Page 1187 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 66 Important Drug Interactions & Their Mechanisms 1173

The metabolism of drugs can be induced or inhibited by produce such effects. In theory, drugs acting on the same receptor
concurrent therapy, and the importance of the effect varies from or process are usually additive, eg, benzodiazepines plus barbitu-
negligible to dramatic. Drug metabolism primarily occurs in the rates, until the receptor is saturated or the effect is maximal. How-
liver and the wall of the small intestine, but other sites include ever, two drugs competing for the same binding site may result in
plasma, lung, and kidney. Induction of cytochrome P450 isozymes less than an additive effect. Drugs acting on different receptors
in the liver and small intestine can be caused by drugs such or sequential processes may be synergistic, eg, nitrates plus silde-
as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine, nafil or sulfonamides plus trimethoprim. Conversely, drugs with
phenytoin, primidone, rifampin, rifabutin, and St. John’s wort. opposing pharmacologic effects may reduce the response to one
Enzyme inducers can also increase the activity of phase II metabo- or both drugs. Pharmacodynamic drug interactions are relatively
lism such as glucuronidation. Enzyme induction does not take common in clinical practice, but adverse effects can usually be
place quickly; maximal effects usually occur after 7–14 days and minimized if one understands the pharmacology of the drugs
require an equal or longer time to dissipate after the enzyme involved. In this way, the interactions can be anticipated and
inducer is stopped. Inhibition of metabolism generally takes place appropriate counter-measures taken.
more quickly than enzyme induction and may begin as soon as the
tissue concentration of the inhibitor is sufficient to cause reduced
enzyme activity. However, if the half-life of the affected (object) COMBINED TOXICITY
drug is long, it may take a week or more (3–4 half-lives) to reach a
new steady-state serum concentration. Drugs that may inhibit the The combined use of two or more drugs, each of which has toxic
cytochrome P450 metabolism of other drugs include amiodarone, effects on the same organ, can greatly increase the likelihood of
androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, organ damage. For example, concurrent administration of two
clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydr- nephrotoxic drugs can produce kidney damage, even though the
amine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, dose of either drug alone may be insufficient to produce toxicity.
fluvoxamine, furanocoumarins (substances in grapefruit juice), Furthermore, some drugs can enhance the organ toxicity of
indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, another drug, even though the enhancing drug has no intrinsic
mexiletine, miconazole, omeprazole, paroxetine, quinidine, rito- toxic effect on that organ.
navir, sulfamethizole, sulfamethoxazole, verapamil, voriconazole,
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