken in high doses. b. Myocardial ischemia and fatal arrhythmias can occur in young individuals without

a

history of heart disease. c. The pleasurable, euphoric effects of cocaine result from augmentation of synaptic dopamine. The symptoms may resemble paranoid schizophrenia. d. Intoxication during pregnancy can cause fetal death from placental abruption. fetus survives, mental retardation and behavioral problems can occur.

If the

of cocaine intoxication requires a calm, supportive environment, urine acidification to enhance excretion, phentolamine or nifedipine for hypertension, and a neuroleptic (e.g., haloperidol) for psychosis.

e. Tieatment

2. Cocaine withdrawal is most commonly seen in individuals who use "free base" or "crack" cocaine or who use large amounts of very pure cocaine. Withdrawal is characterized by hypersomnia, depression (suicide is a risk), and hyperphagia. Antidepressant medications may reduce the craving.

E. Amphetamine or similarly acting sympathomimetic-related disorders

l.

Amphetamine intoxication symptoms are virtually identical to cocaine intoxication. Tieatment is also similar.

2. Amphetamine withdrawal. Within 3 days of cessation or reduction of amphetamine use, a syndrome characterized by depressed mood, fatigue, disturbed sleep, and increased REM sleep develops. Although the symptoms often abate within a few days, in some cases the depression persists, and there is an increased risk of suicide.

3. Stimulant delusional disorder is a psychosis caused by chronic use of stimulants. Persecutory delusions and ideas of reference (i.e., believing the behavior and remarks of other people hold special significance for oneself), aggression and hostiliry anxiety or agitation, and jerky movements commonly occur. Motor stereotypes and frontal lobe signs may also occur.

F. Phencyclidine (PCP) or similarly acting acyl cyclohexylamine-related disorders 1. PCP intoxication is characterized by nystagmus, elevated blood pressure, analgesia,

ataxic gait, dysarthria, and dizziness. Anxiety, euphoria, emotional labiliry grandiose ideas, a sense of slowed time and synesthesias (sensory cross-overs, e.g., sounds are "seen") occur. Full-blown mania with psychosis can occur. Sometimes these individuals are combative and aggressive; with higher doses they may lapse into catatonic and comatose states. Seizures may occur in higher doses.

226

lliBhicat

Psychopathology

2. The likelihood of combativeness and the increased risk of suicide in these patients requires the placement of restraints and rapid treatment. Treatment includes acidifting the urine to enhance excretion and benzodiazepines for sedation; neuroleptics (e.g., haloperidol) are given if the patient is psychotic. One should not maintain these patients in mechanical restraints for more than24 hours due to a danger of renal compromise. G. Hallucinogen-related disorders are caused by ingestion of substances such as lysergic acid diethylamine (LSD), dimethyltryptamine (DMT), psilocybin, and mescaline.

l.

Hallucinogen intoxication is characterized by a sense of intensification of stimuli, changes in body image, hallucinations (usually visual and sometimes kaleidoscopic), or synesthesias. The person remains alert. Classically, the hallucinations are recognized as being unreal. Other signs include pupil dilatation, tachycardia, dizziness, sweating, nausea, tremors, and impaired cognitive function. If the intoxication is mild, a calm reassuring attitude in a sensory reduced setting is sufficient. A single dose of a benzodiazepine or a neuroleptic may be needed if the intoxication is more severe.

2. Drug-induced psychosis is characterizedby continued hallucinations or delusions lasting 24 hours after hallucinogen use has stopped. These psychoses are treated based on the form they take (e.g., mood disorder, delusional disorder). H. Cannabis-related disorders 1. Cannabis intoxication is characterized by euphoria, indifference, intense perceptions, and a sense of slowed time. Thchycardia is always present but is more marked in occasional users than in chronic users. Conjunctival injection is also common. Dry mouth and increased appetite may occur. Pupillary changes are variable. Maladaptive behavior, such as extreme anxiety, persecutory ideas, or cognitive impairment, is necessary for the diagnosis.

2. Chronic cannabis disorders. Chronic heavy use can very rarely cause brief, emotionally intense psychoses. More commonly, chronic use results in an apathetic, amotivational syndrome and diffirse, moderate cognitive impairment. Tieatment is symptomatic. 3. Memory problems are apparent for the chronic user. Because the THC molecule has an affinity for neural receptors in the hippocampus, acquisition of new information is compromised.

I. Anticholinergic

toxicity. Many prescription and over-the-counter drugs have anticholiner-

gic properties. 1. Examples include atropine, scopolamine, most allergy and cold preparations, over-the-

counter sleep medications, antidepressants, neuroleptics, and antiparkinsonian agents.

2. Due to excessive self-medication or physician polypharmacf, toxicity can develop. Toxicity is characterized by flushed, hot skin ("red as a beet"), dry mouth ("dry as a bone"), pupillary dilatation ("blind as a bat"), and delirium ("mad as a hatter"). 3. Treatment is subcutaneous physostigmine for

I-2

days.

use. The major sequela of steroid abuse is atrophy of the gonads in the chronic user and aggressive behavior in the acutely toxic person. The latter is referred to as a "roid rage."

J. Steroid

K. Inhalants. The use of inhalants (e.g., gasoline, glue, nitrous oxide, paint, etc.) occurs predominantly in youth and dispossessed individuals. The effects are usually euphoric in nature with mild excitability. However, in the chronic user one can see compromised function of the liver, lungs, cranial nerves, brain, and other organs.

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L. Tobacco. The use of tobacco for the ingestion of nicotine remains widespread. Nicotine

is

addicting (i.e., the craving for the effects is intense), relatively inexpensive in most areas, and readily available; therefore, the motivation to terminate use is minimal. 1. Roughly

300/o

of the American population currently smokes cigarettes. An additional

3olo

uses smokeless tobacco.

2. The chronic long-term effects are disastrous: Iung cancer, chronic obstructive pulmonary disease, cardiovascular compromise, etc.; but most important, they are preventable. 3. Current levels of treatment success are poor. At the end of 1 year, only 25o/o of people who attempt to quit are still abstinent. Recent techniques of self-administered titrated withdrawal and media campaigns that decrease the attractiveness of smoking may have improved these success rates. The number of people who terminate use without official treatment is unknown.

FACTITIOUS DISORDERS AND MATINGERING These two conditions are different from the somatoform disorders because in factitious disorder and malingering the patient is consciouslyfabricatingthe symptoms. In factitious disorder, the patient is seeking the patient or "sick" role to achieve primary gain. In malingering, there is a conscious intent to deceive others for some secondary gain. A. There are three types offactitious disorders 1. Factitious disorder with psychological symptoms a. When psychoiogical symptoms are reported, the symptoms correspond to the patient's conception of a mental disorder and do not precisely fit any diagnostic category. b. The results of psychological tests are inconsistent. c. The patient may be quite suggestible and admit to many additional psychological symptoms or the patient may refuse to respond to any questions. d. The complaints and apparent symptoms may worsen when the patient is aware of being watched. e. Factitious disorders are more common in individuais with personality disorders and in medical professionals.

2. Factitious disorder with general medical symptoms a. These symptoms may be totally fabricated, self-inflicted, or an exaggeration

of

real

complaints. b. The patient's presentation of symptoms is rypically dramatic; often insists on hospitalization and readily submits to invasive procedures. c. The patient may produce symptoms through specific acts (e.g., secretly ingesting drugs, injecting contaminated water into the bloodstream), or the patient may simply give verbal reports of the complaints. d. Narcotic addiction is common in these patients.

3. Chronic factitious disorder with physical symptoms a.

In this disorder, also called Munchausen syndrome, the presentation of factitious physical symptoms is a way of lit-e and may result in frequent hospitalizations.

22s iliBtiical

Psychopathology

b. The patient is often noncompliant and demanding during treatment.

c. The patient frequently has a history of recurrent hospitalizations and multiple surgical procedures (physical examination will often reveal numerous postoperative scars).

d. These individuals complain of physical symptoms but rarely receive psychiatric care and usually have difficulty accepting a psychiatric diagnosis.

4. A new condition that is not included in the DSM-IV is factitious illness byproxy. In this condition, a person induces an illness in another individual (e.g., a mother induces an illness in her child by injecting urine into the child's bloodstream) to get primary gain of being seen as a nurturing, Ioving, caring parent. B. Malingering. Unlike factitious disorders, this is not

a

mental disorder and requires no psy-

chiatric treatment. 1. The patient reports psychological or general medical symptoms to achieve some easily recognizable secondarygain (e.g., to avoid undesired activities such as conscription into the armed forces, to obtain financial gain by suing a physician or hospital, to obtain narcotic drugs from emergency room physicians, etc.).

2. The patient exhibits no pathology upon examination and may become resistant when confronted with the lack of findings. 3. In practice, factitious disorder and malingering may be difficult to distinguish.

SEXUAT AND GENDER DISORDERS These disorders include disorders of gender identiry the paraphilias, and conditions associated with specific phases of the sexual response rycle.

A. Gender identity disorders. Gender identity is the sense that one is either male or female. Although gender identity encompasses sexual activiry it is far broader because people communicate their masculinity or femininity to others in many additional ways. Gender identity disorders involve a discrepancy between anatomic sex and gender identity. Tiue gender identity disorders are rare and do not include the much more common instances in which individuals feel they are performing inadequately in their role as a male or female. In such cases, these individuals clearly consider themselves to be male or female, and the role identity is in agreement with the anatomic sex. 1. Transsexualism a. In this disorder, there is persistent discomfort with one's anatomic sex and a wish to exchange one's genitals for those of the opposite sex and live as a member of the opposite sex. Transsexuals feel they are trapped in the wrong body. The duration of the feelings must be at least two years in order to make the diagnosis. The disorder is at Ieast twice as common among males than females.

b. To lessen the discord, transsexuals may cross-dress, that is, wear the clothing of the opposite sex (7 5o/o of male transsexuals begin cross-dressing before age 4). They may also assume the behavior and mannerisms of the opposite sex. Some seek out sexchange surgery, an emotionally, physically, and financially demanding procedure. c. The sexual history of transsexuals is variable. Some have had few experiences of sexual arousal and few sexual encounters. Others report active heterosexual lives, are married and have children. Still others indicate that they have engaged primarily in homosexual activity but, because they believe that they really belong to the opposite

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gender, they do not label their actions as homosexual. Feelings anxiety often accompany transsexualism.

of depression and

d. Certain factors seem to be associated with development of transsexualism.

(1) Often, girls who later become transsexuals

seem excessively masculine, whereas boys appear unusually feminine. For example, there is likely to be cross-dressing during childhood and a preference for toys usually associated with the opposite sex.

(2) Usually' the parent--child relationship is disturbed, most likely due to a parental reaction to the childt cross-gender behaviors rather than a cause ofthose behaviors. (3) In some cultures, this sexual variant is valued, and the person

assumes a very

important and sometimes religious position in the culture. e. Transsexualism is distinguished from transvestism, which is a variety of paraphilia in which cross-dressing is used for sexual excitement only and there is no disturbance of gender identity.

f.

Sex-change surgery is most likely to benefit individuals whose feelings trapped in the wrong body extend back to childhood.

of being

2. Gender identity disorder of childhood. As in transsexualism, this disorder is marked by discomfort with one's own sex and a desire to be the opposite sex. Children may insist that they actually are a member of the opposite sex or will grow up to have the genitals of the opposite sex. There is little interaction with peers of the same sex. Instead, a strong preference for playmates of the opposite sex exists, and the child chooses activities that are normally associated with the opposite sex. Cross-dressing is more likely in boys. This diagnosis does not apply to a boy or girl who does not fit the cultural gender stereotype. Gender identity disorder requires a rejection of one's own sex gender, as well as a strong desire to be the opposite sex. B. Paraphilias are disorders in which arousal is primarily adrieved with nonhumans or objects, through the suffering or humiliation of seH or others, or with drildren or nonconsenting adults. The person may not experience guilt or distress as a result of these activities, although society generally considers them unacceptable or illegal (e.g., with children). Social and sexual relationships may become strained as a result of these actions, particularly if the sex partner does not wish to cooperate. Physical harm to the partner may occur. These disorders are far more reported and convicted among men than among women.

Note Transvestic fetishism has

been reported to be as high as

in

I

in 40 males. They often

are only discovered in the emergency room after

a

traumatic event.

1. Fetishism. The preferred or only means of achieving sexual excitement is through the use of nonliving objects, such as shoes, stockings, or undergarments; or less commonly, isolated body parts such as feet or hands. a. Although many people are sexually aroused by looking at or touching specific parts

of

their partner's body, in fetishism the preoccupation is so strong that the rest of the person is disregarded.

b. Fetishism is not diagnosed in cases where the object is specifically designed for sexual gratification (e.g., vibrators) or when female clothing is used exclusively for crossdressing.

Note Because women are allowed

to cross-dress in traditional "male" clothes, this is an exclusively male condition.

zro iliEtical

2. Transvestic fetishism. In this disordeq a heterosexual male repeatedly cross-dresses to achieve sexual excitement. One or more articles of female clothing are involved, and some individuals with this disorder progress to dressing entirely as a woman. 3. Pedophilia. Sexual excitement is achieved primarily or exclusively though the act or fantasy of sexual activity with prepubescent children. Either boys or girls may be the favored sexual obiects.

Psychopathology

a. To make the diagnosis, the pedophiliac must be over age l6 and must be at least 5 years older than the child. Pedophiliacs who prefer boys prefer those over 10 years old, whereas those who prefer girls prefer those who are 8-10 years old. b. Homosexual pedophiliacs generally prefer somewhat older children and know their victims less well than heterosexual pedophiliacs; most pedophiles are heterosexual.

c. Individuals who seek out children for sexual activities at isolated times, e.g', when under marital stress or after the loss of a loved one, do not qualifr for this diagnosis because in these cases children are serving as substitutes for an unavailable adult and are not the preferred sexual partner. d. Incest is a special case ofpedophilia

(l)

Most commonly reported and prosecuted is "father" (grandfather, uncle, stepfather, mother's boyfriend) and daughter incest.

(2) Mother/son incest is reported to be relatively rare; however, recent data it is not that uncommon. (3) Sibling

sexual involvement is quite common; however,

it

suggest

is usually considered to

be normal during development.

(a) Twenry percent of American families report

incest.

(5) The primary etiologic variables for incest include the availability of the relationship; the perpetrator's inability to inhibit sexual arousal toward family members who are too close to marry; substance abuse by the perpetrator; hostility toward the spouse displaced onto the child; childhood sexual abuse of the perpetrator as a social learning variable; and dementia or other psychopathology.

(6) A need for affection, not

sex, may be

the overriding motivation.

(7) Ax expression of hostility may figure importantly. Often families tend to avoid discussion of the possibility of incest, and, in cases where it is occurring, the child may not be immediately believed if he or she reports the incident. Incest is taboo across mosl cultures.

4. Exhibitionism. In this disorder, sexual excitement is achieved by repeatedly exposing NOte one's genitals to unsuspecting strangers (adults, children, or both) and observing their

reactions. a. There is no further sexual activity attempted with the strangers and no threats physical harm. The individual may masturbate while exposing himself.

Exhibitionism and

of

voyeurism are prosecuted almost exclusively in males'

b. Exhibitionists often report that the urge to expose themselves is uncontrollable and compulsive.

c. They are usually immature individuals and are almost always male. 5. Voyeurism. In this condition, sexual arousai is obtained primarily or solely by observing unsuspecting people, generally strangers, who are naked, undressing, or are engaged in sexual activity. a. The voyeur achieves orgasm either by masturbating while watching others or later while recalling what he has seen.

b. There is no attempt at contact or sexual relations with the person(s) being observed. In fact, the person often enjoys thinking about how embarrassed the observed individuals would be if they knew they were being watched. c. Voyeurism and exhibitionism together account for most sexual offenses.

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Behavioral Sciences

6. Sexual masochism. Masochists derive sexual excitement chiefly from being humiliated, beaten, or otherwise made to suffer. a. Fantasies of such acts do not by themselves constitute masochism. b. There is the possibility of sustaining lasting physical damage as a result of these practices.

7. Sexual sadism. Sadists derive sexual arousal from inflicting pain, humiliation, or other forms of suffering on a consenting or nonconsenting partner. a. Some rapists have been found to have this disorder.

b. Often, sadism and masochism coexist in sexual partners. c. Women are more likely to be involved in a sadomasochistic sexual relationship than to be diagnosed as having other paraphilias.

8. Atypical paraphilia is a residual category for individuals who achieve sexual excitement through unusual objects or acts not otherwise classified. For example, necrophiliacs crave sexual activity with corpses, and zoophiliacs prefer animals. 9. Treatment of the paraphilias. Most individuals with these disorders come to the clinician's attention through the involvement of the legal system. a. These patients are often unmotivated to change because of the gratification the acts provide. Individuals who experience guilt or depression as a result of their behavior are generally more motivated to change.

b. Some males whose paraphilias result in rape or other antisocial acts respond to antiandrogen medications such as medroxyprogesterone. c. Behavior modification techniques, such as aversion therapy, have inconsistent efficary. d. There is no evidence that long-term psychotherapy is effective

in the treatment of

paraphilias. e. The recidivism rate among paraphiliacs is high, even activities result in iail terms.

for those individuals whose

EATING DISORDERS A. Anorexia neryosa 1. General considerations. Anorexia nervosa is defined as the obsessive pursuit of extreme thinness, leading to emaciation, disturbance of body image, and, in females, amenorrhea. a.

It may be increasing in frequenry in females ages 12-30. (Onset is mostly in teenage years.)

b. Ninety percent of patients are female.

c.

It is familial

(60/o

of relatives), and the monozygotic and dizygotic twin concordance

rates are 50 and 100/0, respectively.

d. Some anorexics may have a variant of a mood disorder. Persons with anorexia also have endocrine disturbances similar to those seen in mood disorder patients. Twentyfive percent also meet criteria for obsessive-compulsive disorder.

2. Clinical features a. Odd behavior around food, binge eating, induced vomiting, abuse of laxatives, and

ritualistic exercise are classic features.

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Psychopathology

b. Anorexics are not "anorectic"-they have normal appetites, but with overvalued and obsessive ideas of being overweight and needing to diet. Despite losing 15-25olo of their body weight, however, anorexics still have high energy levels. c. Amenorrhea is common. Associated features include lanugo hair (blond hair previously dark-haired individual) and Raynaud phenomenon.

in

a

B. Bulimia nervosa

l.

Bulimia nervosa is compulsive binge eating followed by pur$ng (e.g., vomiting, laxative abuse). Weight loss may be minimal, and many patients are overweight before the illness. Amenorrhea is less common than in anorexia nervosa.

2. Onset is in the early twenties; 1olo of women may be affected, and, 90o/o of patients are female. Higher socioeconomic groups have a higher incidence of disease. Alcohol abuse and mood disorder are both more common in bulimics and in their families than in the general population. C. Biologic correlates of eating disorders

l.

Anorexics have more severe abnormalities than do bulimics.

2. General medical problems include anemia, abnormal liver function tests, hypercholesterolemia, dehydration resulting in elevated BUN and electrolyte imbalances, osteoporosis, tooth decay (from acidic vomitus), abnormal glucose tolerance with fasting hypoglycemia, elevated cortisol levels, nonspecific EEG abnormalities, hlpothermia, etc.

DISORDERS OF CHITDHOOD AND ADOTESCENCE The principles of diagnosis and treatment are the same for children and adults. Teachers are often involved in the recognition of the problem and in its management. In most cases, the clinical features of childhood-onset psychiatric conditions are similar to their analogous adultonset conditions. Family theory. For children, intensive family involvement is required for history taking, medical compliance, supervision, psychotherapy, and behavioral management. Although there are a variety of theoretical approaches contained under the heading of family theory, all share the view that psychological distress in a child is inseparable from the family as a whole. Most people who work in this area agree there are roles established in the family structure. The roles are stable, but who fills which role may change. If one of the roles is an "illness" role, and if the person filling it is "cured" without the family structure being changed, then someone else will fill the role.

Family therapy. The identified patient's problems are defined in the context of family interaction patterns. Treatment will then involve all who have a role in maintaining the problem or who could help alleviate the dysfunction.

A. Mental retardation 1. The prevalence of mental retardation in the United States is approximately l%.

2. Criteria for diagnosis a. Subaverage intellectual functioning, defined as an IQ that falls at least 2 standard deviations below the mean on an individually administered intelligence test, i.e., an IQ

of 70 or less. b. Deficits in adaptive behavior. The degrees to which the individual is able to function independently and to meet culturally imposed demands regarding social responsibility are impaired relative to other individuals of the same age.

ilitsticat

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Behavioral Sciences

3. Classification

of mental retardation is dependent upon the

degree

of

intellectual

impairment. a.

Mild retardation (IQ 50-70) is roughly equivalent to the educational category of "educable" and accounts for approximately 75-90o/o of individuals classified as retarded. (

I

) Mild mental retardation

is often not apparent until a child enters school.

(2) Mildly retarded individuals can achieve academic skills up to approximately the 6th grade level.

(3) As adults, they are able to hold unskilled or semi-skilled jobs and are fairly independent.

(4) Etiology is usually multifactorial but may be caused by a single

gene.

b. Moderate retardation (IQ 35-49) is roughly equivalent to the educational category of "trainable" and accounts for approximately 6-200/o of individuals classified as retarded.

(1) As children, most moderately retarded individuals are placed in

classes that

emphasize self-care skills rather than academics; they can achieve up to approximately the 2nd grade level.

(2)

As adults, they can attend sheltered workshops and are likely to require guidance.

c. Severe retardation (IQ 20-34) includes approximately 3olo of individuals diagnosed as retarded. They may be able to communicate basic needs and to engage in some selfcare activities with appropriate training. Severely retarded individuals need constant supervision. d. Profoundretardation (IQ below 20) includes approximately 1% of individuals diagnosed as retarded. Profoundly retarded individuals are very limited in self-care and communication skills. They require constant supervision and nursing care; they may have severe physical deformities and extensive neurologic damage and may be nonambulatory.

4. Chromosomal abnormalities lead to various disorders, many of which have behavioral manifestations. In addition to spontaneously occurring abnormalities, external agents such as viruses, chemicals, and ionizing radiation may cause chromosomal abnormalities. a. Down syndrome occurs in both males and females with an extra chromosome 21 (trisomy 21).

(l)

Physical manifestations include a flat nasal bridge, epicanthic folds, a short trunk, and cardiac anomalies, such as ventricular septal defect.

(2) It

is the most common chromosomal abnormality leading to mental retardation and accounts for at least l0%o ofmoderately to severely retarded children.

(3) The risk of having a child with Down syndrome nal age

(l in 1,500 for a mother

increases with increasing materin her 20s; 1 in 65 for a mother over 45).

b. Fragile-X syndrome, caused by a mutation of the FMR gene (expanded trinucleotide repeat), is the second most common single cause of mental retardation. Affected males have moderate to severe mental retardation, testicular enlargement, and macrocephaly. Affected individuals are also prone to mood disorders. Carrier females may have mild to moderate retardation.

c. Klinefelter syndrome occurs in males with an extra X chromosome. Approximately 25o/o of males with this syndrome are mildly or moderately retarded.

2t4 iliBficat

5. Recessive genetic disorders causing mental retardation a. Phenylketonuria (PKU) results from a deficiency in the enzfme phenylalanine hydroxylase, which converts the amino acid phenylalanine to tyrosine. (

l

acid and other metabolites build up, causing extensive neurologic damage by interfering with myelination'

) As a result, phenylpyruvic

(2) Untreated PKU results in mental retardation. Other characteristics include retarded motor and speech development (speech is absent in over 600lo of the cases),

irritability, and erratic behavior, such as destructiveness, rocking, and arm

waving.

(3) The restriction of phenylalanine from the diet until

age 6 may

permit normal or

nearly normal intellectual development. b. Tay-Sachs disease is caused by a deficiency of hexosaminidase A and results in the accumulation of Gm2 gangliosides. It is most commonly found in Ashkenazic jews and is generally fatal before age 4. c. Niemann-Pick disease is caused by a deficiency of sphingomyelinase activity, which results in the accumulation of sphingomyelin. It is characterized by gastrointestinal disturbances, malnutrition, and progressive paralysis.

syrup urine disease is caused by a defect in branched-chain amino acid metabolism. It is usually fatal before age 1.

d. Maple

e. Lesch-Nyhan syndrome is a sex-linked disorder found in males caused by a deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT). It results in gout, impaired renal function, and aggressive self-mutilating behavior (e.g., head banging

and chewing off fingers and toes).

f. Hunter syndrome is an X-linked defect in mucopolysaccharide metabolism. Affected individuals present with a large head with a protruding forehead, thick lips and eyebrows, and deformed limbs. It is often fatal in the teens.

6. Infectious diseases causing mental retardation a. Rubella (German measles) may result in defects to the fetus if the mother is infected

during the first trimester; defects are especially likely during the first month of

pregnancy. Rubella may cause deafiress, blindness, and heart disease as well as mental

retardation. b. Congenital syphilis results in defects to the fetus during the second half of the pregnanry. Development of eighth-nerve deafrress may occur.

c. Toxoplasma gondii is a protozoa acquired from the ingestion of rysts in undercooked meat. If the child is infected during development, it may cause encephalitis, hepatosplenomegaly, intracranial calcifications, and chorioretinitis as well as mental retardation. d. Cytomegalovirus is a herpesvirus that causes cytomegalic inclusion disease in the

fetus

if the mother acquires the primary infection during pregnancy. It may

cause

deafness, microcephaly, and chorioretinitis as well as mental retardation.

7. Miscellaneous causes of mental retardation

If the mother is Rh-negative and the fetus is Rh-positive, the mother may produce anti-Rh antibodies, causing a severe hemolytic anemia and kernicterus. This occurs only after the first pregnansy with an Rh-incompatible fetus.

a. Rh factor.

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Behavioral Sciences

b. Cretinism can result in profound mental retardation, dwarf-like appearance, course features, and stubby limbs if the defect is not corrected by thyroid extracts given to the infant at birth. Thyroid function screening at birth is mandatory by law. c.

Malnutrition during pregnancy can result in low-birth weight infants with

delayed

development and mild retardation. Childhood malnutrition may slow development well.

as

d. Lead and mercurypoisoning. Lead poisoning may result from automobile emissions or from ingestion of lead-based paints, and mercury may be found in water that has been a dumping ground for certain industrial wastes. e. Anoxia at

birth can cause mental retardation

associated

with cerebral

palsy.

8. Cultural-familial or psychosocial causes of mental retardation account for approximately 75o/o of all cases. It should be considered in individuals with mild retardation who have no evident neurologic impairment and in whom retardation is evident in at least one immediate family member. Cultural-familial retardation is generally found in lowincome families where nutrition, medical care, and intellectual stimulation are often inadequate. Statistics suggest that a child growing up in poverty is 15 times more likely to be diagnosed as retarded than is a child from a family with a higher income. The likelihood of retardation increases if the mother's IQ is significantly below average (i.e., less than 80). Children whose mother's IQ is near average are less likely to be retarded. B. Pervasive developmental disorders (PDD) is a clinically heterogeneous and severely incapacitating group of disorders with a prevalence of approximately 15/10,000. Affected children display distortions in basic psychological functions and have odd social patterns and language. There is wide range of severity.

1. Infantile autism is the most severe form months.

of PDD. By definition, onset is before 30

a. The child lacks normal responsiveness to other people.

b. Impairment in language is invariably present and may include echolalia, abnormal speech melody, and, occasionally, total absence of language. c. A need for sameness in the environment may lead to catastrophic reactions from minor changes such as the position of furniture. d. The child also displays investment of ualistic behavior.

trivid objects with extreme importance and rit-

e. There is no shared inheritance between autism and schizophrenia.

2. Childhood-onset pervasive developmental disorder. By definition, this disorder has its onset between 30 months and 12 years of age. As with autism, there is a profoundly distorted response to other people. Affect and behavior are odd, and there may be abnormalities of speech reminiscent of infantile autism. C. Childhood affective disorders. Depression can occur in all ages. Depressions in childhood are similar to those in adult life, but young children may have more somatic complaints. Childhood suicide is rare but adolescent suicide is increasing in the United States and is the third leading cause of death in teenagers. Only a small number of bipolar patients develop manic episodes before adolescence. Psychotropic medications, family therapy, and individual therapy are the treatments of choice. D. Childhood anxiety disorder

l. 25G

iiiBtical

Specific phobias most often begin in childhood, with animal phobias being the most common. Tieatment is the same as for adults.

Psychopathology

2. Separation anxiety disorder is characterized by fear ofbeing away from one's parent or other familiar adults. a. Fears include being alone, leaving home, going to sleep, and going to school (75o/o

of

cases ).

Clinical Correlate Note the relation of separation anxiety disorder to "normal" separation anxiety in infants.

b. Usually, the onset of this condition follows illness in the mothering figure, with the child becoming fearful that if the child leaves, the mother will die. This may be a precursor to adult social phobia or agoraphobia. c. Treatment for this disorder is in vivo desensitization, which requires the child to go to school, and, once there, to call home to verifi the mother's well being, to are allowed on an as-needed basis. This treatment is cuite effective. E. Disruptive disorders 1

. Attention deficit hyperactivity disorder (ADHD) affects approximately l0olo of boys and 2o/o of girls.It is the most common reason for referral to a child psychiatrist. a. Children present

with attention difficulties, distractibility, short-attention span,

and hyperactivity (fidgeting, running around, speaking excessively, intruding into actions of others). b. The treatment of choice is short-acting stimulants (dextroamphetamine or methylphenidate). After treatment, most children are able to function adequately in school. However, it is important to note that children do not outgrow this disturbance. They simply accommodate to the dysfunction. 2. Conduct disorder affects approximately I0o/o


children, boys more than girls.

a. Children present with bullying, fighting, stealing, and the triad of cruelty to animals, fire setting, and enuresis (bed wetting). Truancy and running away from home often occur. b. Thirty-seven percent

of these children have antisocial personality disorder

as

adults. c. Operational defiant disorder. The behavior is very much like the child who is in the "terrible two's"; however, the child is in the age range (4 to adolescence) where it is developmentally inappropriate. Behavior is hostile, quite negative, confrontational, and defring. It tends to get worse with age. They deliberately do tiings to annoy others, and their behavior is worse at home or with people they know than with strangers (e.g., their physician).

Elimination disorders 1. Enuresis occurs in approximately

I

0% of boys and 2o/o of girls. It is strongly familial.

a. Children are diagnosed with the disorder when they wet the bed or wet their clothing

frequently after age 5. b. Secondary enuresis can result from low bladder threshold for elimination, urinary tract infection, excessive use of caffeinated beverages, and reduced night-time ADH

production. c. Tieatment for primary enuresis includes restriction of fluids after 6:00 ln, taking the child to the bathroom 1-2 hours after sleep onset, and behavioral techniques such as the bell-and-pad device, in which a bell is triggered by nocturnal urination.

iliBbical

2r7

Behavioral Sciences

2. Encopresis occurs in approximately l.5o/o of the population, more frequently in boys than

in girls. a. Children are diagnosed with the disorder when they are incontinent of feces several times montily for several months after age 4. b. Secondary encopresis can result from hypothyroidism, anal fissure, lactase deficiency, Hirschsprung disease, and overeating of fatty foods.

c.

ln

75-95o/o of cases, the child has chronic constipation with fecal impaction and overflow incontinence. Occasionally, a child withholds feces because of fear of falline into the toilet.

d. Treatment for primary encopresis includes education of the family, treating the con-

stipation and impaction, instituting a high-fiber diet, and rewarding normal bowel movements.

2t8 ifiiitii cal

SECTION VI

U.S, Health Care

U.S. Health Care

There are demographia and developments within the health care system that are important for the understanding and planning of health care delivery. This chapter tocuses on the present characteristics, changes, and future directions in health care. lt also examines alternative models of

health care deliverv in other countries.

DEFINITIONS A. Morbidity data: The prevalence of a given condition within disability created by the condition

a

population and the degree of

B. Mortality data: This figure is expressed as the number of deaths per 100,000 in a population. It be can sorted by different variables, e.g., cause of death, o/oby age grouP' o/o by race, etc. C. Reportable diseases: These are diseases that must be reported to responsible agencies' Syphilis, gonorrhea, and AIDS are the only sexually transmitted diseases that must be reported in all states. Individual states may have additional reportable diseases.

Note Questions related to the U.S. Health Care System

have become relatively rare on the USMLE Step L Donl spend too much time

HEAIIH CARE CHARACTERISTICS

reviewing this chapter.

issue at this time is health care costs, which inflation rate and show no signs of slowgeneral the higher rate than at have been increasing (GNP) is devoted to health care product national the gross percent of ing down. Fourteen

A. Current problems in U.S. health care. The major

expenditures.

B. The American population is aging. There is one birth every 8 seconds, but there is one death every 14 seconds. As the population ages, more people will have chronic illnesses. Although the aged currently represent about I2o/o of the population, they consume 30olo of the health care costs.

C. There are 45 million Americans without health care insurance. This figure is growing, particularly as more people turn to part-time and temporary employment. Most of the uninsured are children. D. Life expectancies trends. Today, more people are living to be elderly. Previously, many infants and children died from infectious diseases. Today, with the advent of effective antibiotics and disease control, fewer people are dying )roungr and the general life expectanry figure is increasing.

l.

Females live longer than males.

2. White females > black females > white males > black males 3. Being poor is hazardous to your health.

iiiBhical

241

U.S. Health Care

E. Trends in health care 1. Hospital stays are shortened. With the advent of outpatient surgery and "managed care," the length of hospital stays has decreased to the point that many hospitals are fiscally compromised and must consider closure. This is more of an issue for rural hospitals than for urban facilities.

2. Females use services more than males. This is true even when the data are controlled for pregnansy and childbirth. 3. The frequency of physician visits increases with age. Eighty-five percent of the elderly population have one or more chronic conditions that require increasing management as the patient ages.

4. Physician supply. There is an ongoing argument regarding the number of licensed physicians. There are currently over 700,000 MDs and DOs licensed to practice in the U.S. a. Some argue that there are too many physicians produced by the education systems and licensing procedures.

b. Others argue that there are too few, given that rural and inner city areas do not have an adequate supply of physicians. c. Most everyone agrees that there is uneven distribution of the geographic sites of practice. That is, there are too many physicians who locate their practices to affluent areas, thereby yielding a relative shortage of physicians in inner ciry and rural areas. d. Presently, there is an increased use and greater expansion of the practices of physician extenders, e.g., physician assistants and clinic nurse practitioners, to address the problems of inner city and rural areas.

HEATTH CARE DETIVERY A. Facts about health care expenditures 1. Hospitals consume most of the fiscal resources paid. Hospitals are large businesses that have fixed expenses and variable expenses relative to patient census.

2. The most orpensive component of anyhospital budget is personnel. Again, these expenses can be fixed or variable, dependent on patient census. The fixed expenses (mainly administration personnel) are being addressed via the mergers of hospitals to create an economy of scale. The variable expenses are those employees who deal directlywith patients. If the patient census is low, the number of these employees can be decreased. Also, outpatient performance ofpreviously inpatient procedures lowers a 24-hour hospital personnel roster.

3. Physician costs are the second highest expense. For this reason, many health care facilities are using physician extenders such as physician assistants and nurse practitioners. Physicians then supervise the practice of these less extensively trained caregivers. 4. Medication costs are the third highest expense. To address this issue, many facilities are now using a restrictive formulary in which they stock only lower-cost medications (e.g., generics). Rarely used and expensive medications are available only via special order.

B. Hospitals and related facilities 1. Types a. General medical-surgical (GM&S). Acute care facilities that may or may not have subspecialty units (e.g., mental health)

z4z ilits[ical

U.S. Health Care

b. Psychiatric. Some hospitals are devoted entirely to the acute and chronic care of the

mentally ill. c. Nursing homes. Facilities that care for individuals who are unable to care for themselves due to physical and/or mental disability (

1) Only 5% of the elderly population lives in nursing homes.

(2) Most nursing homes

are proprietary (for

profit),

(3) Medicare does not pay for nursing home

and 4lo/o are owned by chains.

stays.

of the total payment for nursing homes comes from Medicaid; however, Medicaid is available only to those individuals whose total

(4) Forty-eight percent

resources are depleted. d. Adult care facilities. Adult day care centers give daytime supervision and some medical care to disabled individuals whose families are unable to care for them during the day.

e. Respite care. Adult day care centers that offer 24-hour care for several weeks to permit family members a "break" (respite) during that time. This gives the family enough relaxation time to let them provide care for the rest of the year.

2. Ownership. Most hospitals and related facilities are owned and operated by federal, state, city, or nonprofit organizations. For-profit hospitals are being merged by large companies to concentrate ownership and develop "economy of scale." 3. Structure and organization a. Governance. The governing and legally responsible body of the hospital is the board of trustees or a similar group. They are responsible for hiring the chief executive officer (CEO). b. Medical staff. The staff may be open, i.e., anyone has the authority to hospitalize, or it may be closed, with only those approved by the hospital's governing body given the authority to admit and treat patients. A medical staff typically has subcommittees to handle credentials, medical records, etc.

c. Internal organization. TypicalLy, there are departments that oversee large divisions such as nursing, laboratories, administration, etc.

HEATTH CARE FINANCING: WHO PAYS FOR HEATTH CARE? A. Government programs: Federal, state, and Iocal = 4lo/o 1. Federal. The Health Care Financing Administration (HCFA) is usually responsible for the management of government programs. a. Indian Health Service (IHS) b. Medicare. 100o/o Federal funding for the aged (65+) and disabled

c. Medicaid. Federal and State combined funding for those who qualify

for public

In a Nutshell

assistance (welfare)

d. United States Public Health Service (USPHS) e. National Institutes of Health (NIH)

f. Substance

Abuse and Mental Health Administration

Medicare: Federally funded care for the elderly (6S+)

Medicaid: Federally and statefunded care for the poor and/or incapacitated

ilitsbicat

24t

U.S. Health Cate

2. State (often for the indigent) a. Mental hospitals

b. GM&S c. Teaching hospitals 3. County and city hospitals (often for the indigent) a. GM&S b. Mental hospitals

c. Teaching hospitals (usually by affiliation) B. Third-party carriers (insurance companies) = 3lo/o C. Patient :260/o

l. Direct

Benefit limits, co-insurance' co-Payments, deductibles

2. Indirect: Premiums on health insurance carriers D. Charity (e.g., physician doesn't bill; free clinics, etc.) = unknown

MODETS OF HEATTH CARE DETIVERY A. Definitions Subscribers pay a fixed amount each month to receive a full benefits packof whether they seek care. However, certain benefits can be "carved out" of the beneflts package, e.g., mental health, alcohol and drug abuse' etc'

L Capitation:

age, regardless

a. Covered lives is the number

(carrier)

of enrolled individuals a given health

care provider

has.

b. The financial goal of the provider is to enroll as many health subscribers as possible and to treat them efficiently and inexpensively'

c. This is the foundation of health maintenance organizations (HMOs) and provider groups that receive contracts from HMOs.

2. Cost management: To contain costs, Iimits are set on the practices of physicians. HMOs and other systems (e.g., preferred provider organizations, PPOs) control such factors as the length of hospital stay, the variety of drugs in the formulary that can be prescribed, the number of outpatient visits allowed for certain condition, etc. Other cost management components are deductibles, coinsurance, and copayments. a. Deductibles: The amount of money the patient must pay out-of-pocket before the carrier will begin to reimburse. b. Coinsurance: That part of the "after-deductible" costs that the patient must pay' e.g.' the carrier pays 80% and the patient must pay the remaining20o/o'

c. Copayment An additional amount that the patient pays for certain added services, e.g., an additional fee for a prescription' 3. HMOs are a type of managed care. a. Totallycapitated care. Fee-for-service is not paid. b. Disincentives to use expensive hospital or laboratory services

244 iiiBbical

U.S. Health Care

c. Must see a physician who is on the plan's "panel": The list of physicians who receive money from the HMO and who agree to follow the guidelines of the HMO. Referral to specialists must be by the patient's primary care physician. d. Different types

(l)

Staff/group modet Salaried staff physicians are paid to

see

the patients on the

HMO plan. (2) Closed panel model Physicians

are paid on a capitated basis or a fee-for-service basis to see the patients on the HMO plan. However, the physicians may see nonHMO patients on a fee-for-service basis. A variant of this is the network model,

where the HMO contracts with both individual physicians and groups.

(3) Individual (or Independent) Practice Association (IPA) modet Physicians work in their own offices, but they contract with an HMO to see the HMO'5 patients at a discounted reimbursement rate.

4. Managed care Primary

care "gate keeping"

to specialist referral

a. Primary care: General internal medicine, general pediatrics, family medicine b. Number of enrollees is increasing each year.

5. Prospective Payment systems: Assigning specific payments in advance for given diagnoses and physician activities. There are two major fires: a. Diagnostic-related groups (DRGs): This is a prospective payment system in which a given diagnosis is reimbursed a fixed amount. If the provider (e.g., hospital) can do it for less, the excess reimbursement can be retained by the provider. If it costs more, the

provider covers the cost. b. Resource-based relative value scale (RBRVS): This is another prospective payment system in which the provider (the resource) checks boxes on a form for all procedures performed on a patient. Reimbursement is based on a fixed amount for each procedure. The actual cost and the amount reimbursed canvary widely.

B. Solo practice: A physician who is practicing alone and handling all patient care, billing, collecting, etc. C. Partnerships: TWo or more physicians share the same space, office personnel, laboratories, etc. Partnerships may be single specialty or multiple specialty. Partnerships are usually informal and not incorporated. D. Group practice: Three or more physicians formally organized into a single practice setting. Group practices may be single or multiple specialty.

E. Preferred provider organizations (PPOs): A group of physicians organize to offer services to a carrier at reduced rates in order to get all of the referrals from the carrier. This is usually a feefor-service arrangement, but the patient gets significant savings by using the PPO physicians. If patients choose to go outside the PPO group, they bear more of the costs themselves and they may not get a reduced rate.

F. Other health care systems 1. TheCanadiansystem a.

All Canadians are covered. There is universal

coverage

for basic medical care for

everyone. b. Single payer. The Canadian government pays for all basic care; however, the rates are negotiated with provincial representatives on an annual basis. Physicians are paid on a fee-for-service basis.

iliBtical

245

U.S. Health Care

c. Freedom of physician choice. Because all physicians paid by the government, patient can see the physician ofher choice.

a

d. No deductible. The patient does not have to pay a given amount of fees before government reimbursement begins. e. Rationing of services. Some services may be covered in one province but not another. Availability of some specialty procedures may be on a waiting list basis.

f.

Due to the rationing of some services, there also exists a private system with private coverage for the rationed procedures. In addition, many Canadians come to the United States to seek care.

2. The British system (Note: The British health care system frequently changes.) a. Two coexisting systems:

(1) National Health Service for everyone. This is similar to the Canadian system. Common procedures and care are covered by the government.

(2) A private system for those who can pay. All physicians can work in this system and are given time off to do so. The private system handles those services and issues that are not readily available from the National Health Service.

b. Most care is via general practitioner with referral to specialists. However, if a person can afford it, she can see the specialist of her choice.

246 iiiB&ical

sEcTroN

vtl

Biostatistics and Epidemiology

Biostatistics

Biostatistics uses quantitative methods to analyze and interpret data obtained from scientrfic study. These methods allow investigators to understand how certain risk factors might affect the outcome

of disease, how certain drugs might affect the body's physiologic responses, and even how one physiologic process may affect another. The final results may be used for further research studies or may be applied directly to clinical decisions and patient care.

TYPES OF DATA The observations made in clinical care or medical research can be broadly divided into several types.

A. Binary or dichotomous variables can take on only two values, such as absent or present, positive or negative, male or f'emale, alive or dead. range ofvalues. These types ofvariables are found when measuring items such as age, systolic blood pressure, serum sodium, and survival in months. Continuous variables are scalar; the distance between units of measurement remains constant over a range ofvalues. For example, the distance between a serum sodium of 125 and 130 is equal to the distance between 135 and 140.

B. Continuousvariables can take on

a

C. Ordinal variables have inherent ranking (i.e., each higher value connotes a greater degree of the attribute being measured or described), but they need not be scalar. For example, the interpretation of a lung scan as low, medium, or high probability connotes a worsening of disease, but the difference between low and medium probability is not equal to the difference between medium and high probability. D. Categorical variables have no inherent ranking and have meaning only within their category. For example, eye color can be measured as blue, green, or brown; no one color is greater than the otheq and none of the colors can be used as measurements in another category.

iiiBhical

24s

Biostatisliclq{ Epidemiology

UN

IVARIATE COMPARI SON S

Given the measurerlent of a variable in a series of experiments, a population of individuals, or another setting, it is often useful to quantitatively summarize the characteristics of the phenomenon being described.

A. Frequency counts are most commonly used to describe the attributes of noncontinuous variables, but they may also be used to describe the attributes of continuous variables. Examples include the percentage of a population that is male or female; the percentage of In a Nutshell

patients who had prostate biopsies revealing benign prostatic hypertrophy; or the percentage of plasma specimens, received by a laboratory, with sodium values that fall within a given range.

Mean =

number of the values of the observations

number of observations

The mean will not show the distrrbution of the sample and can be influenced by extreme values.

B. Mean (or a'"'erage, X) is often used to summarize the attributes of continuous variables. The mean is the sum of all the values of the observations within a sample divided by the number

of observations. Mathematically, the mean is given by

i,

where rr is the number of values in

the sample, and x is each individual value. For example, in a classroom of children, the are 4, 9, 5, 8, and 4. The mean age is theretbre 30/5

=

6.

A drawback of the

n.rean is

ages

that it

cannot convey the distribution of the sample, i.e., how the actual values in the sample cluster around the mean. Another drawback of the mean is that it may be influenced by extreme values. For example, in a classroom of 10 children, a child who is 6 feet tali will dramatical-

ly change the mean so that it may not accurately reflect the average height of most children

in the In a Nutshell Median = the middle value, above and below which fall an equal number of observations.

class.

C. The median, which is also used to summarize the attributes of continuous variables, is the value that divides in half the number of observations within a sample. In the example used previously, the median is 5, i.e., half of the children are above age 5 and half of the chiidren are belorv age 5. The median has the advantage of being less dramatically influenced by extreme values than is the rnean. For example, if the oldest child in the class was 19 instead of 9, the new mean would be 40/5 or 8, but the median would be unchanged. D. Other percentiles may be used to describe the distribution of a continuous variable. Whereas the median represents the 50th percentile, the sample could also be divided in quarters (quartiles), thirds (terciles), or tenths (deciles). Percentile rankings are often used in an academic setting, i.e., describing a person's academic status as performing in the "top tenth" of his class.

Note The mean, median, and mode are described as measures of central tendency.

250 lliBhicar

E. The mode is the most commonly occurring value in a sample of observations. For example, in a study of normal male development, the most comrnon age fbr the onset puberty was i2; 12 is therefore the mode of this study sample. In a perfectly normal curve, the mean, mode, and median are all the same.

Biostatistics

DISTRIBUTION A distribution is the "spread" or "shape" of a variable as measured in a population. Typically, a distribution is represented graphically by plotting the values of the variable of interest on rhe ,r axis and its frequency (the number of observations per discrete value) on the 7 axis (Figure VII- I - l ). Naturally occurring phenomena tend to adhere to a handful of commonly recurring distributions, the most important of which is the Gaussian, or normal. distribution.

q)

G -c (g

c)

c

= = o (u

f

E :>

o

.c

mean \

6

_o

E

z=

Note Value of attribute beino measured (e.g., systolic blood pressure)

In a normal distribution, the

mean=median=mode.

Figure Vll-1-1 . Gaussian, or normal! distribution.

A. The normal distribution is characterized by a classic bell-shaped curve. It is important for several reasons.

1. Clinical and physiologic measures often confbrm to the normal distribution. For example, the measurement of a physiologic measure (e.g., systolic blood pressure in a group of 52-year-old men) typically reveals a peak at the mean or average, with more or less extreme values occurring less frequently as one moves farther away from that rnean.

2. Repeated measurements of the same phenomenon conform to the normal distribution. For example, the same observer measuring the height of the same individual will obtain slightly diff-erent values with each attempt due in part to measurement error. A plot of the frequency with which each height was obtained versus the measured heights conforms to the normal distribution. 3. Many statistical tests used to compare nleans assume that the variables being tested normally distributed. If they are not, the statistical test may be invalid.

are

B. Other distributions frequently used in biostatistics include:

l.

Bimodal distributions show two peaks reflecting two commonly occurring

values

(Figure VII- 1-2).

lii$hicar

2sl

Biostatistics and Epidemiology

q)

f

(g

-c Cu

o _c

'=

65 .>

.c (D

zf Value of atribute being measured

Figure Vll-1 -2. Bimodal distributions.

Note 2. Skewed distributions show a normal distribution curve shifted slightly right or left of the mean (Figure VII-1-3). The skew is named by the longest tail; e.g., the distribution in Figure VII-1-3 is a positive skew.

In distributions with a positive

skery the mean is greater than the median. ln

a

negative skew, the mean less than the medtan.

is

C. Parametric tests make some assumption about the distribution of the data being compared. For example, Student's f test, which is used to compare the means of two samples, assumes that within each of the samples, the variabies being compared follow a distribution known as the t distribution. Thus, Student's t test is a parametric test in that it makes assumptions about a certain parameter of the data. Most parametric tests assume the distribution will be Gaussian.

q)

f

6 _c (d (D

_c

=3 o

(5

f E :>

.c

z Value of attribute being measured

Figure Vll-1-3. Skewed distributions. D.

252 liiBhical

Nonparametric tests make no assumptions about the underlying distribution of the data being compared in the two groups and are therefore sometimes called distribution-free tests.

Biostatistics

The Fishel Exact test, itr rvhich pertrutations o1'r.roncontinuous variables are generated and compared with the observed clata, is an examp'le of a nonparar.netric test. Nonparametric tests are generally used on small samples or o11 sarnples that are noncontinuous.

DEVIANCE, VARIANCE, STAN DARD ERRO& AND STANDARD DEVIATION A. General considerations. A variable that is norrnally distributed

says nothing about how most of the values apprclximate the mean of the sample (i.e., the area under its curve). For example, all of the values of systolic blood press,rre may cluster immediately around the mean (yielding a tal1, thin curve), or there may be a wide rar.rge of values (yielding a broader l-run-rp). The standard deviation is used to express tl-re proportion of values that falis within a section of the curve (for example, the inner 95%). Caiculation of the standard deviation requires a calculation ofthe deviance and variance.

B. The deviance (also called the sum of squart-s) is given by )(x, - X)r, where x; is each individual value irr the series arrd X is the rrrearr. The deviarrce, theret'ore. is calcuiated by subtracting the mean fiorn each individual value, squarins that value, and then summing the sum of all the squared values. Note that the deviance rnust be positive. C. The variance is obtained by clividing the cleviance by N -tr = the saml.le: -

l(-t, X): N-l

.

-

I, the number of observations in

Variance is the measure that indicates the extent to which the

values in the distribution depart trom the mean.

D. The standard deviation,

,s,

is calculated by taking the square root of the variance:

tr=l(r;-X)2

\'-

It is easier io visualize the

N-1

standard deviation than

E. Attributes of the standard deviation. The standard deviation is a useful descriptor of the distributior.r of a norrnal sarnple. In a normally distributed sample, 95o/o of the values will be includedLrfheinter-val rrl Xt l.9tr.s. lTlrisissornt'tirnesreterrecltoasag5,,uconflclenceinterval.) For example, if the rnean systolic blood pressure of a group of 5O-year-old men is reported to be 1 30 mm Hg with a standard deviation of 10, then 95olo of men rvill have systolic blood pressure readings between 110.,1 and 149.6 rnm Hg (i.e., 130 + 19.6) (FigureVil-l-4).

100 110 120 130 140 150 160

Note

the variance because the units in the standard deviation are the same

as

in the original observations

170

Systolic blood pressure (mm Hg) Figure Vll-1-4. Systolic blood pressures in a group of men.

IiiBhical

255

Biostatistics and Epidemiology

BIVARIATE COMPARISONS The comparison
prevention of stroke.

Stroke

No

Stroke

Total

Aspirin

6

)+

60

Placebo

t2

68

80

Total

l8

t22

140

The rate of strokes in patients on aspirin was

10olo

{6/60) compared ivith

15o/0 (12180)

for

patients taking placebo. The improvement in strokc- rate for patients on aspirir-r can be expressed

in several different

ways:

A. Absolute difference. Patients taking aspirin had a I -year stroke rate that rvas those taking placebo (15o/o

In a Nutshell Relative risk

= ratio of the

incidence rates of the disease in the treated group and those rn

the placebo group. Relative

risk can only be calculated for

nrn
ctr rdip<

-

70o/o

=

57o lower

than

5o/o).

B. Percent reduction. Patients taking aspirin had a reductior.r ir.r I-vear stroke rate of compared with those taking piacebo ([1506 - 1rJ%]/1592u = 1396).

-139o as

C. Relative risk. Patients taking placebo had a relative risk of 1.5 tlf having a stroke at 1 veal as cornpared with patients taking aspirin (15o/oll0o/o = t.5)..tlternatively, patients taking aspirin had a relative risk of 0.6tj of having a stroke at i year compared with patients taking placebo (10o/ol15Vo = 0.66).

D. Comparison of the means. Fo; continuous data, bivariate cornparisc--ns nray involve a comparison of means, i.e., comparing the nrean systolic [--lood pressures in pirtients irfier receiving two ditferent antihypertensive medications.

STATISTICAI. SIGNIFICANCE Having only shorvn that patients taking aspirin had an inrprovement in I -year stroke incidence over patients taking placebo would not satisfy the critical re:rder of nreclical lesearch. The reader might argue that the observed difference in strokes was not due to the aspirin, but rather due to chance. The argument would be that there were only 140 patients in tire study and that the outcome of interest (stroke) was too infrequent to drar.v nreaninsful ct'rrclusior.rs about the efficacy of aspirin. The reader would feel much mrtre cornfcrrtrblc irbout the conclusior.r if the study had several thousand patients in it (and therefore several hundred strokes) ar.rd the results remained the same, i"e., roughiy the same percentage of treated and untreated patients had strokes at 1 year. Instead of running a secorrci large-scale study to test the hypothesis, certain statistical tests can be used to calculate the probability that the obseri'ed diffe-rence could have arisen by chance. If that probability is low, it would seem likelv that aspirin was responsible for the decline in strokes and that the results are therefore statisticallv significir.nt. (Note, however, that even if the results are determined to be statistically sigr.rilicant, tliev n'ray r.rot necessarily bc clinically important, i.e., patients may show a decrease in stroke late after taking aspirin, but the decrease may not be substantial enough to wirrrant those at risk actuall,v takrng the aspirin.)

254 iliBbical

Biostatistics

A. The null hypothesis states that there is no difl-erence between the two groups being compared. Depending upon the data generated, the null hypothesis may be accepted (i.e., the difl'erence bet'ween the two groulrs is not statistically significant) or rejected (i.e., the difference betr,veen thr' trvo sr'()r.lFs is st;rtisticaliy signilicant).

B. Alpha is a level of plobability that represents the experimenter's tolerance for rejecting the null lrypothesis due to chance alone, terrned a type I error. The level of alpha is chosen before the research is started and, by convention, is generally set at 0.05. At an alpha of 0.05, the probabiiity of the resr-rlts occurring by chance alone, when the null hypothesis is rejected, is I in 20. The smaller the alpha, then, the more rigorous the standard for testing the null hypothesis.

C. p Value. The data from the experiment are used to calculate an appropriate test statistic. Test statistics are used rvith stirndard tables to generate a p value for the set of data. The p value represents the probability that the observed dift'erence between the two groups arose by chance aione in the given exprerirnent. The smaller the p value, the less iikeiy the between group differences are cirie to chance. 1. The chi square test is commonly useci to compsls noncontinuous data in two groups, i.e.,

ln a Nutshell p Value = the probability of obtaining a value of the tesl statistic that is larger than the

one calculated from the data

when in reality no significant drfference exists.

It involves the calculation of a chi square statistic, which is tiren used to derive a p value that is compared to alpha (typically where o is the observed value in 0.0-5).The fbrmr-rla for cl-ri square is -t2 = t lq#L, it

compares the two distributions

of

scores.

each cell of the table under ccnsideration, and E is the expected value. eft-ect on 1--vear stroke incidence, the deaths occurring in the entire study would be equally distributecl between treated and untreated patients. For the whole study, 18 out of 140 patients irad strokes, or approximately 12.9o/o. If the aspirin had no effect on strokes, then lve rvould expect 12.9%r o1 tire 60 treated patients and 12.9o/o of the 80 placebo patients to have strokes at 1 year. The expected vaiue fcrr each cell is calculated by multiplying

2. If aspirin had no

cel-['s row total by its column total and dividing by the total number of patients in the table. For the left upper'-most cell, the expected vaiue would be 60 x 18/140 - 7.7.The expected values fbr Table VIi- I -2 rvould then be:

that

Table

VII-l-2. Expected values of l-year incidence

of stroke.

Stroke

No Stroke

Total

Aspirin

7.7

52.3

60

Placebo

10.3

69.7

80

18

122

140

Note It is highly unlikely that you

will be expected to perform such calculations on the

Total

USMLE. You are much more

likely to be expected to know

For the lefr up1.gv11,,st cell then.

tO- Err

ali cells) is 0.38 + 0.06 + 0.21r + 0.04

-

tn-r'.;'

'2 -

0.J, and chi square {the sum for

0.76.

3. The p value is then deterniined fiom a chi square table using the chi square value calculated. In this case, the p value is approximately 0.40, which is greater than 0.05, the level

when to use a certain test (e.g, chi square test, student's I test). So don't worry about memorizing the formulas on

ihc nevt <erieral

naopq

set for alpha.

D. Rejection or acceptance of the null hypothesis. The generated p value is compared with the predetermined boundary for alpha, such that if p < alpha, the null hypothesis is rejected, and the diff'erence between the groups can be considered statistically significant. If p > alpha,

iii$hical 25s

Big.slatistics

a{

Eprlem

i

o

logy

the null hypothesis is not rejected, and the clifference betlveen the trvo groups is attributed to chance alone.

OTHER TESTS FOR STATISTICAT SIGNIFICANCE In additior.r to chi squirre, several other tests can be used to compare two groups for similarity or dissirnilarity. A. Student's f test is a parametric test used to compare two meiurs derivecl tiom two sarlples. The t statistic is calculated from the eouatiolt: X.ta-X-

\

-s,/4, *.sr/lr.

f I ancl f2 are the means in each group, -s, aucl -s. are standard errors in each group, and rtr and rt, are the number of observations in each gioup. A table of rvalues is then used to derive a probability p, which is compared with tl.re level of alpha. where

B. The paired f test is tvoically ernployed n hen an observation is macle twice on a sample. Thus, if the rnean systolic biocld pressure of l0 patients is taken before and after treatmelt with an angiotensin-converting enzyrne inhibitor, the paired I test would look at the mean dii{erer.rce between the values obtained before and after the intervention and compare it to 0 (the expected ditlbrence if the intenention has no ellbct). The^fbrmula fbr the pairecl r rest is: o

Vs/l where 5 = tlre before and after difTerence,

number of subjects.

-s

-

standard error of tl-re difference, and rr

-

the

C. Permutation tests such as the Fisher's Exact test and the Pittman Welch permutation test consider all possible permutations of the dirta :rnd compare them with the values actually observed.

D. Ranking tests. In these nonplrirnetric test:, such as the Wilcoxon test, the Wilcoxon rank sum test, and the Mann-Whitney U test, com;rarisons are made of ranks of data as opposed to the actual data. For example, instead of comparinr the average blood pressur-e changes in two groups of five patients treated with drug or placebo, a comparison would be macle on their ranks: The patient r,vith the greatest trlood pressure chanse would be ranked first, the patient with the next greatest change would be ranked second, and so on, without regarcl for whether the patients received drug or placebo. It could then be seen how the patients with the greatest blood prressure changes (i.e., those with the highest ranks) were distributed between the drug and placebo groups. The statistical test would be performed on the sum of the ranks in each of the two groups. E. A correlation coefficient is a numeric way of describing the direction and strength of the linear relationship between two variables. Different formuias are used depending on the nature of the data.

l.

The Spearman rank order formula is used tor data that are continuous and based upon some ranking. For example, the severity of syr.nptoms can be rankecl tiom 0 to ,5, whe- e 0 represents no symptotns and 5 reirresents severe syntptoms.

2. The Pearson product-moment correlation formula can be used fbr rankecl data that have no ii.rtrinsic numerical value, where the rankine system represents equal intervals between lneasurement units. For example, the syn-rptoms associated with a severity score

2i6 lli8hicat

Biostatistics

of 4 are twice as severe as those ranked with a score of 2. It can also be used for data ranked at equal intervals with intrinsic numerical value that do not change when mathematically manipulated (e.g., multiplied or divided). These data can be analyzed. in more sophisticated ways than standard ranked data. 3. The Pearson correlation coefficient (r) can have any value from +l to -1, such that the two variables measured with values closest to I have a stronger relationship. A positive sign for the coefficient represents a direct correlation, i.e., when one variable increases, the other increases as well. A negative sign for the coefficient represents an inverse correlation, i.e., when one variable increases, the other decreases.

4. Correlation studies are widely used but are of limited value they provide no "cause and effect" information, regardless of the strength of the correlation. For example, fever and rash in rubella are highly correlated, but the correlation per se explains nothing about the underlying disease process causing both phenomena.

Note A correlation between two variables can always be

interpreted in three ways:

(l)

a leads to b; (2) b leads to a; and

BETA ERROR AND POWER

(3) a and b are related

In determining the statistical significance of patients taking aspirin and reducing their stroke rate, the only error tested for was that of the false positive, i.e., rejecting the null hypothesis when in fact the two Sroups do not differ significantly (a type I error). Specifically, the focus was on incorrectly declaring aspirin better than placebo based on the observed l-year stroke incidence because the numbers were too small and the difference could have arisen by chance. To safeguard against this, a probability level of alpha was set, below which the null hypothesis would be rejected. Because the p value generated was greater than the level of alpha, the null hlpothesis was not rejected, indicating that aspirin does not appear to be better than placebo. Comparing the generated p value with alpha, however, does not test for the false negative, i.e., accepting the null hypothesis when, in fact, the two groups differ significantly (termed a type II error). Specifically, perhaps the true effect of aspirin is more significant than actually observed, but because there were so few patients involved in the study, this difference could not be detected.

A. Beta is a level of probability that

represents the power of the study, i.e., the level at which the

null hypothesis will be rejected because the study was powerfirl enough to detect a true difference between the two groups, and the difference is

through a third variable,

ln a Nutshell

. Type I error = accepting the alternative hypothesis when

the null hypothesis is true;

a

indeed exists.

B. Before rejecting or accepting the null hypothesis, both type I and type II errors must be tested for. When pcr is less than alpha, the null hypothesis is rejected, and the difference between the two groups is considered statistically significant, i.e., aspirin is superior to placebo in reducing

is

the probability of

makingatypelerror.

. Type ll error = accepting the null hypothesis when the

not due to chance alone. Beta therefore tests

for the possibility of a false-negative or type II error. (As with alpha, it is also typically set at 0.05.) A p value (sometimes referred to as pB to distinguish it from the more commonly cited alpha p value, or pcr) is compared with the level of beta. If no difference was noted between the two groups and pB was (0.05, there would be a I in 20 chance that there was a difference, but it could not be detected because there were not enough patients in the study, i.e., the study was not powerful enough to detect a true difference. When beta is equal to or greater than 0.05, the study is considered to have 95%o power to detect the association if it

c.

alternative hypothesis is

true; p is the probability of making a type ll error.

.

Power of a study

=

probability of rejecting the

null hypothesis when it

is

false,i.e.,1-p.

. To reduce both c and B, increase the sample size.

stroke risk. However, when pc is greater than alpha, a decision about definitively accepting the null hypothesis cannot be made until the level of pB is calculated as well. If pp is less than beta, the null hypothesis can be accepted, concluding that the study was powerfi.rl enough to determine that aspirin is no better than placebo in reducing stroke risk. If pa is greater than alpha and pp is greater than beta, the null hypothesis cannot be accepted or rejected: pcr indicates that the difference between the two groups is statistically significant, so the null hypothesis cannot be accepted, whereas pB indicates that the sample size was too small, i.e., the study was not powerfi.rl enough to detect a significant difference to reject the null hypothesis.

iliBbical

257

Biostatistics and Epidemiology

Note

CORRETATION AND REGRESSION

Regression techniques can

The statistical tests previously described are used to detect differences in a single set of continuous data between two samples. Correlation and regression studies, by contrast, are used to detect differences in two or more sets of continuous data between two studies or more. These studies would be used, for example, in measuring how the dose of a diuretic affects urine output. Both the dependent variable, or the variable that is affected by the manipulation (the urine output), and the independent variable, or the variable that is being manipulated (the dose of diuretic), are continuous and would therefore have to be compared together to fully appreciate the effects of the one on the other.

be used to:

. Look for trends in the data . Adju$ for a confounding variable

.

Predict future events

A. Simple linear correlation or regression with two variables

l.

The basic algebra equation for a straight line, where the coordinates of the iine are depicted such that the abscissa.r is the horizontal axis and the ordinate 7 is the vertical axis, has the equation / = mx + b, where x and y represent individual coordinates of points on the

line,m=theslopeoftheline,andb=theyintercept.Inalgebra,mandbareusually

known, and a line dictated by this equation can be drawn. Conversely, given several different points denoted by its coordinates, one can determine if any single point lies on the line by determining whether its values of x and I satisfi the equation, given tixed values of m and b. 2. In biomedical statistics, however, the points are known from the data provided, and it is the equation of the line (i.e., m and b) that must be determined. Although, in most cases, the data do not conform to a straight line, it would be useful to know how rnuch the data differ from the line. For example, consider an experiment in which l0 patients are given various of furosemide. After administration of the diuretic, the urine output of these patients measured is over a 1-hour period, and the data are collected (Table VII-1-:). (By convendependent variable is y, and the independent variable is x.) A plot of urine output tion, the the on 7 axis versus diuretic dose on the x axis is shown in Figure \rII- l-5. doses

VII-l-3. Urinary output in response to furosemide in l0 adult patients.

Table

Patient

258

iliB[ical

Furosemide Dose

(mg)

Urine Output (mt/h)

I

10

15

2

10

10

3

t0

1)

4

20

l5

20

20

6

20

22

7

30

30

8

30

25

9

40

35

10

40

44

Biostatistia

^35 )

E30

=3- zs 3zo

5rs 10

10 y intercept

20

30

Furosemide dose (mg)

(0,2.33)

Figure Vll-1-5. Urine output in response to furosemide dose.

Linear regression is a process by which the data collected are fitted to the best straight line. Given the data on the patients taking furosemide, then, a linear regression would allow one to predict urine output based on the dose of diuretic administered simply by plugging the x value into the equation and calculating the I value. a. The slope of the line in which diuretic dose is regressed upon urine output is given by:

Itx,

m

=

-D q -?)

ln a Nubhell Linear Regression

. Thexvariable

is a

single value,

.

The y variable is the

outcome value and

>(r,_b,

is

measurable.

where X is the average x coordinate, 7 is the average 7 coordinate for all data points, and xi and 1 are the individual coordinates for each data point. The slope is the sum of the product of the differences between r andT and their mean values divided by the sum of the squared x differences. Using the example in Thble VII-1-3, the mean diuretic dose is 23 mg and the mean urine output is 22.8 ml/h. The mean coordinate (x, y) therefore is (23, 22.8). Solving for m in the equation above, the slope of the line that best fits the data is m = 0.89 mLlmg/h. Thus, on average, 0.89 mL of urine output couid be expected from each milligram of the diuretic administered. Note that m is positive, indicating that the two variables are directly proportional, i.e., as diuretic

. A graph ofx versus y yields a straight line.

dose increases, urine output increases.

b. To draw the line that best fits the data in Table VII-1-3, the next step is to calculate b, the 7 intercept. Ti*e any single point (e.g., the mean point) and then solve for b. In this case, b, or 2.33 mL, represents the urine output that could be expected when no diuretic is given. A line drawn connecting the 7 intercept (0,2.33) and the mean point (23,22.8) is the straight line that best fits the data, as shown in Figure VII-1-5. 4.

Linear regression, however, does not address the issue

of

correlation between the

dependent and independent variables.

iiiEfical

zis

Biostatistics and Epidemiology

a. The Pearson correlation coefficient, R, can be used to determine the correlation by the

following equation:

R_

s/- -x) 2(*;-

X)2

(y,

-v)

2(r;-Y)2

-l and l. When R is 1, there is a perfect correlation between the dependent and independent variables; when R is 0, there is no correlation; and when R is -1, there is a perfect inverse correlation. For the data depicted in Figure VII-1-5, R is 0.95, suggesting an excellent correlation between the two variables. R may range between

b. Another important quantity derived directly from R is the explained variance, referred to as R2. The higher the explained variance, the more likely it is that the independent variable is responsible for all of the variation in the dependent variable. In the preceding example, because the explained variance is high, most of the variation in urine output can be attributed to the diuretic dose given. When the explained variance is low, additional factors would be responsible for the variability in urine output.

B. Correlation when data are not continr.lous. The Pearson correlation coefficient is used when both the independent and the dependent variables are continuous. When the data are not continuous, e.g., comparing the influence of high and low furosemide doses on urine output, other correlation coefficients, such as Spearman's Rho and Kendall's Thu, would be used instead.

M U TTIVARIAB

tE

ANATYS I S

The study previously described assumed that there was one independent variable, diuretic dose, that affected the dependent variable, urine output. In actuality, however, there are many things that might influence a patient's urine output besides diuretic dose, such as the patient's renal function at baseline. If patients with very poor renal function who had a poor response to diuretics were used in this study, then the simple model in which diuretic dose was regressed onto urine output would fail to explain much of the variance observed in the urine output.

ln a Nutshell Multiple Linear Regression

. There are two or morex variables.

. The y variable is the measured variable.

.

Used

to determine the

influence of one x variable

while adjusting for the effect of the other

In a Nutshell Logistic Regression

.

There is one or more

x

variable.

.

y is a binary variable (e.g., infected/uninfected).

260 ilits[icat

A. Multiple linear regression is used to consider the impact of more than one independent variable on the dependent variable. In addition to furosemide dose, consider serum creatinine as a measure of renal function on urine output. The new equation would be y = mtx, + m2x2 + b, where x, is the furosemide dose, x, is the serum creatinine level, and m, and m, are the partial regression coefficients for furosemide dose and serum creatinrne, respectively. They are termed partial regression coefficients because no single coefficient or slope can be used to explain the behavior of the dependent variable. Large values for m,, for example, would suggest that the furosemide dose is playing a more significant role in influencing urine output than is renal function. B. Types of multivariable models 1. Logistic regression is used when the dependent variable is dichotomous. For example, suppose a study is conducted to determine the factors that predict survival after cardiopulmonary resuscitation. In a standard bivariate analysis, women are found to be much more likely to survive than are men. However, if most of the men are diabetic, it is possible that the diabetes is responsible for the poor survival of the men. A simple 2 x 2 table of survival versus gender would not be sufficient to evaluate the extra variable. A stratified analysis or a logistic regression, however, would be able to reveal that the diabetes is the more important independent variable, influencing survival more than gender.

Biostatistics

2.

is often used when the outcome of interest is categorical. For example, in predicting a patient's liver disease based on laboratory tests, the indepen-

Discriminant function analysis

dent variables might include bilirubin, AST, AIT, and alkaline phosphatase, and the dependent variable would be categorical, with outcomes like hepatitis, cirrhosis, and hemochromatosis. Analysis of variance (ANOVA) is used when the means of a continuous variable are being compared in three or more groups or when the independent variables responsible for a difference in means is being sought. For example, a study shows that Native Americans have an average serum cholesterol of 176, African Americans have an average serum cholesterol of2ll,andCaucasianAmericanshaveanaverageserumcholesterolof 189.An ANOVA test could be used to demonstrate that these values are significantly different from one another, and if other information is collected about these groups, it could be used to analyze the variance and determine which factor is responsible for most of the differences. If very high average exercise levels are found in Native Americans, and a high cholesterol diet is found in the other groups, an analysis of the variance among the three groups may discover the factors most resDonsible for the observed difference.

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261

Epidemiology

Epidemiologic studies allow physicians to measure and predict the effects of disease or treatment 0n a particular population. Different types of studies are used to analyze different types of data and to take into account the many variables that may affect the result. Using these studies and proving an association between the treatment and the effect, however, in no way proves causality. Epidemiologic studies, then, are useful in generalizing associations and conelations across the

population. This chapter discusses the different types of studies used, the methods used to interpret the results, and the outside variables that may affect the reliability and validity of the study.

DEFINITIONS OF EPIDEMIOTOGIC TERMS A. Incidence and prevalence 1. The incidence of a disease is the number of new cases of that disease within a population over a specific time divided by the total number of individuals in the population. For example, if 100,000 people live in a certain town, and over a 1-year period 50 people in the town develop lung cancer, the incidence rate for lung cancer in this town would be 50/100,000 per year. Specific incidence more accurately describes the incidence of a disease for a particular subset of the population by calculating the number of patients with the disease within a particular age group (termed age-specific incidence) or gender (gen-

In a Nutshell number of new cases of disease per

lncrdence =

unI Irme number of persons in population at risk

to be a new case

der-specific incidence).

2. The prevalence of a disease is the total number of existing cases of that disease within a population at a specific point in time divided by the total number of individuals in the population. Prevalence therefore differs from incidence in that it does not take into account when the disease developed, only if the disease exists or not. The relationship between incidence and prevalence will depend on the characteristics of the disease. For example, a disease that lasts a lifetime but does not shorten life span appreciably is likely to have a much higher prevalence than incidence because as more people develop the disease each year, the total number of patients with the disease will be very large, even if only a few people get ill each year.

In a Nutshell number of existing cases of disease at a grven trme Prevalence

=

number of persons in populatron at rrsk

to have the disease

B. Birth and death rates 1. The crude birth rate is the number of new live births divided by the total population. The crude rate may be misleading as an indicator of population growth because it also includes babies who may survive only a short period of time. Thus, a community that has very high crude birth rates but aiso very high infant mortality rate may experience very little population growth. The crude birth rate in 1990 was 8.7/1,000 live births, compared with 9.5/1.000 in the 1960s.

iliBhical

26t

Biostatistics and Epidemiology

2. The crude mortality rate is the number of deaths from all causes in a population per year divided by the total population; disease-specific mortality rate is the number of deaths per year from a specific disease. Specific mortalifF rates describe the mortality within a particular subset of the population. For example, the infant mortality rate is the number of deaths occurring until the first birthday divided by the total number of live births; the neonatal mortality rate is the number of deaths occurring within the first 4 weeks of life divided by the total number of live births; and the postnatal mortality rate is the number of deaths occurring after the first 4 weeks of life but before the first birthday divided by the total number of live births. The infant mortaliW rate in 1990 was lOi 1,000 live births, compared with 4711,000

in 1979.

3. The crude rate of natural increase is defined as the crude birth rate minus the crude death rate. Ifthe crude birth rate is less than the crude death rate, the value will be negative, and the population will be decreasing in size.

4. Life erpectancy is the median survival time. Half the population is expected to die before the life expectancy and half afterward. Life expectancy at birth uses cross-sectional mortalify rates for each age to summarize mortality across the life-cycle for a given population. The best way to increase life expectancy is to reduce infant mortaliry. C. Bias may be defined as any force that causes the answer obtained in a study to deviate from the "true answer" or the answer that would have been obtained if there was no bias. Although it is impossible to eliminate all bias, in a well done study, the bias may be small, and the obtained answer will deviate little from the true answer. 1. Detection bias occurs when more information is solicited from the treatment group as opposed to the placebo group. This type of bias can be avoided if the investigators are "blind" to which subjects are enrolled in which group in the study; in double-blind studies, the subjects also do not know whether they have received treatment or placebo.

2. Proficiency bias occurs when the intervention under consideration is delivered with unusual skill (or incompetence) so that it cannot be reproduced in typical settings. For example, if in a trial of coronary bypass versus medical care for coronary artery disease the surgeons operating on the patients were the best in the world, bypass might appear to be better, but the results could not be duplicated in the real world for the average patient.

3. Referral bias (sarnpling bias) occurs when the sample of patients used in a study is not typical of the general population. For example, if an academic medical center sees the most acutely ill patients admitted for bypass surgery, their overall bypass mortality rates will appear deceivingly high.

4. Susceptibilitybias occurs when patients receive one intervention or another based on the severity of their disease. For example, because sicker patients would be less likely to survive a coronary bypass operation, they might be assigned to receive medical therapy instead. This, however, may result in poorer outcomes for the medical therapy group. Susceptibilitybias can be avoided by"randomizing" subjects to the different study groups. In this case, patients would be randomly selected to receive either surgery or medicine, so that the trial results reflect the treatments under investigation and not an underlying difference in prognosis. 5. Recall bias occurs in retrospective studies: Patients may not remember the severity of their symptoms or how much intervention was used over the specified course of time. This would, obviously, result in data that are unreliable and possibly misleading. 6. Ascertainment bias occurs when patients with the suspected outcome are more extensively probed about their symptoms and histories than are patients without the suspected outcome. For example, if smoking is suspected of causing lung cancer, ascertainment bias

264

ilitsliical

Epidemiology

would exist if patients who already have lung cancer are examined more closely than those who do not have cancer. 7. Lead time bias occurs when a screening test allows detection of a disease earlier than previously. This might lead to the perception of increased survival times, when in fact the patient merely found out about the disease sooner. 8. Measurement bias occurs when the fact of measurement changes what is being measured. This might occur when the anxiety of blood pressure measurement raises a patient's blood pressure. One form of measurement bias, the Hawthorne Effect, occurs when patients who know they are being assessed act differently because they are being observed.

STUDY DESIGNS A. Experirnental designs are used to measure the outcome of the trial. They set up "experiments" such that one group receives a treatment and a second group receives either placebo or a second treatment. The study would measure the subjects' responses to the treatment.

l.

The randomized controlled trial is considered the most rigorous and powerfrrl approach to answering a clinical question in which two treatments, strategies, or therapies are compared, or when one therapy is compared with placebo. Subjects are assigned to different experiments and conditions randomly. Consider, for example, a study comparing the efficary of coronary bpass surgery versus medical therapy for the relief of anginal symptoms in patients with coronary artery disease. Surgery is typically associated with an operative mortality of approximately l-2o/o in the United States and high immediate cost; drugs have no operative mortality and low immediate cost, but they must be taken indefinitely. A randomized controlled study would be able to take these different variables into account to determine which treatment method has a better 5-year survival rate'

2. The cross-over randomized controlled trial is slightly different from a standard randomized controlled trial. In this design, for the first half of the study, one group of subjects would receive the treatment and the other group would receive placebo; in the second half of the study, the two groups are switched, so that the group that previously received placebo would now receive treatment and vice versa. Measurements are made at baseline, before the cross-over, after a "wash-out period" (to get a new baseline), and again at the end of the trial. The major advantage of the cross-over trial is analltic: In addition to the treatment group being compared with the control group in each phase of the trial, each group can be compared to itself on and off the drug. This may decrease the sample size needed to show a clinical effect. Cross-over trials may not be a valid research strategy when diseases change very rapidly or are unpredictable.

3. In "blinded" studies, the subject and/or the experimenter does not know the identity of the subjects, medication, doses, etc. This is to eliminate bias. B. Nonexperimental designs are used when experimental designs would be either unethical or impractical. For example, it would be impractical to conduct study measuring the long-term effects of diet and exercise on the development of a rare form of cancer because it would require following thousands of people over a long period of time. Nonexperimental studies, then, are retrospective, i.e., they evaluate data on the intervention after the outcome has already been observed. Although nonexperimental designs are likely to have more bias, they are the only designs presently practical to study some research questions. 1. In a case-control study, groups of individuals are assembled on the basis of outcome and their previous experiences with various exposures are compared. For example, a group of patients with lung cancer (termed the "cases") is matched to a group of patients without lung cancer (termed the "controls"). Because the two groups are similar except for the

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265

Biostatistics and Epidemiology

outcome, investigators can compare their smoking habits over the course of their lives and make assumptions about the correlation between smoking habits and the development of Iung cancer. The odds ratio describes the relative chance of having a risk factor, giuen that a

patient has the disease.

Lung Cancer Smokers

No Lung Cancer

b

a

Nonsmokers a

odds ratio =

cad Dbc d

For example, if the odds ratio were 7.5 for the above table, a patient with lung cancer is 7.5 times more likely to have been a smoker. 2. In a cohort study, patients are assembled on the basis of some common experience (such as place of employment or exposure to an agent suspected to be toxic) and are then monitored for a specified amount of time at regular intervals until they develop the outcome of interest or the follow-up period ends. For example, a cohort of school-aged children who were exposed to lead may be followed over the course of a number of years to determine its long-term effect on academic performance. The association between the exposure and outcome in a cohort study is usually expressed as a relative risk. The relative risk is the rate of the disease in patients who are exposed to the suspected agent as compared with those who are unexposed.

Academic

Failure

NoAcademic Failure

a

b

Exposure to lead

No Exposure to lead

- i,

= incidence in the exposed

incidence in the unexposed (c+d) = n ^r .t:_.^ ..: .r_ Kelatlve flsk =

Incidence (exposed ) Incidence (unexposed)

-c

(a +b)

(..d)

Attributable risk, by contrast,- estimates how many of the observed to the exposure.

Attributable risk = Incidence (exposed)

(unexoosed)-[ a l-[ '

-

t I l(a+b)j lrc+d)

266 iliBhical

|

Incidence

cases can be

linked

Epidemiology

3. There are several advantages ofthe cohort design over the case-control design. The cohort study minimizes many of the biases that may be present in a case-control study and is thus the definitive observational clinical study. For example, because the case-control study of smokers versus nonsmokers relies on their smoking habits, recall bias may affect the data obtained and therefore affect the result of the study. It may also be easier to detect "dose-response" relationships in cohort studies because intensiry duration, and frequenry of the exposure are more meticulously quantified.

4. Cross-sectional studies usually have more modest goals than those of case-control and cohort studies. A variable or group of variables is measured in a sample of a larger population to get an idea of the distribution and interrelationships of those variables in that population. For example, a cross-sectional study may be used to measure the percentage of minors who smoke cigarettes and how the family incomes of minors who smoke differ from the family incomes of minors who don't smoke. All measures are taken at the same "cross-sectional" point in time.

5. Longitudinal studies identifr subjects and follow them over a given period of time. For example, the study of cholesterol-lowering drugs on cardiovascular events requires that the same subject is observed over a significant period of time, e.g., 10 years.

INTERPRETATION OF STUDY RESU1IS A. Sensitivity and specificity 1. The sensitivity of a diagnostic test is the probability that individuals with the disease would be correctly identified as having the disease by the diagnostic test. For example, if 100 HlV-positive patients are given a new diagnostic test for the rapid diagnosis of HIV and 80 of these patients are correctly identified as HIV positive by the new test, the new test has a sensitivity of 800/o. These 80 patients would be considered "true positives," whereas the remaining 20 would be "false negatives," i.e., they were incorrectly identified as being HIV negative.

2. The specificity of a diagnostic test is the probability that individuals without the disease would be correctly identified as nondiseased by the diagnostic test. For example, if 100 HlV-negative patients are tested with the new test, and 80 are correctly identified as HIV negative, the new test has a specificity of 800/o. These 80 patients would be considered "true negatives," whereas the remaining 20 patients would be "false positives," i.e., they were incorrectly identified as being HIV positive. B. Positive and negative predictive value 1. The positive predictive value of a test is the probability that individuals who test positive for the disease actually have the disease. For example, if 100 patients test positive for HIV and only 80 really are HlV-positive, the test has a positive predictive value of 800/o.

2. The negative predictive value of a test is the probability that individuals who test negative for the disease are really disease free. For example, if 100 patients test negative for HIV and only 80 are really HlV-negative, the test has a negative predictive value of 800/o. C. Algebraically, these probabiiities can be depicted as follows:

= B:

A

Number of patients with the disease and a positive test (the true positives) Number of patients without the disease and a positive test (the false positives)

= Number of patients with the disease and a negative test (the false negatives) D = Number of patients without the disease and a negative test (the true negatives) C

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Biostatistics and Epidemiology

Sensitivity = ofo-, ot the number of diseased patients with

a

positive test divided by the

total number of diseased patients. ._D Speciticity =

ti5,

ot the number of disease-free patients with

a

negative test divided by

the total number of disease-free patients. Positive predictive value =

oh,

or the number of diseased patients with a positive test

divided by the total number of patients with a positive test. Negative predictive value =

ah,

or the number of disease-free patients with

test divided by the total number of patients with a negative test. Table VII-2-1. Disease Present

Total Absent

Positive Test Results

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c

Negative Total

(A

B

(A

D

(s

+

+ B) i

D)

D)

(A+B+C+D)

a

negative