Antiarrhythmics are typically classified according to their predominant electrophysiologic effect on myocardial cells. However, the electrophysiologic effects of some agents span more than one class, and some have ancillary properties unrelated to their antiarrhythmic effects. However, this classification scheme typically does not aid in selection of an antiarrhythmic for a specific clinical indication (eg, ventricular vs supraventricular arrhythmias). Many antiarrhythmics have never been used with any frequency in veterinary medicine (and are not covered here). In addition, many of these agents (in particular the class I medications) have fallen out of favor for treatment of arrhythmias in people, and as a consequence their availability and costs are becoming problematic.
Class I Drugs
Class I agents comprise the group of agents generally known as "membrane-stabilizing drugs" such as quinidine, procainamide, and lidocaine. These agents work by selectively blocking a proportion of the fast sodium channels in cardiomyocytes, leading to depression of phase 0 of the action potential and subsequent reductions in conduction velocity. These agents are often subdivided into three subclasses (A, B, and C) based on their concurrent effects on repolarization; however, this has little clinical relevance.
Class IA Drugs:
Class IA drugs used in veterinary medicine include quinidine and procainamide.
Quinidine is related to the antimalarial drug quinine. In addition to its membrane-stabilizing properties inherent to Class I agents, it also has indirect, antivagal (“atropine-like”) effects in the atria. It has efficacy against supraventricular and ventricular arrhythmias. Its main indication in veterinary medicine is to treat atrial fibrillation. It has the potential to convert atrial fibrillation to sinus rhythm and is used for this indication in horses. In dogs, it is used to facilitate synchronized cardioversion of atrial fibrillation. It is not typically used for rate control of chronic atrial fibrillation in dogs or horses, or to treat ventricular arrhythmias. 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.
Dosages of quinidine sulfate are as follows: in dogs, 5–10 mg/kg, IV, qid, or 6–20 mg/kg, PO, tid-qid; and in horses, 22 mg/kg, PO, every 2 hr. Dosages of quinidine gluconate are in dogs, 6–20 mg/kg, IM, qid, or 6–20 mg/kg, PO, tid-qid; and in horses, 1–1.5 mg/kg, IV, every 5–10 min. Individualized therapy is necessary because of significant pharmacodynamic variation among animals and the potential for toxicity. Cardiotoxicity can manifest in the form of ventricular arrhythmias. The atropine-like effects of quinidine may result in increased impulse conduction through the AV node to the ventricles and paradoxical acceleration in ventricular response in animals with atrial fibrillation. Quinidine, particularly in the sulfate form, can cause vasodilation and GI adverse effects (25% of dogs). In horses, swelling of the nasal mucosa, urticarial wheals, and laminitis are other potential adverse effects. The most important clinical problem limiting use of quinidine is exacerbation of heart failure after administration, likely as a consequence of its negative inotropic effects. In general, quinidine use should be avoided in dogs with severe myocardial failure or in dogs that have, or have had, heart failure. Quinidine should not be used in cats. Monitoring the ECG and serum quinidine concentration can reduce the likelihood of adverse effects.
Procainamide effects are similar to those of quinidine. However, its effects on the autonomic nervous system are significantly weaker (less antivagal effect). Procainamide has efficacy against ventricular and supraventricular arrhythmias and has been used for both indications in dogs. It is often used parenterally in combination with lidocaine to treat life-threatening ventricular arrhythmias. The parenteral formulation has also been used to treat supraventricular arrhythmias, including conversion of recent onset atrial fibrillation. The oral formulation is useful to treat ventricular arrhythmias and supraventricular arrhythmias secondary to accessory pathways. It has little efficacy in longterm management of atrial fibrillation. 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. Both oral ("regular" and sustained-release) and parenteral formulations (IV and IM administration) are available. The "regular" formulation necessitates dosing every 4 hr for maintenance in dogs, severely limiting its use for longterm treatment. The sustained-release product has fallen out of favor in people, limiting its availability; it is not currently available in the USA.
Procainamide is dosed in dogs at 2 mg/kg, slow IV bolus, to a maximum cumulative dose of 25 mg/kg over 10–15 min, continuing if needed as a CRI at 25–40 mcg/kg/min or at 10–20 mg/kg, tid-qid, IM or SC. The oral (regular) formulation is dosed at 4–6 mg/kg, PO, every 2–4 hr (maintenance dose every 4 hr), and the sustained-release formulation at 10–20 mg/kg, PO, tid.
Toxicities include hypotension and AV block (IV administration only), proarrhythmia (longterm administration), alteration in coat color (longterm administration), and GI disturbances with the oral formulations.
Class IB Drugs:
Class IB drugs used in veterinary medicine include lidocaine, mexiletine, tocainide, and phenytoin.
Lidocaine is used predominantly for acute treatment of ventricular arrhythmias. It has no efficacy against supraventricular arrhythmias and minimal effects on the autonomic nervous system. It is ideal for acute treatment because it has a rapid onset of action and short half-life (~1 hr in a dog) and is effective and safe. The short half-life facilitates rapid changes in serum concentrations and, therefore, titration to effect. Lidocaine is extensively metabolized by the liver; thus, hepatic disease and reduced hepatic blood flow can prolong the half-life. Hypokalemia seriously impairs the efficacy of lidocaine. Lidocaine is available only as a parenteral formulation for IV administration. It should not be infused through the same catheter or line as other medications. The typical clinical approach in dogs is to administer 2 mg/kg, IV boluses over ~1 min to effect (slowing the ventricular arrhythmia or conversion to sinus rhythm) or to a cumulative dose of 8 mg/kg over ~30 min. Given the very short half-life, repeat boluses or a CRI (25–75 mcg/kg/min) is needed to maintain rhythm control. Lidocaine is rarely indicated in cats, because clinically significant or life-threatening ventricular arrhythmias are rare in this species. The dosage in cats is 0.1–0.4 mg/kg, IV bolus over ~1 min, then increase to a total dose of 0.25–1 mg/kg, IV slowly, if no response. This can be followed by a CRI (10–20 mcg/kg/min). Lidocaine has few undesirable effects. Toxicity is manifest in dogs primarily as GI and 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 oral analogue of lidocaine used to treat ventricular arrhythmias in dogs. It is rarely used as monotherapy for ventricular arrhythmias. It is most often an adjunctive treatment in severe, chronic ventricular arrhythmias not well controlled by sotalol alone or in dogs that do not tolerate sotalol. It has fallen out of favor for treatment of people; thus, its availability is limited and cost is increasing. It should be administered at its lowest effective dose with food to limit toxicity. Common adverse effects include anorexia, vomiting, tremors, and hepatic toxicity. Hepatic enzymes should be evaluated before treatment and periodically (approximately every 6 mo) during chronic treatment as well as any time GI disturbances develop during treatment. The dosage in dogs is 4–6 mg/kg, PO, tid.
Tocainide is an analogue of lidocaine used to treat ventricular arrhythmias in dogs. Similar to mexiletine, it is rarely used as monotherapy for ventricular arrhythmias. It is most often an add-on treatment of choice for severe chronic ventricular arrhythmias not well controlled by sotalol alone, in dogs that do not tolerate sotalol, or if mexiletine is not available or cost prohibitive. It has fallen out of favor for treatment of people; thus, its availability is limited and cost is increasing. Potential adverse effects include CNS and GI disturbances (35% of dogs), hypotension, bradycardia, tachycardia, other arrhythmias, and progressive corneal edema. Because of these adverse effects, use of tocainide is limited if other efficacious agents are available. Tocainide has been used in dogs at 15–20 mg/kg, PO, tid.
Phenytoin has a limited spectrum of antiarrhythmic activity. Its primary use is in management of digitalis-induced arrhythmias, because it abolishes digitalis-induced abnormal automaticity. The recommended dosage in dogs is 30 mg/kg, PO, tid, or 10 mg/kg, IV, over 5 min.
Class IC Drugs:
Examples of drugs in this class include encainide, flecainide, and propafenone. These drugs are not typically used in veterinary medicine.
Class II Drugs
Class II antiarrhythmic drugs are the β-adrenergic receptor blocking agents. β-Blockers are classified as nonselective (block both β1 and β2 receptors) or selective (block predominantly β1 receptors). As a class, all β-blockers are dose-dependent negative inotropes and chronotropes. Although characterized as class II antiarrhythmic agents, β-adrenergic blockers are used for a variety of indications in veterinary medicine, including control of inappropriate or undesirable sinus tachycardia, treatment of ventricular and supraventricular arrhythmias, management of chronic hypertension in dogs and cats, and palliation of adverse effects of uncontrolled hyperthyroidism in cats and pheochromocytoma in dogs. They are well recognized for their cardioprotective effects in people with heart failure, leading to improved survival. Data and experience supporting this indication in veterinary medicine is lacking in dogs and cats, and the relative risks of initiation of a β-blocker in the face of heart failure should not be ignored. The earliest generation of this class was nonselective, blocking both β1 and β2 receptors (eg, propranolol). Subsequent generations became selective β1-receptor blockers in an attempt to limit the adverse effects associated with β2-receptor blockade (eg, atenolol). Third-generation β-blockers (eg, carvedilol) were developed to be more complete adrenergic blockers and are β1, β2, and α1-receptor blockers. Carvedilol may also have some important antioxidant effects that have contributed to its proven efficacy for treatment of heart failure in people.
Propranolol, the prototype, is competitive and nonselective, blocking both β1 and β2 receptors. The dosage in dogs is 0.2–1 mg/kg, PO, tid (titrate dose to effect) and in cats is 0.4–1.2 mg/kg (2.5–5 mg/cat), PO, tid. Use of propranolol should be avoided in dogs and cats with evidence of primary respiratory disease (eg, asthma).
Atenolol is a β1-selective blocking agent and is the most commonly used β-blocker in veterinary medicine. Because it is β1-selective, it has less potential to cause or contribute to bronchospasm in predisposed dogs and cats, although the β1-selectivity is likely limited or absent at high doses. The dosage in dogs is 0.2–1 mg/kg, PO, bid, and in cats 1–2.5 mg/kg, PO, bid, or 6.25–12.5 mg/cat, PO, bid. Some references suggest cats can be dosed every 24 hr, but most cardiologists believe that continuous β-blockade (the clinical target) is not possible with daily dosing. In both dogs and cats, titrating up gradually is required, especially if atenolol is initiated in the face of active or stable CHF or in DCM. In general, dogs and cats without CHF and normal systolic function can tolerate higher initial and target dosages. Abrupt discontinuation should be avoided; if cessation is indicated, titrating down gradually is recommended. If CHF develops in an animal receiving atenolol, the dosage may need to be reduced and the drug eventually discontinued, but unless the CHF is life-threatening, abrupt cessation should still be avoided. Potential adverse effects are dose related and more likely if underlying systolic function is present. Adverse effects include myocardial depression, bradycardia (sinus and AV block), and hypotension.
Carvedilol is a third-generation β-blocker that has a more complete adrenergic blocking spectrum. Carvedilol blocks β1, β2, and α1 receptors and has some ancillary antioxidant effects. It is routinely used in treatment of heart failure in people. Its oral bioavailability is highly variable in dogs. Carvedilol has been mainly evaluated in veterinary medicine for its potential survival benefits in canine DCM and cardiovascular disease with and without CHF, but experience to date is limited and thus it is not routinely used for this indication. If β-blockers are used for this indication, the general rule of thumb is to never initiate in the face of active heart failure (pulmonary edema), start low (initial dose), go slow (and titrate up), and aim high (target dose tolerated). The initial dosage in dogs is 0.15–0.25 mg/kg, PO, bid, titrated up by increasing the dose ~25% every 2 wk while monitoring for clinical signs suggestive of decompensation. The target dosage is 1 mg/kg, PO, every 2 hr (if tolerated). Higher target doses may be tolerated in dogs concurrently receiving pimobendan and in dogs with cardiovascular disease (vs those with DCM).
Class III Drugs
The predominant electrophysiologic effect of class III drugs is potassium channel blockade leading to prolongation of the cardiac action potential and its refractory period. The two drugs in this class commonly used in veterinary medicine are sotalol and amiodarone.
Sotalol is an oral class III drug with nonselective β-blocking activity. Sotalol is the most commonly used longterm treatment for hemodynamically significant ventricular arrhythmias in dogs and cats. It is often used as monotherapy for this indication but can be combined with mexiletine if rhythm control is suboptimal with sotalol alone. It has some efficacy in treatment of atrial fibrillation (rate control), but it is not as efficacious as other agents and is not commonly used for this indication. Sotalol is safe and well tolerated and is often used in combination with other drugs commonly used to treat heart disease and heart failure, including ACE inhibitors, furosemide, spironolactone, and pimobendan. Because it has β-blocking effects, it should not be combined with other β-blockers (eg, atenolol) or other negative inotropes (eg, diltiazem). In addition, it should not be combined with another class III agent (eg, amiodarone). The dosage in dogs and cats is 1–2.5 mg/kg, PO, bid. It should be used with caution and at the lower end of the dosage range in patients with CHF or DCM or when combined with mexiletine. In this situation, titrating up (dosage increases every 10–14 days) to a higher target dose may be attempted if lower doses are not efficacious. Dogs and cats with normal systolic function can tolerate higher initial and target doses. Possible adverse effects include negative inotropy, bradyarrhythmia (sinus and AV block), and proarrhythmia.
Amiodarone is a class III drug with a variety of other properties. Its predominant electrophysiologic effect is to prolong the refractory period of atrial and ventricular myocardium and the AV junction. In addition, it has class I effects (sodium channel–blocking properties), some class II effects (β- and α-receptor blockade), and some class IV effects (calcium channel blockade). Amiodarone is used to treat life-threatening ventricular arrhythmias (rhythm control) and atrial fibrillation (rate control) in dogs refractory to other, more common treatments. In some cases, it is used because of its effectiveness in treatment of both ventricular and supraventricular arrhythmias. It is rarely used as a first-line drug.
Amiodarone has unusual pharmacokinetics. After repeated administration in dogs, it has a long half-life of 3.2 days, with myocardial concentrations reaching 15 times that of plasma. The long half-life suggests a long time is needed to produce a significant effect once treatment is initiated as well as for effects to end if treatment is discontinued. However, some clinical effect appears to occur within hours of PO administration, especially if a higher loading dose is used, which is likely a consequence of the large and variable number of metabolites.
Amiodarone is often used in combination with other drugs commonly used to treat heart disease and heart failure, including ACE inhibitors, furosemide, spironolactone, and pimobendan. Because it has β-blocking effects it should not be combined with other β-blockers (eg, atenolol) or other negative inotropes (eg, diltiazem). In addition, it should not be combined with another class III agent (eg, sotalol). Amiodarone has a number of known common adverse effects that limit its longterm (>6 mo) use clinically. Adverse effects seem to be related to dose and duration of treatment and include significant increases in liver enzymes, GI signs, thyroid dysfunction, blood dyscrasias (neutropenia), and proarrhythmia. The liver effects seem to be the most common adverse effect encountered clinically and are typically reversible after cessation of therapy. The oral dosage in dogs is 8–10 mg/kg, PO, once to twice daily for 7–10 days, and then decreased to 4–6 mg/kg/day for longterm treatment; the parenteral dosage in dogs is 2–5 mg/kg, IV, infused over 30–60 min. Formulations preserved with polysorbate 80 should not be used IV because of risk of anaphylactoid reaction and angioedema.
Class IV Drugs
The predominant electrophysiologic effect of class IV antiarrhythmic drugs is blockade of the slow calcium channels in cardiac cells and vascular smooth muscle. The two drugs in this class commonly used in veterinary medicine are diltiazem and amlodipine. The relative affinity of a drug in this class for cardiac versus vascular tissue determines its predominant effect. Amlodipine (see above) is most active in vascular smooth muscle, where it causes vasodilation and is thus considered to be a vasodilator. Diltiazem is most active in cardiac cells.
Diltiazem blocks entry of calcium into cardiomyocytes during the action potential, leading to a dose-dependent reduction in calcium release from the sarcoplasmic reticulum, limiting the availability of calcium to the contractile apparatus, and resulting in negative inotropy and positive lusitropy. It also blocks calcium channels in the specialized conduction tissue in the heart, on which automaticity of intrinsic pacemaker cells and AV conduction depend for normal function. Blockade of these calcium channels can therefore slow heart rate and AV conduction. Diltiazem is therefore typically indicated for treatment of atrial fibrillation (rate control) and other supraventricular arrhythmias in dogs and cats. Another historical indication is for treatment of feline hypertrophic cardiomyopathy. However, limited practicality in combination with its unconfirmed efficacy for feline hypertrophic cardiomyopathy has caused diltiazem to fall into disfavor for this indication. Diltiazem has no effect on ventricular arrhythmias.
The dosage in dogs is 0.05–0.2 mg/kg, IV, over 5 min, which can be repeated to a cumulative dose of 0.3 mg/kg, after which the dog should be reassessed or an oral formulation initiated. In dogs, the dosage of the standard oral formulation is 0.5–2 mg/kg, PO, tid, and of the sustained-release formulation 1–4 mg/kg, PO, bid. In cats, the dosage of the standard oral formulation is 7.5 mg/cat, PO, tid, and of the sustained-release formulation 30–60 mg/cat, PO, once to twice daily. Initial doses should be at the lower end of the dose range and titrated up to a clinically effective dose. Blood pressure and heart rate and rhythm should be monitored during IV administration. Dogs and cats without CHF and with normal systolic function can tolerate higher initial and target dosages. The sustained-release formulation cannot be made into suspensions but can be reformulated into lower-dose capsules.
Possible adverse effects include systemic hypotension, negative inotropy and bradycardia (sinus or AV block), and exacerbation of CHF. GI signs are the common noncardiac adverse effect and are more common in cats, especially with sustained-release preparations. Diltiazem is often used in combination with other drugs commonly used to treat heart disease and heart failure, including ACE inhibitors, furosemide, spironolactone, and pimobendan. Because diltiazem is a negative inotrope and chronotrope, it should not be administered concurrently with a β-blocker.
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.