What's New With Antiarrhythmic Drugs?

The information gleaned from the study of anti-arrhythmic drugs is often complicated by the multiple mechanisms by which arrhythmias are generated, and by the fact that we often do not fully understand the relationship between risks and benefits of a given drug.¹ This brief overview will attempt to put some of these issues into a current perspective. The Vaughn-Williams anti-arrhythmic drug classifications, current agendas for arrhythmia control and prevention, and some of the promising new drugs will be reviewed.

Vaughn-Williams Drug Classification System²

The Vaughn-Williams drug classification system for antiarrhythmic drugs has been used to describe the actions of antiarrhythmic drugs for two decades. Though the proponents of the Sicilian Gambit Group³ have suggested the Vaughn-Williams system is not specific enough for all situations, the research community continues to embrace the original system. Thus, most of the research on antiarrhythmics continues to describe Class II, Class IA, etc. effects of new drugs. Table 1 reviews the various classes in the Vaughn-Williams system and lists currently approved drugs that fall within each category. Class I agents are the sodium channel blockers and are further subcategorized into subclasses IA, IB and IC. Class IA sodium channel blockers exert their effect by moderately blocking the effect of the Na channels, leading to conduction impairment and prolonged repolarization. Drugs which fall within this category are quinidine, procainamide and disopyramide. Class IB sodium channel blockers cause a minimal blocking effect and tend to shorten repolarization. Lidocaine, mexiletine and tocainide represent this category. Class IC drugs possess marked Na channel blocking effects and result in significant conduction impairment. Flecainide, propafenone and ethmozine fall into this group. Class II antiarrhythmics are the beta-receptor blockers. Theses agents act by depressing automaticity and conduction in the slow response cells (sinus and AV node) and impairing calcium release to reduce contractility. All beta blockers possess these effects. Class III agents are potassium channel blockers. Potassium channel blockade results in a lengthening of refractoriness by delaying the recovery of the membrane potential. Most of the drugs assigned to this class are not pure potassium blockers and have properties of other classes. Drugs from this group include amiodarone, sotalol, bretyllium, azimilide, dofetilide and ibutilide. Class IV agents include the calcium channel blockers (Class IVA) and the adenosine receptor agonists (Class IVB). The calcium channel blockers predominantly block calcium entry in slow response cells (SA and AV nodal cells). These drugs include verapamil and diltiazem. The one adenosine receptor agonist commonly used is adenosine. Stimulation of adenosine receptors results in opening of potassium channels with a predominant effect of hyperpolarization. This depresses automaticity in SA nodal cells and conduction in AV nodal cells. There is a minimal effect of repolarization shortening. Table 2 lists the various types of ion channels which may be affected by the actions of antiarrhythmics. As we learn more about these channels and the role they play in arrhythmia production, researchers continue to discover diverse ways to alter their function and attempt to treat arrhythmias.

Current Agendas and Serendipitous Results

The currently identified needs in the antiarrhythmic drug realm include agents for atrial fibrillation rate and rhythm control and agents to use in the primary prevention of sudden cardiac death.⁴ The study of atrial fibrillation has risen to a top priority level for many researchers. A greater understanding of the electrophysiologic basis of atrial fibrillation has led to the finding that the rhythm is sustained by a short refractory period. Research efforts, therefore, are being directed toward prolonging the refractory period, a ‘pure class III effect.⁵ This prolongation results in an increase in the amount of atrial tissue required for reentry to be sustained and a decrease in the number of reentry circuits which can be maintained in the atrium, thereby terminating the rhythm. Class III agents are being used increasingly for the conversion of atrial fibrillation to sinus rhythm and as agents to prevent recurrence. The downside to use of the Class III agents and other antiarrhythmics in the past, however, has been the associated side effects.6 One approach to alleviating this problem is the attempt to develop drugs that only target atrial tissue, with the hope that atrial proarrhythmia will be avoided. Data from the AFFIRM trial⁷ has suggested that either rate control or rhythm control are acceptable treatment approaches for atrial fibrillation. Thus, the use of drugs which control the ventricular rate in atrial fibrillation is seen as a viable alternative to sinus rhythm maintenance for many patients. The second identified research direction is the prevention of sudden cardiac death.^4,8-18 Beta blockers (Class II) have been found useful in prevention of the process of ‘electrophysiological remodeling, but have not been found to be effective in arrhythmia conversion. Other drugs recently observed to prevent sudden cardiac death do not include the usual suspects. These have included fish oil, ACE inhibitors, statins, and aldosterone receptor antagonists. Fish oil and statins are thought to be effective in preventing sudden cardiac death through an electrical stabilizing action. It has also been suggested from the data that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can prevent atrial fibrillation by preventing atrial dilation and stretch-induced arrhythmias or by blocking the rennin-angiotensin system.¹⁹ A list of various drugs under investigation for their antiarrhythmic properties is shown in Table 3.

New Drugs and New Indications/Formulations

The following is a review of some of the new drug formulations which are thought to be promising.^20-22 The first is an aqueous version of amiodarone. Hypotension has been the most frequently reported adverse event associated with the administration of intravenous amiodarone. This effect has been attributed to vasoactive solvents within the formulation and does not seem to be dose related. The new aqueous amiodarone formulation has been compared to lidocaine in clinical trials and was found to be at least as safe as lidocaine when given as a rapid IV injection.²³ Azimilide was studied extensively in the ALIVE trial and found to have no effect on survival; however, the rate of atrial fibrillation in the participants was decreased due to the drug s ability to maintain sinus rhythm. Azimilide exerts its effects by blocking multiple potassium currents, increasing the atrial effective refractory period in a frequency independent fashion and not significantly altering conduction velocity.The drug is completely absorbed by the gut, and peaks seven hours after administration. It is metabolized by the liver and has a half-life four to five days.²⁴ Dronedarone is a benzofuran derivative of amiodarone, which is being tested for maintenance of sinus rhythm in patients with a history of atrial fibrillation. It works by blocking multiple potassium currents and shortening ventricular repolarization by inducing a homogenization of repolarization, thus decreasing the potential for torsades de pointes. It appears to be more potent than amiodarone in its ability to prolong action potential at various cycle lengths and is hoped to be less toxic. An 800 mg daily dose has been shown to be safe and effective for atrial fibrillation relapse after cardioversion. No thyroid side effects or proarrhythmia have been noted.²⁵ DTI-0009 is an adenosine receptor blocker that has been used to control ventricular response in atrial fibrillation. Piboserod blocks atrial serotonin in 5-HT4 receptors. 5-HT4 receptors are present in human atrial cells. When these cells are stimulated, atrial arrhythmias may occur. Piboserod is being used for sinus rhythm maintenance in atrial fibrillation. RSD1235 acts through atrial action potential prolongation. It is being tested for sinus rhythm maintenance in atrial fibrillation. Tecadenoson (CVT-510) is an adenosine receptor blocker which, unlike adenosine, appears to terminate AV node dependent supraventricular tachycardias without the hypotension and bronchoconstriction. In clinical trials, it was found to terminate PSVT after sinus rhythm restoration with minimal AH interval prolongation without HV interval or sinus cycle length prolongation.²⁶ It is also being tested for rate control in atrial fibrillation. Tedisamil (KC-8857) was originally developed as an antianginal agent. Its antiarrhythmic properties involve a blockade of multiple potassium currents, resulting in a lengthening on the monophasic action potential and refractory periods in the atrium and a decrease in atrial pacing rates. Ventricular effects include an increase in the refractory period, reducing the inducibility of ventricular tachyarrhythmias while having no effect on ventricular contractility. Tedisamil shows promise for sinus rhythm maintenance in the treatment of atrial fibrillation.^27-28

Conclusion

The future holds great promise for some exciting new drugs to treat what seems to be electrophysiology's last great frontiers.