PHARMACOKINETIC INTERACTIONS
Absorption
In addition to direct interaction within the gut lumen (see
above), drugs that influence gastric emptying (e.g. metoclo-
pramide,propantheline) can alter the rate or completeness of
absorption of a second drug, particularly if this has low
bioavailability. Drugs can interfere with the enterohepatic
recirculation of other drugs. Failure of oral contraception can
result from concurrent use of antibiotics, due to this mech-
anism. Many different antibiotics have been implicated.
Phenytoinreduces the effectiveness of ciclosporinpartly by
reducing its absorption.Distribution
As explained above, interactions that involve only mutual
competition for inert protein- or tissue-binding sites seldom, if
ever, give rise to clinically important effects. Examples of com-
plex interactions where competition for binding sites occurs in
conjunction with reduced clearance are mentioned below.Metabolism
Decreased efficacy can result from enzyme induction by a
second agent (Table 13.3). Historically, barbiturates were clin-
ically the most important enzyme inducers, but with the
decline in their use, other anticonvulsants, notably carba-
mazepineand the antituberculous drug rifampicin, are now
the most common cause of such interactions. These necessitate
special care in concurrent therapy with warfarin,phenytoin,
oral contraceptives, glucocorticoids or immunosuppressants
(e.g.ciclosporin,sirolimus).Drugs with negative inotropic effects can precipitate heart
failure, especially when used in combination. Thus, beta-
blockers and verapamilmay precipitate heart failure if used
sequentially intravenously in patients with supraventricular
tachycardia.
Warfarininterferes with haemostasis by inhibiting the coagu-
lation cascade, whereas aspirininfluences haemostasis by
inhibiting platelet function. Aspirinalso predisposes to gastric
bleeding by direct irritation and by inhibition of prostaglandin
E 2 biosynthesis in the gastric mucosa. There is therefore the
potential for serious adverse interaction between them.
Important interactions can occur between drugs acting at a
common receptor. These interactions are generally useful
when used deliberately, for example, the use of naloxone to
reverse opiate intoxication.
One potentially important type of pharmacodynamic drug
interaction involves the interruption of physiological control
loops. This was mentioned above as a desirable means of
increasing efficacy. However, in some situations such control
mechanisms are vital. The use of β-blocking drugs in patients
with insulin-requiring diabetes is such a case, as these patients
may depend on sensations initiated by activation of β-receptors
to warn them of insulin-induced hypoglycaemia.
Alterations in fluid and electrolyte balance represent an
important source of pharmacodynamic drug interactions (see
Table 13.2). Combined use of diuretics with actions at different
parts of the nephron (e.g. metolazoneandfurosemide) is
valuable in the treatment of resistant oedema, but without
close monitoring of plasma urea levels, such combinations
readily cause excessive intravascular fluid depletion and pre-
renal renal failure (Chapter 36). Thiazide and loop diuretics
commonly cause mild hypokalaemia, which is usually of no
consequence. However, the binding of digoxin to plasma
membrane Na/K adenosine triphosphatase (Na/K
ATPase), and hence its toxicity, is increased when the extracel-
lular potassium concentration is low. Concurrent use of such
diuretics therefore increases the risk of digoxin toxicity.
β 2 -Agonists, such as salbutamol, also reduce the plasma
potassium concentration, especially when used intravenously.
Conversely, potassium-sparing diuretics may cause hyper-
kalaemia if combined with potassium supplements and/or
angiotensin converting enzyme inhibitors (which reduce cir-
culating aldosterone), especially in patients with renal impair-
ment. Hyperkalaemia is one of the most common causes of
fatal adverse drug reactions.
HARMFULINTERACTIONS 75Table 13.1:Interactions outside the body
Mixture Result
Thiopentone and suxamethonium Precipitation
Diazepam and infusion fluids Precipitation
Phenytoin and infusion fluids Precipitation
Heparin and hydrocortisone Inactivation of heparin
Gentamicin and hydrocortisone Inactivation of gentamicin
Penicillin and hydrocortisone Inactivation of penicillin
Table 13.2:Interactions secondary to drug-induced alterations of fluid and
electrolyte balance
Primary drug Interacting drug Result of
effect interaction
Digoxin Diuretic-induced Digoxin toxicity
hypokalaemia
Lidocaine Diuretic-induced Antagonism of anti-
hypokalaemia dysrhythmic effects
Diuretics NSAID-induced salt Antagonism of
and water retention diuretic effects
Lithium Diuretic-induced Raised plasma lithium
reduction in lithium
clearance
Angiotensin Potassium chloride Hyperkalaemia
converting and/ or potassium-
enzyme inhibitor retaining diuretic-
induced
hyperkalaemia
NSAID, non-steroidal anti-inflammatory drug.