3

CHAPTER PHARMACODYNAMICS
R.S. TELANG AND C.VARSHNEYA

3.1 GENERAL INTRODUCTION

Pharmacodynamics can be defined as the study of the biochemical and physiological
effects of drugs and their mechanism of action. This aspect of pharmacology deals with
the action of drugs within the body. In simple words, pharmacodynamics is what drugs
do to the body, and so its knowledge is essential for right choice of drug
therapy.
A drug is broadly defined as any chemicalsubstance that affects living processes. Effects
produced by a drug are quantitative in nature. A drug can not impart a newfunction to a cell
of which it is not naturally capable, whereas it merely modulates the ongoing process or
function of the organism. Although therapy challenge this
gene may soon
principle.
3.2 CONCEPT OF DRUG ACTION AND RECEPTORS
The term 'drug action' is used to describe the method by which the drug influences
a cell and the term Drug effect or response' is a sequel to this action.
Modification of physiological function or a biochemical process induced by a drug
generally results from interaction between the drug and a macromolecular component
of the organism (tissue) called A is defined
as
receptor. "receptor" as that component
of a cell or organism that interacts with a drug and initiates the chain of biochemical
events leading to the drugs observed effects. The receptors are usually protein
molecules, which undergo a change in conformational status whenever acted upon by
a
drug, thereby inducing changes in systems within the cell
The existence of receptors was inferred from the experimental observation of
Paul Ehrlich and J.N. Langley
the end of nineteenth century. They
at
by the chemical and physiologic specificity of drug effects.
were
impressed
Ehrlich noted that certain synthetic organic
agents had characteristic antiparasitic
effects while other agents did no, although their chemical structures differed
slightly. Langley noted the ability of the South American arrow poison, curare, only
to
inhibit the contraction of skeletal muscles caused
by nicotine ; however, the tissue
remained responsive to direct electrical stimulation.
They also studied the mutual
antagonism of pilocarpine and atropine on the salivary secretion in the cat.
 52 Veterinary Pharmacology and
Toxicol
In order to produce a drug molecules
pharmacological response,
the
les must get
molecules of the necessitates
cell. This a
very close to
distribution
the receptor
of the drug molecules within the body or tissu meaning that drug molecules n-uniform
constituent of cells and tissues in order to pr
must be bound to particular cean
in his phrase 'corpora non agunt nisi fixata' (
effect. Ehrlich summed it up
not work unless it is bound).
But quite a number ot drugs disobey/escane #h wil
to any tissue constituent e.g, osmotic diuretice
and act without being bound motic
metal chelating agents, etc.
purgatives, antacids, heavy
and basic to pharmacology as tha
The receptor theory is as important mic
theory is to physical sciences
The drug-receptor interaction implies a mutual molding of drug and receptor .
il
a lock and its matching key. The drug receptor interaction is usually reversihla
obeys the law of mass action and usually involves 1onic bonds, hydrogen bonda t
van der Waals forces. In situation of irreversible interaction, the drugs have exceeding
and duration of action in the body.
ingly
long persistence
Radioligand binding studies have shown that the receptor numbers do not remain
constant but change according to circumstances. When tissues are continuously exposed
to an agonist, the number of receptors decrease (down-regulation) and this may beea
cause of tachyphylaxis i.e., loss of efficacy with frequently repeated doses. Prolonged
contact with an antagonist leads to formation of new receptors (up-regulation). These
conditions sometimes invite pharmacological idiosyncrasies. There are two theories
for relationship between durg-receptor interaction and response generated, as follows:

3.2.1 Occupation Theory of Drug Action

It was propounded by A.J. Clark and proposed that the extent to which a tissue
responds depends on the proportion of its receptor population which has become occupied
by a drug and the maximal response is reached when the total number of receptors are
ocCupied. He presumed that each occupied receptor delivered a constant unit of response
and that this individual occupancy stimuli summated in mathematical fashion to give a
linearly proportional response.
However, one difficulty was in the case of partial agonists, which is unable to elicit
a maximal response as much as that of a full agonist even after full receptor occupancy
Stephenson modified this theory to incorporate this difficulty and invoked the concept
of
efficacy. A drug
of high efficacy elicits a maximal
response after occupying ony
Small proportion of the receptor population and leave a number of spare receptors.
contrast a drug of lower has to occupy a greater proportion of elicit
a
efficacy receptOTS O
maximal response. The partial agonist still fails to induce a maximal response E ven

when all the

receptors are occupied because its efficacy is too low to allow a a i al
response. However, still the theory cannot explain the IS.
phenomenon of tachpiy a
3.2.2 Rate Theory of Drug Action
It was introduced by W.D.M. Paton at the end of 1950's when
failed to justify different drug actions. The theory considered that occupation theory was

of no
importance to the action of agonists, instead it is the act ofoccupation aond
receptor associate which donates a unit of stimulus to the cells. The making the a arugot
of associations made unit time the greater i to
be maintained, the per greater is the stimulus provided. For a
complex has to break and be re-made. The more apidly the con mDlex
dissociates, the more rapidly can new rap
associations take place. Each as
association bett
ween

drug molécule
it is the rate and a
receptor provides one quantum of stimulation. Inus gonist
of dissociation which determines potency and this is constant ch drug
(dissociation constant-Ka). io
 53

Pharmacodynamics

association constant
D+R K DR Ka -

dissociation constant
Ka -

but
rapidly
according to this hypothesis, makes complexes
The antagonist
dissociates relatively slowly.
3.2.3 Recent Theories between drug
envisaged a static relationship
While the occupation theory this relationship,
had a m o r e dynamic view of
molecules and receptors. The rate theory More recent observations
have
and regeneration of receptors.
by way of complexation and a m o r e complex models
of drug- receptor
carried this dynamic view further, is the postulate
Common to all receptor theories,
interactions have been proposed.
with a site on a receptor and
the receptor becomes
that an agonistic drug combines the receptor
from the cell. When the drug leaves,
activated, so triggering a response essential for further
or resting) state and this
is
returns to the non-activated (inactive to the
an allosteric site adjacent
On the same receptor is also present
response cycles. and either obscure or distort the
active
active site, at which an antagonist may bind,
with the receptor.
site so that the agonist can no longer complex
on nicotinic receptors of
Based on studies of the action of acetylcholine
of two-state model has been proposed
neuromuscular junction, an alternative theory exist in two states "resting (R) and
in this model, it is envisaged that thereceptor can
'activated' R* either of which can bind a drug molecule. Normally when no ligand/
favours the resting state.
drug is present, the equilibrium
R R
In the presence of agonist the of the binding site changes to activated
conformation
form and increases its affinity for the agonist. Removal of agonist allows the binding
site to revert to the resting state. An antangonist has a higher affinity for the receptors
in resting state, thereby stabilizing a high proportion of receptors in the resting state,
for which an agonist has low affinity. In contrast, a partial agonist is able to stabilize
receptors in an intermediate, i.e., partially activated state in which tissue response
reveals evidence of both stimulation and inhibition. The two-state model can also
explain for the phenomenon of inverse agonists, which occurs with benzodiazepines.
It is postulated that these réceptors for benzodiazepines, in the absence of any ligand,
are distributed more-or-less equally between the two states, so the equilibrium can be
shifted in either direction, producing opposite effects.
Evidence has been produced in support of the claim that changes in receptor
populations are produced by factors other than drugs, e.g., electrolyte concentration,
temperature etc.
3.3 SOME TERMS RELATED TO RECEPTORS
3.3.1 Spare Receptors
A highly active agonist with a high eficacy can produce a maximal response with
a concentration that does not occupy all the receptors. The receptors that remain
unoccupied are termed as spare receptors or reserve receptors. They are in no way
different from those whose occupation has
been estimated that highly active
produced the maximum response. It has
in concentrations just sufficient to
agonists may occupy as few as 0.1% of the receptors
produce a maximal response. The interaction of an
agonist with any of these spare receptors can evoke a response, but the maximum
effect is produced as soon as the
stimulus to the effector organ.
appropriate number of receptors have delivered their
 eterinary Pharmacology and
54 xicology
3.3.2 Silent Receptors but whi
attached
A silent receptor is to which the agonist may become
one
response. They adsorbents o s
act as
pharmacological
incapable of producing This has the effect of reducing the immediate effertthe
a
cell.
plasma membrane of reach the 'pharmacological receptors
in the tissue e
drug because fewer molecules
action of drug as it gets slowly
released from but
the
it has a effect of prolonging for 'pharmacological receptors.
These silent recoh
then available
receptors and are and back again unds
into pharmacological receptors
This is one of the hypothesic e
transformed
can be readily
a chemical environment.
influence of changing on drugs and
the development of physical dependence ation
seeks to explain
striated muscles.
supersensitivity in
Desensitization
3.3.3 Tachyphylaxis and
dose of a powerful agonistic drug, usuallv prodso.
Successive applications of the
same

the limits of biological variation), provided

that'modo
constant responses, (within
time is not too prolonged, and a sufficiently lon
concentrations are used, the exposure
enable the tissue to recover from the response. However. wi
rest period is allowed to
some drugs, the responses gets
smaller, even when above conditions are maintained
This suggests that drug blocks or
this phenomenon is known as tachyphylaxis.
nicotine's action o n ganglion cells is to stimulate
antangonizes its own action. For example
them initially and then to block them. This effect is attributed to a conformational change
to an inactive torm of the receptor.
Another type of tachyphylaxis is exhibited by some drugs that act indirectly, that
is, drugs that owe their pharmacological activity to the release of an active agent
within the tissue which brings about tissue response eg Allergens or histamine
releasers. Here, tachyphylaxis occurs because the amount of histamine available for
release on subsequent stimulations is exhausted, and also because the receptors become
desensitized after exposure to a considerable concentration of histamine.
Desensitization is another term closely related to tachyphylaxis. When small doses to an
agonist are given at appropriate intervals, the tissue shows reproducible responses. However,
when the tissue is exposed to a high concentration of agonist; the subsequent responses to
small doses are depressed, but slowly recovers. This is known as desensitization (Fig 3.1)
For example cholinoceptors on neuromuscular end plate exhibit such property.

AAMAAAALIAMA
II

..

Fig. 3.1 Figure showing microelectrade

muscle recording from ganglia (i) and motor end plates i
(i) (i) shows tachyphylaxis or reduction
frog
in response on successive
dose of a powerful
agonist whereas (i) shows desensitization application o
of receptors after
larger dose.
Note the response is reduced compared to initial applicato
one with same small dos
and show a
tendency to recover.
Pharmacodynamics 55

Many a times the terms

desensitization 100
tachyphylaxis and are
used synonymously.
A drug which can combine with 80
receptors and elicit a positive response
from the tissue in which the receptors
are located is called an agonist. The 60

tendency of that agonist to combine

with a particular kind of receptors is lin
known as affinity, whereas the ability
40 PartialAgonist
to initiate a observable effect is known
as intrinsic activity a These
or efficacy. 20
two properties of drug a consideredare
to be unrelated. An agonist can activate
the receptor because it resembles the O 67
1 2 3 4
endog-enous regulatory compound Drug Concentration
such as neurotransmitters or hormones,
and they have greater capacity to resist Fig. 3.2 Afull
agonist shows maximal response at a
lower drug dose. Whereas a partial agonist shows sub-
metabolic degradation, thereby acting
for a longer duration than their natural maximal response at a comparatively higher dose.
counterparts. Agonists are roughly
classified as : full agonists, partial agonists and inverse agonists.
A full agonist is able to elicit the greatest response of which the respective tissue
is capable of. This maximal response is defined as that response beyond which no
further increase in response is obtained by further increases in agonist concentration.
For a full agonist, the intrinsic activity a is equal to unity or 1 e.g., salbutamol.
A partial agonist is that compound which has high affinity to receptors, but
possess a low or moderate intrinsic activity. For a partial agonist the intrinsic activity
is less than 1. They have both agonist and antagonist action and hence sometimes
referred to as dualist eg., pindolol and oxprenolol. A partial agonist cannot produce
a maximal response even at 100% receptor occupancy. (Fig 3.2)
If a partial agonist occupies on functionally significant fraction of the receptors it
will antagonize the actions of agonist e.g, Naloxone and Nalorphine.

Some substances produce effects that are specifically opposite to those of the
agonist. For example, the action of benzodiazepines on the benzodiazepine receptors
in the CNS produces sedation, anxiolysis, muscle relaxation and control convulsions.
This is the conventional agonistic activity of benzodiazepines, but recently, a new type
of drug has been discovered, B-carbolines, which binds to benzodiazepine receptors
and exerts the opposite effect, producing stimulation, anxiety, increased muscle tone
and convulsions; they are known as inverse agonists.
Antagonists are drugs that interact with the receptor or other component of the
effector mechanism and inhibit the action of an agonist. They possess a high atfinity
to the receptor but are devoid of intrinsic pharmacological activity. Antagonists are
classified as competitive and non-competitive antagonists.
the implies, is based on the competition between
Competitive antagonism as name
the antagonist and an agonist for the receptors to which both have affinity. This class of
drugs when given in appropriate dosage are capable of reversing or blocking agonistic
effects. Competitive antagonism is completely reversible, an increase in the biophasic
Concentration ot the agonist will overcome the ettect of the intagonist.
56 Veterinary Pharmacology and Toxicol
logy
For example, atropine, propranolol, diphenhydramine.
These antagonists ha.
for the purpose of reversing or blocking the
great therapeutic value, especially
of agonist overdosage.
effects
the agonist from producing its effect
A non-competitive antagonist prevents irreversible interaction of the a n at a
site. This could result from
given receptor or with different sites, in a manner suest
either with the same site as the agonist
its receptors or its efficacy is alterodat
the capacity of the agonist to combine with h
essential feature of non- competitive antagonism 1S that the agonist has no inflten
its reversibility with respect to concentration
upon the degree of antagonism or the
biophase (Fig. 3.3).
For exanmple, Phenoxybenzamine, organophosphorus pesticides
100
Agonist alone

Agonist +
751 Agonist+ Competitive
Non competitive antagonist
antagonist

50

251

O 10 20 40 80 160
Dose or Concentration (Log Scale)
Fig. 3.3 Dose response curves
showing different antagonism note
dose-response curve of agonist in presence of a right ward shift in
shift in presence of competitive antagonist and a downward
non-competitive antagonist.
Depending on the site of action,
antagonism can be divided into
physiological, chemical and physical
antagonism. pharmacologica
When a
drug reduces another's
called as effect by binding to same receptor species,
pharmacological
are both
examples of such antagonism. Competitive and non-competitive
When a type.
m
antag
drug reduces another's effect by
activation of a second eliciting an opposing response au
species of receptors, the
antagonism/functional reduction is termed
effectby virtue of antagonism e.g., heart, atropine blocks the physiolO8
on

acetylcholine pharmacological
effect by virtue of antagonism whereas adrenaline acetyichoo
oppos
the
The administration of a physiological antagonism.
second
of the first or
nullifying drug for the purpose of ture

chelators EDTA removes lead,

the effect of first changing
drug is known as chemical
the
st .
antacids for gastric
acidity.
antagonisn
Adsorbents,
such as
and remove them. This charcoal, bind to the free form of
drug gut
is known
physical antagonism.
as
or
poisons n u
Pharmacokinetic antagonism is the
situation
reduces the concentration of the active drug at itsinsite of action.
which This can happevely
the antagonist
effecuv
 57
Pharmacodynamics
increased or the
active drug may be
the metabolic degradation of the
various ways like renal
reduced or the rate of
of the active the GIT may be
drug from
rate of absorption induce hepatic
microsomal
phenobarbitone in known to
excretion may be increased, e.g., rate of other drugs
administered concurrently.
which will increase metabolism
enzymes, terms of the dose
ratio
antagonism can be measured in
Dose Ratio: The effect of and in the absence of
equiactive
out the doses of agonist in the presence
by finding
the competitive antagonist.
ED50 after antagonist
Dose ratio =
ED50 before antagonist
must be multiplied
dose-ratio is the factor which the concentration of agonist
by
The the dose ratio,
in the presence of antagonist. Higher
to maintain a given response
increases with the time of exposure,
more specific is the antagonist. Dose ratio generally in very long experiments.
hence it is desirable to adopt a standard time of exposure
another method/
Lineweaver and Burk: This is
Double Reciprocal Plot of is plotted
antagonism. In this, the reciprocal of effect
procedure for analyzing drug
against the reciprocal of the dose (Fig 3.4)
Non Competitive Competitive
antagonism
antagonism

Ago+ Ago+
Antago. 1 Antago.
1 Effect
Effect Agonist
Agonist

Max
effect

1/Dose 1/Dose
Fig. 3.4.

and the intersects

straight line
By this procedure, linearization of graph is obtained
the Y-axis at 1/max-effect. f the plotted straight lines of agonist alone and in presence
of antagonist intersect X-axis (negative side) at a single point, the antagonism is of
non-competitive nature, whereas if both the straight lines intersect y-axis at a single
point, the antagonism is said to be of competitive nature.
3.4 SOME TERMS RELATED TO AGONIST-ANTAGONIST INTERACTION
PK,: This is an expression for affinity and is defined as negative logarithnm of
the molar concentration of a drug that elicits an effect representing x% of the maximal
response the drug can produce. Usually PK50 is taken for routine calculation.
PAx It is the negative logarithm of the molar concentration of antagonist in the
presence of which the potency of the agonist is reduced by X times; that is, X times
more agonist is required to produce a given response in the presence of than in
absence of the antagonist. Generally PA2 value is taken, but sometimes PA 10 is also
considered. A method of testing competitive or non-competitive nature of an antagonist
 Veterinary Pharmacology and
Toxicolr
58
values for agonist-antagonist pair on the sa
is to determine both PA2 and PAj0 be 0.95 or between 081°me
tissue. If the difference between these two values is to 8-1.2 then
to be competitive.
the antagonism is likely
affinity of a reversible competitive
antao.

PAz is PD>2 of
measure the
specificThe
for a PD'x: receptor, a
is a measure of the aftinity of a reversible non-com
mpetitive
for a specific receptor.
well as irreversible competitive antagonist
an
as
of molar concentration of non
PD2 is defined as the negative logarithm the
reduce the effect of an agonist to 1/x of its maxima
which will
competitive antagonist
(50% if it is PD'2).
value is determined as per the following equation :
PD2
PD', =
PD'x * EAM-11
6 EABM
Where P'D is the negative logrithm of the molar concentration of the antagonist

employed.
EAM and EaBM are the maximal response in the absence and in the presence of
the antagonist, respectively.
PD,: It is defined as the negative logarithm of the molar concentration of the
agonist which produces an effect equal to 1/x that of the maximum response. This
value is directly proportional to the logarithm of the affinity of an agonist for its
receptors, because the concentration of agonist required to produce half its max. effect
is inversely related to the drugs affinity.
3.5 SOME TERMINOLOGIES RELATED TO DRUG ACTION

3.5.1 Potency
It refers to the dose of a drug that must be administered to
effect of given intensity. In simple words, it is the amount of
produce a particular
drug in relation to its effect,
e.g., if drug A has a greater effect than drug B, then drug A is more potent than drug d
(fig. 3.5). The diuretic effect of bumetanide 1 mg is equivalent to furosemide 50 mg, thus
bumetanide is more potent than frusemide. Potency is influenced by the affinity of a
drug for its receptor sites. Potency is a relative term rather than an absolute
so for
potency determination a standard must be defined. Low potency andexpressIOn,y
high potency, both can be dangerous. exre
Potency is useful in therapeutics for calculating rational drug
salicylates are potent somatic analgesic and morphine is a combination, g a
combination of both will give a potent visceral anaig
potent analgesic for mixed type of pains.
3.5.2 Efficacy
Efficacy is the capacity of a drug to produce an effect and it refers h the
magnitude of maximal response that drug can produce.
intrinsic activity of a drug and unlike potency, it is an Efficacy is influencE
absolute expression. (T& 3.5)
e.g,It drug A can produce a therapeutic effect that with
can not be obtained
drug B, however, much of drug B is given, then A has
The dose the higher therapeutic
required to produce a same degree of response e
is lower with aru
compared drug A denoting that drug B is more
to
potent than
by drug B is only 75%, while drug drug
A.
maximal response exerted
A
Wheremal
response of 100%, hence drug A has a exerts a
max
higher therapeutic efficacy than drug D.
Pharmacodynamicss
59
Drug A

100T

Drug B
75

50

ED50
25
ED50

20 30 40 50 60 70 80 90 100
10
Dose
B.
Fig. 3.5 Dose Response curve of hypothetical drug A and
3.5.3 Dose Response Curve
administered and
It is the mathematical description of relationship between dose
of drug action. It is assumed that the effect of
response obtained by quantitative analysis and that maximal
a drug is proportional to the fraction of receptors occupied by drugs
effect results when all receptors are occupied.
It is frequently convenient to plot the magnitude of effect versus log [Dose],
because a wide of rangeconcentrations is easily displayed and the potency of
drug
different drugs can be easily compared Since the dose-response curve becomes linear

particularly at the middle part. (fig 3.6)

100
1001 Therapeutic
II ToxicI
effect
effect
75
75

50
ED50 50
Certain SafetyfactorI LDso
L

25
IED99
(LD1A.5 LD,
25

O
5 10 20 O
Dose Therapeutic index
(LD50/ED50)
Fig. 3.6 Quantal log-dose response curves for therapeutio () and toxic (I) effects of a drug

The demonstration of a dose response relationship is the first step in the

investigation of a compounds pharmacological activity. There are two types of
60
Veterinary Pharmacology and Toxicol.
ology
seen in individual organism and
DR-relationship; viz graded DR-relationship quantal
DR- relationship seen in the population.
A dose-response relationship by following
is characterized parameters
referred to as Emax or
efficacy
(i) Maximal or ceiling effect commonly It ie
the
maximal response a drug can produce.
Median Effective dose : It is the effective dose of a druo to
(ii) ED50 or
50% of maximal response.
elicit
(iii) Therapeutic index (T1): When the dose of a drug is increased progressivel.
the desired response in the patient usually rises accordingly upto mavi
beyond which a further increase in dose elicits unwanted or toxic effects.Th
every drug has two different dose-response curves; one for therapeutic or
hus,
beneticial effects and another for toxic etfects (as shown in fig 3.6 I and In
The dose response curve for toxic effects of a drug is characterised by LD
which is the dose that kills half of the test population.
The therapeutic index of a drug is a measure of a drugs safety and is obtained
by dividing LDso by ED50 The higher the value, the safer is the drug.
LD50 2010
TIED50 2
A TI value of 10 or more on a log scale for a drug is considered to be safe.
The TI value of a drug also gives a rough idea of drug's selectivity. A higher
value indicates that the drug is highly selective in its action while a lower
value indicates that the drug is non-selective in its action.
It seems logical that drug safety could be better assessed by using a ratio

derived from extremes of the respective quantal curve, such as ED99 LD1 Iis
This
ratio is known the certain
to be
as
safety factor A value of 4 or more is considered
adequate as
regards drug's safety. Generally values of minimum toxic
(LD) and maximum therapeutic (ED99) doses are less
(LD50, ED50) and hence therapeutic index values areprecise
than the
preferred overmealai
certaln
safety factors.
(iv) Position and Slope of the Curve The position of the curve in relation to e
aose
when
axis gives an idea about the
affinity or potency of the
exanmp drug. For
the curve is more
towards the left, it is more potent and vice versa.
The steepness, or slope of the linear part of the curve indicates the by
which dOsage must be
increased to secure an increase in extent
1.e., tne eper
the curve the smaller the response,
dose increment to secure the same sit
() response inCic
Selectivity and
Specificity : No drug produces only a single ettect. Most
drugs produce multiple effects and thus have several nse

dose-resp
relationships. e.g morphine is a narcotic analgesic, but it also causes
respiratory depression, release of ADH, seadu
drug is said to be relatively selective;constipation,
A etc.
if it produces a particular effect
preferentiallythan other and that
characteristic effect of the drug 15 luced partieudded
at a lower
doses than those proive
drug would produce only a required
to elicit other A
responses. truly,s od
single effect. The anticoagulant heparin 13
good
Pharmacodynamics 61
example of a drug that has selective action. The distribution pattern ot a
drug, lipid solubility, route of administration, etc. can influence selectively
When all effects produced by a drug are due to a single mechanism ot action,
the drug is said to be specific. A specific drug acts at only one type of receptor
but may produce multiple pharmacological effects because of location of receptors
in various organs. Atropine is a best example of a specific drug while
phenothiazine derivative acepromazine is an example of a non-specific drug
For therapeutic applications, the more specific the nature and the greater the
selectivity of drug action, the less the likelihood of undesirable effects and
the wider the margin of safety.
Chemical specificity refers to the fact that changes in chemical structure of a
drug molecule may have a large or small effect on its pharmacological activity

Non Selective drug Selective drug

Drug

+Receptors
A

Toxic Beneficial Toxic Beneficial Effect

Fig.3.7 Receptor selectivity. Receptor A and B mediate toxic or beneficial effects, respectively.
A non selective drug binds equally well to both types of receptors, while a selective drug
binds with higher affinity to receptor B than to receptor A.

(vi) Structure-Activity Relationship (S.A.R.): Both the affinity of a drug for its
receptor and its intrinsic activity are intimately related to its chemical structure.
The relationship is frequently quite stringent. Relatively minor modifications
in the drug molecule, including such subtle changes as stereoisomerism, may
result in major changes in pharmacological properties. Exploitation of S.A.R.
It
has on many occasions led to the synthesis of valuable therapeutic agents.
has been possible to develop a congener with a more favourable ratio of
therapeutic to toxic effects, enhanced selectivity among different cells or tissues,
or more acceptable secondary characteristics than those of the parent drug.
Therapeutically useful antagonists of hormones or neurotransmitters have been
developed by chemical modification of the structure of the physiological agonist.
Minor modifications of structure can also have profound effects on the
pharmacokinetic properties of drugs. Given adequate information about both
the molecular structures and pharmacological activities of a relatively large
to identify those properties that are
group of congeners, it should be possible
Tequired for optimal action at thereceptor-size, shape,
the position and
orientation of charged groups or hydrogen bond donors, and so on.
 Veterinary Pharmacology and Toxicot
62 ology
OF RECEPTORSS
3.6 CLASSIFICATION
elements in the system of ch
Receptors can be regarded as the sensirng
all the different cells in the hod
communications that coordinates the function of
chemical messengers being hormone or
transmitter substances. There are
many sune
or antagonists o n receptors for endogenous madte
drugs that act either as agonists useful substances. The function af
forming the largest group of therapeutically such
physiological receptors, many of which are
component ot
the plasma membrane comconsist
of binding the appropriate ligand and propagating its regulatory signal in the taro
target
A. Receptors
Direct ion Channel opening
enzyme activation/inhibition
Agonist
C Transduction
mechanism
lon channel modulation
DNA transcription

Antagonist No effect. Endogenous mediators blocked

B. lon-Chan nels

Blockers Permeation blocked

Increased or decreased
Modulators
opening probability

C. Enzymes

Inhibitor Normal reaction inhibited

False
Substratee
O Abnormal metabolite produced

Prodrug Active drug produced

D. Carriers

O -pii
Normal
Transport
O
Inhibitor
Transport blocked

False Unnatural compound

Substrate accumulate in cell

Agonist/normal substrate Antagonist/ inhibitor

Abnormal product
Pro-drug
Fig. 3.8 Types of Target for Drug Action
 63
Pharmacodynamics
cell, either by virtue of direct intercellular effect or by promoting
a synthesis or the
release of another intercellular regulatory molecule known as a second messenger.
The principle targets for drug action on mammalian cells (fig. 3.8) can be broadly
divided into-

(i) Receptors (ii) lon-channels

(ii) Enzymes (iv) Carrier molecules
At present there are four main types of receptor classified according to the nature
of the receptor-effector linkage. (fig 3.9 and table 3.1)
1. Receptors for Fast Neurotransmitters: These are coupled directly to an ion-
channel. These receptors are involved mainly in fast synaptic transmission. Here the

A Direct control of ion-channel

lons Hyper polarisation Cellular effects

or depolarisation
T (in milliseconds)

B. Indirect (G-Protein) coupling via second messengers/ion Channels

Substrate
Ca2t release
Second Protein
messengers Phosphorylation
Cellular
or Other
R effects
(In seconds)

lons-
oor Change in excitablity

C. Direct Control of protein phosphorylation

Cellular effects
Protein
(in minutes)
R/E Phosphorylation

D. Control of DNA transcription

O- Cellular
Protein
MRNA effect
Synthesis Synthesis
(in hours)
nucleus

Fig. 3.9 Types of Receptor-Effector Linkage

64 Veterinary Pharmacology and Toxicol
millisecond time scale e.g., the n.
occur on a
drug binding and channel opening
acetylcholine receptor (nAChR), the GABAA receptor, the glutamate Jinic
mate receptor.
receptor.
2. Receptor for many Hormones and Slow Transmitters : These are c
pled to
effector systems via a G-protein. The G-protein coupled receptor family com
most of the receptors that are familier to pharmacologist for example muscaprises
acetylcholine receptor (mAChR), adrenergic receptors, dopamine receptor, sero
serotonin
receptors and many others.
Table 3.1 The Four Main Types of Receptors

Type 1 Type 2 Type 3 Type 4

Location Membrane Membrane Membrane Cytosol
Effector Channel Enzyme or Tyrosine Kinase Gene
channel
transcription
Coupling Direct G-protein Direct Via DNA
Example nAchR, GABAA mAchR, insulin Steroids
Adrenoceptors
3. Receptors for Insulin and Various Growth-Factors : These are directly linked
to tyrosine kinase and are involved mainly in events
controlling gene transcription.
They cause phosphorylation of tyrosine residues in various proteins and stimulate
transcription of particular sections of the genome.
4. Steroid Receptors: These are soluble cytosolic or nuclear
proteins, to
the steroid molecule binds after crossing the cell membrane. This complex is believed
which
to unfold and expose the normally buried DNA
binding domain, which recognises
specific base sequences, thus activating particular The effects
genes.
a result of increased protein synthesis, and thus are slow in onset. The difterent
produced are as
steroid hormones are able to activate different genes, and thus initiate
completely
different pattern of protein synthesis, and
produce different physiological etfects
Example: Thyroid hormones, glucocorticoids, mineralo-corticoids etc.
3.7 SECOND MEsSENGERs
Many hormones, neurotransmitters, autacoids and drugs act on specific me
brane
receptors, the immediate consequence of which is activation of a cytoplasmic compO
of the receptor, which may be an enzyme such as se

or activation of a
adenylate cyclase, guanylate y
transport systems or opening of an ion-channel. These cytopla
components which carry torward the stimulus from the receptors are known as cond

messengers the first messenger beng the receptor itself. Examples of second messe gers

are-cAMP, cGMP, ca*, G-proteins, IP3, DAG, etc., (See table 3.2)
The role of cAMP as a second work of
messenger was by the
first revealed by
Sutherland in late 1950's. This discovery demolished the barriers thatexisted betw
biochemistry and pharmacology. cAMP is a nucleotide synthesised within the fro existea from

ATP by the action of adenylate ceu otors.

cyclase in response to activation of many rees

It is inactivated by hydrolysis to 5-AMP, by the action of enzyme
phosphodie
Pharmacodynamics 65

CAMP has varied regulatory effects on cellular functions, for example, energy
metabolism, cell division and cell differentiation, ion-transport, ion-channel function,
smooth muscle contractility etc. These varied effects are brought about by a common
mechanism, namely the activation of various protein kinases by cAMP.
Many different drugs, hormones of neurotransmitters produce their effects by
reasing or decreasing the catalytic activity of adenylate cyclase and thus lowering
or raising the concentration of cAMP within the cell. The cAMP levels in the cell can
also be raised by inhibiting the metabolizing enzyme phosphodiesterase.
Cyclic guanosine monophosphate is another interacellular messenger synthesised
by the enzyme guanylate cyclase from GTP. It has been identified in cardiac cells,
bronchial smooth muscle cells, and other tissues. For most of the effects produced,
cAMP seems to be stimulatory while cGMP seems to be inhibitory in nature.
When the cAMP and cGMP systems are both present in a single cell or tissue,
they are linked to receptors through which drugs produce opposite effects. For examples
in cardiac tissue cells, B-adrenoceptors increase the frequency and force of contraction
by increasing cAMP levels, whereas cholinergic receptors have opposite effect by
increasing cGMP levels.
The IP3 and DAG system is another important intracellular second messenger
system, and was identified first by Michell in 1975. Both are degradation prcducts of
membrane phospholipids; by an enzyme phospholipase C. IP3 acts very effect.vely to
release calcium from intracellular stores. This Ca is known to regulate the function
of various enzymes, contractile proteins and ion- channels. DAG directly activates
protein kinase C and controls phosphorylation of amino acids of a variety of intracellular
proteins. This causes release of hormones from endocrine glands or modulates neuro-
transmitter release or modulates smooth muscle contactility or inflammatory responses
or ion-transport or tumour promotion etc. There exist at least six different types of
PKC distributed unequally in different cells.
Activation of another enzymes phospholipase A2 leads to production of arachidonic
acid from the membrane phospholipids, which are further broken down to
prostaglandins, leukotrienes, thromboxanes etc. They are well known for their role as
local hormones, but it is of interest that arachidonic acid itself and its metabolites have
recently been shown to function as intracellular, messengers, controlling potassium
channel function in certain neurons.
Calcium ions are of great importance amongst many other intracellular second
messengers. Many regulatory actions are mediated by Ca* bound to its intracellular
regulatory protein, calmodulin. Ca" ions are also involved in release of arachidonic
acid from membrane phospholipids by activated phospholipases and so initiate the
synthesis of prostaglandins and leukotrienes. Ca" in synergism with PKC have been
shown to activate cellular function like hepatocyte glycogenolysis, insulin release from
pancreas. Ca" also plays an important role in contraction and relaxation of skeletalI
and smooth muscles of body.
G-Proteins : G-proteins represents the level of middle management in the cellular
organisation and are able to communicate between the receptors and the effector
enzymes or ion-channels. They were called G-proteins because of their interaction
with the guanine nucleotides, GTP and GDP.
66 Veterinary Pharmacology and Toxicoloou

Receptor
Resting OCcupied
State

Receptor Target Receptor

-bg
Target
L GTP

Target Protein
GTP hydrolysed activatedd

Receptor Target Receptor Target

LS GDP

Fig. 3.10 The Function of the G-Protein

The G proteins are bound to the
cytoplasmic surface of the plasma membrane.
They are heterotrimeric molecules consisting of 3 subunits a, B and y (fig 3.10). Their
classification as stimulatory or inhibitory is based on the
subunit. The ß and Y subunits remain associated as identity of their distinct a
surface of the membrane when the B y complex with the cytoplasmic
to the a subunit. Whenever an
system is inactive or in resting state, GDP is bound
agonist interacts with the receptor, this facilitates GlP
binding to a subunit and promotes dissociation of GDP from its place. Binding of GTP
activates the a subunit and a-GTP is then
with a membrane bound effector. thought to dissociate from ß and interact
The process is terminated when
the
GTpase activity of the a-subunit. The hydrolysis
of GTP to GDP occurs
through the
effector, and reunites with By resulting a-GDP then dissociates from the
subunit to an effector molecule completing
the response
cycle. Attachment of the
of this increase varies for different actually increases its GTpase activity, the magnituae
types of effector.
Mechanisms of this type in
general result in amplification because a
receptor complex can activate several G-protein molecules single agonist
in turn, and each of these
can remain
associated with the effector
molecules of product. The enzyme for long enough to
product is often a second produce many
occurs before the final messenger,
cellular response is produced. It is the
and further
amplificationor
an
organism for judicious use of its transmitter substances. biological adaptation
Pharmacodynamics 67

G-proteins are not all identical, the a-subunit in particular shows variability. It
isbelieved that there are three main varieties of G-protein viz G, Gi and Gq. Gs and
Gi produce respectively stimulation and inhibition of the effector system(fig. 3.11). It
is not unusual for several receptors in an individual cell to activate a single G protein
and a single receptor regulating more than one G-proteins. It is now known that the
membrane enzymes like adenylate cyclase, phospholipase C, phospholipase A, as well
as a variety of ion-channels are controlled through this intramembrane managers,
G-proteins metabotropic receptor is the term used for G-protein coupled receptors
which operate through intracellular second messengers e.g, mAChR, adrenoceptors
and neuropeptide receptors

Inhibitory
receptor Target Enzyme Stimulatory
receptor

TE
bg Rs

Gi

S Stimulatory
i= Inhibitory

Fig.3.11 Bidrectional Control of Adenylate Cyolaseby Gs and Gi.

Table 3.2
Second Messengers Receptors operating through them
1. CAMP Adenosine, a2 & ß adrenoceptors, Angiotensin (AT),
Dopamine GABAp., Histaminic H2, 5H T1 ,& 5HT4, 5HT6,7
muscarinic M2, neuropeptide Y,opioid (u, o, K), VIP.
2. cGMP Angtotensin (AT2), ANP
3. IP/DAG a adrenoceptors,, Bombesin,, Angiotensin (AT,), Bradykinin
chemokine, cholecystokinin. Endothelin, Histamine H1, 5HT2,
leukotrienes, muscarinic M1 & M3, PAF.

3.8 RECEPTOR SUBTYPES AND THEIR SIGNIFICANCE

As the diversity and selectivity of drugs have increased, it has become clear that
multiple subtypes of receptors exist within many defined classes of receptors. Knowledge
of
receptor subtype is of interest to the researcher and of utility to the clinician who
desires to manipulate them. For example for nicotinic cholinergic receptor, there are
distinct differences in receptors that are found in
ganglia of ANS and somatic
neuromuscular junction. This difference is exploited for therapeutic benefit. Thus,
antagonists that act preferentially at the nicotinic receptors in ganglia can be used to
control blood pressure ; they do not affect skeletal muscle.
Different receptor subtypes
may also be found within a single tissue at different of
stages growth and
again presumably reflecting altered needs of the organism. development,
Subtypes of same classes of receptors; e.g., d1- 2 - adrenergic or M1 - and
M2 muscarinic also display fundamental differences in their biochemical regulatory
activities. Such differences allow an agonist to evoke unique
responses
in
specific cells
 Veterinary Pharmacology and Toxicn
68
the development of
Oxicology
umber of
a
facilitated
classification have
tissues. Receptor
or
selectivity for specifiç types o r subtypes of recent. eptors and
therapeutic agents that have unwanted effects.
or intensity of
limit the frequency
MEDIATED BY RECEPTORs
NOT
3.9 DRUG ACTIONS
drugs of are the result of druo
majority
by the without
interactions.
AlthoughSome
effects produced
exert their effect combining with receptors. Actioneptor
ith receptors. ptorof
attributed to their overall physicochemical properties.
CO
certain drugs can be
inhalation anesthetics, diuretics,
osmotic saline catnd
that act in this m a n n e r include
aciditiers and alkalinizing agents. Usuall
antiseptics, chelators, antacids urinary hese
Since their actions on a partics
concentrations,
drugs are effective in rather high cular
dependent on their prsence there.
system are

that of normal biological chemicals mau

structural analogs
Certain drugs are
their function. This pronar
incorporated into cellular components and thereby alter
has been termed a "counterfeit incorporation mechanism". It is useful with analogue
of pyrimidines and purines that can be incorporated into nucleic acids, yielding drugs
that have utility in cancer and viral chemotherapy.

3.10 MECHANISMS OF DRUG ACTION

An overview of the mechanisms of drug action shows that drugs act on
The cell membrane by:
1. Action on specific receptors
2. Interference with selective passage of ions across membranes.
3. Inhibition or stimulation of membrane bound enzymes and pumps.
4. Physicochemical interaction
The metabolic processes within the cell by
1. Enzyme inhibition or stimulation.
2. Inhibition of transport process.
3. Incorporation into
larger molecules like DNA, RNA.
4.Altering metabolic processes unique to
Outside the cel, by
microorganisnms.
1. Direct chemical interaction.
2. Osmosis.
3. Chelation.