USMLE Road Map Pharmacology
Transcript of USMLE Road Map Pharmacology
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E OND
ITI
ZUN
VOR
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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
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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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ection
rinciples
o
harmacology
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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
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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--
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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
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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
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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
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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
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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'
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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
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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
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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).
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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
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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
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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).
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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
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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
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~
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
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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.
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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
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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
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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,
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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
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32 Section
II/
Autonomic Nervous System
State the clini
ca
l u
se.
Pilocarpine is extremely good for
stimulatinf ; miosis and opening the
lrah
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Chapter 6 Cholinergic Agonists 33
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
acetylcholinesterase
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
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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
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
.
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Chapter 6 Cholinergic Agonists 35
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
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6 Section II/ Autonomic Nervous System
What is the clinical u
se?
Because of its long durati
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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
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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
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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
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ection
ll
entral Nervous
System
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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
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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
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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
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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
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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.)
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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>
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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
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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
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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
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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,)
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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)
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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
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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
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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)
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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.
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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
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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
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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
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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
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