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