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 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>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.

ilitsbical

20l

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

iiiBhical

2or

Behavioral Sciences

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.

204

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

ilitsbical

205

Behavioral Sciences

(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

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.

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255

Biostatistics and Epidemiology

BIVARIATE COMPARISONS The comparison