●Introduction 6
●Receptors and signal transduction 6
●Agonists 7
●Antagonism 8●Partial agonists 9
●Slow processes 9
●Non-receptor mechanisms 10CHAPTER 2
MECHANISMS OF DRUG ACTION
(PHARMACODYNAMICS)
INTRODUCTION
Pharmacodynamics is the study of effects of drugs on biological
processes. An example is shown in Figure 2.1, demonstrating
and comparing the effects of a proton pump inhibitor and of a
histamine H 2 receptor antagonist (both drugs used for the treat-
ment of peptic ulceration and other disorders related to gastric
hyperacidity) on gastric pH. Many mediators exert their effects
as a result of high-affinity binding to specific receptors in
plasma membranes or cell cytoplasm/nuclei, and many thera-
peutically important drugs exert their effects by combining with
these receptors and either mimicking the effect of the natural
mediator (in which case they are called ‘agonists’) or blocking it
(in which case they are termed ‘antagonists’). Examples include
oestrogens (used in contraception, Chapter 41) and anti-
oestrogens (used in treating breast cancer, Chapter 48), alpha-
and beta-adrenoceptor agonists and antagonists (Chapters 29
and 33) and opioids (Chapter 25).
Not all drugs work via receptors for endogenous medi-
ators: many therapeutic drugs exert their effects by combining
with an enzyme or transport protein and interfering with its
function. Examples include inhibitors of angiotensin convert-
ing enzyme and serotonin reuptake. These sites of drug action
are not ‘receptors’ in the sense of being sites of action of
endogenous mediators.
Whether the site of action of a drug is a receptor or another
macromolecule, binding is usually highly specific, with precise
steric recognition between the small molecular ligand and the
binding site on its macromolecular target. Binding is usually
reversible. Occasionally, however, covalent bonds are formed
with irreversible loss of function, e.g. aspirin binding to cyclo-
oxygenase (Chapter 30).
Most drugs produce graded concentration-/dose-related
effects which can be plotted as a dose–response curve. Such
curves are often approximately hyperbolic (Figure 2.2a). If plot-
ted semi-logarithmically this gives an S-shaped (‘sigmoidal’)
shape (Figure 2.2b). This method of plotting dose–response
curves facilitates quantitative analysis (see below) of full agonists
(which produce graded responses up to a maximum value),
antagonists (which produce no response on their own, but
reduce the response to an agonist) and partial agonists (which
produce some response, but to a lower maximum value than that
of a full agonist, and antagonize full agonists) (Figure 2.3).RECEPTORS AND SIGNAL TRANSDUCTION
Drugs are often potent (i.e. they produce effects at low concen-
tration) and specific (i.e. small changes in structure lead to pro-
found changes in potency). High potency is a consequence of
high binding affinity for specific macromolecular receptors.012345678910112233Median gastric pHPredose Postdose≥ 5.4.1-5.2.0-4.< 2.0 21
1525374138379090nPredose Postdose Predose PostdosePre Rx
pHFigure 2.1:Effect of omeprazole and cimetidine on gastric pH in a
group of critically ill patients. This was a study comparing the
effect of immediate-release omeprazole with a loading dose of
40 mg, a second dose six to eight hours later, followed by 40 mg
daily, with a continuous i.v. infusion of cimetidine. pH monitoring
of the gastric aspirate was undertaken every two hours and
immediately before and one hour after each dose. Red,
omeprazole; blue, cimetidine. (Redrawn with permission from
Horn JR, Hermes-DeSantis ER, Small, RE ‘New Perspectives in the
Management of Acid-Related Disorders: The Latest Advances in
PPI Therapy’. Medscape Today
http://www.medscape.com/viewarticle/503473_9 17 May 2005.)