█ Intro

oductory definitions

Medica al pharma acology is a basic c science.. It the science

s deealing with
h small
molecu ules used tot prevent, diagnose , or treat diseases.
d
Clinicaal pharma acology is s the scieence concerned with the raational, sa afe and
effectivve use of drugs
d in hu
umans. It ccombines elements of o basic phharmacoloogy with
clinical medicine e; in other words, it involves the
t complex interacction betweeen the
drug and the pattient.
A drug g is any chemical molecule that can interact with w bodyy systems at the
molecu ular level and produc ce effect.

The drrug-body interaction

ns

Part 1
1: Ph
harmaco
odynamiics (Mec
chanism of drug a
action)

Pharmaacodynam mics is summmarized a

as what a drug does to the b
body; a drug may
produc
ce its effectts through:
■ Interraction witth body co
ontrol systtems (regulatory prote
eins):
(a
a) Receptorrs (b) Ion
n channelss
(c
c) Enzymess (d) Caarrier molec
cules

■ Direc
ct chemica
al or physic
cal mecha
anisms.
■ Interraction with certain metabolic
m p
pathways.

1
 A. REC
CEPTORS
S

Receptors: they are protein macrom molecules. When

W they
y combine with a dru ug, they
may be e activated d or blocke
ed.
Ligand d: is any molecule tha at can com
mbine with the recepptors. A ligaand that ac
ctivates
the rec ceptor is called agonist.
a A ligand that
t block
ks the reeceptor is called
antago onist.
Affinity
y: it is the empathy ofo the rece
eptor to the ligand. It determinnes the nummber of
receptoors occupied by the drug.

█ Typ
pes of rec
ceptors

■ Ion channel--linked re
eceptors (direct
ligand-gated
d ion channnels):
- The receptor is an ion s of 5
n channell consists
transsmembran ne subunits
s (α1, α2, β,, γ, δ).
- Bindding of thee agonist to
t the extrracellular part
p of
the rreceptor causes
c opeening of th he channe el for a
speccific ion.
- The response of these re eceptors iss very fast and their duration
d is very shortt.

- Exam
mples:
 N
Nicotinic Ach
A recepttors in the motor end
d-plate: the
e ion channnel opens for Na+
ions in ressponse to stimulation
s n by Ach.
 The Gama a aminobuteric acid (GABA) re eceptors in
n the brainn: the ion channel
c
opens for Cl ions in response to stimulation by GA
-
ABA.

■ G-protein-lin
nked rece
eptors:
onsists of 7 membran
- The receptor co ne subunits.
- Bind
ding of the
e agonist too the extra
acellular part
of the receptor ca auses ac ctivation of
intra
acellular G--protein.
- Wheen the G-p protein is activated,
a its α subu
unit
bindds to GTP to be pho osphorylateed and bring
stimulatory or inhibitory response.
- Their responsse is slow wer than ion chann nel
receeptors but their
t duration is long
ger.

- Stim
mulatory G-protein
G (Gs) leadss to increa
ase
ade
enyl cyclase enzyme → ↑ cAMPP → activation
of specific proteins s (proteinn kinase es).
Exa
amples of Gs-couple
G ed receptorrs are the β1
and
d β2-adrenergic receptors.

2
- Inhibitory G-protein (G
Gi) leads to
o decrease
e adenyl cy
yclase enzzyme → ↓ cAMP
c →
inhibition of protein kinases. Exxamples of
o Gi-coup pled recep
ptors are the
t α2-
adreenergic rec
ceptors an
nd M2 musscarinic rec
ceptors.

- Gq--coupled receptorrs: they increase inositol triphosp phate (IP3 3) and

diac
cylglyceroll (DAG). IP3
3 increasess free intrac
cellular Ca . Exampl es of Gq-c
2+
coupled
rece
eptors are the α1-ad drenergic reeceptors, M1M and M3 3 muscarinnic recepto
ors.

■ Tyro
osine kinase (TK)--linked re
eceptors::
- The receptor consists of 2 largee domainss: an
extraacellular hormone-b
h binding doomain and d an
intra
acellular TKK-binding domain c onnected by a
transsmembran ne segment.
- Bindding of the e agonist to the hoormone-binnding
dommain cause es activattion of th
he intrace
ellular
dommain to ac ctivate TK enzyme → activatio on of
seveeral protein
ns known as
a “signalin
ng proteinss”.

- Exam
mples: insu
ulin recepttors.

■ Intra
acellular recepto
ors:
- Theyy are located inside the
t cell eith her in the cytoplasm
c or directlyy on the DNA.
D
- Theyy regulate transcripti
t on of genees in the nuucleus or the mitoch ondria.
- Their agonist must
m enter inside the
e cell to reaach them.
- Theyy have twoo importantt features:
 Their response is slo ow (time iss required for
f synthes sis of new proteins).
 Their effeccts persist for long tiime after the agonistt is removeed.
mples: receptors for corticoste
- Exam eroids, sexx hormone
es, thyroxinn, etc.

Types
s of drug
g-recepto
or bonds
s

■ The ionic bon nd:

It is an electric
cal attraction betwee
en two opp
posing cha
arges. It
is strong but reeversible.

■ The hydrogen n bond:

It is an attraction betwe
een two h
hydrogen bonds.
b It is weak
and reversible.

■ The covalent bond:

Veryy strong an
nd irreversible.
If oc
ccurred bettween drugg and rece
eptor, the receptor
r be
ecomes
permmanently blocked.
b

3
 █ BIOL
LOGICAL RESPONS
SE TO DRU
UG-RECE
EPTOR BIN
NDING
(Dose
e-response relatiionship s
studies)

When a drug com

mbines with a recepto
or, this ma
ay lead to one
o of the following:
■ Agoonist effect: meanss that the drug com mbines with the recceptor andd gives
resp
ponse.
■ Anttagonist effect:
e mea
ans that thhe drug combines with
w the reeceptor bu ut gives
NO response e, and prev
vents the re
eceptor fro
om binding
g to anotheer drug.

▌Agon
nist effe
ect

ding to the “dose-rresponse relations

Accord ship curve
es”, theree are 2 ty
ypes of
responses to drugs:

Graded respon
nse Qu
uantal res ponse

- The response is increase

ed - The
T respon
nse does nnot increas
se
prop portionally y to the do
ose of the proportiona
p ally to the agonist bu
ut it is
agon nist e.g. the response e of the he
eart all-or-none
a e responsee e.g. prevvention
to addrenaline. of
o convulsions by anttiepileptic drugs
nse to mos
- It is tthe respon st drugs. - Itt is responnse to few drugs.
- The response could be tested in on ne - The
T respon nse could nnot be testted in
or mmore anima als. one
o animal and mustt be tested d in a
group
g of animals.

Effecttiveness
s and saffety

■ Effic
cacy
- It is tthe ability of a drug to
t produce
e response
e (effect) affter binding
g to the receptor.
- It is measured d by the Emax (the m
maximal re
esponse that a drug g can eliciit at full
conc
centration)):

4
 ■ Full agonist is the d drug that gives maximal
m rresponse at full
conceentration (aat full occu
upancy).
■ Partia
al agonistt is that ag gonist givees submax
ximal resp
ponse even
n at full
conceentration i..e. never g ives Emax

■ Pote
ency
- ED5
50 (Effectiv
ve Dose) is the dose
e of the dru
ug that giv
ves 50% o
of the Emaxx, or it is
the d
dose that gives
g the desired
d effe
ect in 50%
% of a test populationn of subjec
cts.
- A drug that givves ED50 byb smaller doses is described
d a “potentt” drug.
as
- Poteency of dru
ugs is gene erally less clinically importantt than efficcacy becauuse you
can increase the dose of o a less po otent drug to obtain the effect of a moree potent
one (provided that it is not toxic).

ety
■ Safe
- TD5
50 (Toxic Dose)
D is th
he dose o f the drug needed to cause a harmful effect
e in
50%
% of a test population
n of subjec
cts.

- LD5
50 (Lethal Dose) is th
he dose ne
eeded to cause
c deatth in 50% of a test group
g of
anim
mals. It is experiment
e al term tha
at can be determined
d d in animalls.

5
 - Therrapeutic in
ndex (TI) LD50/ED5
L 50:
- It is the ratio between
b th
he LD50 an
nd the ED5
50. It is a measure
m off safety; if there is
a larrge differe
ence betweeen the do ose of a drug
d that produces
p tthe desired
d effect
and the dose that
t producces a toxic
c effect, it is said tha
at the drug has a large TI.
- Druggs with higgh TI are more
m safe ffor clinical use, and vice
v versa (e.g. warfa
arin has
a na
arrow TI and requires careful th erapeutic monitoring g).

▌Anta
agonist effect
e

 Anta
agonist is the ligand
d that com
mbines with ptor and d
h the recep does not activate
a
it. Itt has no intrinsic activity, bu ut may cause a pha armacolog gical respoonse by
inhibbiting the actions
a of endogenou
e us substan nces or othher drugs.
 If thee antagoniist binds to
o the same e site of thhe agonist on the recceptor, it is
s called
com mpetitive antagonist
a t. If the an
ntagonist binds
b to an
nother sitee on the re
eceptor,
and prevented d the action
n of the aggonist, it is called nonn-competiitive antag gonist.
 Com
mpetitive antagonism
a m may be reversible
e or irreve
ersible:
 R
Reversible
e antagonist makess weak bo
ond with th
he recepto
or so as you
y can
o
overcome the
t block byb giving h high dosess of the ago
onist, and even you can get
th
he maximaal response in prese ence of the
e antagonisst (i.e. surm
mountable effect).
T
The duratio
on of block
k is short b
because the antagonist can be easily was shed off
th
he recepto
ors.
 Irrreversible
e antagon
nist make s covalen
nt bond with the recceptor so as you
ccannot oveercome the block o r get the maximal responser b
by increas
sing the
ddose of the
e agonist (ii.e. non-su
urmountable effect). TheT occup
pied recepttors are
ppermanently blocked d, so the d duration off block is long, and the bodyy has to
ssynthesize new recepptors to reg gain the orriginal state
e.

6
Other types of drug anttagonism

■ Che
emical anttagonism: e.g. one acidic dru
ug when added
a to a basic drrug can
causse precipita
ation of ea
ach other’ss
Exammple: the addition of
o gentamyycin (basic drug) to carpenicilli
c in (acidic drug)
d in
the ssame syrin
nge causes
s chemical complex.

■ Physsical antaagonism: antagonissm betwee

en two
drug
gs carrying opposite charges.
c
Exammple: pro otamine is
s used ffor treatm ment of
hepa arin overd
dose because protammine carries +ve
charrge while heparin
h arries –ve charge. One
ca O mg
of prrotamine can
c neutrallize 100 un
nits of hepa
arin.

■ Phys siological antagonism: antaggonism be etween

two drugs producing opposite effe
ects by acttivation
of diifferent rec
ceptors.
Exammple: adre
enaline is the physio ological an o histamin
ntagonist of ne becausse while
hista
amine cauuses hypo otension a and bronchoconstric ction throuugh activa
ation of
hista
amine H1 receptors,, adrenalin ne causes hypertens sion and bronchodiilatation
throu
ugh activa
ation of adrrenergic α & β recepttors respec
ctively.

■ Pharmacokinetic antag gonism: (seee drug intteractions)).

- One drug mayy prevent absorptio
a on of anoth her drug e.g. antacidds ↓ absorption of
iron & aspirin.
- One drug maay increas se metabo olism of another
a drrug e.g. ri fampicin induces
i
hepaatic enzymmes and ↑ metabolism
m m of oral co
ontraceptivve pills.
- One drug mayy ↑ excretion of anoother drug e.g. NaHC CO3 causee alkalinizaation of
urine
e and ↑ exc cretion of acidic
a gs like asp
drug pirin.

B. ION
N CHANNE
ELS

How drugs could modulatte ion cha annels?

 Phyysical block: e.g. blocking of Na+
channels by lo ocal anesth
hetics.
 Thee ion chaannel mayy be parrt of the
receeptor e.g. ion
i channe el-linked re
eceptors.
 Thee ion chann nel may be modulatted by G-
prottein linked receptors.
 Ion channels may be modulated
m by intracellular ATPP e.g. ATPPase senssitive K+
channels in the pancre eatic β cellls, rise off intracellu
ular ATP ccauses clo
osure of
pancreatic K channels.
+

7
 C. ENZ
ZYMES

How drugs could affect enzymes?

 Thee drug mayy act as a competitivve inhibito or of the enzyme e.g
g. neostigmmine on
cholinesterasee enzyme.
 Thee drug mayy act as irrreversible inhibitor of
o the enzy yme e.g. o
organophos sphates
on ccholinesterrase enzym
me.
 Thee drug mayy act as a fa
alse subst rate for the
e enzyme e.g.
e α-metthyldopa is s a false
substrate for dopa
d deca
arboxylase..
 Thee drug mayy induce orr inhibit hep
patic microosomal enzymes acttivity (see later).

D. CARRIER MO
OLECULES

 Theese are sm
mall protein
n molecule
es that carrry organic
c moleculees across the cell
memmbrane whhen they arre too large
e or too po
olar.
 Drug
gs could affect
a carrie
er molecul es by bloc
cking their recognitio
on site.

Part 2
2: Fac
ctors afffecting dose-re
esponse relation
nship

A. FAC
CTORS RE
ELATED TO
O THE DR
RUG

1. Drug
g shape (s
stereoisom
merism):
- Mosst drugss have
multtiple stere eoisomers
(enaantiomers) (e.g. L-
thyrooxin an
nd D-
thyrooxin). The receptor
site is usually sensitive
for one sterreoisomer
and not suittable for
anotther, like the hand
and the glo ove. This
mea ans that on ne isomer
mayy be hundrred times
more e potent than the
otheer. In other instances one isome er is benefficial while the other is toxic.
- This phenomeenon may explain hhow a sin ngle drug could actt as agon nist and
antaagonist (i.ee. partial agonist)
a b ecause many
m drugss are pressent in “ra acemic
mixttures” rath her than asa pure isoomers; or how one isomer is effective and a the
otheer isomer iss toxic.

8
2. Molecular weight (MW):
- Most drugs have MW between 100-1000 Da. Drug particles larger than MW 1000
Da cannot be absorbed or distributed. They should be given parenterally.
- Drug particles larger than MW 1000 Da cannot cross placental barrier.

3. Time of drug administration (Chronopharmacology):

- Many body functions (e.g. liver metabolism, RBF, blood pressure, HR, gastric
emptying time, etc.) have daily circadian rhythm. Some enzymes responsible for
metabolism of drugs are active in the morning or evening.
- Also many diseases (e.g. asthma attacks, myocardial infarction, etc.) are circadian
phase dependent.
- Chronopharmacology is the science dealing with tailoring drug medication
according to the circadian rhythm of the body to get better response and/or to
avoid possible side effects.
- Examples:
- Episodes of acute bronchial asthma are common at night due to circadian
variation of cortisol and other inflammatory mediators, so it is better to give the
anti-asthmatic medications in the evening.
- Blood pressure is at its peak during afternoon, so it is better to give the
antihypertensive medications at morning.

4. Drug cumulation:
Cumulation occurs when the rate of drug administration exceeds the rate of its
elimination (especially in patients with liver or renal disease). Some drugs are
cumulative due to their slow rate of elimination e.g. digoxin.

5. Drug combination:
Drug combination is very common in clinical practice. When two or more drugs
are combined together, one of the following may occur:

a) Summation or addition:
- Summation means that the combined effect of two drugs is equal to the sum
of their individual effects (i.e. 1+1=2). It usually occurs between drugs having
the same mechanism, for example, the use of two simple analgesics together.

b) Synergism and potentiation:

- Synergism means that the combined effect of two drugs is greater than the
sum of their individual effects (i.e. 1+1=3). The two drugs usually have
different mechanisms of action, for example, the use of penicillin with
aminoglycosides to exert bactericidal effect.

9
 - Potentiation is similar to synergism but, in potentiation, the effect of one drug
itself is greatly increased by intake of another drug without notable effect (i.e.
1+0=2), for example, Phenobarbitone has no analgesic action but it can
potentiate the analgesic action of aspirin.

c) Antagonism:
One drug abolishes the effect of the other i.e. 1+1=0 (see before).

B. FACTORS RELATED TO THE PATIENT

1. Age, sex, and weight.

2. Pathological status:
Liver or kidney diseases significantly alter the response to drugs due to altered
metabolism. Also the failing heart is more sensitive to digitalis than the normal heart.

3. Pharmacogenetic factors (idiosyncrasy):

It is abnormal response to drugs due to genetic abnormality in drug metabolism.
These are some examples:

▌Examples of heritable conditions causing EXAGGERATED drug response:

a) Pseudocholinestrase deficiency:
Succinylcholine is a neuromuscular blocker metabolized by pseudo-
cholinestrase enzyme. Some individuals with deficient PsChE, when they take
succinylcholine, severe muscle paralysis occurs due to lack of succinylcholine
metabolism, and may lead to death from respiratory paralysis (succinylcholine
apnea).

b) Glucose-6-phosphate dehydrogenase (G6PD) deficiency:

- G6PD is the most common human enzyme defect. G6PD enzyme catalyzes
the reduction of NADP+ into NADPH which maintains glutathione in the RBCs
in its reduced form. Reduced glutathione keeps Hb in the reduced (ferrous)
form and prevent formation of methemoglobin and cell membrane injury
(hemolysis) by oxidizing drugs.
- Individuals with deficiency of G6PD may suffer acute hemolysis if they are
exposed to oxidizing drugs e.g. nitrates, antimalarial drugs, and others.

c) Thiopurine methyltransferase (TPMT) deficiency:

- Thiopurine methyltransferase (TPMT) is an enzyme that methylates thiopurine
anticancer drugs (e.g. 6-mercaptopurine and 6-thioguanine) into less toxic
compounds.

10
 - G eficiency in TPMT lea
Genetic de ads to incre
eased conversion of parent thiopurine
d
drugs into more toxic compou unds, leadiing to seveere myelottoxicity an
nd bone
m
marrow supppression which mayy be fatal.
- T
TPMT defiiciency prrevalence is 1:300. Screening for TPM MT deficieency is
n
necessary in patients
s treated byy thiopurin
ne anticanc
cer drugs.

d) Acetylator phenotyp
p es:
M
Many drugs are me etabolized in the liver by ac cetylation (e.g. isoniazid).
Ac
cetylation reaction is under g genetic co ontrol and
d people ccan be classified
ac
ccording to
o their rate ation into rapid
e of acetyla r and slow acetyylators:
- In
n rapid ac
cetylators: excessive
e isoniazid toxic mettabolites aaccumulate
e in the
liver causin
ng hepatoc cellular nec
crosis.
- In
n slow acetylators s: isoniazzid accum mulates in
p
peripheral tissues causing
c peeripheral neuropathy
d
due to inteerference with
w pyrido oxine metaabolism, (so
p
pyridoxine “vit B6” iss added to o isoniazid therapy to
p
prevent neu urotoxicity
y).
- S
Some drug gs that are metabolize ed by acettylation can
c
cause systtemic lupus erythem matosis-like
e syndrome
(S
SLE) in slo
ow acetylattors (see bbox).

amples off heritable

▌Exa e condition
ns causing
g DECREA
ASED drug
g respons
se:

a) Resistance
e to couma
arin (warfa
arin) antic
coagulants
s:
- In
n normal individuals, warfarin anticoagu
ulant acts by
b inhibitinng the enzzyme vit
K epoxide reductase
r ble for redu
responsib uction of th
he oxidized
d vit K (inac
ctive) to
itts reduced
d form (active).
- S
Some indivviduals havve another variant of this enzymme making g them nee eding 20
times the usual
u dose of coumarrin to get the response.

b) R
Resistance
e to vit D (v
vit D-resisstant ricke
ets):
C
Children witth vit D-res
sistant rickkets need huge
h doses
s of vit D to
o be treate
ed.

c) Re
esistance
e to mydria
atics:
Dark eyes are esponsive to the effect of mydrriatics.
a genetically less re

4. Hypo
oreactivity
y to drugs
s:
(Tolera
ance; tach
hyphylaxiss; drug res
sistance)

Tolerance mean ns progressive decre ease in drug respon nse with suuccessive admin-
istration. The sam
me respons se could b
be obtained d by highe
er doses. Itt occurs ovver long
period.. Tachyphy ylaxis is an acute typ
pe of tolerance that occurs
o verry rapidly.

11
 Mechanism of tolerance:
 Pharmacodynamic tolerance: may occur due to:
 Receptor desensitization: prolonged exposure to the drug leads to slow
conformational changes in the receptors by which the receptor shape
becomes no longer fitted well with the drug.
 Receptor down-regulation: prolonged exposure to the drug leads to decrease
number of the functional receptors.
 Exhaustion of mediators: e.g. depletion of catecholamines by amphetamine.

 Pharmacokinetic tolerance:
 Due to ↑ metabolic degradation of a drug by induction of hepatic enzymes
e.g. with chronic administration of ethanol.

 Behavioral tolerance:
 It occurs by a drug independent learning of the brain how to actively
overcome a certain drug-induced effect through practice e.g. with
psychoactive drugs.

5. Hyperreactivity to drugs:
(Rebound and withdrawal effect)

Rebound effect: is recurring of symptoms in exaggerated form when a drug is

suddenly stopped after a long period of administration.

Mechanism: prolonged administration of the antagonist leads to up-regulation

(increase number) of receptors. When the antagonist is suddenly stopped, severe
reaction occurs e.g. severe tachycardia and arrhythmia occurs after sudden stopping
of beta-blockers.

Withdrawal effect (syndrome) is recurring of symptoms in exaggerated form plus

addition of new symptoms when a drug is suddenly stopped e.g. withdrawal effects
that occur after sudden stopping of opioids in opioid addicts.

N.B. Some examples of drugs should not be stopped suddenly:

Drug Sudden withdrawal can lead to:

Beta-blockers : Severe tachycardia, arrhythmia, and even myocardial infarction.
Clonidine : Severe hypertension (hypertensive crisis).
Cimetidine : Severe hyperacidity and even peptic ulceration.
Corticosteroids : Acute Addisonian crisis.
Morphine : Withdrawal symptoms (see CNS).
Warfarin : Thrombotic catastrophes

12
Part 3: Cllinical pharmac
cokinetic
cs

Definittion: it is th
he journey of the dru g inside th
he body. It includes 4 processe
es:

Abssorption Distribu
ution Metabolism
M m Excreetion

█ ABS
SORPTION
N OF DRUG
GS

Definittion: it is th
he passage
e of drug from the sitte of administration tto the plas sma.
The ma ain routes s of administration: o
oral, sublin
ngual, recta
al, inhalatio
on, injection, etc.

Factorrs affectiing drug absorptio

a on:

A. Facttors relate
ed to the drug
d

- Mollecular sizee: small mo olecules arre absorbe

ed than large molecuules.
- Dosse: absorpttion increa ases with in
ncreasing the dose (up to limit)).
- Drug formulattions: e.g. sustained--release ta ablets are slow
s in abssorption.
- Loccal effects of the drugg: e.g. druggs producing VC ↓ thheir own ab bsorption.
- Drug combina ation: e.g. vit
v C ↑ abssorption off iron.
- Lipid solubilityy, drug ion
nization, an
nd the pKaa of the dru
ug.

B. Facttors relate
ed to the absorbing
a g surface:

- Rouute of administration: i.v. route is the fastest while rectal

r is thee slowest.
- Inte
egrity of the
e absorbinng surface: may ↑ or ↓ absorptio on.
- Loccal blood flow: ischemmia ↓ abso orption.
- Speecific facto
ors: e.g. ap
poferritin syystem for iron, etc.

The pK
Ka and drug ioniz
zation

Princip
ples
- Ionized (polarr; charged d) drugs a are poorly absorbed d,
while unionized (non-p polar, non--charged) drugs are e
more absorbe ed.
- Mosst drugs are a weak acids or b bases. Theey become e
ccording to the pH aro
ionizzed or non--ionized ac ound them.
- Acid dic drugs (e.g.
( aspirin) are morre ionized in alkaline pH and vicce versa.
- Bassic drugs (ee.g. amphe etamine) a re more ionized in ac cidic pH annd vice verrsa.
- pKa
a of a drug
g: is the pH at whic h 50% of the drug is ionized and 50% is non-
ioniized. (W
Where p = inverse log
g; Ka = association/d
dissociatio
on constant).

13
 Examp
ple of pH variation
v and
a drug k
kinetics with
w aspirin
n:

Aspirin is an acid s pKa = 3.5

dic drug; its 5
The pH omach is 1.5
H of the sto e is 8.5
Th e pH of the intestine

►Wheen aspirin is put in th he stomac ch:

 Asppirin is acid
dic drug annd become es more abbsorbable in acidic p
pH.
 Logg (Unionize ed /Ionized)* = pKa – pH = 3.5 – 1.5 = 2 (log
( 2 =1022 ).
 Thiss means th hat the rattio of union
nized: ionized = 100/1 (or accuurately 0.9
99 parts
are absorbed and 0.01 parts are n non-absorbbed).

►Wheen aspirin is put in thhe intestin

ne:
 Asp
pirin is acid
dic drug annd become es less abssorbable in
n alkaline p
pH.
 Log
g (Unionize ed/Ionized)* = pKa – ppH = 3.5 – 8.5 = – 5 (log -5 =1 0–5 ).
 Thiss means thhat the ratio of union
nized/ionize
ed = 1/1000000 (or acccurately 0.00001
0
partts are absoorbed and 0.99999 p parts are non-absorb bed).

*N.B. T
The above rule applies only to a
acidic drugs
s like aspirrin. For bassic drugs, the
t ratio
would b
be reversed
d.

►Ion ttrapping of
o aspirin:
In the stomach, aspirin is more abssorbable in nto
stomacch cells buut once entered the cells, the pH
changees from 1.5 outside to 7.4 insside the cell.
So asppirin becom mes ionize
ed inside tthe cells and
a
can’t diffuse outsside them again
a → ga
astric ulcer.

al significa
Clinica ance of pK
Ka
 Know
wing the site of drug
g absorptio
on from the
e GIT (see principles)).
 Treaatment of drug
d toxicitty:
- Tooxicity witth acidic drugs
d (e.g . aspirin) could be treated byy alkaliniza
ation of
urrine, which
h renders this drug m more ionize ed in urine and less reeabsorbab
ble.
- Tooxicity with basic drrugs (e.g. aamphetam mine) couldd be treateed by acidiification
off urine, which renderrs this drugg more ionized in urinne and lesss reabsorb
bable.
 Ion ttrapping in
n breast milk:
- Thhe pH of the
t breast milk is 7 i.e. it is coonsidered acidic in rrelation to plasma
(p
pH 7.4).
- Basic drugss (with pKa
a > 7.2) ten
nd to be ionized, and thus trappped, insidee breast
m
milk more thhan acidic
c drugs; heence, the milk/plasm
m a ratio (M//P ratio) would be
hiigh.

14
█ DIST
TRIBUTIO
ON OF DRU
UGS

Sites o
of drug disstribution
 Plassma: 3 liters
 Extrracellular water:
w 9 liters
 Intraacellular water:
w 29
2 liters

me of dis
▌Volum stribution
n (Vd)

Definittion: The apparent

a volume
v of water into
o which
the druug is distributed in the body after distrribution
equilibrrium.

Calcula
ation:
Total amount
a off the drug in the body y
Vd
d = ————————————— —————————— ————— L
Plassma conc of the drugg (after dis
stribution equilibrium)
e )

Clinica
al significa
ance:
 Deteermination of the site
e of drug d
distributio
on e.g.:
- A total Vd < 5 L: means that the e drug is confined
c to
o the vascuular compartment
an
nd can be removed by b dialysiss.
- A total Vd 5-15 L: mea ans that thhe drug is restricted
r to
t the ECF F.
- A total Vd > 41 L: me eans that tthe drug is s highly bo
ound to tisssue prote
eins and
ca
annot be reemoved by y dialysis.
 Calcculation of the total amount o of drug in the body y by singlee measuremment of
plasma concen ntration (from the eq quation).
 Calcculation off the loading dosse (LD) needed to attain a desired plasma
conccentration (Cp): LD = Vdd x Cp.
 Calcculation of drug cleaarance:

▌Binding of dru
ugs to pla
asma pro
oteins

 Mosst drugs wh
hen introdu
uced into tthe body are
a bound tot plasma proteins.
 Albu
umin: the most
m impo
ortant plasmma protein
n and it ca
an bind –vve or +ve charged
c
drug
gs.

Clinica
al significa
ance:
 The pharmaco
ological efffect of the y to its fre
e drug is related only ee part no
ot to its
bounnd part (th
he bound part
p acts o
only as a re
eservoir fro
om which tthe drug is
s slowly
relea
ased).

15
  Bind
ding of drugs to plasm ns prolong
ma protein gs their effe
ects.
 Wheen the drugg has high
h plasma pprotein bin
nding (e.g. 99% for warfarin), the
t free
part that exertts the phaarmacologiic effect is s 1%. Anyy small dissplacement of the
boun nd part by another drug
d (say fo
or example e another1% is displlaced) can lead to
drammatic toxic
city (double
es the amo ount of the free part in plasma)..
 Man ny disease e states (e.g. chron nic liver disease, pregnancy, renal failuure) can
affec
ct the level of albumiin and the nature of plasma pro oteins, thuus causing serious
probblems with some drugs.

CRETION AND ELIM

█▌EXC MINATION
N OF DRUG
GS

Elimina
ation of dru
ugs may fo
ollow one o
of 2 proces
sses (orderrs):

First-ord
der elimin
nation Zero-order elim
mination

- Occcurs to mo ost drugs. - Occurs

O to limited nuumber of drugs.
- Connstant ratioo (%) of th
he drug is - Constant
C amount
a off the drug is
i
elim
minated per unit time i.e. the ratte of eliminated
e per unit ti me i.e. the
e rate of
mination is proportional to plassma
elim elimination
e n is not pro oportional to
conncentrationn. The higher the plasma
p concentratio on. A familiar
conncentrationn, the greatter the rate
e of example
e is
s ethanol, cconcentrattions of
elim
mination. which
w decline at a co onstant ratte of
approxima
a ately 15 mg g/100 mL/h h.
- mination do
Elim oes not deepend on - Elimination
E n depends on satura able
satuurable enz zyme system. enzyme
e sy
ystem.
- Thee t1/2 of the drug is co
onstant. - T t1/2 of the drug iss not consttant.
The
- Drug cumulation is not common
c - Drug
D cumu ulation is ccommon

Examp
ples of drugs elimina
ated by zerro-order: prednisolon
p ne, theophyylline.

N.B. S
Some drug gs are elim
minated b
by first-ord ation in low
der elimina w doses and by
zero-orrder elimination in hig
gh doses e.g. aspirin and phenytoin.

16
Clinica
al significa
ance of ze
ero-order
elimina
ation:
 Mod
dest chan
nge in dru
ug dose may
prodduce unexxpected toxxicity.
 Elim
mination off drugs or attainmennt of
Cpsss takes lo
ong time.
 Chaanges in drug form mulation may
prodduce adveerse effects
s.
 Drug cumulattion and innteractionss are
commmon.

▌Elimination half-life (t1/2)

Definittion: It is the time taken forr the

concen ntration of a drug in n blood to
o fall
half to its originall value.

Calcula
ation:
 From
m the plasm
ma concen
ntration ve rsus
time
e curve.
 From
m the equaation:

Clinica
al significa
ance:
 Deteermination of inter-d
dosage intterval: dru
ugs are giv
ven every t1/2 to avo
oid wide
flucttuations off the peakk level (the highest plasma con ncentrationn of the drug) and
trouugh level (the lowest plasma co oncentratio on).
 Time e-course of drug accumulat
a tion: if a drug
d is started as a constant infusion,
i
the CCp will accuumulate to approach ssteady-statte after 4-5 5 t1/2.
 Time e-course of drug elimination
e n: If a drug g is stopped after aan infusion, the Cp
will d
decline to re
each comp plete eliminaation after 4-5 t1/2.
 Drug gs having long t1/2 could be give en once daily to imp prove patieent compliiance.

▌Stead
dy-state plasma concentra
c ation (Cps
ss)

Definittion: the steady le evel of d drug in plasma achieved whhen the rate of
adminisstration eq
quals the ra
ate of elim ination.

The rule of 5:
 Thee Cpss is re
eached aftter 4-5 t1/2.

17
  If w
we changedd the dose, the new CCpss is reaached afte
er 4-5 t1/2.
 If do
osing stop
ps, complete eliminattion of drug 5 t1/2.
g from plasma occurrs after 4-5

18
▌Therrapeutic drug
d mon
nitoring (T
TDM)

Definittion: monittoring of se
erum drug concentra ations to optimize druug therapy
y.
 Serum drug samples
s are
a usuallyy taken wh hen the drrug has reeached the e CPSS
(e.g
g. at the tro
ough level, just beforre the next dose).
 TDM M can be done by monitoring g drug effect rather than con centration e.g. in
warrfarin theraapy, TDM is s done via
a monitoring the INR (see bloodd).

Clinica
al significa
ance:
 To a
avoid toxiicity in the
e followingg situation ns:
- Drugs withh a low ‘the erapeutic i ndex’ e.g. lithium, diigoxin, andd warfarin.
- PPresence of disease e states (e..g. liver or renal dysffunction) thhat can afffect the
d
drug’s pha
armacokine
etics.
 To improve efficacy
e of drugs ha
aving pharrmacokinettic problem
ms e.g. ph
henytoin
and
d other drugs with no
on-linear kinetics.
 Diffferentiatio
on betwee
en drug ressistance an
nd patient non-comp
pliance.

▌Clearance as a channe
el of elim
mination

Definittion: plasm
ma clearan
nce of a su
ubstance means
m the
e volume o
of plasma cleared
from th
his substannce per min
nute.

Calcula
ation:

Clinica
al significa
ance of renal cleara
ance:
If the drug is clea
ared by the kidney, cle earance caan help to determine whether th his drug
is eliminated by reenal filtrattion or sec
cretion: a drug
d that is
s eliminateed only by filtration
f
cannot exceed 12 27 ml/min. If clearanc ce > 127 ml/min
m → th
he drug is eeliminated also by
tubularr secretion.

Routess of eliminnation:
 Kidn ney (the major
m route)).
 Bilee and liver.
 Lunngs, intestine, milk, saliva and ssweat.

Clinica
al importance of kno
owing the
e route of eliminatio
e on:
 Help
p to adjustt the dose to avoid c
cumulation.
 Avo
oid drugs eliminated
e by a disea
ased organ
n.
 Targ
geting theerapy: e.g g. drugs eliminatedd by the lung couuld be used as
exp
pectorants..

19
 █ MET
TABOLISM
M OF DRUGS (biotra
ansformattion)

 e liver is the major site of drug metabolism but

The b other organs ca an also
mettabolize drrugs e.g. kidney, lung
gs, and adrenal gland ds.
 Manny lipid soluble drugs must bee converted d into a wa
ater-solub
ble form (p
polar) to
be e
excreted.
 Som
me drugs area not me etabolized a
at all and excreted
e unchanged (hard dru
ugs).
 Mettabolism of
o drugs may
m lead tto:
- Conversion of activ
ve drug in
nto inactiv
ve metabo
olites → terrmination of drug
effect.
- Conversion of activ ve drug in nto active metabolittes → prol ongation of drug
effect e.g. codeine (a
active drug
g) is metab
bolized to morphine
m ((active pro
oduct).
- Conversion of inactive drug in nto active metabolites (prodru ugs) e.g. enalapril
e
(inactive drug) is mettabolized tto enalaprilat (active metabolitee).
- Conversion of non--toxic dru ug into toxxic metab
bolites (e.g
g. paracetamol is
converted into the to
oxic produ ct N-acety
ylbenzoquinone).

Bioch
hemical reactions
r s involve
ed in dru
ug metab
bolism

The drug must enter

e phasse I of che emical rea
actions be excreted as water--soluble
compoound. If thee drug is not
n liable tto convers sion into water-solub
w ble compo ound by
phase I, it must enter
e phase II to incrrease solub
bility and enhance
e el imination.

▌Phas
se I reac
ctions

- Pha
ase I reactions include oxidation,
red
duction, an
nd hydroly
ysis.
- Enzzymes cataalyzing pha
ase I react ions includ
de
cyto
ochrome P450, ald dehyde a and alcoh hol
deh
hydrogenasse, deam minases, esterase es,
amiidases, and
d epoxide hydratase es.
- Thee majority of phase I reactionss is done by b
the cytochro ome P450 (CYP45 50) enzym me
systtem locate ed primarily inside mmembranou us
vesicles (micrrosomes) on o the surrface of th he
smo ooth endoplasmiic retic
culum of
pareenchymal liver cells s. CYP450 0 activity is
also
o present in otherr tissue e e.g. kidneey,
testtis, ovariess and GIT.

20
- Although this class has more than 50 enzymes, six of them metabolize 90% of
drugs. The most important subfamily is CYP3A4 which is responsible for
metabolism of over 50% of drugs.
- Genetic polymorphism of several clinically important CYP450 enzymes is a
source of variability of drug metabolism in humans.
- Drugs may be metabolized by only one CYP450 enzyme (e.g. metoprolol by
CYP2D6) or by multiple enzymes (e.g. warfarin).
- Some drugs and environmental substances can induce (increase activity) or
inhibit certain CYP450 enzymes leading to significant drug interactions.
- Other examples of non-microsomal oxidation include xanthine oxidase
(converts xanthine to uric acid) and monoamine oxidase (MAO) (oxidizes
catecholamines and serotonin). Only the microsomal enzymes are subjected to
induction or inhibition by drugs.

Microsomal enzyme induction Microsomal enzyme inhibition

 Microsomal inducers ↑ rate of  Microsomal inhibitors ↓ rate of

metabolism of some drugs leading to metabolism of some drugs leading to
↓ their serum levels and therapeutic ↑ their serum levels and toxicity.
failure.  Enzyme inhibition can occur after
 Induction usually requires prolonged short period of exposure to the
exposure to the inducing drug. inhibiting drug.
 Examples of inducing agents:  Examples of inhibiting agents:
phenytoin, phenobarbitone, macrolide antibiotics (e.g.
carbamazepine, rifampicin, smoking, erythromycin), ciprofloxacin,
chronic alcohol intake, St John's cimetidine, ketoconazole, ritonavir,
Wort, grapefruit juice.
 Clinical examples:  Clinical examples:
- Rifampicin accelerates metabolism of - Ciprofloxacin inhibits metabolism of
contraceptive pills leading to failure of warfarin (anticoagulant) leading to
contraception. accumulation of warfarin and
- Phenytoin accelerates metabolism of bleeding.
cyclosporine-A leading to graft - Erythromycin inhibits metabolism of
rejection. theophylline leading to toxicity of
theophylline (cardiac arrhythmia).

▌Phase II reactions (conjugation)

- It involve coupling of a drug or its metabolite to water-soluble substrate (usually

glucuronic acid) to form water-soluble conjugate.
- Glucuronyl transferase is a set of enzymes that is responsible for the majority
of phase II reactions. This set of enzymes is also located inside liver

21
 miccrosomes and is the on that is inducible b
e only phasse II reactio by drugs and
a is a
posssible site of drug in
nteractionss e.g. phen nobarbital induces gglucuronida
ation of
thyrroid hormoone and reduces theiir plasma levels.
- Som me glucuroonide conjjugates seecreted in bile can be
b hydrolyyzed by in ntestinal
bac cteria and the free drug
d can bbe reabsorbed again (enteroheepatic circu
ulation),
thiss can exten
nd the actio
on of somee drugs.
her examples of non
- Oth n-glucuro unide con
njugation reactions include sulphate
s
con
njugation (steroids), glycine conjugatio
on (salicylic acid), and gluttathione
con
njugation (e
ethacrynic acid).

▌Firstt-pass me
etabolism
m (pre-sys
stemic elimination
n)

Definittion: metaabolism off drugs a at the sitee of administration before re eaching

system
mic circulattion e.g. th
he liver aft er oral administratio
on, the lung
g after inh
halation,
the skin
n after topical adminnistration, e
etc.

Hepatiic first-pas
ss metabo
olism:
 Com
mplete: lido ocaine.
 Parttial: propraanolol, morphine,
nitro
oglycerine
 Non ne: atenolo
ol and mon
nonitrates

How to
o avoid?
- By iincreasing the dose of the drugg.
- By ggiving the drug throu
ugh other rroutes e.g. sublingua
al, inhalatio
on, or i.v.

vailability
▌Bioav y

Definittion: it is the
t fraction of the d
drug becom me availab ble for sysstemic effe
ect after
adminisstration. The bioavailability of d
drugs given i.v. is 100%.

22
Factors affecting bioavailability:
 Factors affecting absorption.
 Factors affecting metabolism.
 First-pass metabolism.

Part 4: Adverse drug reactions (ADR)

An ADR is any response to a drug which is noxious, unintended, and occurs at

doses used in man for prophylaxis, diagnosis or therapy.

Predisposing factors:
 Multiple drug therapy.
 Extremes of age: due to age related changes in pharmacokinetics and dynamics.
 Associated disease: e.g. impaired renal or hepatic function.
 Genetics: can affect the pharmacokinetics.

Classification:

▌Type A (Augmented):

These reactions are predictable from the known pharmacology of the drug. They
may result from an exaggerated response (e.g. hypotension from an
antihypertensive) or non-specificity (e.g. anticholinergic effects with tricyclic
antidepressants).

Prevention
 Take a careful history for predisposing factors.
 Use the smallest dose of the drug adequate for the desired effect.
 Adjust dosage to therapeutic end-points, e.g. blood pressure or INR.
 Adjust dosage to optimum plasma concentrations, e.g. digoxin.
 Adjust dosage in relation to renal function, hepatic function, or other drugs.

▌Type B (Bizarre):

These are less common, less predictable, and may be severe. Examples are:
 Immunologic: penicillin allergy
 Genetic: haemolysis in G6PD deficiency
 Disease: amoxycillin rash in glandular fever
 Idiosyncratic: malignant hyperpyrexia in anesthesia.

Prevention
 Take a careful drug history, especially of allergies

23
  Fam
mily historyy: allergies or genetic
c disease
 Avo
oid drugs susceptibl
s e to ADRss in particular diseas
se states, e.g. cloza
apine in
bon
ne marrow depressio
on.

Type A (Augmen
nted) Ty
ype B (Biz
zarre)
- Pred
dictable - Unpredictable
- Dosee-dependeent - Dose-independent
- High
h incidence
e - Low incid
dence
- Mayy respond to
t dose ad
djustment - Generally
y need to sstop the drrug

█ Drug
g-induced
d liver injjury (DILII)

DILI ac
ccounts forr up to 10%
% of all advverse drug
g reactionss and may be fatal.
It may be classifie
ed into:
 Acccording to time courrse: acute or chronic.
 Acccording to mechanis sm: dose-d dependentt, idiosynchhratic, or im
mmune me ediated
 Acccording to histologic cal finding
g: hepatoceellular, cho
olestatic, o r mixed picture.

Hepato
ocellular (cytotoxic)
( ) DILI Cholestatic
C c DILI
Featurres: Features:
F
 The e drug or its metaboliites affectss  The drug or its meetabolites affect
a
pareenchymal liver cells leading
l to the bilia
ary canalicuuli leading to
cell necrosis and
a initiatioon of narrowin ng or dest ruction of biliary
infla
ammatory process. passage es.
 It m
may be spo otty, zonal, or diffuse..  Clinically it resemb bles obstruuctive
 Clinnically it ressembles viral hepatittis jaundice e with prurritus and ↑ALP.
A
withh ↑ ALT and AST.

Commmon drugs:: Common

C drugs:
d
Parace
etamol – methyldopa – Chloroprom
C mazine – suulfonylureaas –
amioda
arone – iso
oniazid – va
alproic acid
d oral
o contrac ceptive pil ls – anabo
olic
steroids
s – macrolides
m s – co-amo oxiclav

24
█ ADR on pregnancy

Key facts:

 Fetal birth defects represent 2-3% of all births, the majority of which are related
do drugs.
 Some fetal defects may be impossible to identify, or can be delayed e.g. the use
of diethylstilbesterol (estrogenic compound) during pregnancy is associated with
development of adenocarcinoma of girls’ vagina at teen age.
 Three factors determine the risk of teratogenicity: dose of the drug; duration of
administration; and stage of pregnancy.
 Most drugs with a MW <1000 can cross the placental barrier.
 All drugs should be considered harmful until proven otherwise.

Mechanism of teratogenicity according to pregnancy stage:

 Before implantation: (0-17 day): The effect is all-or-none i.e. either death of the
embryo (abortion) or no effect.

 Early pregnancy: (3-10 weeks):

- It is the most dangerous period because it is period of organogenesis.
- Selective interference can produce characteristic anatomical abnormality e.g.
aminoglycosides cause damage to 8th cranial nerve.

 Late pregnancy:
- Gross anatomical abnormalities are less liable to occur.
- Functional defects rather than anatomical abnormalities can occur especially
in organs having delayed formation e.g. brain, testes, and bone.

Examples of teratogenic drugs:

 ACE inhibitors and angiotensin receptor blockers cause fetal pulmonary and
renal dysfunction.
 Antithyroid drugs can cause fetal goiter and hypothyroidism.
 Tetracycline antibiotics inhibit growth of fetal bones and stain teeth.
 Aminoglycosides cause fetal 8th cranial nerve damage.
 Warfarin can cause fetal intracerebral bleeding.
 NSAIDs cause premature closure of ductus arteriosus.
 Benzodiazepines cause cleft lip and palate.
 Sex hormones can cause inappropriate virilization or feminization.
 Antiepileptic drugs cause neural tube defect (spina bifida).
 Cytotoxic drugs can cause multiple structural damage.

25
 The FDA pregnancy categories:

Category Definition Animal Human

Adequate studies in animal and human did
A not show a risk to the fetus either in the  
first or in the late trimesters.
Animal studies did not show risk to the  ?
fetus but there are no adequate studies in
human.
B
or: Animal studies showed a fetal risk, but
adequate studies in human did not show a  
risk to the fetus.
Animal studies showed a risk to the fetus
but there are no adequate studies in  ?
C humans; the benefits from the use of the
drug in pregnant women may by
acceptable despite its potential risks. Benefit > Risk

There is evidence of human fetal risk, but  

D the potential benefit of the drug may
outweigh its potential risk. Benefit > Risk
Studies in animals and humans showed  
evidence of fetal risk. The potential risk of
X
use in pregnant women clearly outweighs
Risk > Benefit
any potential benefit.

Part 5: Principles of drug-drug interactions

Classification:
■ Pharmacokinetics interactions.
■ Pharmacodynamic interactions.

█ PHARMACOKINETIC INTERACTIONS

Drug interactions in vitro:

e.g. antipseudomonal penicillins and aminoglycosides form complexes in the infusion
fluid (see chemotherapy).

26
Drug interactions in vivo:

Absorption

 Formation of complexes:
- Tetracycline forms complexes with Ca2+, Mg2+ and Al3+
- Cholestyramine forms complexes with digitalis and thyroxin.

 Absorption can be blocked:

- Adrenaline ↓ absorption of local anesthetics due to VC.
- Colchicine ↓ absorption of vitamin B12

 Change in intestinal motility:

- Anticholinergic drugs ↓intestinal motility → ↑ absorption of some drugs.
- Prokinetic drugs ↑ intestinal motility → ↓ absorption of some drugs.

 Changes in gastric pH:

- Antacids ↓absorption of salicylates.
- Ketoconazole is poorly absorbed in absence of gastric acidity.

Distribution

- Sulfonamides displace bilirubin from pl pr in premature infants → kernicterus.

- Phenylbutazone displaces warfarin → excessive bleeding.

Metabolism

- Inhibition or induction of microsomal metabolism (see before).

- Inhibition of non-microsomal enzymes:
- MAO inhibitors ↓ metabolism of some drugs e.g. benzodiazepines, serotonin
and norepinephrine.
- Disulfiram inhibits acetaldehyde dehydrogenase enzyme → ↓ metabolism of
acetaldehyde → accumulation of acetaldehyde causes flushing, nausea,
vomiting, and tachycardia.

Excretion

 Reduction in urinary elimination:

- Probenecid ↓ renal excretion of penicillin.
- Quinidine ↓ renal excretion of digoxin.

 Changes in urinary pH:

- Alkalinization of urine (e.g. sodium bicarbonate) ↑ excretion of weak acids
- Acidification of urine (e.g. ammonium chloride) ↑ excretion of weak bases.

27
  Changes in urinary volume:
Diuretics can increase toxicity of some drugs by reducing plasma volume e.g.
thiazide can increase lithium toxicity.

 Stimulation of biliary excretion:

Phenobarbital ↑ biliary excretion of many drugs by increasing both bile flow and
the synthesis of conjugating proteins.

██ PHARMACODYNAMIC INTERACTIONS

 Antagonism: competitive, non-competitive, chemical, physical, etc.

 Synergism: e.g. MAO inhibitors can cause toxic synergism with TCA.
 Potentiation: e.g. ethanol can enhance CNS depression caused by opioids
 Changes in the intracellular or extracellular environment: e.g. diuretic-
induced hypokalemia can ↑ digitalis toxicity.

28
29
30
Review Questions

Define the following pharmacokinetic parameters:

 Volume of distribution
 pKa of drugs
 Elimination half life
 First-pass metabolism
 Bioavailability

Mention the clinical significance of each of the following:

 Volume of distribution
 pKa of drugs
 Plasma protein binding of drugs
 Elimination half-life
 Zero-order elimination
 Microsomal enzyme induction
 Hepatic conjugation of drugs

Mention the main differences between:

 Reversible and irreversible antagonism.
 Graded response and quantal response.
 First order elimination and zero order elimination.
 Potency and efficacy.
 Physical and physiological antagonism.
 Habituation and addiction.
 Oxidation and conjugation of drugs.

Discuss 2 pharmacogenetic conditions associated with toxic drug response

Discuss 2 pharmacogenetic conditions associated with reduced drug response
Write short account on antagonism between drugs

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 Of each of the following questions, D. Sex hormones act on these types of
select ONE BEST answer: receptors
E. Corticosteroids act on these types of
1. A drug may act by all the following receptors
mechanisms EXCEPT:
A. Interaction with protein 5. The following statements are true
macromolecules embedded in the cell for graded dose-response relationship
membranes EXCEPT:
B. Interaction with cell membrane ion A. It is the response to most drugs
channels B. The response is directly proportional
C. Interaction with intracellular enzymes to drug concentration (linear relation)
D. Interaction with cell membrane C. It could be tested in one animal
phospholipids D. It can be used for comparing the
E. Interaction with gene functions potencies and efficacies of drugs
E. It can be used for calculation of the
2. Ion-channel-linked receptors (direct LD50 of drugs
ligand-gated ion channels) are
characterized by: 6. The following statements are true
A. They are the type of receptors for quantal dose-response relationship
principally present in autonomic EXCEPT:
ganglia and skeletal ms motor end A. It is the response to anticonvulsant
plate and antiarrhythmic drugs
B. They are the type of receptors B. The response to the drug is not
principally present in vascular directly proportional to drug
endothelium concentration (all-or-none)
C. They are rosette-shaped structures C. It could be tested in one animal
consist of 7 membrane subunits D. It helps in calculation of the ED50 and
D. Their response is slower than other LD50 of drugs
receptors E. It helps in estimation of the degree of
E. Activation of these receptors leads to drug safety
activation of a second messenger
7. When a drug has a steep dose-
3. Which of the following is classified response curve, this means:
as belonging to the tyrosine kinase A. The drug is lethal
family of receptors:
B. The drug is expensive
A. GABA receptors
C. The drug is efficacious
B. β-Adrenergic receptors
D. The drug is safe
C. Insulin receptors
E. Minimal change in the dose can lead
D. Nicotinic acetylcholine receptors to dramatic effect.
E. Hydrocortisone receptors
8. The following statements are true
4. All the following are true for for drug’s therapeutic index EXCEPT:
intracellular (DNA-linked) receptors A. It is the relation between the lethal
EXCEPT: dose in 50% of animals to the curative
A. They regulate transcription of genes dose in 50% of them
inside the nucleus B. The lower the TI, the safer will be the
B. Their response is very fast but drug.
persists for long time C. It should be done to any drug before
C. Their agonists must enter inside the it’s being approved for human use
cell to reach them inside the nucleus

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D. For theoretically useful drugs, it must E. Is described as addition if the action
be greater than 1 of one drug abolishes the effects of
E. It could be applied in animal testing another

9. The following is true for competitive 13. A drug may interact with ion
antagonism: channels by all of the following
A. It never occurs with enzymes mechanisms EXCEPT:
B. Is the same as physiological A. The drug may change the ion channel
antagonism structure
C. The agonist can never abolish the B. The drug may block the channel
effect of the antagonist physically
D. Is best exemplified by the use of C. The drug may change an intracellular
neostigmine to treat curare toxicity ATP on which the channel depends
E. Best described as non-surmountable D. The ion channel may be part of ion
process channel-linked receptors
E. The ion channel may be modulated by
10. A drug is said to be reversible G-protein linked receptors
antagonist when:
A. It blocks the receptors by making 14. Failure of the patient to breath after
covalent bonds with them surgical operation may be due to:
B. The duration of blockade is too long A. Pseudocholinestrase deficiency
C. Increasing the dose of the agonist will B. Methemoglobin reductase deficiency
reverse the block C. G-6-PD deficiency
D. The response curve of the agonist in D. Vitamin K epoxide reductase
presence of this drug is not parallel to deficiency
that of the agonist alone E. Monoamine oxidase deficiency
E. Termination of the drug effect dep-
ends on synthesis of new receptors 15. Hemolysis that may occur with
sulfonamides therapy may be due to:
11. The interaction that may occur A. Pseudocholinestrase deficiency
between acidic and basic drugs is B. Methemoglobin reductase deficiency
called: C. G-6-PD deficiency
A. Chemical antagonism D. Vitamin K epoxide reductase
B. Physical antagonism deficiency
C. Physiological antagonism E. Monoamine oxidase deficiency
D. Biological antagonism
E. Receptor antagonism 16. Severe myelosuppression following
6-mercaptopurine therapy is most likely
12. The following is true for interactions due to:
between drugs: A. Pseudocholinestrase deficiency
A. Is not harmful if occurred between B. Methemoglobin reductase deficiency
drugs having steep dose-response C. G-6-PD deficiency
curves D. Vitamin K epoxide reductase
B. Is not harmful if occurred between deficiency
drugs having narrow therapeutic E. Thiopurine methyltransferase
ratios deficiency
C. Is not harmful if occurred between
drugs undergoing zero-order kinetics 17. Hepatic toxicity that may
D. May lead to valuable therapeutic accompany isoniazide therapy may be
effects due to:

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 A. Defective oxidation reaction D. Phenobarbital (pKa = 7.4)
B. Defective conjugation reaction E. Propranolol (pKa = 9.4)
C. Defective deamination reaction
D. Slow acetylation reaction 22. The following statements are true
E. Rapid acetylation reaction for Vd of drugs EXCEPT:
A. It can exceed the volume of water in
18. Failure of some children with rickets the body
to respond to therapeutic doses of B. Drugs with large Vd can be removed
vitamin D is most likely to be due to: by dialysis
A. Differences in sex C. Would be expected to be 5L if the
B. Differences in body weight drug is confined to the blood.
C. Genetic variation D. Highly lipid-soluble drugs would be
expected to have large Vd
D. Tolerance
E. Intolerance E. It can help in the calculation of the
total amount of the drug in the body
19. The following are true for overshot
phenomenon (drug intolerance)
23. The plasma half-life (t1/2) of drugs:
EXCEPT: A. Is expressed as the percentage that
remains ½ hour after administration
A. It occurs due to down-regulation of
receptors B. Will be short if the drug gets into the
enterohepatic circulation
B. It occurs after sudden stoppage of
some drugs given for long time C. Cannot be calculated if the drug is
excreted through the bile
C. It may lead to serious withdrawal
effects D. Is constant for drugs having zero-
order elimination
D. It can be avoided by gradual
cessation of drugs E. Can be prolonged by slowing the rate
of drug elimination
E. It is best exemplified by occurrence of
severe tachycardia after sudden
stopping of beta blockers. 24. The bioavailability of a drug:
A. Is defined as the actual blood
20. The following statements are true concentration required to produce a
for pKa of drugs EXCEPT: pharmacological effect
A. Ionized drugs are poorly absorbed B. Will be unaffected by changes in
while unionized drugs are more formulation
absorbed C. May be affected by liver damage
B. Ionization of most drugs depends on D. Must be 100% for a drug given by
the pH of the medium around them mouth and is completely absorbed
C. pKa of drugs can help knowing the E. Is a term applied only to oral
site of drug absorption. administration
D. Acidic drugs become more
absorbable in alkaline pH 25. All the following are phase I
E. Basic drugs become more biotransformation reactions EXCEPT:
reabsorbable in alkaline urine A. Sulfate conjugation
B. Xanthine oxidation
21. Which of the following drugs will be C. Nitroreduction
absorbed to the LEAST extent in the D. Ester hydrolysis
stomach: E. Oxidative deamination
A. Ampicillin (pKa = 2.5)
B. Aspirin (pKa = 3.5)
C. Warfarin (pKa = 5.0)

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26. Metabolism (biotransformation) of E. Drug X will have a shorter duration of
drugs can lead to all the following action than drug Y because less of
results EXCEPT: drug X is present for a given effect.
A. Conversion of active compound into
inactive metabolites 30. Which of the following terms best
B. Conversion of active compound into describes the antagonism of
active metabolites leukotriene’s bronchoconstrictor effect
C. Conversion of inactive compound into (mediated at leukotriene receptors) by
active metabolites terbutaline (acting at adrenoceptors) in
D. Conversion of non-toxic compound a patient with asthma?
into toxic metabolites A. Pharmacologic antagonist.
E. Conversion of water-soluble B. Partial agonist.
compound into lipid-soluble C. Physiologic antagonist.
metabolites D. Chemical antagonist.
E. Noncompetitive antagonist.
27. All the following statements are true
for First-order kinetics EXCEPT: 31. Which of the following provides
A. Apply to most drugs in clinical use information about the variation in
B. Apply to salicylate (aspirin) sensitivity to the drug within the
metabolism within small dose. population studied?
C. The concentration versus time curve A. Maximal efficacy.
is non-linear. B. Therapeutic index.
D. The rate of elimination depends on C. Drug potency.
plasma concentration of the drug D. Graded dose-response curve.
E. Steady state plasma concentration E. Quantal dose-response curve.
can be reached after 5 half lives
32. Which of the following provides
28. All the following statements are true information about the largest response
for zero-order kinetics EXCEPT: a drug can produce, regardless of
A. Elimination rate is independent of the dose?
dose A. Drug potency.
B. Elimination depends on saturable B. Maximal efficacy.
enzyme system
C. Mechanism of receptor action.
C. Plasma concentration of the drug D. Therapeutic index.
cannot be expected at any time
E. Therapeutic window.
D. The t1/2 of the drug is not constant
E. There is no fear from drug cumulation 33. A pro-drug is:
or interactions
A. The prototype member of a class of
drugs.
29. Drugs X and Y have the same
mechanism of diuretic action. Drug X in B. The oldest member of a class of drugs
a dose of 5mg produces the same C. An inactive drug that is transformed in
magnitude of diuresis as 500 mg of the body to an active metabolite.
drug Y. This suggests that: D. A drug that is stored in the body
A. Drug Y is less efficacious than drug X tissues and is then gradually released
in the circulation.
B. Drug X is about 100 times more
potent than drug Y. E. Ionized drug trapped in breast milk.
C. Toxicity of drug X is less than that of
drug Y. 34. If the rate of infusion of a drug were
doubled, what response in the steady
D. Drug X is a safer drug than drug Y.

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 state concentration would be E. About 99%
expected?
A. Remain unchanged 40. Concerning the renal excretion of
B. Doubled drugs:
C. Increase 50% A. Drugs that are ionized in the renal
D. Decrease 50% tubules are more likely to undergo
E. Decrease 100% passive reabsorption.
B. Low MW drugs are much more likely
35. Half-life of a drug may be helpful to to be actively secreted than filtered.
determine: C. Only the fraction of the drug that is
A. Elimination of the drug unbound (free) to plasma proteins is
filtered by the glomerulus.
B. Level of absorption
C. Rate of absorption through the GIT
D. Decreasing urinary pH enhance
excretion of weakly acidic drugs.
D. Time to reach the steady state
E. Renal clearance cannot exceed the
E. Distribution into body systems. GFR (125 ml/min).

36. What determines the degree of 41. In which of the following cases
movement of a drug between body could a graded dose-response curve be
compartments? constructed?
A. Partition constant A. Prevention of convulsions
B. Degree of ionization B. Prevention of arrhythmias
C. pH C. Reduction of death
D. Molecular size D. Reduction of fever
E. All of the above E. Relief of insomnia
37. For intravenous (IV) dosages, what 42. Which of the following can be used
is the bioavailability assumed to be? as a relative indicator of the margin of
A. 0% safety of a drug?
B. 25% A. T.I.
C. 50% B. LD50
D. 75% C. ED50
E. 100% D. EC50
E. TD50
38. Which of the following can produce
a therapeutic response? A drug that is: 43. Flurazepam has a pKa of 8.2. What
A. Bound to plasma albumin percentage of flurazepam will be
B. Concentrated in the bile ionized at a urine pH of 5.2?
C. Concentrated in the urine A. 0.1%
D. Not absorbed from the GI tract B. 1.0%
E. Unbound to plasma proteins C. 50%
D. 99%
39. Aspirin is a weak organic acid with E. 99.9%
a pKa of 3.5. What percentage of a
given dose will be in the lipid-soluble 44. Which route of administration is
form at a stomach pH of 1.5? most likely to subject a drug to first
A. About 1% pass metabolism?
B. About 10% A. Intravenous
C. About 50% B. Sublingual
D. About 90% C. Oral

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D. Inhalation E. Phase I metabolism of Drug A will
E. Intramuscular increase its intracellular access and
actions
45. If a drug was given by a constant
infusion rate, which of the following 48. The FDA assigns the letters A, B, C,
factors determines how long it will take D, and X to drugs approved for human
for the drug to reach a steady-state use. To which of the following does this
concentration (Cpss) in the blood? classification apply?
A. Apparent volume of distribution A. Amount of dosage reduction needed
B. Bioavailability as serum creatinine clearances fall
C. Clearance B. Fetal risk when given to pregnant
women
D. Half-life
E. Infusion rate (mg of drug/min) C. Amount of dosage reduction needed
in presence of liver dysfunction
46. Which of the following best D. Relative margins of safety/therapeutic
index
describes what the term
“tachyphylaxis” means? E. The number of unlabeled uses for a
drug
A. An increase in the rate of the
response, for example, an increase of
the rate of muscle contraction 49. Which effect may lead to toxic
reactions when a drug is taken
B. Immediate hypersensitivity reactions
continuously or repeatedly?
(i.e., anaphylaxis)
C. Prompt conformational changes of the A. Refractoriness
receptor such that agonists, but not B. Cumulative effect
antagonists, are able to bind and C. Tolerance
cause a response D. Tachyphylaxis
D. Quick and progressive rises in the E. Intolerance
intensity of drug response, with
repeated administration, even when 50. Tolerance and drug resistance can
the doses are unchanged be a consequence of:
E. Rapid development of tolerance to the A. Change in receptors, loss of them or
drug’s effects exhaustion of mediators
B. Increased receptor sensitivity
47. Drug A undergoes a series of Phase C. Decreased metabolic degradation
I metabolic reactions before being D. Decreased renal tubular secretion
eliminated. Which of the following
statements best describes the
E. Activation of a drug after hepatic first-
pass
characteristics of Drug A, or the role of
Phase I reactions in its metabolism?
51. If two drugs with the same effect,
A. Complete metabolism of Drug A by taken together, produce an effect that
Phase I will yield products that are
is equal in magnitude to the sum of the
less likely to undergo renal tubular
effects of the drugs given individually, it
reabsorption
is called as:
B. Drug A is a very polar substance
A. Antagonism
C. Drug A will be biologically inactive
until it is metabolized B. Potentiation
D. Phase I metabolism of Drug A C. Synergism
involves conjugation with glucuronic D. Additive effect
acid or sulfate E. Supersensitivity

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 52. All of the following statements
about efficacy and potency are true
EXCEPT:
A. Efficacy is usually a more important
clinical consideration than potency
B. Efficacy is the maximum effect of a
drug
C. Potent drugs usually given in small
dose.
D. Potency is a comparative measure,
refers to the different doses of two
drugs that are needed to produce the
same effect
E. The ED50 is a measure of drug’s
efficacy

Answers

1D 11 A 21 E 31 E 41 D
2A 12 D 22 B 32 B 42 A
3C 13 A 23 E 33 C 43 E
4B 14 A 24 C 34 B 44 C
5E 15 C 25 A 35 D 45 D
6C 16 E 26 E 36 E 46 E
7E 17 E 27 C 37 E 47 A
8B 18 C 28 E 38 E 48 B
9D 19 A 29 B 39 E 49 B
10 C 20 D 30 C 40 C 50 A
51 D
52 E

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