Antiarrhythmic Agents

Chapter 190 Antiarrhythmic Agents



Kathy N. Wright, DVM, DACVIM (Cardiology)



KEY POINTS



• Antiarrhythmic agents are useful for managing various tachyarrhythmias, but the clinician must have knowledge of the patient, the arrhythmia, and the indications for and side effects of each medication.

• Drugs that prolong atrioventricular (AV) nodal refractoriness are useful for AV node–dependent and atrial arrhythmias, whereas drugs that prolong myocardial refractoriness are used in atrial, accessory pathway, and ventricular tachyarrhythmias.

• Most antiarrhythmic agents have multiple channel effects, not simply those of their Vaughan-Williams class. This must be considered in predicting their potential beneficial and adverse effects.

• Disappointing results in the ability of antiarrhythmic agents to prevent sudden death have emerged from several large-scale human studies, and this goal now largely falls into the realm of device or catheter-based therapy. Antiarrhythmic agents can be useful in limiting clinical signs related to tachyarrhythmias, thus potentially preventing euthanasia of veterinary patients.


INTRODUCTION


Antiarrhythmic agents have undergone critical reevaluation during the past 10 to 15 years with the publication of large-scale human studies that brought to light some of the risks and shortcomings of drug therapy for arrhythmias.1,2 Once more cavalier in their use of these agents, veterinarians and physicians alike are having to analyze carefully the potential benefits and risks (including proarrhythmic effects) in each patient. Basically, there are two reasons to treat arrhythmias: (1) to alleviate significant clinical signs such as weakness, syncope, or precipitation or exacerbation of congestive heart failure by an arrhythmia, and (2) prolonging survival. Antiarrhythmic drugs, in general, have not been shown to do the latter; this predominantly falls into the realm of antiarrhythmic devices. Drugs can be very useful, however, in alleviating clinical signs in an individual patient.



CLASSIFICATION SCHEMES


No completely satisfactory or intuitive classification scheme for antiarrhythmic agents has been developed. The most commonly used is the Vaughan-Williams classification system, which attempts to group drugs according to their major ion channel or receptor effects. The limitations of this system have been well documented, including the fact that most antiarrhythmic drugs act on multiple channels or receptors, and one must know that when predicting their beneficial and adverse effects. The actions of antiarrhythmic drugs are actually very complex and vary according to species (important to veterinarians because much of the data are from humans), age, tissue drug concentration, acid-base and electrolyte balance, presence or absence of myocardial damage, and indirect hemodynamic or autonomic actions.3


In spite of its shortcomings, the Vaughan-Williams system remains the most widely used to date. An attempt to improve on this system led electrophysiologists to develop the Sicilian Gambit in 1991.4 This approach attempted to identify the vulnerable parameter for various arrhythmias and did account for the multiple channel and receptor actions of each antiarrhythmic agent, but was too unwieldy for widespread general use.


Grouping antiarrhythmic agents into their main uses (i.e., supraventricular arrhythmias, ventricular arrhythmias) would seem logical (Box 190-1), but many agents are used for multiple arrhythmias, hence overlap would be inevitable. Despite its inherent limitations, the Vaughan-Williams classification is used as the framework for this chapter. Agents that are commonly used in small animal cardiology are discussed.



Box 190-1 Antiarrhythmic Agent General Uses



Drugs Used to Manage Ventricular Tachyarrhythmias



Class Ia: procainamide, quinidine

Class Ib: lidocaine, mexiletine

Class Ic: flecainide, propafenone

Class II: β-blockers: atenolol, propranolol

Class III: d,l-sotalol, amiodarone


Drugs Used to Manage Supraventricular Tachyarrhythmias



Drugs Used to Slow Atrioventricular Nodal Conduction



Class II: β-blockers: atenolol, propranolol

Class IV: calcium channel blockers

Other: digoxin


Drugs to Inhibit Intramyocardial Conduction or Prolong Myocardial Repolarization



Class Ia: procainamide

Class Ic: flecainide, propafenone

Class III: d,l-sotalol, amiodarone


CLASS I ANTIARRHYTHMIC AGENTS


Class I agents act primarily by inhibiting the fast sodium channel and decreasing the slope of phase 0 of the action potential. The relative potency of their sodium channel effects, whether blockade of the activated or inactivated channel occurs, and their effects on other channels and receptors determine their subclassification.



Class Ia Antiarrhythmic Agents


Class Ia agents have powerful, fast sodium channel–blocking effects and also exhibit moderate blockade of the rapid component of the delayed rectifier potassium current (IKr). This IKr blockade results in action potential prolongation and can account for the proarrhythmic effects associated with these drugs in some genetically predisposed individuals.5 In addition, potent depression of conduction velocity can predispose to the reentrant phenomenon. Quinidine, procainamide, and disopyramide are class Ia drugs.


Procainamide is the prototypical agent of this class used in small animal cardiology. It depresses conduction velocity and prolongs the effective refractory period in a wide variety of tissues, including the atrial and ventricular myocardium, accessory atrioventricular (AV) pathways, and retrograde fast AV nodal pathways.5 Procainamide can thus be effective in a wide variety of arrhythmias, either as a single agent or combined with other agents. It can be administered parenterally for acute termination of severe ventricular or supraventricular tachyarrhythmias. It must be administered slowly intravenously (over 5 to 10 minutes) to prevent hypotension.


Agents that prolong AV nodal conduction time are given first for acute treatment of atrial tachyarrhythmias, because procainamide can enhance AV nodal conduction, thus worsening the ventricular response rate. Procainamide is more effective than lidocaine for acutely terminating these rhythms in human patients.6 Parenteral procainamide is administered in doses of 6 to 8 mg/kg IV over 5 to 10 minutes or 6 to 20 mg/kg IM in dogs. A constant rate infusion (CRI) of 20 to 40 μg/kg/min can be used once a therapeutic response is obtained with bolus administration. Parenteral procainamide in cats is used cautiously at dosages of 1 to 2 mg/kg IV or 3 to 8 mg/kg IM and a CRI of 10 to 20 μg/kg/min.


Adverse effects commonly are associated with procainamide but appear to be more frequent in humans and cats than in dogs. Gastrointestinal side effects such as anorexia, nausea, and vomiting are seen most commonly in dogs. Side effects reported in humans soon after procainamide is instituted include rash and fever. Later side effects include arthralgia, myalgia, and agranulocytosis. The development of systemic lupus erythematosus is identified rarely in veterinary patients, but is reported in one third of human patents who take procainamide for longer than 6 months.7 A four-way trial of antiarrhythmic drugs in Boxer dogs with ventricular tachyarrhythmias showed that procainamide administered at 20 to 26 mg/kg PO q8h. reduced the frequency of ventricular ectopy but did not alter the frequency of syncope.8



Class Ib Antiarrhythmic Agents


Class Ib antiarrhythmic agents inhibit the fast sodium channel, primarily in the open state with rapid onset-offset kinetics. The window sodium current is also inhibited, resulting in shortening of action potential duration in normal myocardial tissue. Their rapid kinetics explain why class Ib agents have minimal effects on the shorter atrial action potential. The ability of lidocaine and its congeners to block INa is enhanced in the presence of acidosis, increased extracellular potassium concentrations, and partially depolarized cells. Thus these drugs selectively suppress automaticity and slow conduction velocity in ischemic and diseased ventricular myocardium.


Lidocaine is an intravenous antiarrhythmic agent and is typically the first drug used in the acute treatment of serious ventricular tachyarrhythmias in dogs. It has the benefit of minimal hemodynamic, sinoatrial, and AV nodal effects at standard dosages. A bolus dose of 2 to 4 mg/kg is administered IV over 2 minutes. The bolus can be repeated to a maximum of 8 mg/kg within a 10-minute period, provided adverse effects do not occur. If successful in converting the ventricular tachycardia to sinus rhythm, a lidocaine bolus can be followed by a CRI of 25 to 75 μg/kg/min.


Hepatic clearance of lidocaine determines its serum concentration, and this is directly related to hepatic blood flow. Heart failure, hypotension, and severe hepatic disease can therefore result in decreased lidocaine metabolism and predispose the patient to lidocaine toxicity. The incidence of side effects in cats is much higher, with earlier reports of bradyarrhythmias and sudden death; for this reason, caution is recommended. Lower dosages of 0.25 to 0.75 mg/kg are administered slowly IV, followed by infusion rates of 10 to 20 μg/kg/min.


The most common adverse effects of lidocaine include nausea, vomiting, lethargy, tremors, and seizure activity. These typically resolve quickly with cessation of the infusion. Diazepam may be administered to treat lidocaine-induced seizures.


Mexiletine is the most commonly used oral class Ib agent in dogs. It is highly protein bound and eliminated by renal excretion. Its use and side effect profile mirror those of lidocaine. It has been used in dogs in which ventricular tachyarrhythmias are acutely responsive to lidocaine and can be combined with class Ia, II, or III agents. Typical dosing in dogs is 4 to 8 mg/kg PO q8h. There are no data on its use in cats. Tocainide, another lidocaine congener, rarely is used in small animals because of the high incidence of serious side effects, including renal failure and corneal dystrophy.9,10

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Antiarrhythmic Agents

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