Antiarrhythmics

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 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).

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.

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.