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Antiarrhythmic drug therapy in treating AF
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Atrial fibrillation is the most common sustained cardiac tachyarrhythmia for which antiarrhythmic drug therapy is prescribed. It affects 2 million to 5 million patients in the United States.
In the 2006 American Heart Association’s guidelines for the treatment of AF, restoration and maintenance of normal sinus rhythm with drug therapy is assigned a level-2a recommendation, indicating that its use is reasonable and that intermittent episodes of breakthrough AF are an acceptable outcome. Medications employed for the restoration and maintenance of normal sinus rhythm include the class Ic sodium channel antagonists propafenone and flecainide, which also antagonize cardiac potassium channels, and the antagonists of the delayed rectifying potassium current, IKr: sotalol, dofetilide and ibutilide, as well as the multimechanistic agent amiodarone. The efficacy of these compounds is variable and often unpredictable, with failure rates ranging from 22% to 70%.
Antiarrhythmic drug therapy is not without risk, including prolongation of the QT interval and the development of the polymorphic ventricular tachycardia, Torsade des Pointes (TdP). Although numerous risk factors for drug-induced QT interval prolongation have been identified, the risk of TdP remains highly variable among patients with similar risk profiles and equivalent QT intervals. One explanation may be mutations in ion channel genes (ie, KCNH2, KCNQ1, SCN5A), although variants in these genes have been implicated in only 5% to 10% of cases.
Clinically, because there is such large inter-patient variability in QT prolongation on exposure to IKr-blocking antiarrhythmics, many of these drugs are usually initiated in-hospital, under continuous ECG monitoring. Because IKr is expressed in both the atrium and the ventricle — and pharmacodynamic block of ventricular IKr leads to TdP at the same time — we are attempting to restore normal sinus rhythm through block of atrial IKr with agents such as ibutilide, sotalol, dofetilide or amiodarone.
Molecular effector site
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Inter-patient variability is an accepted consequence of the response to drug administration of antiarrhythmic drugs. Therefore, a key determinant of the magnitude of any drug effect in patients is the drug concentration achieved at the molecular effector site, and variations in drug metabolism are a well-recognized determinant of the biological variability in drug concentration. More recently, delivery of drug to and removal from the intracellular compartment by xenobiotic transporters has become increasingly well-recognized as a modulator of intracellular drug concentration at the molecular effector site.
Because drugs such as ibutilide, dofetilide, sotalol and amiodarone suppress IKr by binding to the intracellular face of the potassium channel, drug access is limited (or enhanced) by the necessity of the drug to cross cell membranes to reach their molecular effector site in an appreciable concentration to warrant a clinical response. Accordingly, the presence of drug update and efflux transporters in the heart is an important and under recognized cause of drug interactions leading to TdP with antiarrhythmic drugs.
Evolutionary development of transport proteins is thought to have occurred as a mechanism to deliver or remove nutrients or endogenous toxins from cells or organ systems. They were initially discovered in treatment-resistant neoplastic disease and can be broadly classified as uptake or efflux transporters. Efflux transporters that export drugs out of cells to the extracellular space are encoded primarily by genes mainly belonging to the ATP-binding cassette superfamily, which includes ABCB1 (formerly known as MDR1) encoding P-glycoprotein.
P-glycoprotein hydrolyzes ATP at its intracellular nucleotide-binding domains to export drugs and xenobiotics. In many tissues, including the heart, expression of multiple efflux transporters has been demonstrated and is proposed to serve two purposes. P-glycoprotein is the most studied efflux transporter to date and transports a number of CV drugs, including certain beta-blockers, quinidine and digoxin. We have recently discovered that the interaction between P-glycoprotein and antiarrhythmic drugs is more broad, influencing the effect of ibutilide, flecainide and verapamil, among others.
P-glycoprotein
The clinical consequence of the broadening number of antiarrhythmic drugs (as well as non-CV QT prolonging drugs) transported by P-glycoprotein means an increased risk of drug interactions with drugs that inhibit P-glycoprotein. This results in a potential increased risk of TdP in a patient. Such drugs include amiodarone, antifungal agents ketoconazole and posaconazole (Noxafil, Schering), as well as macrolide antibiotics.
Interestingly, recent evidence indicates that most known inhibitors of the drug metabolizing cytochrome P450 3A4 enzyme are also inhibitors of P-glycoprotein because of a shared common pathway in the genesis of both proteins. Sharing this common inhibitory characteristic between CYP3A4 and P-glycoprotein sets the stage for a host of drug interactions among patients prescribed antiarrhythmic drugs. Compounding this problem is that many tertiary drug information handbooks and databases (including drug interaction programs) do not include sufficient information on P-glycoprotein mediated drug interactions to permit the clinician to make an informed decision regarding antiarrhythmic drug prescribing and potential drug interactions.
To remedy this problem, clinicians are advised to visit www.drug-interactions.com, which provides a comprehensive list of CYP3A4 inhibitors, before prescribing an antiarrhythmic drug because many CYP3A4 inhibitors also inhibit drug transport by P-glycoprotein.
Brian F. McBride, PharmD, is an Assistant Professor, Marcella Neihoff School of Nursing, Stritch School of Medicine, Loyola University Medical Center, Chicago.
Rhonda Cooper DeHoff, PharmD, MS, Associate Professor, University of Florida College of Pharmacy, Gainesville, is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board.
For more information:
- McBride BF. Pharmacogenomics J. 2009;9:194-201.
- McBride BF. J Cardiovasc Pharmacol. 2009;54:63-71.