Potentially Significant Drug Interactions of Class III Antiarrhythmic Drugs

Abstract

Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin. Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug. Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions. Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism. Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide. It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism. Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically. If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.

Pharmacologic Management of Atrial Fibrillation: Established and Emerging Options

“…Many of these interactions are mediated by cytochrome P-450 (CYP) drug-metabolizing enzymes, specifically potent inhibition of the CYP1A2, 2C9, 2D6, and 3A4 enzymes, which are responsible for significant clinical interaction with drugs such as simvastatin and warfarin. 26 Another method by which amiodarone can cause interactions is via transporter-based mechanisms; for example, digoxin inhibits the P-glycoprotein membrane transporter, resulting in increased serum drug concentrations and a potential risk of increased toxicity.…”

Pharmacodynamic and pharmacokinetic drug interactions reported to VigiBase, the WHO global individual case safety report database

“…Several mechanisms may be relevant for the same drug interaction. (10,26) Protein-binding 'displacement' (10) Drug excretion (10)(11)(12)26) Changes in renal blood flow (10)(11)(12)26) Interference with a biological or physiological control process (10)(11)(12) (10,12) Reduction of gut flora (10)(11)(12) Changes in renal blood flow (10)(11)(12) Drug level in Therapeutic Nausea, Bra Gemfibrozil Cerivastatin 113 Hepatic uptake -induction or inhibition of drug transport proteins (27)(28)(29) Enzyme inhibition (27)(28)(29)(30) Additive/opposed pharmacological effect (27) Rhabdomyo Myalgia (26 Renal failur Valproic acid Lamotrigine 111 Drug metabolism (10,31) Enzyme inhibition (10)(11)(12) Drug intera Stevens-Joh ASA Heparin 102 Additive/opposed pharmacological effect (10)(11)(12) Haematoma Anaemia (1 Cerebral ha ASA Enoxaparin 97 Additive/opposed pharmacological effect (10)(11)(12) Haematoma Anaemia (2 Melaena (1 ASA Diclofenac 93 Additive/opposed pharmacological effect (10)(11)(12) Unidentified mechani...…”

Atrial fibrillation after heart transplantation

“…Метаболизм такролимуса, эве-ролимуса и циклоспорина происходит также в печени при участии изофермента CYP3A4 и бел-ка-переносчика P-гликопротеина. Таким образом, назначение амиодарона ведет к увеличению кон-центрации в крови иммуносупрессивных препа-ратов [29][30][31]. Это диктует необходимость часто-го мониторинга и коррекции назначаемой дозы иммуносупрессантов.…”