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4 Drug interactionMetoclopramide when given as an adjunct for the treatment of migraines reduces
gastrointestinal stasis, which is a feature of the disease, and speeds the absorption
of co-administered analgesics. This is an example of a favourable interaction.Distribution
Drugs that decrease cardiac output (such asβ-blockers) reduce the flow of blood
carrying absorbed drug to its site of action. The predominant factor influencing the
time to onset of fasciculation following the administration of suxamethonium is
cardiac output, which may be reduced by the prior administration ofβ-blockers. In
addition, drugs that alter cardiac output may have a differential effect on regional
blood flow and may cause a relatively greater reduction in hepatic blood flow, so
slowing drug elimination.
Chelating agents are used therapeutically in both the treatment of overdose and
of iron overload in conditions such as haemochromatosis. The act of chelation com-
bines the drug with the toxic element and prevents tissue damage. Sodium calcium
edetate chelates the heavy metal lead and is used as a slow intravenous infusion in
the treatment of lead poisoning. Dicobalt edetate chelates cyanide ions and is used
in the treatment of cyanide poisoning, which may occur following the prolonged
infusion of sodium nitroprusside.
Competition for binding sites to plasma proteins has been suggested to account
for many important drug interactions. This is not generally true; it is of importance
only for highly protein bound drugs when enzyme systems are close to saturation at
therapeutic levels. One possible exception is the displacement of phenytoin, which
is 90% protein bound, from binding sites by a co-administered drug when thera-
peutic levels are already at the upper end of normal. In this case a 10% reduction
in binding, to 81%, almost doubles the free phenytion level. Although hepatocytes
will increase their metabolism as a result, the enzyme system is readily saturated
and this leads to zero-order kinetics and the plasma level remains high instead of
re-equilibrating. Most so-called ‘protein binding’ interactions are actually due to an
alteration in metabolic capacity of one drug by the other. The commonest example
seen in practice is the administration of amiodarone to a patient taking warfarin.
Amiodarone inhibits the metabolism of S-warfarin by CYP2C9, which can signifi-
cantly increase plasma levels of the active form of warfarin and produce iatrogenic
coagulopathy. A similar interaction occurs with the NSAID phenylbutazone.Metabolism
Enzyme induction will increase the breakdown of drugs metabolized by the
cytochrome P450 family. Anticonvulsants and dexamethasone reduce the duration
of action of vecuronium by inducing CYP3A4. Rifampicin can induce a number of the
isoenzymes including 2B6, 2C9, 2D6 and 3A4. Conversely, drugs may inhibit enzyme
activity, leading to a decrease in metabolism and an increase in plasma levels (see
Table2.1); cimetidine is much more potent than ranitidine at inhibiting 1A2, 2D6