What's new in antiarrhythmic therapy (Proceedings)

Cardiac arrhythmias may originate from many factors, such as the examples listed below (Table 1).

This short list of arrhythmias is by no means complete. Identification and correction of the underlying causes of arrhythmias are key to their long-term, successful management. For instance, in a cat with atrial standstill as a result of hyperkalemia from urethral obstruction, the arrhythmia is best addressed by correction of the underlying problem, hyperkalemia, as primary antiarrhythmic therapy is generally unsuccessful when such electrolyte abnormalities are present. Despite this caveat, short-term control of arrhythmias may be necessary while the underlying condition is identified and controlled, such as treatment of digoxin-associated arrhythmias until the plasma digoxin concentration drops to non-toxic levels. Some underlying diseases, such as congestive heart failure (CHF), may not be curable whereas other diseases, such as endocarditis, may require prolonged therapy before the underlying problem can be controlled. Both short-term and chronic therapy with an antiarrhythmic agent may be warranted in such situations.

Table 1. Common sources of cardiac arrhythmias.

As in all pharmacological interventions, the goal of therapy should be clearly identified from the outset of treatment. In the case of antiarrhythmic therapy, the goal may include the treatment of an existing arrhythmia or prophylaxis for anticipated arrhythmias. The use of antiarrhythmic agents for prophylaxis should be considered carefully, as few antiarrhythmic agents have been approved for use in veterinary medicine, and these agents may have considerable risk associated with their use. The successful prophylactic use of beta-blocking antiarrhythmic agents in human medicine has stimulated interest in the prevention of arrhythmias in veterinary patients with conditions that are also associated with sudden death, such as dilated cardiomyopathy. For example, it is well-established that the strategic use of antiarrhythmic therapy can prolong survival in humans with myocardial infarction, where nonselective beta-blocker drugs have been shown in large randomized control clinical trials to decrease mortality.1 Unfortunately, there are few comparable trials in veterinary species. Scientific support for the use of beta-blockers and other antiarrhythmics in dogs with ventricular tachyarrhythmias is primarily based upon retrospective survival studies, decrease in the number of arrhythmic episodes per day, and improved quality of life.

Table 2: Phases of the action potential of the cardiac myocyte.

A good clinical understanding of the appropriate use of antiarrhythmic therapy depends on a generally knowledge of the electrophysiology underlying the generation of the cardiac action potential, as most antiarrhythmic drugs work at the level of the relevant ion channels. The pacemaker cells of the sinoatrial node are responsible for the generation of the normal sinus rhythm. The sinus node depolarizes, followed by the atrial depolarization wave, atrioventricular nodal conduction, bundle branch conduction, and ventricular depolarization. The shape of the action potential differs between the cardiac myocytes and pacemaker cells, reflecting the prominent role that differences in ion channels play in the function of cardiac tissues (Tables 2 & 3).

Table 3: Prominent phases of the action potential of the pacemaker cells.

Differences in ion channels affect the efficacy of different drugs on arrhythmias arising from the pacemaker cells vs. those associated with myocytes. In Phase 0, sodium ions are involved in generating the myocyte action potential, allowing for very rapid depolarization of the cell with a resulting steep slope in Phase 0. In the pacemaker cell, calcium plays a prominent role in the generation of Phase 0, resulting in a shallower slope in the associated increase in membrane potential. However, calcium is employed by the myocyte to produce a long plateau of depolarization, which is necessary to allow full contraction of the myocyte and to generate maximal ventricular force. Contractility is therefore affected by any change in myocyte calcium handling via the voltage-gated calcium channel and the intracellular release of calcium by the sarcoplasmic reticulum. Although Phase 3 is similar between cell types, differences in Phase 4 ion movement produce key differences between the normal myocytes and pacemaker cells, as Phase 4 is responsible for the slow depolarization of the cell. Phase 4 has a shallow slope of increasing membrane potential and is mainly a potassium dependent process in the myocyte, leading to a slow rate depolarization. In contrast, in the pacemaker cell the slope of Phase 4 is steeper because additional ions (calcium and sodium) are involved. As a consequence of the faster rate of depolarization of pacemaker cells, these cells normally set the sinus rhythm by spontaneously depolarizing to the threshold membrane potential prior to the slower rate that would otherwise arise from the myocytes.

The Vaughan Williams system divides the antiarrhythmic drugs into four classes on the basis of their major electrophysiological effects on the myocardium. Because antiarrhythmic drugs are associated with electrophysiological effects on the myocardium, these antiarrhythmic drugs share the paradoxical side effect of being proarrhythmic! Electrolyte abnormalities will potentiate this arrhythmogenic effect, underscoring the value of correcting any underlying or concurrent electrolyte abnormalities whenever possible.

The Class I antiarrhythmic drugs stabilize membranes by selectively blocking fast Na+ channels during their inactive and/or open states. The Class I agent then disassociates from the resting Na+ channel, allowing subsequent activation of the ion channel. The blockade of fast Na+ channels may decrease the resulting conduction velocity (Phase 0). Class I drugs have variable effects on repolarization and may prolong the refractory period. Class I antiarrhythmics are generally useful for supraventricular and ventricular arrhythmias, but they are rarely effective if concurrent hypokalemia is present. Class I agents have differing effects on the duration of time that fast Na+ channels are blocked, providing a useful subdivision in actions and indications.

The Class IA antiarrhythmics include quinidine and procainamide. They block fast Na+ channels for an intermediate duration of time and prolong the effective refractory period. These agents are generally indicated for the therapy of premature ventricular contractions (VPCs), ventricular tachycardia, and atrial fibrillation. Quinidine and procainamide are associated with both arrhythmogenic and other side effects, including AV block, widened QRS complex, GIT disturbances, and sudden death (which is a possible side effect of most antiarrhythmics, due to their proarrhythmic effects).

The Class IB antiarrhythmics include lidocaine, mexiletine, and tocainide. Lidocaine blocks inactive sodium channels for a short duration of time and can even decrease the refractory period. Lidocaine also appears to decrease the slope of Phase 4 of the action potential, decreasing automaticity. Lidocaine is generally not used for the treatment of supraventricular arrhythmias because blockade of fast Na+ channels by lidocaine persists for only a short time, although recent experimental evidence in dogs would appear to contradict this assumption.5 However, it is the first-choice agent for the therapy of ventricular tachyarrhythmias. Lidocaine is well absorbed from the GI tract, but is extensively metabolized and subject to a high first-pass effect, resulting in poor bioavailability. For oral and long-term therapy, several Class IB drugs, mexiletine and tocainide, may be administered to dogs. There are generally few side effects associated with therapeutic lidocaine concentrations, but rapid IV administration can cause hypotension and seizures. Cats have been used as a model species for lidocaine toxicity and have historically been considered to be particularly sensitive to the CNS and arrhythmogenic side effects of lidocaine, such that some clinicians consider lidocaine to be a second-choice agent for ventricular arrhythmias in this species. However, cats can tolerate IV lidocaine administration at lower doses than those generally recommended in dogs. There is some evidence to suggest that the use of combinations of Class 1A and 1B antiarrhythmics (procainamide, quinidine, tocainide, and mexiletine) may increase longevity, as reported in a retrospective study of Doberman Pinchers with severe ventricular arrhythmias.2 Unfortunately, tocainide is no longer sold in the U.S., following reports of bone marrow aplasia and pulomonary fibrosis in humans.

Flecainide is a Class IC antiarrhythmic agent that exhibits a prolonged block of fast Na+ channels. Flecainide is particularly efficacious at prolonging the atrial action potential at fast heart rates, unlike the class IA agents, making it useful for the therapy of atrial fibrillation and supraventricular tachycardia in humans. Flecainide may be similarly useful in veterinary species, and has been investigated in horses, but has only been used in dogs under experimental conditions.8

As the Class II antiarrhythmic agents are β-Adrenergic blockers, they are particularly useful in the blockade of arrhythmias enhanced by catecholamines. By decreasing the down-regulation of receptors in CHF, these agents can also be beneficial in allowing activation of receptors during times of stress and exercise. β-Adrenergic blockers have become a mainstay of both short and long-term treatment of myocardial infarction in humans. These agents vary with respect to receptor specificity, with carvedilol being a nonselective antagonist of β1, β2, and α1 receptors. The prototypical Class II drug is propranolol, which nonselectively blocks both β1 and β2. Selective β- blockers, such as atenolol, preferentially antagonize β1 receptors, although selectivity may decrease at higher concentrations. The concurrent presence of non-cardiac disease may dictate the utility of these agents, as nonselective blockers may potentiate bronchoconstriction in patients with airway hypersensitivity. The nonselective blockers, such as carvedilol, appear to be superior to the selective blockers in extending survival in humans with myocardial infarction. Selective β- blockers may be similarly ineffective for long-term control of arrhythmias in dogs, as oral atenolol therapy did not decrease the number of ventricular arrhythmias in Boxer dogs with ventricular tachyarrhythmias. In contrast, carvedilol therapy appeared to improve quality of life scores in dogs, although contradictory results exist as to its efficacy in producing negative chronotropic effects, reducing arrhythmias, and increasing longevity in randomized control clinical trials of dogs. Both oral and IV formulations of most β-blockers are available, but chronic oral therapy is most commonly used. Bradyarrhythmias and hypotension are typical, dose-dependent side effects that have been observed with the use of class II drugs.

The Class II antiarrhythmic agents, such as sotatlol and amiodarone, are so classified because they are K+ channel blockers. The effect of K+ channel blockade prolongs both atrial and ventricular action potential and increases the refractory period. Like many of the antiarrhythmic drugs, however, these agents actually work at numerous channels and targets. For example, in addition to the blockade of K+ channels, sotalol nonselectively blocks both β1 and β2 receptors. Sotalol is potentially beneficial in dogs with ventricular tachyarrhythmias and has been shown to decrease the severity of arrhythmias in Boxer dogs.3 The second Class II agent used in veterinary medicine, amiodarone, has been used to treat ventricular arrhythmias in dogs. Maintenance therapy with amiodarone is preceded by a loading dose, as a consequence of the drug's long elimination half-life. Hepatotoxicty appears to be the most important side effect associated with amiodarone administration to dogs, although gastrointestinal side effects have also been reported.10 Given the side effects associated with the administration of amiodarone to dogs, it is a second or third-choice antiarrhythmic agent that may be used in dogs with ventricular tachycardia not controlled by other drugs.

The calcium channel blockers are classified as Class IV agents. The Class IV drugs inhibit voltage-gated ("slow") calcium channels on vascular smooth muscle (primarily arterial) and cardiac muscle. Blockade of calcium channels in the pacemaker cells provides the beneficial effects of decreased conduction through the AV node and negative chronotropy. However, this calcium channel blockade also decreases contractility in cardiac myocytes by depressing calcium influx during the plateau of Phase 2 of the action potential. Actions on calcium channels of arterial smooth muscle can also decrease blood pressure, with hypotension possibly resulting. The differential importance of calcium in the pacemaker cells versus myocytes dictates that class IV antiarrhythmic agents be reserved for the treatment of atrial arrhythmias and supraventricular tachycardia. The most commonly used class IV antiarrhythmic agent in veterinary medicine is diltiazem, which slows AV conduction and sinus rate. The more potent negative inotropic agent verapamil is also used, but should be used cautiously in patients with CHF due to concerns for a decrease in contractility and cardiac output.

REFERENCES

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