Withdrawal of an inducing agent during continued admin-
istration of a second drug can result in a slow decline in
enzyme activity, with emergence of delayed toxicity from the
second drug due to what is no longer an appropriate dose.
For example, a patient receiving warfarinmay be admitted to
hospital for an intercurrent event and receive treatment with
an enzyme inducer. During the hospital stay, the dose of
warfarintherefore has to be increased in order to maintain
measurements of international normalized ratio (INR) within
the therapeutic range. The intercurrent problem is resolved,
the inducing drug discontinued and the patient discharged
while taking the larger dose of warfarin. If the INR is
not checked frequently, bleeding may result from an
excessive effect of warfarindays or weeks after discharge
from hospital, as the effect of the enzyme inducer gradually
wears off.
Inhibition of drug metabolism also produces adverse
effects (Table 13.4). The time-course is often more rapid than
for enzyme induction, since it depends merely on the attain-
ment of a sufficiently high concentration of the inhibiting
drug at the metabolic site. Xanthine oxidase is responsible for
inactivation of 6-mercaptopurine, itself a metabolite of aza-
thioprine. Allopurinol markedly potentiates these drugs
by inhibiting xanthine oxidase. Xanthine alkaloids (e.g.
theophylline) are not inactivated by xanthine oxidase, but
rather by a form of CYP450. Theophyllinehas serious (some-
times fatal) dose-related toxicities, and clinically important
interactions occur with inhibitors of the CYP450 system,
notably several antibiotics, including ciprofloxacinandclar-
ithromycin. Severe exacerbations in asthmatic patients
are often precipitated by chest infections, so an awareness of
these interactions before commencing antibiotic treatment is
essential.
Hepatic CYP450 inhibition also accounts for clinically
important interactions with phenytoin(e.g.isoniazid) and
withwarfarin(e.g. sulphonamides). Non-selective monoamine
oxidase inhibitors (e.g. phenelzine) potentiate the action of
indirectly acting amines such as tyramine, which is present in a
wide variety of fermented products (most famously soft
cheeses: ‘cheese reaction’).
Clinically important impairment of drug metabolism may
also result indirectly from haemodynamic effects rather than
enzyme inhibition. Lidocaineis metabolized in the liver and
the hepatic extraction ratio is high. Consequently, any drug
that reduces hepatic blood flow (e.g. a negative inotrope) will
reduce hepatic clearance of lidocaineand cause it to accumu-
late. This accounts for the increased lidocaineconcentration
and toxicity that is caused by β-blocking drugs.Excretion
Many drugs share a common transport mechanism in the
proximal tubules (Chapter 6) and reduce one another’s excre-
tion by competition (Table 13.5). Probenecidreduces peni-
cillin elimination in this way. Aspirin and non-steroidal
anti-inflammatory drugs inhibit secretion of methotrexate
into urine, as well as displacing it from protein-binding
sites, and can cause methotrexatetoxicity. Many diuretics
reduce sodium absorption in the loop of Henle or the distal
tubule (Chapter 36). This leads indirectly to increased proxi-
mal tubular reabsorption of monovalent cations. Increased
proximal tubular reabsorption of lithiumin patients treated
with lithium salts can cause lithium accumulation and
toxicity. Digoxinexcretion is reduced by spironolactone,ver-
apamilandamiodarone, all of which can precipitate digoxin
toxicity as a consequence, although several of these inter-
actions are complex in mechanism, involving displacement
from tissue binding sites, in addition to reduced digoxin
elimination.
Changes in urinary pH alter the excretion of drugs that are
weak acids or bases, and administration of systemic alkalinizing
or acidifying agents influences reabsorption of such drugs76 DRUG INTERACTIONS
Table 13.3:Interactions due to enzyme induction
Primary drug Inducing agent Effect of
interactionWarfarin Barbiturates Decreased anticoagulation
Ethanol
RifampicinOral contraceptives Rifampicin Pregnancy
Prednisolone/ Anticonvulsants Reduced
ciclosporin immunosuppression
(graft rejection)Theophylline Smoking Decreased plasma
theophyllineTable 13.4:Interactions due to CYP450 or other enzyme inhibition
Primary drug Inhibiting drug Effect of
interaction
Phenytoin Isoniazid Phenytoin intoxication
Cimetidine
Chloramphenicol
Warfarin Allopurinol Haemorrhage
Metronidazole
Phenylbutazone
Co-trimoxazole
Azathioprine, 6-MP Allopurinol Bone-marrow
suppression
Theophylline Cimetidine Theophylline toxicity
Erythromycin
Cisapride Erythromycin Ventricular tachycardia
Ketoconazole
6-MP, 6-mercaptopurine.