Clinical Pharmacology and Therapeutics

8 MECHANISMS OF DRUG ACTION (PHARMACODYNAMICS)
Fast (ms)
neurotransmitter
(e.g. glutamate)
Slow (s)
neurotransmitter
or hormone
(e.g. -adrenoceptor)
Direct effect (min) Control (hours)
on protein of DNA/new
phosphorylation protein synthesis
(e.g. insulin) (e.g. steroid hormones)
Ion channel
G
E
E
Cell
membrane
Second messengers
Change in
membrane
potential
Ca 2 release
Protein
phosphorylation
Cytoplasm
Cellular effects
Nucleus
Figure 2.4: Receptors and signal transduction. G, G-protein; E, enzyme; Ca, calcium.
100
100
A
A A[B] 1 A[B] 2
Effect (%)
A[C] 1
A[C] 2
(a)
0
1 10 100
[Agonist]
0
1
10 100
[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).
(b)
ANTAGONISM
Competitive antagonists combine with the same receptor as an
endogenous agonist (e.g. ranitidine at 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 surmountable.
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 addition
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).