THE MERCK VETERINARY MANUAL
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Antiarrhythmics

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Antiarrhythmics have been grouped into 4 main classes according to their dominant electrophysiologic effect on myocardial cells.

Class I Drugs

Class I agents comprise the standard membrane-stabilizing drugs such as quinidine, procainamide, and lidocaine. These agents work by selectively blocking the fast sodium channels and depressing phase 0 of the action potential. This is caused by a direct membrane-stabilizing or “local anesthetic” effect. The decrease in phase 0 depolarization results in decreased conduction velocity. In addition, the class I drugs increase the threshold of excitability and decrease the rate of spontaneous phase 4 depolarization, thus reducing the emergence of ectopic foci. Some of these drugs also are useful in treating re-entrant arrhythmias.

Class I agents can be further subdivided based on their effects on the refractory period and the rate of repolarization.

Class IA drugs include quinidine, procainamide, and disopyramide. Disopyramide has limited use in small animals.

Quinidine is related to the antimalarial drug quinine. It has efficacy against supraventricular and ventricular arrhythmias. It is useful in the treatment of re-entrant arrhythmias, eg, atrial fibrillation. In the atria, quinidine also has indirect, antivagal (“atropine-like”) effects. The sulfate preparation of quinidine is absorbed rapidly after administration PO. The gluconate form is absorbed more slowly. It can be given IM but is painful. Although 90% of quinidine is protein-bound, distribution is rapid to most tissues. The half-life varies among species and is ∼6 hr in dogs and ∼8 hr in horses.

Quinidine (dogs and cats: 4–20 mg/kg, PO, tid-qid; horses: 22 mg/kg, PO, every 2 hr, or quinidine gluconate at 1.0–1.5 mg/kg, IV, every 5–10 min) can be used to treat supraventricular and ventricular arrhythmias. Individualized therapy is necessary because of significant pharmacodynamic variation among animals. Cardiotoxicity may result in AV blockade or ventricular arrhythmias. The atropine-like effects of quinidine may result in increased impulse conduction through the AV node to the ventricles and paradoxical acceleration. Quinidine, particularly in the sulfate form, can cause vasodilation and GI side effects. In horses, swelling of the nasal mucosa, urticarial wheals, and laminitis are other potential side effects. Monitoring the ECG and serum quinidine concentration can reduce the likelihood of adverse drug effects.

Procainamide affects cardiac automaticity, excitability, responsiveness, and conduction similarly to quinidine. However, its effects on the autonomic nervous system are significantly weaker. It does not cause α-adrenergic blockade or paradoxical acceleration. Procainamide is rapidly and almost completely absorbed after administration PO. Only ∼20% is protein bound. Procainamide is extensively biotransformed by the liver to metabolites that are generally inactive in dogs. It is available as oral capsules and tablets for longterm use. IV preparations are available for acute therapy and can also be administered IM.

Procainamide (dogs: 10–30 mg/kg, PO, qid; 2–8 mg/kg, IV over 5 min, then 10–40 μg/kg/min constant rate infusion; cats: 3–8 mg/kg, PO, tid-qid; 1–2 mg/kg, IV over 5 min, then 10–20 μg/kg/min, IV; horses: 25–35 mg/kg, PO, tid; 1 mg/kg/min, IV, to a maximum of 20 mg/kg) is generally more effective in controlling ventricular arrhythmias than atrial arrhythmias. Its actions parallel those of quinidine, and it is useful in animals that have not responded to quinidine therapy. Toxicities include cardiotoxicity similar to that induced by quinidine, hypotension with rapid IV administration (bolus), GI disturbances (anorexia, nausea, vomiting, and diarrhea), and possibly a systemic lupus erythematosus-like syndrome.

Class IB drugs include lido-caine, tocainide, mexiletine, and phenytoin.

Lidocaine is used predominantly for emergency treatment of ventricular arrhythmias. Lidocaine has minimal effects on the autonomic nervous system. It counteracts arrhythmias in abnormal Purkinje and ventricular fibers without affecting normal cardiac tissues. Although well absorbed if given PO, lidocaine is subject to first-pass metabolism and only one-third of the drug reaches the systemic circulation. Absorption is complete after IM administration. Distribution of lidocaine to extravascular tissues is rapid. Lidocaine is extensively metabolized by the liver; hepatic disease and reduced hepatic blood flow prolong the half-life, which is normally <1 hr in dogs.

Lidocaine is prepared for IV administration; no other drug should be included in the solution prepared for treatment of cardiac arrhythmias. It can be administered IV as a rapid bolus or as a continuous infusion (dogs: 1–2 mg/kg, IV bolus, followed by 40–80 μg/kg/min). Lidocaine has few undesirable effects. Toxicity is manifest in dogs primarily as CNS signs. Drowsiness or agitation may progress to muscle twitching and convulsions at higher plasma concentrations. Hypotension may develop if the IV bolus is given too rapidly. In cats, which are more susceptible to toxicity, cardiac suppression and CNS excitation may be seen.

Mexiletine is an analog of lidocaine that is used to treat ventricular arrhythmias in dogs (4–10 mg/kg, PO, tid). After oral administration, it undergoes minimal first-pass hepatic metabolism. Potential adverse effects include GI disturbances and tremor. Mexile-tine may be combined with other class I antiarrhythmic agents in treating refractory ventricular arrhythmias.

Tocainide is an analog of lidocaine that does not undergo extensive first-pass metabolism and thus is effective after administration PO. Tocainide has been used in dogs (15–20 mg/kg, PO, tid) for the longterm control of ventricular arrhythmias that respond to lidocaine. Potential adverse effects include CNS and GI disturbances, hypotension, bradycardia, tachycardia, other arrhythmias, and progressive corneal edema. Because of these adverse effects, tocainide has limited use.

Phenytoin has a limited spectrum of anti-arrhythmic activity. Its primary use-fulness is for the management of digitalis-induced arrhythmias because it abolishes digitalis-induced abnormal automaticity. The recommended dosage in dogs is 30–50 mg/kg, PO, tid.

Class II Drugs

Class II antiarrhythmic drugs are the β-adrenergic receptor blocking agents. While characterized as Class II antiarrhythmic agents, β-adrenergic blockers are increasingly important in the clinical management of mild to moderate forms of CHF. Their main value is the blunting of the sympathetic nervous system response in heart failure.

Propranolol, the prototype, is competitive and nonselective, blocking both β1 and β2 receptors. As a β1 blocker, propranolol has a negative chronotropic effect in conditions of supraventricular tachycardia. Propranolol is also a negative inotrope. This pharmacologic effect can be detrimental in animals with limited cardiac reserve (eg, animals with severe CHF) but is beneficial in cats with hypertrophic cardiomyopathy.

Clinical indications for propranolol include reduction of ventricular rate in cases of supra-ventricular tachycardia, atrial fibril-lation, or atrial flutter, and treatment of hypertrophic cardiomyopathy, hypertension, and thyrotoxicosis. Propranolol (dogs: 0.1–2 mg/kg, PO, tid; cats: 2.5–5 mg/cat, PO, tid) is used clinically as a negative chronotrope in dogs and cats with supraventricular arrhythmias and as a negative chronotrope and negative inotrope in cats with hypertrophic cardiomyopathy. Digitalization may be necessary before propranolol is used in dogs with CHF. β-Blockers may be preferred over calcium-channel blockers in treating the obstructive form of hypertrophic cardiomyopathy in cats. Use of propranolol should be avoided in cats with evidence of respiratory disease (eg, asthma).

The toxic effects of propranolol are the result of β-receptor blockade and include bradyarrhythmias, hypotension, heart failure, bronchospasm, and hypoglycemia, particularly in diabetic animals. Administration of a β-blocker to an animal with little myocardial reserve must be done cautiously by initiating therapy at the low end of the dose range.

Atenolol is a β1-selective blocking agent that may be effective in treating supraventricular tachyarrhythmias, systemic hypertension, and hypertrophic cardiomyopathy. In addition to relative safety in animals with bronchospastic disease, atenolol requires less frequent dosing than propranolol (dogs: 0.25–1 mg/kg, PO, sid-bid; cats: 2–3 mg/kg, PO, bid). In mild to moderate CHF in dogs in which β-adrenergic receptor blockade is desired, a starting dosage of 0.5–0.8 mg/kg, PO, sid, followed by gradual dose increases over a few weeks to 2–5 mg/kg, PO, sid, has been suggested.

Carvedilol is a relatively new β-adrenergic blocker used to treat cardiac disease in dogs. Like propranolol, carvedilol is a nonselective β1and β2 blocker. Unlike propranolol, carvedilol also blocks α-adrenergic receptors and possesses antioxidant properties. Because the negative inotropic effect of β-blockade poses a risk during severe CHF, carvedilol use should be limited to mild or moderate cases of CHF. However, carvedilol may have reduced negative chronotropic and inotropic effects compared with other β-blockers, which may decrease its potential to worsen symptoms of heart failure. Reduced mortality has been demonstrated in humans with left ventricular failure who received carvedilol. Experience in veterinary medicine has been chiefly in treating dilated cardiomyopathy in large-breed dogs. The recommended starting dosage in large-breed dogs is 3 mg, PO, daily for 2 wk, and then titrating upward (eg, 3 mg bid for 2 wk, etc) based on clinical response up to a maximum of 25–50 mg, PO, divided bid. In small dogs with atrioventricular valve disease, the suggested starting dosage is 0.25 mg/kg, PO, bid, with staged, upward dose titration every 2 wk to a maximum of 1.0–1.25 mg/kg, PO, bid.

Class III Drugs

Class III drugs prolong the cardiac action potential and refractory period. They have no effect on the fast sodium conductance. There are 3 drugs in this class—bretylium, amiodarone, and sotalol. At present, none have practical clinical application in veterinary medicine. In addition to the Class III effect on action potential, sotalol is a nonselective β-adrenergic blocker.

Class IV Drugs

Class IV antiarrhythmic drugs are referred to as calcium antagonists or calcium-channel blocking drugs. Those used in veterinary medicine include diltiazem, amlodipine, and verapamil.

Calcium-channel blockers inhibit the entry of calcium into the cell or inhibit its mobilization from intracellular stores in both cardiac and smooth muscle cells. Cardiac and vascular smooth muscle depend on calcium for contraction. In addition, specialized cardiac tissues capable of automaticity and AV conduction depend, in part, on calcium entry or mobilization for depolarization. Calcium-channel blockers slow the sinus rate and AV conduction; the ventricular rate is reduced in animals with atrial fibrillation or flutter. Ventricular arrhythmias are generally unresponsive. Cardiovascular side effects of calcium-channel blockers include hypotension, bradycardia, various degrees of heart block, and exacerbation of CHF due to negative inotropic effects.

Diltiazem is indicated for the treatment of atrial fibrillation, supraventricular tachycardias, hypertrophic cardiomyopathy, and hypertension. The dosage for dogs is 0.5–1.5 mg/kg, PO, tid, and for cats 0.5–2.5 mg/kg, PO, tid, with middle range to high-end dosages for hypertrophic cardiomyopathy. Alternatively, sustained-release formulations of diltiazem are available for administration to cats. The benefits of diltiazem for hypertrophic cardiomyopathy include decreased heart rate, edema formation, and possibly ventricular wall thickness, and improved diastolic relaxation and ventricular compliance. To slow the ventricular response to supraventricular tachyarrhythmias, generally a lower dosage is initially administered and increased in 2–3 days as needed to achieve the desired ventricular rate. Diltiazem is well tolerated by dogs and cats. Noncardiovascular adverse effects might include GI or CNS disturbances and increases in liver enzymes. Diltiazem increases the bioavailability of propranolol; concurrent therapy with β-blockers increases the propensity for cardiovascular side effects.

Amlodipine is selective for calcium-channel blockade in vascular smooth muscle with minimal effects on cardiac calcium transport. Amlodipine is recommended for hypertension in cats and dogs.

Last full review/revision March 2012 by Mark J. Novotny, DVM, MS, PhD, DACVCP

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