A Textbook of Clinical Pharmacology and Therapeutics

8 MECHANISMS OF DRUG ACTION(PHARMACODYNAMICS)

ANTAGONISM

Competitive antagonists combine with the same receptor as an
endogenous agonist (e.g. ranitidineat histamine H 2 -receptors),
but fail to activate it. When combined with the receptor, they
prevent access of the endogenous mediator. The complex
between competitive antagonist and receptor is reversible.
Provided that the dose of agonist is increased sufficiently, a
maximal effect can still be obtained, i.e. the antagonism is sur-
mountable. If a dose (C) of agonist causes a defined effect when
administered alone, then the dose (C) needed to produce the
same effect in the presence of antagonist is a multiple (C/C)

known as the dose ratio (r). This results in the familiar parallel

shift to the right of the log dose–response curve, since the add-

ition of a constant length on a logarithmic scale corresponds to

multiplication by a constant factor (Figure 2.5a). β-Adrenoceptor

antagonists are examples of reversible competitive antagonists.

By contrast, antagonists that do not combine with the same

receptor (non-competitive antagonists) or drugs that combine

irreversibly with their receptors, reduce the slope of the log

dose–response curve and depress its maximum (Figure 2.5b).

Physiological antagonism describes the situation where two

drugs have opposing effects (e.g. adrenaline relaxes bronchial

smooth muscle, whereas histamine contracts it).

Fast (ms)

neurotransmitter

(e.g. glutamate)

Slow (s)

neurotransmitter

or hormone

(e.g.-adrenoceptor)

Ion channel

Direct effect (min)

on protein

phosphorylation

(e.g. insulin)

Control (hours)

of DNA/new

protein synthesis

(e.g. steroid hormones)

Cell

membrane

Cytoplasm

Second messengers

Protein

phosphorylation

Ca^2  release

Cellular effects

Nucleus

Change in

membrane

potential

GE

E

Figure 2.4:Receptors and signal transduction. G, G-protein; E, enzyme; Ca, calcium.

1 10 100

0

100

Effect (%)

AA[B] 1 A[B] 2

(a) [Agonist]

1 10 100

0

100

A

A[C] 1

A[C] 2

(b) [Agonist]

Figure 2.5:Drug antagonism. Control concentration/dose–response curves for an agonist A together with curves in the presence of (a) a
competitive antagonist B and (b) a non-competitive antagonist C. Increasing concentrations of the competitive antagonist ([B] 1 , [B] 2 )
cause a parallel shift to the right of the log dose–effect curve (a), while the non-competitive antagonist ([C] 1 , [C] 2 ) flattens the curve
and reduces its maximum (b).