10 MECHANISMS OF DRUG ACTION(PHARMACODYNAMICS)
Conversely, reduced exposure of a cell or tissue to an agon-
ist (e.g. by denervation) results in increased receptor numbers
and supersensitivity. Prolonged use of antagonists may pro-
duce an analogous effect. One example of clinical importance
is increased β-adrenoceptor numbers following prolonged use
of beta-blockers. Abrupt drug withdrawal can lead to tachy-
cardia and worsening angina in patients who are being treated
for ischaemic heart disease.
NON-RECEPTOR MECHANISMS
In contrast to high-potency/high-selectivity drugs which com-
bine with specific receptors, some drugs exert their effects via
simple physical properties or chemical reactions due to their
presence in some body compartment. Examples include antacids
(which neutralize gastric acid), osmotic diuretics (which increase
the osmolality of renal tubular fluid), and bulk and lubricating
laxatives. These agents are of low potency and specificity, and
hardly qualify as ‘drugs’ in the usual sense at all, although some
of them are useful medicines. Oxygen is an example of a highly
specific therapeutic agent that is used in high concentrations
(Chapter 33). Metal chelating agents, used for example in the
treatment of poisoning with ferrous sulphate, are examples of
drugs that exert their effects through interaction with small
molecular species rather than with macromolecules, yet which
possess significant specificity.
General anaesthetics (Chapter 24) have low molar poten-
cies determined by their oil/water partition coefficients, and
low specificity.
Key points- Most drugs are potent and specific; they combine with
receptors for endogenous mediators or with high affinity
sites on enzymes or other proteins, e.g. ion-transport
mechanisms. - There are four superfamilies of receptors; three are
membrane bound:- directly linked to ion channel (e.g. nicotinic
acetylcholine receptor); - linked via G-proteins to an enzyme, often adenylyl
cyclase (e.g. β 2 -receptors); - directly coupled to the catalytic domain of an
enzyme (e.g. insulin)
- directly linked to ion channel (e.g. nicotinic
- The fourth superfamily is intracellular, binds to DNA
and controls gene transcription and protein synthesis
(e.g. steroid receptors). - Many drugs work by antagonizing agonists. Drug
antagonism can be:- competitive;
- non-competitive;
- physiological.
- Partial agonists produce an effect that is less than the
maximum effect of a full agonist. They antagonize full
agonists. - Tolerance can be important during chronic
administration of drugs acting on receptors, e.g.
central nervous system (CNS) active agents.
Case history
A young man is brought unconscious into the Accident and
Emergency Department. He is unresponsive, hypoventilat-
ing, has needle tracks on his arms and pinpoint pupils.
Naloxone is administered intravenously and within 30
seconds the patient is fully awake and breathing normally.
He is extremely abusive and leaves hospital having
attempted to assault the doctor.
Comment
The clinical picture is of opioid overdose, and this was con-
firmed by the response to naloxone, a competitive antag-
onist of opioids at μ-receptors (Chapter 25). It would have
been wise to have restrained the patient before adminis-
tering naloxone, which can precipitate withdrawal symp-
toms. He will probably become comatose again shortly
after discharging himself, as naloxone has a much shorter
elimination half-life than opioids such as morphine or
diacetyl-morphine (heroin), so the agonist effect of the
overdose will be reasserted as the concentration of the
opiate antagonist falls.FURTHER READING
Rang HP. The receptor concept: pharmacology’s big idea. British
Journal of Pharmacology2006; 147 (Suppl. 1): 9–16.
Rang HP, Dale MM, Ritter JM, Flower RD. Chapter 2, How drugs act:
general principles. Chapter 3, How drugs act: molecular aspects.
In:Rang and Dale’s pharmacology, 6th edn. London: Churchill
Livingstone, 2007.