SYSTEMIC ANTIFUNGAL AGENTS - DRUG-INTERACTIONS OF CLINICAL-SIGNIFICANCE

There are 3 main classes of systemic antifungals: the polyene macrolid es (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and th e allylamines (e.g. terbinafine). Other systemic antifungals include g riseofulvin and flucytosine. Most drug-drug interactions involving sys temic antifungals have negative consequences. The interactions of amph otericin B, flucytosine, griseofulvin, terbinafine and azole antifunga ls can be divided into the following categories: (i) additive dangerou s interactions;;ii) modifications of antifungal kinetics by other drug s; and (iii) modifications of the kinetics of other drugs by antifunga ls. Amphotericin B and flucytosine mainly interact with other agents p harmacodynamically. Clinically important drug interactions with amphot ericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents. Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Sy nergism is likely to occur when either QT interval-modifying drugs (e. g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g . amphotericin B) are coadministered. Induction and inhibition of cyto chrome P450 enzymes at hepatic and extrahepatic sites are the mechanis ms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrea se the catabolism of numerous drugs: histamine H-1 receptor antagonist s, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam. triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyl ine. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarb itone), phenytoin and rifampicin (rifampin) can induce the metabolism sf azole antifungals. The bioavailability of ketoconazole and itracona zole is also reduced by drugs that increase gastric pH, such as H-2 re ceptor antagonists, proton pump inhibitors, sucralfate and didanosine. Griseofulvin is an enzymatic inducer of coumarin-like drugs and estro gens, whereas terbinafine seems to have a low potential for drug inter actions. Despite important advances in our understanding of the mechan isms underlying pharmacokinetic drug interactions during the 1990s, al this lime they still remain difficult to predict in terms of magnitud e in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those met abolising enzymes that can either be induced or inhibited by various d rugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions tu be used to advantage in o rder to improve the tolerability of some drugs, as recently exemplifie d by the use of a fixed combination of ketoconazole and cyclosporin.