Drug Interactions (Selection; Amiodarone Preferred)

Drug interactions associated with amiodarone are pharmacodynamic and/or pharmacokinetic in nature. The pharmacodynamic interactions associated with amiodarone occur primarily with other antiarrhythmics and are a consequence of additive or synergistic electrophysiologic effects. As the pharmacologic effects of amiodarone are delayed by several days even with adequate loading doses, concomitant use of another antiarrhythmic is often necessary. Should this be the case, the dose of the secondary antiarrhythmic should, in general, be decreased by 3050% after the first few days of initiating amiodarone therapy. Discontinuation of the second antiarrhythmic agent should be attempted as soon as the therapeutic effects of amiodarone are observed. Conversely, in patients requiring combination therapy, the dose of the second antiarrhythmic should, in general, be decreased by 50% until amiodarone eliminated from the body. Proarrhythmia, including torsade de pointes (Table 1) and monomorphic ventricular tachycardia can and has occurred when amiodarone was administered in combination with any number of antiarrhythmic compounds including Class IA agents, mexilitine and propafenone. Caution should be exercised when amiodarone is administered with any drug with electrophysiologic effects. Amiodarone inhibits the activity of two cytochrome P450 enzymes, CYP2D6 and CYP2C9. As a consequence, it has been reported to reduce the metabolism of certain drugs. Of these drugs, the most significant interactions are reported with anticoagulants, antiarrhythmics, phenytoin, and cyclosporin. The anticoagulant effects of warfarin and nicoumalone are significantly increased when amiodarone is added. Concurrent use of amiodarone with cyclosporin need not be avoided but cyclosporin serum levels can be increased and must be monitored. Cyclosporin dosage reductions are usually required. Amiodarone also increases serum digoxin concentrations. Flecainide concentrations increase by an average of 60% with concomitant amiodarone therapy. Although the exact mechanism of the interaction is unknown, it is postulated that the hepatic metabolism and/or renal clearance of flecainide may be decreased. Careful clinical observation of the patient as well as close monitoring of the electrocardiogram (EKG) and plasma flecainde concentrations is essential with adjustment of the flecainide dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the flecainide dose by 50% is suggested 23 d following initiation of amiodarone therapy. Quinidine serum concentrations generally increase by about 33% in patients receiving concomitant amiodarone therapy. Although the mechanism is unclear, it appears that hepatic and/or renal clearance may be diminished and quinidine may also be displaced from tissue- and protein-binding sites. Prolongation of the QT interval is well documented with quinidine, and the addition of amiodarone may dramatically increase this effect, placing the patient at an increased risk for the development of torsade de pointes. Careful clinical observation of the patient as well as close monitoring of the EKG and serum quinidine concentrations is essential with adjustment of the quinidine dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the quinidine dose by 50% is suggested within 2 d following initiation of amiodarone therapy with consideration given to immediately discontinuing quinidine once amiodarone therapy is begun.

Procainamide and N-acetylprocainamide or NAPA (a pharmacologically active metabolite) concentrations increase by approximately 55 and 33%, respectively, during the first 7 d of concomitant amiodarone therapy. The precise pharmacokinetic mechanism of this interaction has not been elucidated, although a reduction in the renal clearance of both parent and metabolite, as well as a reduction in hepatic metabolism seem likely. Additive electrophysiologic activity occurs with combination therapy and prolonged QT and QRS intervals or acceleration of preexisting ventricular tachycardia may result. Careful clinical observation of the patient as well as close monitoring of the EKG and serum procainamide and NAPA concentrations is essential with adjustment of the procainamide dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. In general, it is recommended to discontinue completely or reduce the procainamide daily dose by 25% during the first week of initiating amiodarone therapy. Concomitant administration of _-blockers, or calcium-channel blockers with amiodarone may result in additive electrophysiologic effects including bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting sinus node dysfunction. In general these drugs should only be continued in patients at risk of significant bradycardia if a permanent artificial pacemaker is in place. In addition, amiodarone can decrease the clearance of drugs eliminated by hepatic metabolism. Severe cardiovascular reactions were observed when amiodarone was coadministered with metoprolol and propranolol. Amiodarone increases serum levels of digoxin when given concomitantly, and an empiric 50% dosage reduction is advised upon initiation of amiodarone therapy. The degree to which digoxin serum concentrations will increase is not predictable and reassessment of the need for both drugs is prudent. As always, careful clinical observation of the patient, and close monitoring of the ECG and serum digoxin concentrations is essential to ensure efficacy and to avoid enhanced toxicity with adjustment of the digoxin dose performed as necessary. The mechanism of the increase in digoxin serum concentration is complex and not well understood, but is thought to result from an amiodarone-induced displacement of digoxin from tissue-binding sites, an increase in bioavailability, and/or a decrease in renal or nonrenal clearance. Furthermore, amiodarone may induce changes in thyroid function and alter sensitivity to cardiac glycosides, and thyroid function should be monitored closely in patients receiving both drugs simultaneously. Concurrent administration of amiodarone with coumarin or indandione anticoagulants (warfarin) results in at least a doubling of prothrombin time (PT), significantly increasing the international normalized ratio (INR) in virtually all patients receiving this drug combination and can cause serious or potentially fatal hemorrhagic complications. This effect can occur as early as 46 d following the initial administration of the drugs in combination but can be delayed for weeks in some cases. Given the extremely long half-life of amiodarone, the interaction may persist for weeks or even months after discontinuance of amiodarone. A 50% reduction in the dosage of warfarin is recommended if amiodarone therapy is initiated with intensive clinical observation and frequent determination of PT and INR values to evaluate the extent of the interaction and guide further adjustments in therapy. Concomitant administration of amiodarone and phenytoin may result in phenytoin toxicity, secondary to a two- or threefold increase in total, steady-state serum phenytoin concentrations likely due to a amiodarone-induced decrease in phenytoin metabolism. Close monitoring for symptoms of phenytoin toxicity including nystagmus, lethargy, and ataxia; and evaluation of serum phenytoin concentrations with appropriate dosage reduction as necessary, is essential in patients receiving these medications. Amiodarone may enhance cardiovascular adverse effects such as hypotension and atropine-resistant bradycardia in patients receiving inhalation anesthetics, possibly

due to a drug interaction. Concomitant use of amiodarone with tricyclic antidepressants, phenothiazines, or any drug with the potential to prolong the QT interval may cause additive prolongation of the QT interval, and, rarely, torsades de pointes. Although limited data exist, anecdotal reports have demonstrated a cholestyramineinduced reduction in amiodarone elimination half-life and subsequently serum concentrations. This interaction may be of benefit in temporally reducing the serum amiodarone, and presumably desethylamiodarone (DEA) concentrations prior to surgery in an attempt to limit the cardiac depressant effects of the drug in the immediate postsurgical period. Two protease inhibitors, ritonavir and nelfinavir, are potent P450 enzyme inhibitors. Theoretically, they would both be expected to produce a large increase in amiodarone concentrations, due to the inhibition of its metabolism. However, there are no published reports of this interaction to date but it is suggested that there may be an increased risk of ventricular arrhythmias, so concurrent use should still be avoided. Possible pharmacodynamic interactions can occur between levomethadyl and potentially arrhythmogenic agents such as amitriptyline, calcium channel blockers, class I antiarrhythmics, class III antiarrhythmics, monoamine oxidase inhibitors, citalopram, fluoxetine, nortriptyline, sertraline, and terfenadine, among others that prolong the QT interval. Levomethadyl is contraindicated in patients being treated with any of these agents. Paroxetine impairs metabolism of the CYP2D6 (cytochrome P450 isoenzyme 2D6) pathway at therapeutic doses. Paroxetine should be used cautiously in patients receiving type 1C antiarrhythmics (such as propafenone, flecainide, or encainide) and quinidine. Competition for hepatic CYP2D6 (cytochrome P450 isoenzyme 2D6) by paroxetine may potentiate the toxicity of these antiarrhythmics. Drug interaction between antifungal drugs and macrolide antibiotics, e.g., ketoconazole and erythromycin, which are metabolized by the same cytochrome P450 3A4 hepatic isoenzyme, can cause LQT-syndrome and torsades de pointes.