USMLE Road Map Pharmacology

8/10/2019 USMLE Road Map Pharmacology

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E OND

ITI

ZUN

VOR


2/496

ontents

PRIN

IPLES OF PH RM COLOGY

I Introduction to Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

4 Drug Dosing and Prescription Writing . . . . . . . . . . . . . . . . . . . . . . . 17

UT

ONOMIC NERVOUS SYSTEM

5 Introduction to Autonomic Nervous System Pharmacology 23

6 Cholinergic Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

7 Cholinergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

8 Adrenergic Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

9 Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

ll

ENT

R L NERVOUS SYSTEM

I 0 Introduction to Central Nervous System Pharmacology . . . . . . . . . 65

I I Anxiolytics Hypnotics and Sedatives . . . . . . . . . . . . . . . . . . . . . . . . 67

2

Ant.ipsychotlcs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

3

Drugs Used

t Treat

Depression and

Mania

. . . . . . . . . . . . . . . . . . .

8

4

Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

IS

Drugs Used to Treat Parkinson s Disease and Other

Movement Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

6

Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I 2

7 CNS Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I IS

18 Alcohol and Other Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . I 19

9

Opioid Analgesics and Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . 125

IV

C RDIOV

S

CUL R SYSTEM

20 Antihypertensive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

2 1

Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

22 Drugs Used to

Treat

Congestive

Heart

F

ai

l

ure

.

6

23 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

67

24 Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

25 Anticoagulant Fibrinolytic and Antiplatelet Drugs . . . . . . . . . . . . . . 179

26 Antihyperlipidemic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

27 Drugs Used to Treat Anemia .

9

5

xill


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xiv Contents

RESPIR TORY SYSTEM

28 Drugs Used to Treat Asthma. Coughs. and Colds 0 0 0 0 0 0 0 0 0 0 0 0 0 0 20 I

VI ENDOCRINE SYSTEM

29 Hypothalamic and Pituitary Hormones 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2

I

30 Thyroid and Antithyroid Drugs

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

215

3

Sex Steroids and Inhibitors

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 22

32 Corticosteroids and Inhibitors 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 229

33 lnsulins and Oral Hypoglycemic Drugs

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

23S

34 Drugs

That

Affect Calcium Homeostasis

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

24

VII MUSCULOSKELET L

SYSTEM

35 Anti inflammatory Drugs and Acetaminophen

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

247

36 Drugs Used to Treat Gout 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 255

37 Autocoids and Autocoid Antagonists 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 262

VIII G STROINTEST IN L SYSTEM

38 Drugs Used to Treat Gastrointestinal Disorders 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 267

IX

IMMUNE

SYSTEM

39 Antineoplastic Drugs

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

277

X NTIMICROBI L DRUGS

40 Introduction to Antimicrobial Drugs

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

293

41 Penicillins o o o o o o o o o o

0

o o o o o o o o o o o o o o o o

0 0 0 0 0 0 0 0 0 0 0

o

0 0 0 0 0 0 0 0

297

42 Cephalosporins and

Other

Cell Wall Synthesis Inhib itors

0 0 0 0 0 0 0 0

303

43 Protein Synthesis Inhibitors 0 0 0

o

0 0 0 0 0

o o

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 I

44 Quinolones and Drugs Used to Treat Urinary Tract Infections 0 0 0 0 320

45 Folate Antagonists

o o o o o o o o o o o o o o

0 0 0

o o

0

o

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 323

46 Antifungal Drugs o o o o o o o o o o o o o o o o o o o o o o o o o o

0 0 0

o

0 0

o o

0 0 0 0 0 0 0

328

47 Antiprotozoal Drugs

o o o

0

o o o o o o o o o o

0

o

0 0

o o

0 0 0 0

o

0

o o

0 0 0 0 0 0 0 0

335

48 Anthelmintic Drugs

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

350

49 Antiviral Drugs

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

357

5

Drugs Used to

Treat

Tuberculosis and

leprosy 0 0 0 0 0 0 0 0 0

0

0 0

369

XI

TOXICOLOGY

5 Toxicology o o o o o o o o o o o o o o o o 0 0 0 0 0 0 0 o 0 0 0 0 0 0 0 0 0 377

XII

PH RM COLOGY POWER REVIEW

52 Pharmacology Power Review

o o o

0 0

o

0 0 0 0

o

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 397


4/496

Contents xv

PPENDICES

A Sample Problems 45

B Recommended Antimicrobial Agents Against Selected Organisms 5

C Compariso n of Antimicrobial Spectra 46

Index

469


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6/496

ection

rinciples

o

harmacology


7/496


8/496

What

s ph

armaco

logy?

What

s

a

dr u

g?

Nam

e

an

d define the fom

major subdjvisions of

ph

armaco

logy.

Fo

r

eac

h of

th

e following

endings, name

th

e classifi

c

al i

on of dr ug

an

d

gi

ve a n

exampl

e:

-az ine

-a

ne

-azepam

Introduction

t

Pharmacology

The study of the interaction between

chemicals and living systems

A drug is broadly defined as any chemical

agent that affects biologic

s y s t e m ~

1. Pharmac

okin

clics--


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4 Section I I Principles o

Pha

rmacology

-hi

al

-c

aine

-c

iiJin

-cycline

-olol

-opril

-slatin

-zosin

Should

trade names

be

memorize

d

for

the

Boards?

Do I n

eed

to

know every

characteristic of every

drug

?

barbiturate sedative hypuotic drugs (e.g .

phenobarbital)

local

ant>sth

t>ti


10/496

Define

pharmacokinetics.

BSORPTION

De fine

ab

sorption.

What

does the

ra te and

e fficncy of

absorption

dep

e nd

on?

In what way docs th e

pH

of

a drug affect its charge?

harmacokinetics

P h a r m a c o k i n t l i c ~ deSltrmirw

hether the

dmg

c;m

permeate t-ell

nwmlmmes.

Drug--


11/496

6 Section 1/ Principles of Pharmacology

How does charge

affect

a

drug's ability to

penneate

a

ceU membrane?

Define bioavailability.

What

is

th

e bioavailability

of an intravenously injected

drug?

What is the bioavaiJabiUty

of

any

drug that is not intra

vascuJaily

injected?

What factor >

affect

bio

availability?

Generally, a drug will

p a > ~

through cell

membranes more eusily

if t

is

uncharged. Therefore, the amount of

drug absorbed depends upon its mtio of

charged to unc:harged sp


12/496

What

factors affec t

bio

av

ailability?

'What is ftst-pass

metabolism?

\Vhat

arc th e ro

ute

s of drug

adminbtnllion?

Na me

th

e fom typ es of

alim

e

nt

ary

r

out

es

of

admin

is

tr

a

ti

o n and s

lat

e

th

e

advantage of each.

Na m

e the fo ur

par

e

nteral

rout

es

of

a

dmin

istration a

nd

sta te

th

e ad vantage of each.

Chapter 2

f

Pharmacokinetics 7

I. F i r s t - p a s ~ metabolism

2. All of the factors that

affect ahsorption

(i.e . p i

I

blood flow ,

drug

soluhilit).

dnag-dlllg interactions. route of

administration)

Riolransformation that occnrs he

fore

the

drug reaches its site of action .

It

111ost

commonly occurs in the liver. (For

example, .ora

ll

y

administered

nitroglycerin is said to have a high first

pass llH:.t,aholism because 901Jf of it is

inactivated

by the lhcr.

lllorphiaw

anotlar

important

drug that

has a h i ~ h

f i r s t p a s ~

metabolism.)

Alinapntaa)'

Pnrenteral

lnhalatio11

Topic;

Tmnsdrnaaal

Subcutaawous

I

Orai-{'Ommoncst

route.

Adrmtlal ,es

includt'

t-om

enience/patient


13/496

8 Section I Principles of Pharmacology

What category

of

drug

s is

commonJy administered by

inhalation?

How

are

inhaled drugs

administered?

When

is topical

administration

used?

When

is

lran

s

dermal

ndmirustration

used?

DISTRI UTION

Define distribution.

By what three bioche mical

mechanisms

re

drugs

absorbed

into

cells?

What do es distribution

depend upon?

2. Jntramusculur-AdcontageN: Usually

more rapid and complete absorption

than with oral administration.

~ i n i m i z ha1.ards of intravcular

injection.

3. Subcutaneous-Ac/V


14/496

BIOTR NSFORM TION

Why does the body

biotransform d1ugs?

What

:ue

th

e two general

sets

of modifications that

occw

in

biotransfonnation?

What

happens in a

phase

I

1eaction?

What types of

phase

I

reactions occur?

What

happens in

phase n

conjugation

reactions?

Specifically,

what

substrates

are

added in

phase

II

conjugation reactions?

n what organ do

phase

I and

phase reactions occur?

Chapter 2 I Pharmacokinetics

of

capillaries varies depending

on

the

organ.

For

example, in the brain the

junction between cells is very tight. In

th

e liver and spleen, the junction

between em.lothelial cells

is

wide,

which allows large molecules to pass

through.

Binding

to pl

asma

proteins such s

albumin This will limit access to

cellular compartments.

Drug sb-uctore mall

Lpophilic

molecules will be able to distt

ibute

to

more compartments thru1 will large

polar molecules.

The lipophilic prop erties of drugs tl1at

allow them to pass through cell

membranes hinder the

ir

elimination.

Therefore, drugs rue modified to become

more polar so tl1at elimination can occur

more

quickly

Th

ey are known as phase

I

and phase

11

reactions.

Lipophilic molecules are converted into

more polar molecules by introduction of,

or

unmasking

of

, a polar functional group.

Oxidation , reduction dehydrogenation),

and

hydrolysis

Formation of a covalent linkage between

functional groups on the parent rug and

anotber

substrate

Glucuronate

Quantitatively

, addition of

this substrate constitutes the most

important conjugation reaction.

Acetic acid

Glutathione

Sulfate

Primarily in

tl1

e liver


15/496

I0 Section I I

Pr

incipl

es

of Pharmacology

Whcte do

th

ese r eaction

occrn

on

a

ce llular level

?

What

factot

s affect drug

biotnamfonna tion?

Arc

th

e .-al

e > for

dr ug

bio

ttamfonnation pre

dict

a

ble?

Define fint-o

rd

er kine tics.

D e > cdbe ze to-

ord

e r

kineti

cs .

P h a . ~ P

I reactions Ot'


16/496

EX RETION

What is excr

etio

n ?

What is the

di

ffer

en ce

be

tw

ee n

exc

aetion and

secaetion ?

Wh at a1e th e major 1outes

of

exc

aelioo?

Chapter

2

Pharmacokinetics I I

later it

will

be

90 mg dL; and so

on.)

Alcohol

is

metabolized according

to

zero-

order

kinetics.

The

process

y

which a

drug

or

metabolite

is

removed from

the

body

xcretion is

the removal of

a

drug from

the

body.

Secretion

occurs when

the

drug is actively

transported from one compartment

into another. (For example: Dmgs are

secreted

into

the

renal

tubule

from

the

medullary

capillaries.)

Renal ur

i

ne is one of the

most common

routes

of

elimination

Fecal

Respiration primarily for anesthetic

gases and vapors

Breast

milk

kin


17/496

Define pha rmacodynamics.

l lo

w is phannacodynami

cs

related to

phannacokinetics?

RECEPTOR

INTER CTIONS

What is a receptor?

What

ar

c

th

e

two maio

flmction

s of receplors?

What is an effector

?

12

harmacodynamics

Ph:u-rnacodynamics clesclibes the actions

of a

umg

on the body. and includes tltc

principles of receptor

interaction),

mechanisms of therapeutic and to\iC

action,

and

dose-response relationships.

The

phannat 'rmine how

quickly and

to

what

cxttnt

a

dru

g will

apppar

at a

target

site.

Ph armacodynamics concepts explain tit


18/496

Dose

of

drug

administered

ABSORPTION

Pharmacologic effect

~ i \

Toxicity Efficacy

Chapte r 3 Pharmacodynamics 13

Pharmaco-

kinetics

ELIMINATION

J

Pharmaco-

dynamics

Figu

re

1. The relationship between dose and effect can

be

separated into pharmaco

kinetic dose-concentration) and pharmacodynamic concentration-effect) components.

Concentration provides

the

link between pharmacokinetics and

p h a r m ~ c o d y n ~ m i c s

and

is

the focus of the target concentration approach to rational dosing. The

three

primary

processes

of

pharmacokinetics are absorp tion. distribution. and elimination. Redrawn

from Katzung BG:

Basic nd

Oinical

Pharmacology

7th ed. Stamford, CT. Appleton

Lange

1998, p 35.)

alter the conductance of ions through

the cell membr-ane channels.

xamples

of ligand-gated ion channel

drugs

are

benzodiazepines and

acetylcholine.

3.

IntraceUular Thyroid a11d

steroid

hormones bind to nuclear receptors to

form complexes that iutcract

with

DNA, which causes changes in gene

expression.

4 Second messen ge r system Drugs

hind to rec:e

ptors

that activate second

messenger systems

involving G

proteins

Figure 3-2).


19/496

14 Section

1/

Principles of Pharmacology

Receptors as

Enzymes

Nicotinic

acetylcholine R

Glutamate R

GABAA

R

Glycine R

G Protein-Coupled Receptor

systems

5HT

3

serotonin R

Cell

Trans

membrane

receptors Catalytic

ctivities

G Proteins

Tyrosine kinases

Effectors

Growth factor receptors Regulated by a subunits:

t Adenylyl cyclase,

Cytoplasm

Neurotrophic factor receptors

Tyrosine phosphatases

Serine/threonine kinases

T B F ~ r e c e p t o r

t

Ca

2

+

currents

+Adenylyl cyclase,

t

K

currents

+Ca

2

currents

Guanylyl cyclase

ANF receptor

Guanylin receptor

Nucleus

Cytosolic

t

Phospholipase

cp

+

Na tw exchange

t

cGMP

Regulation of

Receptor

-phosphodiesterase

vision)

ranscription

0

teroids 1

Aetinoids

Thyroid hormone

Figure

3-2. Classification

of

physiological receptors and their relationships to signaling

pathways. Redrawn from Hardman JG, Limbird L [eds]:Goodman

and Gilman

s

The

Phar

-

macological Basis

o Therapeutlcs, 9th ed

.

New

York, McGraw-Hill. 1996, p 32. Used with

permission of The McGraw-Hill Companies.)

What

are

second messenger

systems?

What are the three best

known second messenger

systems,

and

which enzyme

produces

each

of them?

Second messenger systems allow signals

from

cell surface receptors

to

be

conve1ted and amplified into a cellular

response.

1.

Cyclic adenosine monophosphate

cAMP)

-produced by

adenylate

cyclase

2. Cycllc guanosine rnonophosphate

cGMP)-produced

by

guanylate

cyclase

3. Inositol triphosphate

lP

3

) rocluced

by

phospholipase C


20/496

Ch

a

pter

3 Pharmacodynamics IS

MECH NISM

SOF THER PEUTIC ND TOX IC

C

T ION

What

is

an ag o

nist?

What is a full agonist?

'

What

a1e

parti

al ag

onist

s?

What :-we antagon ists?

What does a co

mp

etit ive

antagonist

do

?

How can a c

omp

e

ti t

i

ve

antagonist

be

overcome?

Wh

at

does a n oncompetitive

an

tag

onist

do?

H ow will th e maximwn

efficacy of a dr ug b e

affected by such

noncompetiti

ve

antagonists?

A dru

g that

binds

to and activates

receptors

drug

that, wh

en bound

to a

recepto

r,

prod

u

ces

100%

of the maximum

o ~ s i l e

biologic response

Drugs

that

produ

ce

less th

an 100 of the

maximum possible biologic response no

ITI ltter

h

ow

high their concenhation

Drugs that bind to receptors or

ot

her

dmgs and i

uhi it

a Liologie response

t

binds

reversibly

to

the same

active si te

of an enzyme

as

an agonist.

By increasing

the

concentration of

the

tbug (agonist).

The maxi

mu

m

efficacy o

the drug

wi

ll not change in the

presence

of

a

competitive

antagonist.

t binds irreversibly

to

a di Terent site on

Lhe enzyme than the

antagon

ist.

Noncompetitive agonists c nnot be

overcome

hy

increasing

concen

trations of

the drug.

Maximum efficacy will

be

reduced in the

p

resence

of a noncompetitive antagonist

(F

ig u

re 3- 3).

DOSE

RESPONSE

REL TIONSHIPS

Wh

at is the difference

b

et wee

n e fficacy a nd

potency?

Give an example of efficacy.

Give an

exampl

e of

po

t

ency.

Efficacy is the ability to

produce

a

biologic

effec

t.

Po

t

ency is

re lat

ed to the

amount of drug uecess:uy to cause a

biologic eflect.

f wo

dru

gs,

drug

A and drug B,

are bo t

h

cla

imed to

reduce

a patien

t'

s heart rate

by

25%, the n they both have the same

efficacy.

Only l mg ofdrug A n

eeds to be

given

to


21/496

6 Section 1/ Principles of Pharmacology

Drug with non-competitive antagonist

'

I

rug concentration

1

EC

50

for rug alone or

in presence of non

competitive antagonist

1

EC

50

for drug in presence

of

partial agonist

EC

50

for rug in

presence of partial agonist

Figure 3 3. Effects of

drug

antagonists

and

partial agonist.

5

= drug dose

that shows

50% of maximal response. (Redrawn from Mycek MJ.

Gertner

SB. Perpecr

MM

[Harvey RA.

Champe

PC. eds]:

Uppincott s Illustrated

Reviews: Phormocology 2nd ed. Philadelphia. Uppin

cott-Raven Publishers, 1997. p

22.)

Wbati . /

What is

EC

50

?

a< hieve

a rec..luction in

heart

ralf' ,

h e r < : a ~

10

mg

o

f

dnag

Bare

needed.

T h e r e f o r ~ > ,

it

can be inferred that drng A is rnure

pole

a t.

Tlw concentration

of

m ~ ;i elding

50

occupanc of

the receptor (dissociation

constant

The

dmg concentration that produces

5 9f

of

the

rn:Lximum

possible response

in

a graded dose-response cun:e see Figm

3-3).


22/496

RUG OSING

What

tlwee

factor

s :ue

involved

in

dete rmining an

appmpriute drug do

se

for a

patie nt ?

What is volume of i ~ i -

bution Vd)?

H

ow

is V

calculated?

What is the s

ignifican

ce of a

large

Vtl?

What

s

a mainte nance dose?

Wh

at is the

eq ua

tion for

ca

lculating a maintenance

dose?

Wh

at is

important to

tcmc

mb

c r

in

pe

rformin

g

Ulis

calculation?

What is a loading dos

e?

rug Dosing nd

Prescription Writing

l

T)pe of

infection or disease

2.

Pati

ent variables

(

l .g

.

weight .

li\ t>r or

lddney disease)

:3.

Plasma

concentration needPd to

achieve efFicacy

The 1pparenl

volume into wl lich

a drug

is

nbk

to

distribute

V,

1

=

total

rug

in the body 7 plasma

conc:cntration

of

the

dwg

Based on the equation prest?ntf'd above. a

larg

e \ s i ~ i f i e s that most of

tlw drug is

being sequestered in some organ

or

compcl

phl,ma concentration

You must be absolutely

certain that the

u

ni

ts arc correct.

In SC)Il1 -' clinical situations

the

desirC'd

plasma

tonecntration

of

a drug

must

bE

achieved

rapiclly. ln these

cases a siuglc

load

ing

do

se

is

injected.

followed b) a

routine maintenance dose.

17


23/496

18 Section 1/ Principles

o

Pharmacology

\Vbat

~ the eq

uation for

calcu

lating a loading do

se?

Define peal.. and trough

concenlnllions.

What variable

affects these

conce

n

tnlt

i

on

. i?

What th

e

t a t e

pla.o;ma concen

t

ra tion

?

How doc > frectuency of

do sing affect

the

steady-

state co

n

ce nt ration?

What factors

will

dosing

frequency

affect?

How many half-lives

arc

requi

c

clto reach s

teady-

state conccnhation?

What is

cle

ar ance?

\Vhat

is an

excretio

n rate?

What

a th

e ra pe ut ic

in d

ex?

PRES RIPTION WRITING

Loading

clo >e

-

Vd X

desired plasma

COllCl'lltration

Th est arc

maximum

and

minimum

plasma

conccut

rations , respectively,

which

are

observed during dosing

intervals.

They will fluctuate

around

the steady

slate

plasma

concentration

(C,.,.).

The poin t at which the rate of drug

availability is equal

to

the rate of dmg

elimination

t will not change.

Using

smaller

doses more frequcutly

will

help miuimiz swin11;s

in

drug

concentration i.e maximum and

minimum p h l . ~ m a concentrations). See

Figure

I

L.

Approximate ) half-lives. At 3.3X,

the half-life

of the drug

will reach

90% of

its ciTec:livr ha.lf-life.

Clearance is

defined

as

the

vo

hune

of

plasrrra

c:btred

of drug per unit

of time.

Th

e rate

at

which a drug

is

eliminated

from the body.

which

is measured by

cleamnce

X

plasma c'Oncentration

Th

e mtio of a

dmg s

toxic dose to its

thcrapc>ulic

dose.

A

safe

drug

will

have a

high therapeutic index. See Appenwx A

for

snmpk problems

illustrating

th

ese

concPpts.

Define th

e foll

owing

abbreviations:

q

en ) hour

qhl CWI)

night


24/496

~

2

I

3

~

:e

. .

g

2

.a

.5

en

2

g

0

c

I

E

hapter 4 I

Drug Dosing and Prescription Writing

19

Injection of

2 U of drug

~

Injection of

1 U of drug

~ }

B

c

- con t i nuous

infusion of 2 U of drug day

,

blood pressure rises, eyes

dilate, blood sugar rises. bronchioles

e\11and, and blood

flow

shifts from

the

skin to skeletal muscles.

With

what rnajo receptos

docs the sympathetic

r v o u system work?

What are th e

actions

of

th

e

parao.ympathctic syste m?

\Vhat

eccptors does

th

e

parasympathetic system

act upo n?

How

arc

the

parasympat

h e tic

and

sym

pa

thetic y ~ > t e m s

ela

ted?

What

arc the

two prin

ci

ple

ncwotransmitters in the ANS?

The

sympathetic ne1vous

syslcm prepares you for

flight

01 llght

situations.

Adrenergic receptors

-alpha-l a

1

,

alpha-2

(cx

2

. beta-1 (j3

1

, beta-2

3

2

, and

dopamine recxptors (Table

5-l

The

parasp11pathetic nervous S)stem is

p r t d o m i m ~ n t under tranquil conditions. It

slows heart rate, lowers blood pressure,

increases intestinal

acti,ity, constrict\ the

p n p i l ~ .

and empties the urinary bladder.

The

parasympathetic neJVous fiJ:'i

system is also known as tlte rest ~ x

and

dig

es t system.

Cholinf'rgic receptors-muscarinicand

HJ


32/496

Chapter 5 / Introduction to Autonomic Nervous ystem Pharmacology 27

Which ion

is required

for the

releas

e of these

neurotrans-

mitters

from their storage

vesicle

s?

How

do

autonomic

drug

s

function?

2. Norepinephrine adrenergic

transmission

T he calcium ion (Ca

2

+ is required for

the release

of

ost

neurotransmitters

from their storage \ esicles.

At

S drugs achieve their effects

by

acti

ng

as either agonists or antagonists at

cholinergic and adrenergic receptors. The

fo llowing four chapters discuss each of

these d rug classes in greater detail.


33/496

What

are

c

holin

e r

gic

agonists

?

What are the two major

famili

es

of cholinergic

t

ec eptors

?

What pharmacologic

s

ubtypes

ofmuscarinic

r

ece

ptors

exist?

Identify the two types of

nicotini

c

receptors

Wh

e re in

th

e body

are

choline rg ic r

ec e

ptors found?

What types of

c

holin

e rgic

agoni

sts

a e available for

cli n

ica

l u

se?

28

Cholinergic gonists

Cholinergic agonists are drugs that mimic

or

potentiate

the

actions

of

acetylcholine.

1 Mu

sc

arini This receptor family

ean1cd its name because it was first

iden tified using muscarine, an alkaloid

found in certain poisonous

mushrooms.

2

Ni

co

tinic

There arc several different subtypes of

mus

ca

rinic receptors, namely, M

1

to M

5

Thty are found in ganglia, smooth

muscle, myocardium, secretory glands,

and the CNS. the USMLE

it is

not necessary to memorize

which

subtype

of

muscarinic receptors a

drug

will

act

upon.)

1. Neuronal nicotinic K , ), located in

autonomic ganglia

2. Muscu

lar

uicot.inic 1 o c a t

in

tlae

nC uromuscular junction

Prcg;tnglionic fibers of the autonomic

ganglia

Preganglionic fibers that terminate in the

adrenal medulla

Postganglio11ic fibers of the

parasympathetic system

Voluntary muscles

of

he

somatic system

CNS

Sweat l a n d ~ innervated

by

post-

gangliunic sympathetic nervous

y s t c m

Se >

Figure 6-1.

Cholinergic agonisls t:an be divided into

two major groups:

1 Direct-acting agonists chemically

hind with and activate muscarinic and

nicotinic receplors in the

body


34/496

Chapter 6 Cholinergic Agonists 29

utonomic

Nervous System

Somatic

Nervous System

Sympathetic

innervati

on

L of adrenal medul

la

i i I I W I I * ' I , - ~ ~ ~

1 8 ' / W ~ Acetylcholine

iu- .

~ N ' ~ c o t i n l c

~

t o r

A d r e n ~ m e d l l a

Epinephrine

{released

into lhe blood)

eceptor

Sympathetic Paresympathetlc

I

cetylcholine

~

Acelylcholin

g

no gangha)

l

Niootinic J i c o t i n i o

receptor receptor

~ t

NOleptnephnne

cetyl

chOline

Acetylcholine

eceptor eceptor

ffector organs

Striated muscle

Figure 6 1

. Sites of action of cholinergic agonists

in

the autonomic and somatic nervous

systems. Redrawn from

Myce

k

MJ

Gertner SB Perper

MM

[Harvey RA. Champe PC,

eds): Uppincott s Illustrated

Reviews

: Pharmacology, 2nd

ed.

Philadelphia. Lippincott-Raven

Publishers 1997, p 36.)

DIRECT-ACTING AGONISTS

Give six examples

of

rurect

acting

agonists.

ACETYLCHOLINE

What are the physiologic

actions of

acety

lcholine?

2.

Indirect acting

agonis

ts inhibit

the

enzyme ac-etylcholinesterase

and

therefore increase the concentration

of acetylcholine within the

sym1pse.

l A c e t y l c h o

e ~ p r o t o t y p e

2. Bethanechol

3. Carbachol

4. Pilocarpine

5. Methacholine

6. Nicotine discussed in

Chapter

7

NS Stinwlants

Acetylcholine affects almost every system

within the body:

Cardiovascu lar

system It

decreases

heart rate, contractility, and blood

p r e s ~ u r e


35/496

30

Section II/ Autonomic Nervous System

What receptors does

acetylcholine

activate?

What are th

e clin

ical

indications?

What

are the

adverse

reactions?

BETH NECHOL

(Urecholine)

What

type

of

chemical

compound i i

bethanechol?

Gasbointestinal system-It increases

motility

of the gastrointestinal tract

and bladder.

Pul mona.y system-

It

increases

secretions

of

the bronchioles

Th

e eyt. -l t causes constriction of the

pupilla1y sphincter muscle, which

causes mlosis and accommodation.

Petipheral netvous

system-It

causes

conhaction

of

skeletal muscle.

Central netvous system-It affects

nemotransmission.

Endocrine system Itcauses release of

epinepluine from

the

ackenal medulla

(via nicotinic receptor),

and

it

stimulates sweat gland secretions.

Bod muscarinic

and

nicotinic

Acetylcholine

s

used to achieve miosis

dming ophthalmicsurgery. In general, it

is

rarely used because

it

has widespread

effects

and

is so rapidly hydrolyzed by

acetylcholinesterase.

The

adverse effects result from excessive

generalized cholinergic stimulation. They

include:

Diarrhea and decreased blood pressme

Urination

iosis

Bronchoconshiction

Excitation of skeletal muscle

Lacrimation

Salivation and sweating

DUMBELS

NOTE: These adverse effects are

typical ofall direct and indirect

cholinergic agonists,

not

just

acetylcholine.

A carbamic acid ester

l fM

\;X,


36/496

What

receptors

does

i t

work

on?

What

are its th

e

rapeutic uses?

What

are

the

adverse e ffects

of be thanccbol administra-

tion?

C RB CHOL

What type of

co mpound

is

carbachol?

State

ts

clinical

use.

What r

ece

ptors

do

es

ca

tbachol work

on?

What are iL > adverse effects?

PILOCARPINE Pilocar)

Wh

at

type

of compound is

piloca.-pin

e?

What

are

pilocarpine s

phys

iologic

actions?

Is

it

cl

eave

d

by acety

lcbolin

e s t e r a ~ e

Chapte r 6 Cholinergic Agonists 31

Bethancchol works primarily on

muscarinic

receptors, but it also

has some

mild nicotinic properties.

Bethanechol increases intestinal motility,

especia

ll

y alter surgery. Because this

drug

l ~ o

stimulates

the

detrusor

mnsclc of the

bladder,

it is

also used to treat

urinary

retention.

BBB

- Bethanechol stimulat

es

the Bladd

er

and Bowel.

\ X,

The

adverse effects are those that

rel.ult

from generalized cholinergic stimulation

(sec above).

A

cnrb


37/496

32 Section

II/

Autonomic Nervous System

State the clini

ca

l u

se.

Pilocarpine is extremely good for

stimulatinf ; miosis and opening the

lrah


38/496


ORGANOPHOSPHATES ISOFLUROPHATE. ECHOTHIOPHATE,

P R THION

)

De

s

crib

e

th

e m

ec

hanism

of action.

Is it

at all

po

ssible to re verse

th

e e ffec ts of

or

ga

nopho

s

phat

es?

What we r

e

these drugs

us

ed

for

in

th

e

pa 1:?

What ar e these drugs used

for tod

ay?

\>Vhat dru g

is used

to

treat

or

g

anopho

s

phat

e

poisoning

?

What a1e the toxicities

of

th

e

01

g

anoph

os

ph

ates?

PHYSOSTIGMINE

when is physos

tigmin

e

administ

ered?

Organophosphates bind covalently to

acetylcholinesterase

and

can permanently

inactivate the

enzyme. The

eflects

of

organophosphates can last as long as a

week, wh ich is approximately the time

needed to synthesize a new mol

ec

ule o

f'

acetylcholinesterase.

In most cases, no. However,

if

pralidox.ime (a cholinesterase reactivator)

is given before the organophosphate

binds to acetylchol inesterasE> d

aging). then it may

he

possible r

pralidoxime to rem ove the

organoph

osphate from


Figme 6- 2.

Organophosphates

wer

e used in wars as

netve gases. They produ

ce

an

immense

stimulation at cholinoreccptors

throughout

the body,

causi

ng

resp iratory

muscle paralysis and

convulsions.

Isoflurophate and echothiophate are used

occasionally for glaucorna

am

l

accommodative esotropia.

Atropine is nsed, along with gastric lavage

and

chmcoal

l:i:xcessive cholinergic stimulation

For glaucoma- second-choice drug after

pilocarpi ne

For overdoses of atropine,

phenotbiazines, and tricyclic

antidepressants

For intestinal ;mel bowel atony

For accommodative esotropia (rarely


39/496

4 Section Autonomic Nervous System

Phosphorylation of Enzyme

Enzyme inactivated

Pralidox1me PAM) can

remove the inhibit

or

0

II

C

3

H

7

0 - P- OC

3

H

7

I

F

Isoflurophate

..0 - H

ctive site

of


Acetylcholinesterase

irreversibly inactive)

..

0 - H

Acetylcholinesterase

active)

Fig

ur

e 2. Covalent modification of acetylcholinesterase

by

isoflurophate. Redrawn

from Mycek MJ, Gertner

SB.

Perper

MM

[Harvey RA , Champe PC. eds]:

Upprncott s

Illus-

trated Revrews:

Phormocology, Znd

ed Philadelphia, Upptncon-Raven Publishers. 1997, p 43

.


40/496


Can

physo .1igmine

entet

the

Yes,

because it is a tertiaryamine

CNS?

State the advetse effects. Convulsions

NEOSTIGMINE (Prostigmin)

Does

this drug

enter the

CNS?

Describe

the tbempeutic

uses.

What is the

duration

of

action?

Muscle paralysis secondary to

overstimulation

Catarac

ts

Generalized excess

iv

e cholinergic

stimulation

No, because it

is

a polar quaternary

carbamate

Tr

eatment

of

myasthenia gravis

Treatment of urinary retention and

paralytic

il

eus

Antidote for nondepolarinzing

neuromuscular blockade such

as wit

tubocurarine

Usually 2 to 4 hours

What are the

advetse

effects?

Excessive cholinergic stimulation

EDROPHONIUM

Enlon)

What

is

its

clinical

use?

Edrophonium

is

similar to neostigmine

except that it

is

used in the

diagnosis of

myasthenia

gravis. t

is

not useful for

maintenance therapy because of ts sh01t

duration of action (approximately 5 to

15

minutes). Edropboniurn

is

also used to

differentiate

myasthenia

gravis

from

cholinergic

crisis. Both conditions can

result in muscle weakness; however,

administration

of ed

rophoniurn helps

myasthenia but worsens cholinergic crisis.

What

ar.e

the adverse effects?

Excessive cholinergic stimulation

PYRIDO

STIGMINE

(Mestinon)

What

is

pyridostigmine s

duration

of action?

Very

long-usuall

y 3 to 6 hours


41/496

6 Section II/ Autonomic Nervous System

What is the clinical u

se?

Because of its long durati


42/496

What

rue

cholinergic

antagonists

?

Na

me

three

s

ubclasses of

choline

rgic antagonists.

Cholinergic

ntagonists

Dnags that

bind to cholinergic receptors

(muscarinic and/or nicotinic),

but

do not

trigger

the

usual intracellular response

1. Muscarinic blockers

2.

Neuromuscular blocking

agents

inhihit the effer

en

t impulses to

ske

lE>talmuscle

via the

nicotinic

muscle receptor (NM)

3.

Ganglionic

blockers- inhibit l

e

nicotinic

neuronal receptor

NN)

of

both parasympathetic

and

sympathetic

ganglia

MU SC RINIC NT GONISTS

Gi

ve

six

examples

of

muscarini

c bl

ockers.

rc

th

ere

other drugs that

exhibit

antimus

carin

ic

properties?

TR OPINE

To what family of compo

u

nds

does atropine belong?

l Atropine (prototype)

2. Scopolamine

3.

l l

omatropine

4.

Cydopentolate

5.

Tropicamide

6.

Pir

enzcpinc

Yes-these

include

tbe

anti-Parkinson s

drugs

(e.g . benztroplne),

the anti

depressants e.g Thorazine),

antihistamines

(e.g.,

diphenhydramint),

and

anti-asthmatics (e.g., ipratropium),

which

are

discussed

further

in lat

er

chapt

rs.

Atropint


43/496

38 Section Autonomic Nervous System

What

is

th

e s igni6cance of

the plant's

na me?

What is atropine s

mechan

ism

of action?

What agent can

be

used to

count

e .-act the effects of

atropine?

Does

this drug

cross

the

blood-brain barrier?

What

arc

the phannacologic

actions of

atropine?

t th

e

th

e

rapeutic

uses

of

atropin

e.

Belladonna in Latin means

pretty lady.

During the Roman

era

the plant was used

to dilate women's pupils. which was

o u ~ i d r d to he attractive.

t

causes rev ers

ible

,

nonselectiv

e

blockadu

of

muscarinic receptors.

High concentrations

of

acetylcholine

or

an

eq u ivalent

muscarinic agonist

:>Jo Atropine docs not readily cross

the

blood-hrain barrier.

CNS

-At toxic doses can cause restless

ness, hallncinations , and delusions

Cardiovascular sys

tem-A

t

low doses,

atropine reduces heart rate through

central stimulation of the vagus

nudeus. At high doses, atropine blcx:l s

muscarinic receptors

of

the

heart and

t h u ~

induces tachycardia.

Gastrointestinal

syst em Reduces

saliva } gland secret ion and GJ

motility

Pulmonary

syste

m

educes

bronchial

sE-cretions and stinmlates

bronchodilation

Urinary syo;

te

m-Bi

ocks muscarinic

receptors in the bladder wall, which

r e ~ u l t s

in

bladder wall relaxation

Eye-Causes

paralysis

of

the sphincter

muse ..: uf thl.' it

C


44/496

Wh

en is the use of atropine

to e ffect my

dria

sis and

cy

clopl

egia contrain

di

ca

ted?

Ho

w long is a

tr opm

es

du

ation of a

cti

on?

How is a tropine

ab

sor bed

a

nd

excre

ted?

What

mc

th

e

to

xic

effe

c

ts

of thi

s cltu

g?

SCOPOLAMINE

Wha t is the

class

ification of

scopola

mine?

Wh

at is its mechanism

of

a c tion ?

How is

sco

po

lamin

e u

se

d

th

c n1pcuti

ca

lly?

How

docs

th is dr u

g diiTer

from alm pin

e?

\Vhat is

sco

polami nes

oute

or

a

dmini

s

t

a

lion

?

Chap

ter

7

I

Cholinergic Antagoni

st

39

whf'n a thorough fundus examination

or an ars

art produced

year

ly.

Primarily in tht>1r

pharmacokinetics

B)

the

-olol

ending

in

their

namt's

Generally tlwy wilJ

be

simila r to those

of

ot

h

f>

r

3

blockers.

INDIRECT DRENERGIC

NT GONISTS

Why

are

guanethidine and

reserpine

considered

indirect adrenergic antag

onists?

GUANETHIDINE

(ISMELIN)

What is th is drug s

mechan

ism of action?

Does guanethidine

have

a

clini

cal

u

se?

What

are

the adverse effects?

RESERPINE

What is it?

\\ hat is reserpines

mechan

ism of action?

How is this

drug

used

clinically?

What are

the

adverse effects?

Th

ey

do not direc

tly block

ex- or 3-

adrenergic receptors.

h

ey do, however,

block

the

release

of no

rep in ephrine from

nerve endings- in effec t,

they

antagonize

the effec ts

of

the system.

t enters the peripheral adrenergic nerve

by a reuptake mechanism for norepin

ephrine and

binds

to

sto

rage

vesicles,

th

e

action

of

which subst>quently blocks

the

release

of

stored norepinephrine.

Yes-treatment of

hypertension

Orthostatic hypotPnsion

and

sexual

dysfunction

A

auwolfia

alkaloid

t

blocks

nor

pin ephrinc

tra

nsp

ort

from

cytoplasm into intracellular storage

vesicles. Subsequently, the neuron is not

able to release any catccholamines .

For treating hyp


67/496


68/496

ection

ll

entral Nervous

System


69/496


70/496

1

Naune the mujor CNS

nc urobansmitters.

What ty pes of receptors a t

c

mo

st

co rnrnonlv

fo

und in

th

e

CNS? .

What arc the primary

functio

ns

of

a

oewotran

s-

rnitlc r?

What arc

EPSPs?

C h e fhe examples of

exc itator

-y neurobansmitters.

What are lPSPs?

C i

\'e

two exam

pl

es of inhib

itory

neurotransmitte

rs.

Introduction

t

entral Nervous

System Pharmacology

Atetyl

Inhibitory p o s t

s , ~ < ~

pi il : potl ntials

iniliated wht>n

an

inhihilof\ ncuro

transmiltrr opPns d d o r i d c ~ : u l n e und

the ce ll mvmhnuw lw< onws

h)1Wr

pohuizcd.

lPSPs

utukt

il111ore d

ifR

eult

For the lll llron to lwto uc atlivatcd

(l igun>

H)

- I

).

1. Gly


71/496

66 Section

Ill/ Central Nervous

System

E

l l Threst}.oj< ___

-

-------- ---------

--

------

IPSP

i m e ~

Figure I

0 1.

Interaction

of

excita[Qry and inhibitory synapses.

On

the left,

3

supra hresh

o ld stimulus is given to an excitat

ory

pathway (E) . On the right, this same stimulus is given

shortly

after

stimulating an inhibitory pathway

(I)

, which

pr

eve nts the excitatory potential

f

rom

reaching

thres

ho l

d.

(Redrawn from Katzung

BG

:

Basic and Clinic lPharmacology 7t

h

ed

. Stamford, CT. Appleton & Lange, 1998, p

3-45

.)

n

ge

n

era

l , h

ow

do

d rugs

affecting

the

CNS

wo r

k?

\Vh a t are th e major differ -

ences between the au tonomic

ncrvou

t t

ystem

and th

e

ce

nt

ntl n

ervous

system?

Most drugs

wi

ll

allCd

production,

releas


72/496

De6nc anxiety.

What a re some of the

ph

ysi

ca

l symp toms

see

n

with anxiety?

Wh

at

a te the major classes

of

dru

gs

u

sed

to

tr

ea

t

anxi

ety?

BENZODI ZEPINES

Give some ex

ampl

es of

be n

zodiazepincs an

d the ir

approximate

duration

of action .

Anxiolytics

Hypnotics and

Sedatives

An

unplea.5ant emotional state consisting

of apprehension, tension, and

f e e l i n g ~

of

danger, without a real or logical c u ~ e

Tachycardia

Tachypnea

Sweating

T r

emb

ling

Weakness

Benzodiazepines the

most frequently

used drugs for anxiety

A?,aspirones-forexample, buspirone

Carbamates for

example, meprobamate

Barbiturates rarely

used today because

of severe side effects

and

a low

therapeutic index. These drugs have

generally been replacetl by the

benzodiazepines.

Short -Ac ting 2-8 hours:

Oxazepam Serax)

Clonazepam

.Kl

onopin)

Midazolam Versed)

Triazolam Halcion)

Interm ediate -Ac ti ng 1

0

20 hou rs):

Temazepam Restoril)

Lorazepam Ativao)

Alprazolam Xanax)

67


73/496

68 Section Ill/ Central Nervous Sys[em

What is GABA?

llow do benz.odiazepines

work?

What arc th

e

therapeutic

indications for

benzodiaz

epioes?

What

is their route of

administration?

Where are benzodiazepines

metaboliz

e

d?

Doe

s dependence

occur?

Long-Acting(J-3 day > ):

Chlordiazcpoxitk(Libriunt)

Diazepam

(Va

lium )

Flurazcpam (Oalmane)

GABA ( y-aminobut}r ic acid)

the

major

inhihitOI) neurot

ran,mitter of the C IS.

When henzodiazcpincs h10d to srwcific

r e c e p t o r ~

that

are ~ > p a r a t e

from

but

adjacent to the GA BA receptor. they

potentiate the binding ofCABA to its

own receptor. Th e i n d i n ~

of

CABA to its

ov

rt>ceptor results in increased chloride

ion comluctance, cell

membrane

hyperpolarization, and decreased

initiation of action poteutial

s.

R

emember

that benzodiw-epines

do not

bind

to

CABA receptors-

th

ey bind

adjacent to them (Figure - 1 .

These r u ~ s are

used clinically as muscle

relaxants

and

in

the treatment

of

the

following:

Anxiety disorders

Panic

disorders-alprazolam is the drug

of choic:e

Stahts epilepticus-diazepam is

the

drug

of choice

Sleep disorders

Insomnia-All bcn1A>diazepines can be

sedating,

hut

o r l l e p ; ~ m and

tcmazepam

arc the

most commonly

used.

Al

co

hol withdrawal--dia:r.ep.un most

commonly used

PO, lV,

or

IM

They


74/496

Receptor Empty No Agonists)

c 1

Chloride channel closed)

-

+

~

l i ' W n ' n i M J H c:r-----1 1lr1Mfrlrrnlf1

~ ~ ~ ~

I

Benzodiazepine receptor Empty receptor is inactive, and

the coupled chloride channel

is closed.

Receptor Binding GABA

Binding of GABA causes the

chloride ion channel to open.

Receptor Binding GABA and Benzodiazepine

Entry of Cl- hyperpolarizes

cell making it more difficult

to

depolarize and

th

erefore

reduces neural excitability

Binding of GABA to its

receptor is enhanced by

benzodiazepine, resulting

in a greater entry of

chloride ion.

Fig

e I 1- 1.

Schematic diagram of

ben

zodiazepine-GABA-chlorlde ion channel complex.

GABA -aminobucyric acid. (Redrawn from Mycek

MJ

Gertner SB Perper MM [Harvey

RA Champe

PC. eds}: uppmcott s Illustrated

Reviews

: Pharmacology nd ed. Philadelphla,lip

pmcott Raven Publishers, 1997, p 91.)


75/496

70

Section Ill/ Central Nervous System

What type of

sy

mptoms may

u

pati

e nt

takin

g be

nzodiaz

c

pincs expe

ri

en

ce?

Drowsiness and con fusion-he most

common

sic lpines. its

effects mav takt 2 H < - k ~ to l>


76/496

Chapter II Anxiolytics. Hypnotics, and Sedatives 71

CARBAMATES MEPROBAMATE

\Vhat is mepro

bamates

mecha n ism of action?

Wh at the clinical u

se?

t is not wPII known.

It is now i r t u l l ~ ohsoiC'te. In the past it

u ~ e d primaril) in tlw trpatment of

all\iel\.

What are the ad

verse

effects?

R


77/496

72 Section Ill Central Nervous System

Coma

,

,

,

,

Barbiturates

,

alcohol

,

,

Medullary depression

,

Anesthesia

,

,

Sedation, anxiolysis

,

Benzodiazepine

s

Increasing ose

Figur

e I 1-2. Comparison of dose-response relationships of benzodiazepines and barbi

turates. Redrawn from Gallia G, Hann Cl, Hewson WH : The Pharmacology Companion

Alert Oriented Publishing Company. 1997, p 33,

Fig

3.1.)

What de termines the

dumti

on

of action of thio

pental

?

Does btu

bitu

ra le depe

nd

ency

occur?

For whom

ae barbiturates

conbRindicatcd?

What or

e

the advers

e e

ffects

of

th

ese

drugs?

OTHER SED TIVES

ZOLPIDEM Ambien)

D escribe

th

is drug s clinical

u

se.

R d i s ~ r i b u t i o n to the

other

t i o ; ~ u P s

Yf s

bn1pt cessation

can lead

to

severe

witltdrawal

symptoms

tremor, restless

ness

nausea,

se

izures, a

nd

cardiac aJTcst).

For

patients who have acute

intcnnitlrnt

porphyria,

because

the

y

increase porphy

rin synthesis

Dr

owsiness and

decreased motor control

Induction of the P-450 system

Addi


78/496

Chapter I I Anxiolytics Hypnotics and Sedatives

7

hat

arc its

adverse

effects? At

drug s adverse

effects.

llypnosis

Sedatiml in childn11 )

Gastrointestinal clistrt ss

Uupleasant taste


79/496

2

What are antipsychotic

d r u g

What b. their mechanism of

action?

Do

antips

y

chotic

agents

dilfe in potency?

Do antip,y

choti

c '

differ in

c fficac\?

How are

antipsyc

hotics

usually administered?

Dcsc

db

c th e abs01-ption

and t a b o l i . of

the

l.-a

clitional a n t i p c s .

What i >

th

e onset of

ac

tion?

4

nti psychotics

Antipsythotirgic, m u s t ~ r i n k and hista111ine

rectp

tor

s. ll owC'wr,

thcir

ptor\

ll

aloptridol amlthio

thi'.t'lll'

1 tlw D

2

rcc't'p

tor-.. lwna ' dclorprom;I/IIW and thio

ridazim aw low-potctlt') lwl'aust

th

t>

\

h;\\ t

low

a

Tinily

for

l'l't

'l'ptors

'o

Tht traditional antp,)


80/496

Can

these

drugs

cure

ill

n

esses

such as

schizo

phrenia?

Ho

w are

th

e

antipsycbotics

cla

isi

fi

ed ?

Chapter 12/ Antipsychotics 75

Nol Antipsychotics only reduce the

symptoms of tlw illness; they cannot

cu

re

the

illness.

Classification is

based

on structural

differences The major classes include

phenothiazines, hutyrophcnoncs, diben

zoxazepines, thioxanthines,

and

benzi

soxazolcs.

TR DITION L

NTI

PSYCHOTICS

PHENOTHI ZINES

What

are some examples

of

ph

e nothiazi

ne

s?

What dis

tincti

ve side etiects

do

cs th ioddazine cause?

BUTYROPHENONES

Nam e two drugs in this

cla is.

Other

than

p

syc

hotic sta tes,

for

what

can haloperidol

be

used?

What type of side effect

s

esp ecially ponounced with

halope-idol?

DIBENZOX ZEPINES

Name

a drug that

belongs

to

this class.

THIOX NTHENES

Name a drug that

belongs

to th is class.

Chlorpromaz

ine (Thorazine

)-prototype

f luphenazi

ne

Prolixin)

TriOuoperazine (Stclazinc)

Thioridazine (Mellaril)

Perph

enaziuc (Trilafon)

Pigmentary retinopathy

May cause cardiac arrhythmias and con

duction block

Haloperidol (Haldol)

Droperidol

(

lnap

sine)

Tourette s syndromE'

Huntington\ disease

Phencyclidine overdose-drug of choice

Extrapyramidal

side

efT

e l s ~ common

board question

)

Loxapine (Loxitane)

Thiothixene (Navane)


81/496

76 Section Ill Central Nervous System

CLINICAL USES AND SI

DE

EFFECTS

What

arc th e c linic

al

appli

cation

s of tr aditional anti

p

syc

hotic

ag ent

s?

\Vhar , an e n ~ way to

rcmc

mb

c t

th

e ueh

as

ddusious.

thought

d i s o r d e r ~ .

and

halldnations.)

t\ntilnwtiC

tlwrap) due

to bl of dopamine ~ d e a . s t ; from

tlw pituitan

An tich o

lin

e rgic e lfects-dr mouth

tonstipation .

urinan

retentiou,

111d

hlurn 1ision


82/496

Table

12 1.

Neuroleptic Drug Side Effect Profiles

Potency Drug Sedation

HfCH

Haloperidol

Fluphenazine

Thiothixene

2

Trifluoperazine 2

Loxapine

2

Chlorproma7Jne 4

LOW

Thioridazine

4

l =

low, 4

= high

Side

EfTects

Extrapyramidal Antichonlincrgic

Effects Effects

4

4 2

3

2

3 2

2 2

2 3

4

a -Aclrenergie

Eflects

2

4

4


83/496

78 Section l / Central Nervous System

What

is hudive dyskinesia?

Is

tardiv

e dyskin

es i

a

reversible?

What

is ne

urol

e

pt i

c malig

nant sy

n dro m e?

What

is

th

e

t.h

e

a

py

for

ne

urol

e

ptic malignant

s

yndrom

e?

Anlia

dr

cne r

gic

effects-watch for

light-headcdness and orthostatic

hypotension ~ e c o n d a r y to

adrenergic blockade. h e n o t h i a z i n e ~

can cause failure to ejaculate.

E xlnlp) lamidal side ef f

ec

ts- akathisia

motor rP.s tlessness), parkinsonian

S)1tdrome (hradykinic rigidity.

tremor), acute dystonic rcactious

slow. prolonged muscle spasms

of

tongue, neck. face), neuroleptic

malignant spulrome. and tardhc

d ~ s k i n c s i a eommon board

question)

Tardive dyskinesia is a symptom Lhat may

occur

after

prolonged therapy with

nenroleplics

6

months to

1

year).

t is

characterized by rhythmical involuntary

movements of the tongue. lips, or jaw.

Patients may also demomtrate puckering

of the mouth, or even chewing

movements.

There is no known treatment for

established cases

of

tardive dyskinesia.

The

y n d r o m e may remit partiaUy or

complete ly irneuroleptic treatment

is

withdrawn, although in

ma

ny cases it is

irreversihle. Anticholinergic agents

actually increase the severity of tardive

dyskinesia.

Patients who receive neuroleptics for

long-term treatment may

ex-perience

rigidity. altered mental status, cardiac

arrh) t.hmias, hypertension,

and

life

threatening h)perpyrexia.

This disorder is treated with dantrolcnc,

a

skeletal mu sc:le relaxant commo n

board question).

TYPIC L N TIPSYCHOTIC DRUGS

N e three examples of

atypi

ca

l a

ntip

syc

hotic drug

s.

1. Clo7.apine (Cio7.aril)

2. Risperidone (Risperdal)

3. Olanzapine (Z) prexa)


84/496

Why a

tlte

se

drugs

considered y p i c a l

Describe the

actions

of

cl

pi

nc.

What

is

it used for?

What ae the s ide

effects?

Desc

rib

e

th

e

actions of

rispet;done

Desc

dbe

the actions of

olanzapinc

Chapter 12 Antipsychotics 79

In addition to bloddng dopmnine

rC ctptors. al)vical antipsychotic-s also

produce

signifieant blockade on serotonin

(5 l iT) reecptors. They also art'

mrdy

assoeiatt.d with f'\t rapyramichl side

(f'b:ts.

This a -(Cilt is a clibenzodiazepine

ckrivativt.

It

eli

f e r ~ from

traditional

a n t i p ~ y c h o t i c s

in its

potent

blockade o

f

~ c r o t o n

(.5- II T

2

) receptors nts

~

common

board

question

).

Weekly bloocl tests are required for

patientl> receiving clozapine therapy.

Risperidone (Risperdal) is

a

henzisoxazole

drug that, like clo:z.. lpine, has a vcty high

aHlnity for 5-

T

2

receptors.

It

also has

anlidopaminergic

2

) activity. However,

risperidone exhibits no anticholinergic

effects and diminished extrapyramidal

effects. Risperidone is a first-line agent

for the treatment ofschizophrenia since

it

is effective for both the positive and

negative symptoms

of the

disease.

The

drug

is

also known to prolong QT

intervals and therefore should

be

used

with caution in patients who have

abnormal QT intervals.

Like risperidone and clozapine, olanza

pine

blocks both dopamine and serotonin

receptors. Effective

in

the treatment of

schizophrenia, it can produce anticholin

ergic effects as well as sedation and ortho

static hypotension.


85/496

3

NTIDEPRESS NTS

What

is

dcpre

>s

ion?

What does

the

biogenic

a

min

e lhem

plc

s of

tr i

cyclic a ntidepr

ess

antp< dfit

nuptak


86/496

Chapter 13 Drugs Used to Treat Depression and Mania 81

What

ar

e

th

e

ph y

siologic

differences b e

twe

en tertiary

amine and

secondary amine

tr icyclic. >?

What is the mechanio;m of

action of all the tr icyclics?

Do

th

ese drugs e leva te

mood in normal

individual

s?

What ar

e

th

e clinical

indication

s for bicyclics?

How ar

e cyclics admin-

is te re d?

How

a1

e th ese

drug

s

metaboliz

ed ?

Which

of th

e bicy

clic.o;

a1e

most efficacious?

When

should: a

ph

ysician

e- llect to see a change

in

th e

pati

ent

s mood

?

The secondmy

am

i

ne

tricyclics

in

general

are less

li

hlv to

cause

sedation. hvpu

te

nsion.

an( '

anticholinergic

ef

fects.

owever they are more likely lo induce

psychosis .

These drngs are thought

to

in cr .

LSe lc,vds

of norepinephrine and serotonin in the

synapt ic cleft hy blocking neuron;tl

re\lptakP.

They

abo

Ll

ock

histamine.

cho

lilwrgic, and u -adrcnergie receptors.

which accounts

for

a large prop'

l ltion of

the

ir side

effects.

Tricyclics

are

also

thought to causf;' a

down-r

egul

ation

of

mo

noamine

recf;'ptors;

this m;ty account

Cor some or

Iheir therapeutic henefit.

No. These drugs are nol CNS

stimulant

s.

Mood dis


87/496

82 Section Ill I Central Nervous System

What arc the

s

igns

and

p t o m

>f

tricyclic

toxicity?

Ctm

tdcyclics and

.MAOis

be

given

together for added

benefit?

Anticholinergic

l l t ciTet ls-hlurred

vision, hot

dry

skin, t'(mstipation,

c o n f u ~ i o n

urinary

reten ti

on

Autonomic eiTects-rthostatic

hn>otcnsion

ECG

h a n ~ e s \vid(ning of

tlw

QRS

complc\, r r h y t h m i a ~

Weight

gain

Sedation

due to

histamint blockade

Possible lowt'ring

of

sdzun

thresholds

No There is a chane


88/496

Chapter

13/

Drugs Used to Treat Depression and Mania 83

'he n are

SSRls

contra-

indicated?

SS Rls ar c contraindicated

in

combination

thcntpy with monoamine oxidase

inhibitors MAO s) because this combi

nation may result in the

..

serotonin

syntlrome, characterized by hypcr

thcnni a, 1nuscle rigidity, myoclonus, and

rapid changes in mental status.

MONO MINE OXIDASE INHIBITORS MAOis)

\Vhat

monoamine

oxidase?

M O b

a

mitochondrial enzyme that is

invoked

in

the metabolism of catechol

amine

m>urot

ransmjtters.

Wh

ere are

the highest con-

centrations of

this enzyme?

Descibe

the mechanism

of

action

of the M O

s.

What

are

the

M.AOls

indicate d for?

Describe the pharmacologic

prope

rtie

s of MAO s.

Vhat ae

the adverse effects

ofMAOb?

In

the

Liver, GI

tract, and

C:r\S

Two types of MAO exist: MAO-A and

MAO-B.

Withln the neu rons, M O-A is

responsible for the inactivalion

of

any

serotonin or norepinephrine that may

leak out

of

presynapticstorage

vesicles.

When MAO-A

is blocked,

these neurotransmitters accumulate

and are released into the synapse.

MAO-l3

is

responsible for the metabolism

of dopamine and works in a sim ilar

1mum

er.

In

general, the M Ois

arc

nonsp

ec

ific inhlbitors ofM O, except

for

se

l

eg

iline, which is a specific

inhibitor of MAO-B.

Treatment of

atypical depression (with

phobm or psychotic features).

Other

classes

of

antidepressants

are

more

frequently used today because they have

fewer toxic effects.

Th

ey arc well absorbed orally.

Th ey are metabolized by acetylation

in

the li

ver (half-life,

2- 3

hours.

Th ey require 2 to 4 wee

ks of

treatment to

reach a steady-state plasma level.

Hypertensi\'e crisis (headache, hyper

tension, arrh)'thmias, and possibly

stroke)

if the

patient does not avoid


89/496


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