Metabolic effects

There are many examples of drugs that affect the metabolism or pharmacology of other drugs. For example, cimetidine (an anti-ulcer drug) and a number of the newer generation of antidepressants inhibit the metabolism of many of the benzodiazepines by a subtype of the cytochrome P450 enzymes, CYP3A. This occurs either by competitive inhibition of the enzyme(s) involved in their mutual metabolism or by inhibition of the enzyme(s). Cimetidine also inhibits the metabolism of opioids. Many of the newer SSRIs (e. g. fluoxetine, paroxetine and sertraline), as well as some of the antifungal drugs (e. g. fluconazole) and antiviral drugs are relatively potent inhibitors of this enzyme.

Cimetidine (used in the treatment of gastric and duodenal ulcers) inhibits the metabolism of opioids that require microsomal cytochrome enzymes.

Monoamine oxidase inhibitors nialamide, phenelzine and tranylcypromine also inhibit P450 enzyme metabolism and have been shown to increase the effects of alcohol, amfetamines, barbiturates, pethidine and other opioids. The analgesic dextropropoxyphene may have similar activity.

A further variable is that drugs such as the barbiturates and the anticonvulsants phenobarbital and phenytoin enhance the production of the enzymes and therefore induce metabolism of drugs metabolised through this and related enzyme systems. In fact, barbiturates also induce their own metabolism, which results in a time-dependent increase in clearance as the liver produces more enzyme. If the presence of more than one drug is detected in a toxicological analysis, the possibility of metabolic effects must be considered.

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