Antiarrhythmic agents - Drug interactions of clinical significance

The management of cardiac arrhythmias has grown more complex in recent year s. Despite the recent focus on nonpharmacological therapy, most clinical ar rhythmias are treated with existing antiarrhythmics. Because of the narrow therapeutic index of antiarrhythmic agents, potential drug interactions wit h ether medications are of major clinical importance. As most antiarrhythmics are metabolised via the cytochrome P450 enzyme syst em, pharmacokinetic interactions constitute the majority of clinically sign ificant interactions seen with these agents. Antiarrhythmics may be substra tes, inducers or inhibitors of cytochrome P450 enzymes, and many of these m etabolic interactions have been characterised. However, many potential inte ractions have not, and knowledge of how antiarrhythmic agents are metabolis ed by the cytochrome P450 enzyme system may allow clinicians to predict pot ential interactions. Drug interactions with Vaughn-Williams Class II (beta -blockers) and Class IV (calcium antagonists) agents have previously been reviewed and are not d iscussed here. Class I agents, which primarily block fast sodium channels a nd slow conduction velocity, include quinidine, procainamide, disopyramide, lidocaine (lignocaine), mexiletine, flecainide and propafenone. All of the se agents except procainamide are metabolised via the cytochrome P450 syste m and are involved in a number of drug-drug interactions, including over 20 different interactions with quinidine. Quinidine has been observed to inhi bit the metabolism of digoxin, tricyclic antidepressants and codeine. Furth ermore, cimetidine, azole antifungals and calcium antagonists can significa ntly inhibit the metabolism of quinidine. Procainamide is excreted via acti ve tubular secretion, which may be inhibited by cimetidine and trimethoprim . Other Class I agents may affect the disposition of warfarin, theophylline and tricyclic antidepressants. Many of these interactions can significantl y affect efficacy and/or toxicity. Of the Class III antiarrhythmics, amiodarone is involved in a significant n umber of interactions since it is a potent inhibitor of several cytochrome P450 enzymes. It can significantly impair the metabolism of digoxin, theoph ylline and warfarin. Dosages of digoxin and warfarin should empirically be decreased by one-half when amiodarone therapy is added. In addition to pharmacokinetic interactions, many reports describe the use of antiarrhythmic drug combinations for the treatment of arrhythmias. By co mbining antiarrhythmic drugs and utilising additive electrophysiological/ph armacodynamic effects, antiarrhythmic efficacy may be improved and toxicity reduced. As medication regimens grow more complex with the aging population, knowled ge of existing and potential drug-drug interactions becomes vital for clini cians to optimise drug therapy for every patient.