Antiarrhythmic drugs. Treatment of cardiac arrhythmias.

Efficacy of Cardiac Therapy

0195-5616/91 $0.00

+ .20

Antiarrhythmic Drugs Treatment of Cardiac Arrhythmias

William W . Muir, III, DVM, PhD , ACVA, ACVECC*

The diagnosis, treatment, and long-term management of cardiac arrhythmias have excited, entertained, and confused veterinary cardiologists and veterinarians in private practice for a very long time . There is no question that a great deal of the confusion surrounding the treatment of cardiac arrhythmias stems from the veterinary clinician's inability to make an accurate diagnosis and from an incomplete or inaccurate knowledge of the pharmacodynamic and pharmacokinetic properties of the drugs used to treat cardiac arrhythmias. Cardiac arrhythmias can be modified or eliminated by a varie ty of clinical maneuvers and che mical substances. Since the purpose of this article is to discuss antiarrhythmic drugs, only those chemical substances that have demonstrated antiarrhythmic efficacy are discussed. An ever-increasing number of drugs, however, are accumulating that are known to produce antiarrhythmic effects. Some of these drugs find their only clinical use as antiarrhythmics, whereas others may possess or have as their principal mechanism of action some unrelated effect. Dopamine (and other catecholamines), for example, is primarily used to increase cardiac output and blood flow to peripheral tissues, particularly the splanchnic and renal beds, but is very effective in treating a variety of bradyarrhythmias and can eliminate ventricular arrhythmias by producing sinus tachycardia (overdrive suppression) in some patients. Ironically, dopamine is also capable of producing both supraventricular and ventricular arrhythmias when administered in large doses or in the presence of other drugs that sensitize the myocardium to arrhythmias (thiobarbiturates, halothane). The following discussion focuses on those drugs that have been specifically developed for the treatment of cardiac arrhythmias. A brief overview of the principal mechanisms responsible for the development of cardiac arrhythmias is also included since it has been the goal of pharmacologists and clinical cardiologists to develop drugs and prescribe specific antiarrhythmic *Chairman, Vete rinary Clinical Scie nces, The Ohio State Unive rsity College of Veterinary Medicine , Columbus, Ohio Veterinary Clinics of North America: Small Animal Practice-Vol. 21, No. 5, September 1991

957

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WILLIAM W . MUIR

Ill

therapy based on a knowledge of these mechanisms with the assumption, if not the belief, that specific antiarrhythmic therapy will be the most efficacious in restoring and maintaining normal sinus rhythm. MECHANISMS FOR CARDIAC ARRHYTHMIAS There are many reasons for the development of cardiac arrhythmias (Table 1). Regardless of cause, the genesis of all cardiac arrhythmias can be attributed to a derangement in the electrophysiologic processes responsible for impulse initiation (automaticity) or conduction. Although relatively sophisticated, experimental techniques involving microelectrode, voltage clamp, and ion replacement have been used to decipher the cellular mechanisms responsible for cardiac arrhythmias, a fundamental appreciation of arrhythmiagenesis can be gained from a knowledge of the ionic fluxes responsible for cardiac electrical activity. Cardiac cells maintain a negative intracellular potential based on the transmembrane distribution of various dominant ions (Na+, K+ , Cl- , Ca2 +) and the concentration, voltage, and time-dependent changes in membrane permeability to these ions. The intracellular resting membrane potential (RMP) of most cardiac cells is very close to the potassium equilibrium potential (the membrane potential that exactly counteracts the tendency for potassium to travel down its concentration gradient and leave the cell). 1• 22 The reason for this is that the permeability of cardiac cells to potassium is relatively high compared with that of other ions. Rapid changes in the RMP (action potential) are produced because of sequential changes in the conductance (permeability) of the cardiac cell membrane to the various dominant ions (Fig. 1). The ionic currents responsible for generating cardiac action potentials are not the same in all cardiac tissues. Atrial, ventricular, and Purkinje fibers produce action potentials that are similar in configuration because of similar RMP values and dependence on similar ionic currents. Action potentials generated in the sinoatrial and atrioventricular nodes, however, originate from much lower (less negative) RMP values and vary quantitatively in their dependence on the same ionic currents. The se quantitative differences Table 1. Mechanisms for Arrhythmias Ill. SIMULTANEOUS ABNORMALITIES OF I. ABNORMAL IMPULSE GENERATION

Normal automatic mechanism Sinus tachycardia Sinus bradycardia Abnormal automatic mechanism Subsidiary pacemakers Drug-induced pacemakers Triggered activity Early afterdepolarization Delayed afterd epolarization

II. ABNORMAL IMPULSE

IM PULSE GENERATION

CON D UCTION

AND CON D UCTION

Slowing and block {S-A block, A-V block) Unidirectional block and reentry Macro reentry Micro reentry Conduction block, electrotonic transmission and re flection

Parasystole Slow conduction because of phase 4 depolarization

Adapted from Rosen RM , Hoffman BF: Mechanisms of action of antiarrhythmic drugs. Circ Res 32:1, 1973; by permission of the American Heart Association, Inc.

959

ANTIARRHYTHMIC DRUGS

Musc1e Cells (atria, ventricles)

Pacemaker Cells (SA,AV nodes)

Na+ ca2+ (2)

ca2+ K+

-K+ (3) -90 mV

(4)

Cardiac Contractility

QT interval Refractoriness

Automaticity (rate)

Figure l. An illustration of the cardiac action potentials from various cardiac tissues and the ions responsible for their generation. The relationship between the cardiac action potential and the surface ECG is illustrated (lower left). The various phases of the action potential are used to assess conduction velocity, cardiac contractility, and refractoriness (QT interval). The phases of the action potential are numbered for clarity (0, l , 2, 3, 4).

result in significant configurational differences in action potential characteristics and have important pharmacologic implications (see Fig. 1). Most cardiac cells maintain a relatively stable RMP (- 90 to -80 m V) until activated by an electrical, mechanical, or pharmacologic stimulus. Once the threshold for activation is reached, an action potential is generated, which results in rapid depolarization of the cardiac cell. The initial rapid phase of depolarization is due to the rapid entry of sodium ions into the cell, which is caused by a dramatic increase in membrane conductance (permeability) to sodium ion once the threshold potential is reached. This initial depolarizing phase is frequently referred to as phase 0 and is produced by an inward fast sodium current passing through the fast sodium channel (see Fig. 1). The membrane potential is carried toward the sodium equilibrium potential ( +50 m V) but never attains this value because of inactivation of sodium channels and activation of repolarizing currents. Cardiac cells, unlike nerve and skeletal muscle cells, do not immediately repolarize but exhibit action potentials from 50 to several hundred milliseconds duration, depending on the intrinsic rate of excitation and the specific cardiac tissue being excited (atrial, ventricular, Purkinje tissue). The duration of depolarization is prolonged, plateau phase (phase 2), because of activation of a second depolarizing (inward) current carried by calcium ion through the slow calcium channel (Fig. 1). The calcium channel permits calcium and some sodium to enter the cell, thereby maintaining depolarization until the calcium current begins to deactivate and repolarizing currents carried primarily by potassium (leaving the cell; outward current) cause the membrane potential to return to the resting potential. Once the RMP is restored, the conductance of the membrane to the various ions involved

960

WILLIAM W. MuiR III

returns to normal (reactivated) and the small quantity of sodium, calcium, and potassium that have been translocated are returned to their original location by the cell membrane sodium-potassium, adenosine triphosphate (ATP)-dependent, and calcium (pumps calcium out) pumps. It is worth repeating that the sinoatrial and the atrioventricular nodes normally have much less negative diastolic or resting membrane potentials than atrial, ventricular, and Purkinje tissues. The reduction in the diastolic potential inactivates the fast sodium current, making these tissues much more dependent on the slow inward (calcium) current for their depolarization. One of the most unique and important properties of the heart is its inherent rhythmicity (automaticity). Cells in and around the sinoatrial node and atrioventricular node and within the Purkinje network are all capable of being self-excitatory. The process of automaticity is brought about by a time-dependent decrease in membrane conductance to potassium ion and the presence of a background inward current carried primarily by sodium or calcium ion, depending on the membrane potential at the time of activation (see Fig. 1). Tissues with less negative membrane potentials, for example, are more dependent on the background calcium current for excitation than sodium. Purkinje cells, which normally demonstrate markedly negative diastolic potentials, are more dependent on the background sodium current for their activation. These differences have important physiologic and pharmacologic implications since a decrease in the timedependent potassium current alone will not result in spontaneous depolarization. Spontaneous depolarization is also referred to as spontaneous phase 4 depolarization or "pacemaker current" and normally occurs at the fastest rate in the sinoatrial node. The sinoatrial node, therefore, serves as the pacemaker for the electrical activation of the heart and triggers the development of the body surface P-QRS-T complex. Changes in autonomic tone (sympathetic, parasympathetic) and disease can result in tissues other than the sinoatrial node assuming pacemaker responsibility. Subsidiary pacemakers such as the tissues in and around the atrioventricular node and the Purkinje fibers frequently assume pacemaker responsibility when the sinoatrial node is depressed or when their rates of phase 4 diastolic depolarization are enhanced by increases in sympathetic tone, drugs, or disease processes that enhance normal automatic mechanisms or result in the development of abnormal automatic mechanisms (Table 2). Abnormal automatic mechanisms are most frequently caused by a decrease in the maximum diastolic potential of subsidiary pacemakers. The decrease in membrane potential of cardiac cells required for abnormal automaticity to occur may be caused by a variety of factors related to cardiac disease, most notably inflammatory processes, hypoxia, and ischemia. Notably and unlike normal automaticity, abnormal automaticity is difficult to overdrive suppress. Therefore, transient or prolonged pauses in normal automaticity permit the abnormal automatic mechanism to capture the heart rhythm for one or more impulses. A unique form of abnormal automaticity termed triggered automaticity occurs as a direct result of prior electrical activity. Triggered automaticity is caused by one or multiple depolarizations that occur during the repolarization process (early afterdepolarizations, EAD) or after full repolarization (delayed afterdepolarizations,

Table 2. Drugs that Induce Arrhythmias DRUGS

ARRHYTHMIA

Digitalis

Atrial and ventricular

Inhalation anesthetics (halothane, methoxyflurane)

Ventricular

Thiobarbiturates (thiamylal, thiopental) Narcotics (fentanyl-droperidol, morphine)

Ventricular

Catecholamines (epinephrine, dopamine, dobutamine) Bronchodilators (aminophylline, terbutaline)

First-, second-, and third-degree A-V block Atrial and ventricular

Atrial and ventricular

*Drugs are given in order of preference.

~

Q)

MECHANISM

Abnormal automaticity Delayed conduction Sensitization to catecholamines

Sensitization to catecholamines Delayed conduction Increased parasympathetic tone; decreased normal automaticity Increased normal and abnormal automaticity Increased normal and abnormal automaticity

THERAPY*

Lidocaine Phenytoin Lidocaine Esmolol Propranolol Lidocaine

REMARKS

Withdraw or reduce digitalis therapy temporarily Change to an alternative anesthetic if possible Generally self-limiting

Glycopyrrolate

Therapy usually produces temporary tachycardia

Lidocaine Esmolol Propranolol Lidocaine Propranolol

Self-limiting; reduce or withdraw therapy Reduce therapy

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WILLIAM W.

MuiR III

DAD; or transient depolarizations, TO). Both EAD and DAD can induce one or more triggered impulses. EADs usually occur during the terminal portion of the plateau phase (phase 2) or early portion of repolarization (phase 3) and are therefore believed to be primarily dependent on the inward movement of calcium ion for their initiation. DAD, on the other hand, occur after complete repolarization and are most likely carried by sodium ion and perhaps some calcium ion. Both EAD and DAD have been experimentally produced in atrial, ventricular, mitral valve, and Purkinje fibers. 1 Abnormalities in conduction of the cardiac impulse can result in the development of cardiac arrhythmias. Clinically this can be most easily appreciated and recognized during the development of first-, second-, or third-degree atrioventricular block. Many cardiac disease processes, however, can cause delays in impulse propagation or a decrease in RMP, resulting in a decrease in the conduction of propagated impulses and unidirectional block, which are the substrate for reentry (Fig 2). Unidirectional block enables an excitable pathway to persist through which a retrograde impulse can return to reexcite regions that have already been excited. The wavelength of the reentrant impulse must be shorter than the length of the circuit so that the tissue into which the impulse is reentering has had time to recover excitability. Reentry can be promoted by slowing conduction velocity, shortening the refractory period, or a combination of both. It is clear that the relationship between the conduction path, conduction velocity, and tissue refractory period is crucial. Reentrant excitation of cardiac tissue has been demonstrated to occur both in vitro and in vivo. 1• 22

A

B Figure 2. Mechanisms for reentry. A, Unidirectional block and retrograde conduction. B, Slow orthograde conduction and unidirectional retrograde block.


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CLINICAL CLASSIFICATION OF CARDIAC ARRHYTHMIAS: WHY TREAT CARDIAC ARRHYTHMIAS? The ability to interpret the electrocardiogram, particularly cardiac rate and rhythm disorders, is crucial to knowing when and what drug to use to treat cardiac arrhythmias. Very simply, cardiac rate and rhythm abnormalities can be assessed based on alterations in heart rate, the frequency of occurrence of the abnormal event, the site of origin or location of the abnormal event, and the timing of the event relative to the normal sinus originated P-QRS-T complex (Table 3). Abnormalities in hear( rate or rhythm must be interpreted relative to the known hemodynamic and electrical changes that accompany them. 21 A very slow ventricular rate can result in a low cardiac output (cardiac output = stroke volume X heart rate) and marked reduction in arterial blood pressure. Similarly, an extremely rapid heart rate may reduce cardiac output by not allowing adequate time for ventricular filling and producing marked increases in myocardial oxygen consumption, which could predispose to myocardial hypoxia and failure . Furthermore, both slow and rapid heart rates predispose the heart to electrical instability by altering cellular membrane conductance to the various ions, changing the conduction velocity of cardiac impulses, producing electrical differences (inhomogeneity) in adjacent cells, and altering the activity of the sodium-potassium and other membrane pumps. The frequency of the abnormal electrical events can have important clinical consequences. Whether the heart is normally or abnormally activated, all disturbances in cardiac rate or rhythm that result in ventricular rates that are excessively rapid or slow should be treated. The occurrence of a single premature atrial depolarization is unlikely to produce significant hemodynamic or electrical consequences, but the development of very rapid ventricular tachycardia that persists for a prolonged period could result in deterioration of hemodynamics and predispose the patient to ventricular fibrillation. Generally, abnormal electrical impulses that occur as single events and at a rate of fewer than 20 to 30 times each minute are not treated . Clinical cardiologists have developed several methods of categorizing the frequency of abnormal electrical events, primarily for Table 3. Clinical Evaluation of Rate and Rhythm Disorders Frequency or rate Sinus tachycardia or bradycardia Atrial or ventricular tachycardia or bradycardia Accelerating atrial or ventricular rhythms Origin or location Sinus Atrioventricular nodal Specialized conduction system Right or left atrial Right or le ft ventricular Timing Late (escape) Early (extra systole) R on T phenomena

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WILLIAM W.

MuiR III

descriptive purposes but also to imply their significance. 9 A paroxysm, for example, implies the sudden onset of abnormal electrical activity that may last for several seconds to many hours. The terms nonsustained (lasting for fewer than 20 to 30 seconds) and sustained (lasting for longer than 30 seconds) have been added to help clarify the term. A nonsustained ventricular tachycardia, for example, implies the development of ventricular depolarizations that assume the cardiac rhythm and last for a period of no longer than 30 seconds. Changes in rate during the period of abnormal electrical event can have important hemodynamic and electrical consequences similar to those described for the slow and rapid heart rates described earlier. 21 An accelerating nonsustained ventricular tachycardia is a brief (fewer than 30 seconds) period of ventricular depolarizations during which the ventricular rate is increasing. This type of arrhythmia is known to produce more hemodynamic and electrical instability than a relatively slow ventricular tachycardia. The site of origination or location of the abnormal electrical event has important consequences regarding both the hemodynamic an~ the electrical stability of the heart. Single premature supraventricular or junctional depolarizations are unlikely to produce significant hemodynamic or electrical consequences. Even atrial fibrillation does not produce significant changes in hemodynamics in the resting animal, provided that ventricular rate does not become excessively rapid. Impulses originating in the ventricles, on the other hand, may result in markedly abnormal patterns of ventricular activation with resultant reductions in stroke volume. Impulses originating from the right ventricle, particularly the right ventricular outflow tract, frequently produce prolonged and bizarre patterns of ventricular activation that are associated with a marked reduction in stroke volume. 21 Impulses originating in the left ventricle may produce similar hemodynamic effects but may also result in relatively normal hemodynamics. Impulses originating from several locations (multifocal) within the atria or ventricles are more likely to produce poor hemodynamics and a greater degree of electrical instability than unifocal events. Multifocal ventricular tachycardia, for example, is usually associated with poor ventricular function and is more likely to result in electrically unstable cardiac rhythms. The clinical development and use of echocardiography and other noninvasive methods for assessing hemodynamics (indirect blood pressure measurement) have helped differentiate those patients with relatively poor from patients with adequate ventricular function. The timing of the abnormal electrical event relative to the normal PQRS-T complex has important consequences relative to both hemodynamics and electrical stability of the heart. Generally the more premature the event, whether supraventricular or ventricular, the less effective the subsequent ventricular contraction. Those events that are late (occur after the next anticipated P-QRS-T complex) are more likely to result in an adequate stroke volume and peripheral pulse, provided that the site or origin of the impulse is not too abnormal. Premature ventricular depolarizations that occur in the preceding T wave of normal (sinus originating) or abnormal electrical events (R on T phenomena) are considered extremely dangerous since there is a high correlation between their occurrence and

965


the development of a deterioration of ventricular rhythm and ventricular fibrillation (Table 3). 21 Based on this discussion, it should be clear that heart rate, frequency of the abnormal event, site of origin of the abnormal event, and timing of the abnormal event relative to the preceding depolarization are all important when considering whether or not to implement therapy. Clinically, cardiac arrhythmias that do not produce significant changes in hemodynamics or that do not lead to electrical instability are considered benign, whereas those that result in poor hemodynamics are considered potentially ·lethal or lethal (Table 4). Cardiac arrhythmias that lead to a deterioration of cardiac electrical or mechanical activity are considered malignant and lethal. An accelerating multifocal sustained ventricular tachycardia would be expected to be hemodynamically disruptive and malignant and therefore to require immediate therapy. These same criteria are also important in determining which drug to use to treat rate or rhythm abnormalities. Digitalis glycosides and beta-adrenoceptor-blocking drugs, for example, are very effective in controlling ventricular rate, while drugs like quinidine, procainamide, and lidocaine are more effective in reducing the frequency of or abolishing abnormal impulses. Quinidine and digitalis and more recently drugs like verapamil (class 4 antiarrhythmic) are very effective in the treatment of supraventricular arrhythmias. Drugs like bretylium and amiodarone are more effective in treating ventricular than supraventricular arrhythmias and may have their best use in the prevention of ventricular fibrillation (Tables 5-7). Other considerations that are related to the pharmacologic profile of the various drugs used to treat cardiac arrhythmias must be considered when selecting antiarrhythmic drug therapy and are discussed next. Table 4. Significance of Cardiac Arrhythmias CLINICAL CONCERN

BENIGN

POTENTIALLY LETHAL

LETHAL

Risk of sudden death

Minimal

Moderate

High

Heart disease

None or minimal

Cardiac function usually reduced

Cardiac dysfunction or failure present

Type

Most atrial arrhythmias Occasional extrasystoles (< 30/min) Nonsustained ventricular tachycardia

Freque nt ventricular extrasystoles (< 30/min) Ventricular couplets or paroxyms Non sustained ventricular tachycardia

Sustained ventricular tachycardia (monomorphic or polymorphic); torsades de pointes; hemodynamic symptoms with NSVT*

Hemodynamic consequence

None

None

Present

Treatment

Eliminate symptoms: occasionally antiarrhyth mic drugs

Eliminate symptoms if present; prevent sudden death

Eliminate hemodynamic symptoms; prevent sudden death

*Nonsustaine d ventricular tachycardia.

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WILLIAM W. MUIR

III

CLASSIFICATION OF ANTIARRHYTHMIC DRUGS Of the many drugs used to treat cardiac arrhythmias, many can be categorized based on their principal pharmacologic effect (e. g., local anesthetic, beta-adrenoceptor blockade) or chemical structure (e.g., catecholamine, dihydropyridine). 6 · 7• 9 · 25 Clinical cardiologists and cardiac electrophysiologists have attempted to categorize the many drugs used to treat cardiac arrhythmias based on their clinical efficacy or cellular electrophysiologic properties, respectively. 9· 25 The latter scheme, the categorization of antiarrhythmic drugs based on their cellular electrophysiologic properties, was developed in an attempt to be able to prescribe the one best drug or group of drugs for the treatment of a specific arrhythmia. This latter scheme also presumed that all the electrophysiologic mechanisms for cardiac arrhythmias could be traced to an abnormality in the transmembrane flux of one or more of the major ions involved in the generation of the cardiac action potential (active properties) and that antiarrhythmic drugs produced specific enough effects to be relatively selective in their actions. Most schemes that have characterized antiarrhythmic drugs based on their active properties contain four categories (Table 5). Class 1 antiarrhythmic drugs are generally referred to as membrane stabilizers and are believed to produce the majority of their antiarrhythmic effects by blocking the rapid sodium channel, although secondary effects on both calcium and potassium currents are common (see Fig. 4). Because of these secondary effects and the wide disparity of action on action potential configuration automaticity, conduction velocity, and the body surface electrocardiogram, this group has been further subdivided into three subclasses (Table 5). Class lA drugs, of which both quinidine and procainamide are members, depress normal and abnormal automaticity conduction velocity and prolong the cardiac action potential, thereby increasing cardiac refractoriness (Fig. 3). Class lB drugs, of which lidocaine, tocainide, and mexiletine are members, produce minimal if any effect on normal automaticity, depress abnormal automaticity, minimally depress and on occasion e nhance conduction velocity, and shorten action potential duration, thereby reducing cardiac refractoriness. Class lC drugs, of which flecainide, encainide, and propafenone are members, produce marked reductions in both normal and abnormal automaticity, markedly depress conduction velocity, and generally do not alter the duration of the action potential. Class lC antiarrhythmic drugs as a group are also noted for their proarrhythmic and profibrillatory effects in patients with cardiovascular disease. Class 2 antiarrhythmic drugs include all the beta-adrenoceptor-blocking drugs and produce all of their clinically relevant antiarrhythmic effects by competitively blocking beta1adrenoceptors. Blockade ofbeta1..adrenoceptors decreases normal automatic mechanisms, has variable effects on abnormal automatic mechanisms, and produces minimal, if any, effects on conduction velocity except in the sinoatrial and atrioventricular nodes, where conduction is depressed. Class 3 antiarrhythmic drugs, which include amiodarone, bretylium, and sotalol, are noted for their ability to prolong action potential duration and cardiac refractoriness. Increases in cardiac refractoriness are believed to decrease the susceptibility of the heart to the development of ventricular arrhythmias

Table 5. Classification of Antiarrhythmic Drugs

BASIS

DRUG CLASSIFICATION

Class l lA Quinidine Procainamide Disopyramide lB Lidocaine Tocainide Mexiletine Phenytoin lC Flecainide Encainide Propafenone Acecainide* Cibenzoline* Class 2 Propranolol Atenolol Metoprolol Esmolol Class 3 Amiodarone Bretylium Sotalol*

Class 4 Verapamil Diltiazem

DOMINANT CELLULAR ELECTROPHYSIOLOGIC PROPERTIES

-.1

*Investigational.

PROTOTYPE

Generally local anesthetics on nerve and myocardial membranes (more sensitive) that slow conduction

Decrease maximal rate of depolarization (dV/dt) without changing the resting potential

i i

Quinidine

! !

Threshold of excitability Effective refractory pe riod Conduction velocity Spontaneous diastolic depolarization

Role of sympathetic nervous system in the genesis of certain cardiac dysrhythmias

Depress adrenergically enhanced phase 4 depolarization via !3-receptor blockade

! ! ! t

Neurologically induced automaticity Excitabilityt Conduction velocityt Effective refractory periodt

Propranolol

In patients with thyrotoxicosis, atrial dysrhythmias are common; these are rare in patients with hypothyroidism (myxedema) Thyrotoxicosis: APD:j: Hypothyroidism: APD

Homogenous prolongation of action potential duration

t

Effective refractory pe riod

Amiodarone

The calicum-dependent slow response may be the basis of certain dysrhythmias (both reentry and automaticity)

Inhibit slow response dependent automaticity and action potential

i

Effective refractory period (atrioventricular node, atria) Atrioventricular coiiduetion Spontaneous diastolic depolarization (sinus node)

Verapamil

~

0')

ELECTROPHYSIOLOGJC MANIFESTATIONS

tHigh doses only.

:j:Action potential duration.

! !

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WILLIAM W.

Mum III

/Contractility Slow conduction-

,,,,~

••

----("'---, I I ~ - - -

: t PR

if

~·

QT

Figure 3. Example of class 1 antiarrhythmic drugs' effects upon conduction velocity, contractility, and refractoriness in cardiac tissue. Phase 0 (conduction) is depressed. Phase 2 (contractility) is abbreviated and depressed. Phase 3 (refractoriness) is unchanged or prolonged. Automaticity (rate) is depressed.

and ventricular fibrillation . Class 3 antiarrhythmic drugs have become noted for their ability to prevent ventricular fibrillation, and in some instances to convert ventricular fibrillation to sinus rhythm, and are frequently referred to as antifibrillatory drugs. Class 4 antiarrhythmic drugs, also referred to as calcium entry antagonists (or blockers), calcium channel blockers, or slow channel inhibitors, include verapamil, diltiazem, and nifedipine. They are noted for their direct depressant effects on sinoatrial and atrioventricular automaticity and depression of conduction velocity. As a group, class 4 antiarrhythmic drugs produce their therapeutic effects by decreasing the transarcolemmal flux of calcium during phase 2 of the cardiac action potential or by decreasing calcium release from the sarcoplasmic reticulum (depression of calcium-induced calcium release). Since both the sinoatrial and atrioventricular nodes normally have a less negative resting membrane potential compared with atrial and ventricular muscle and Purkinje fibers, they are more dependent on the transmembrane flux of calcium for the generation of an action potential. Depression of the transmembrane flux of calcium ion in these tissues produces depression in normal automaticity and marked delay in the transmission ofthe electrical impulse across the atrioventricular node. Regardless of mechanism, class 4 antiarrhythmic dnigs, or calcium inhibitory drugs as they are sometimes called, depress and eliminate oscillatory afterpotentials (early or late), abolishing triggered automatic impulses (a mechanism for abnormal automaticity; see Table 1) and the resultant cardiac arrhythmias they produce (Fig. 4). Although the classification of antiarrhythmic drugs described here has been relatively useful from a descriptive standpoint, it has not served the purpose for which it was originally intended and that is as a scheme for identifying a specific group of antiarrhythmic drugs to treat a specific, spontaneously occurring cardiac arrhythmia. The reason this latter goal has not been realized is partially explained by the increasing body of knowledge that suggests that most cardiac arrhythmias are caused by multiple electrophysiologic abnormalities and that most antiarrhythmic drugs produce a variety of direct and indirect (neurally mediated) effects, which may be

969


Class 4 verapamil Class 1 Class 1a quinidine 1b lidocaine

Class 3 amiodarone Class 2? propranolol

Class 2 Class 4

Figure 4. Primary action potential site of action of various antiarrhythmic dru~s.

antiarrhythmic or proarrhythmic (Table 6). This latter point is further supported by clinical evidence that indicates that combinations of two and sometimes three different classes of antiarrhythmic drugs are much more effective than one drug. Because of the shortcomings of classification schemes based on active properties, several alternative methods for classifying antiarrhythmic drugs based on "passive properties" have been proposed. 4 Passive properties include the determinants of the resting potential, changes in membrane conductances in the subthreshold range, and cable properties (membrane resistance, capacitance, and time constant). This classification me thod, although somewhat more revealing regarding the mechanisms for cardiac arrhythmogenesis and somewhat more enlightening regarding the actions and efficacy of different types of antiarrhythmic drugs, has not provided that much new practical information. Finally, clinical cardiologists have developed detailed antiarrhythmic protocols and classification schemes based on what can be called the "use what works" method (Table 7). 2· 9 Although for the most part anecdotal, this method is the most useful clinically and takes into account each drug's multiple electrophysiologic properties, direct and indirect effects, and other major pharmacologic actions. The pharmacologic effects of commonly used antiarrhythmic drugs are discussed (Tables 5-10). Table 6. Sympathetic and Parasympathetic Effects of Antiarrhythmic Drugs SYM PATH ETIC EFFECTS

DRUG

Quinidine

n-adrenoreceptor blocking

PARASYMPATHETIC EFFECTS

Vagolytic

~ 1 -stimulation?

Procainamide Phenytoin Flecainide Propafenone Propranolol Atenolol Esmolol Amiodarone Verapamil Digitalis

Ganguon blocking Sympatholytic-CNS effect Mild vagolytic ~1. 2 -adrenoceptor blocking ~ u-adrenoceptor blocking ~ 1 -adrenoceptor blocking ~ 1 -adrenoceptor blocking ~u-adrenoceptor blocking

n 1-adrenoceptor blocking n-adrenoceptor blocking; noncompetitive sympatholytic Sensitizes baroreceptors; stimulates CNS sympathetic activity; stimulates postganglionic sympathetic nerves; releases norepinephrine from sympathetic nerve terminals

Increases vagal tone

_.

~

0

Table 7. Electrocardiographic Properties of Antiarrhythmic Drugs

SINUS RATE

Quinidine Procainamide Lidocaine Tocainide Mexiletine Phenytoin Flecainide Propafenone Propranolol Atenolol Amiodarone Verapamil Diltiazem Digoxin Glycopyrrolate

t

= Increase;

t

0 Of t Oft Oft 0 0 ~ ~ ~ ~

t t t

t

t =

QRS DURATION

t

Oft 0 0 0 0 0 0 0 0 0 0 0 0 0

QT DURATION

t

Of t

on on on 0 0 0 0 0

t

0 0 0 0

VENTRICULAR RESPONSE DURING ATRIAL FIBRILLATION

t

0 0 0 0 0 0 0 ~ ~

t t ~ t t t

t

decrease; 0 = no effect; + = beneficial effect;

VENTRICULAR RATE

ACCESSORY PATHWAY

SUPRAVENTRICULAR ARRHYTHMIAS

~

~ ~

++ +

t

~

t

~ 0

on Of~

~ ~ 0 0 0 0 0

on on on

~ fO ~ ~ ~ ~ ~ ~ ~

on on on

= detrimental effect.

0

0 0 0 0 0

+ + + + ++ ++ ++ 0

VENTRICULAR ARRHYTHMIA

ANTIFIBRILLATORY

++ ++ +++ ++ ++ + ++ ++

0 0

+ ++ + + + 0

+ +? +? 0

0 0

+ 0 0

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Table 8. Hemodynamic Effects of Antiarrhythmic Drugs* HEMODYNAMIC EFFECT

Cardiac Contractility

DRUG

Quinidine Procainamide Lidocaine Mexiletine Tocainide Phenytoin Flecainide Propafenone Propranolol and esmolol Amiodarone Bretylium Verapamil Diltiazem

No change No change No change No change No change No change Decreases No change Decreases

or or or or or or

decreases decreases decreases decreases decreases decreases

or decreases

Decreases Increases or decreases Decreases No change or decreases

Cardiac Output No change No change No change No change No change No change Decreases No change No change

or or or or or or

decreases decreases decreases decreases decreases decreases

or decreases or decreases

Decreases Increases or decreases Decreases No change

Arterial Blood Pressure Decreases No change No change No change No change No change Decreases Decreases Decreases

or decreases or decreases or decreases or decreases or-decreases

Decreases No change Decreases No change

*Electrocardiographic and hemodynamic depressant effects are dose-dependent. Adapted from Muir WW: Pharmacodynamics of antiarrhythmic and diuretic drugs in dogs and cats. Proceedings of the Ninth Annual Kal Kan Symposium for the Treatment of Small Animal Diseases, Columbus, ·oH, 1985; with permission.

CLASS 1 ANTIARRHYTHMIC DRUGS Drugs with Class 1 antiarrhythmic activity are referred to as membrane stabilizers and many produce local anesthetic effects. Most antiarrhythmic drugs regardless of class possess some class 1 antiarrhythmic activity (see Tables 5-10). Table 9. Pharmacokinetic Properties of Some Antiarrhythmic Drugs in Dogs and Cats DRUG

For use in dogs Quinidine Procainamide Lidocaine Phenytoin Mexiletine Tocainide Propranolol Esmolol Verapamil For use in cats Phenytoin Quinidine Lidocaine Propranolol

MAJOR ORGAN OF ELIMINATION

Liver Liver Liver Liver Liver Liver Liver Plasma Liver Liver Liver Liver Liver

t 112 HR 5.6 2.0

THERAPEUTIC RANGE

BIOAVAILABILITY

(%)

0.4 0.4 Low 040 > 0.6 0.85 Low

5 (min) 0.8

3-5 g/mL 4-10 g/mL 2-6 g/mL 10-16 g/mL 0.5-2 g/mL 6-10 g/mL 40-120 ng/mL 10-40 ng/mL NA

< 24 1.9 0.7 8.5

10-16 g/mL 3-5 g/mL 2-4 g/mL 40-100 mg/mL

Good NA Low Low

l.O 3.3 NA 4.7 l.l

Low

NA = Data not available . Adapted from Muir WW: Pharmacodynamics of antiarrhythmic and diuretic drugs in dogs and cats. Proceedings of the Ninth Annual Kal Kan Symposium for the Treatment of Small Animal Diseases, Columbus, OH, 1985; with permission.

"'

-l ~

Table 10. Characteristics of Antiarrhythmic Drugs DRUG

TRADE NAME

DOSE

5-15 mg/kg TID, PO; 5-10 mg/kg IV

Nausea; vomiting; diarrhea; hypotension; proarrhythmia

10-20 mg/kg TID, PO; 5-10 mg/kg IV, 20-50 mg/kg/min; infusion 4 mg/kg IV; dogs, 2 mg/kg IV; cats, 40-80 flog/kg/min; infusion

Anorexia; hypotension; AV block; proarrhythmia Depression; tremor; vomiting; seizures; sinus tachycardia or bradycardia; proarrhythmia Same as lidocaine Same as lidocaine Depression; seizures Depression; vomiting; hypotension; sinus bradycardia Same as flecainide Depression; hypotension; bronchoconstriction; bradycardia; AV block Same as propranolol but less bronchoconstriction Hypothyroidism; bradycardia; anorexia; hypotension; AV block Depression; hypotension; bradycardia; AV block Same as verapamil but less severe and less frequent Anorexia; vomiting; diarrhea; proarrhythmia Sinus tachycardia

Lidocaine

Quinidine Sulfate Quinidine Gluconate Quinidine Dura-tabs Pronestyl Procan SR Xylocaine

Tocainide Mexiletine Phenytoin Flecainide

Tonocard Mexilil Dilantin Tambocor

5-10 mg/kg TID, PO 5-10 mg/kg BID, TID; PO 30 mg/kg TID PO; 5-10 mg/kg IV; 5-10 mg/kg TID PO

Propafenone Propranolol

Rhythmol Inderal

5-10 mg/kg TID; PO 5-40 mg TID PO; 0.05-0.3 mg/kg IV

Atenolol

Tenormin

0.5-1 mg/kg BID PO

Amiodarone

Cordarone

10-20 mg/kg BID PO

Verapamil Diltiazem

Calan lsoptin Cardiazem

1-5 mg/kg BID, TID PO; 0.05-0.2 mg/kg IV 1-3 mg/kg BID, TID; PO

Digoxin

Lanoxin

Glycopyrrolate

Robinul-V

0.1 mg/kg divide BID PO; 0.0050.01 mg/kg IV 0.005-0.01 mg/kg IV

Quinidine

Procainamide

*See text fo r discussion.

ADVERSE EFFE CTS

DRUG INTERACTION*

Digoxin; verapamil; amiodarone; calcium channel blockers Captopril (immune disorders) Beta-blockers; cimetidine; halothane Same as above Same as above Beta-blockers; quinidine Same as flecainide Lidocaine; halothane

Same as propranolol Digoxin; quinidine; flecainide Beta-blockers; quinidine Same as verapamil Quinidine; verapamil; amiodarone


973

Class lA

Quinidine. Quinidine is the oldest antiarrhythmic drug in clinical use and serves as the prototypic class lA antiarrhythmic. 12· 13• 14• 18 Normal and some abnormal causes for increased automaticity are depressed by quinidine, as is conduction of the cardiac impulse (conduction velocity). Atrial refractoriness is prolonged. Sinus rate is increased, and atrioventricular conduction is enhanced owing to a vagolytic effect. Quinidine is useful therapy for the treatment of supraventricular and ventricular arrhythmias of all types. Supraventricular tachycardias, particularly paroxysmaJ atrial tachycardia (PAT), and the acute onset of atrial flutter or atrial fibrillation are susceptible to quinidine's antiarrhythmic effects. It is not known, but is unlikely, whether quinidine prevents sudden death from arrhythmias or prolongs life . 10• 24 Hemodynamics are relatively unaffected by low oral dosages of quinidine, although negative inotropic effects, as a result of interference of transmembrane calcium flux, and peripheral vasodilation caused by alpha-adrenoceptor blocking effects are observed following large oral or intravenous doses. Quinidine is most frequently administered orally every 6 to 8 hours. Daily dosages range from 5 to 15 mg/kg and produce serum concentrations ranging from 2 to 6 f.LglmL. Intravenous dosing is discouraged because of hemodynamic depression but can be used if myocardial performance is normal or only minimally impaired. Intravenous dosages range from 5 to 10 mg/kg administered slowly in 1 to 2 mg/kg boluses over a period of I to 2 minutes. A total dose of 10 mg/kg intravenously should not be exceeded. Quinidine is highly protein bound, and serum concentrations are increased and effects enhanced during hypoproteinemia, metabolic acidosis, hyperkalemia, and renal disease. 15• 16 The administration of sodium bicarbonate increases quinidine protein binding and can temporarily reduce both electrophysiologic and hemodynamic signs of toxicity. The most common side effects associated with quinidine administration are anorexia, nausea, vomiting, and diarrhea, which are the principal reasons for discontinuing therapy and infrequent use in dogs and cats. Thrombocytopenia, dermatopathies, and fever can occur. More subtle but important side effects include sinus tachycardia, increased ventricular rates in patients with atrial fibrillation, hypotension, syncope, and proarrhythmic effects. A 25% increase in the duration of the QRS complex, atrioventricular block, the development of ventricular depolarizations of varying configuration, and an acceleration of a ventricular tachyarrhythmia are signs of quinidine toxicity. Drug interactions are an important consideration during quinidine therapy. Quinidine increases digoxin, amiodarone, and verapamil serum concentration and enhances the negative inotropic and hypotensive effects of beta-adrenoceptor- blocking drugs and calcium antagonists (verapamil). 16 · 18 Cimetidine decreases the metabolism of quinidine, thereby enhancing quinidine's effects. Finally, concomitant therapy with other antiarrhythmic drugs usually enhances quinidine's effects. Procainamide. Procainamide has a similar electrophysiologic profile to that of quinidine, although clinically it is less effective than quinidine in eliminating supraventricular arrhythmias and is not as likely to produce as marked an increase in ventricular rate during atrial flutter or fibrillation. Procainamide, like quinidine, has not been de monstrated to prevent sudden

974

WILLIAM

w . MUIR III

death from arrhythmias or to prolong life. 2 · 12·· 24 Indications for procainamide therapy are atrial premature depolarizations and ventricular arrhythmias. Cardiac output, aterial blood pressure, and peripheral vascular resistance are minimally affected by oral dosages of quinidine, although large intravenous doses depress arterial blood pressure, glomerular filtration rate, and effective renal plasma flow. 5 Dosages range from 5 to 15 mg/kg administered orally three to four times per day and 5 to 10 mg/kg intravenously. Therapeutic plasma concentrations range from 4 to 8 J.Lg/mL. Procainamide may be administered by infusion at rates ranging from 30 to 50 t-tg/kg/min. Renal failure will prolong procainamide elimination and result in increased serum concentrations. Dogs, unlike humans, do not acetylate procainamide and therefore do not produce n-acetyl procainamide, a chemical that is known to produce class 1A and class 3 antiarrhythmic and antifibrillatory effects. 19• 20 The importance of n-acetyl procainamide in cats is unknown but believed to be relatively minor. Procainamide produces few clinically objectionable side effects. Proarrhythmic effects are rare, as are anorexia, nausea, vomiting, and fever. Procainamide should not be used to treat ventricular arrhythmias in dogs or cats with atrioventricular block. Agranulocytosis and elevated antinuclear antibody titers have bee n reported following prolonged (2 to 3 months) therapy in dogs. Hyperkalemia enhances procainamide' s effects, and cimetidine prolongs procainamide's elimination by inhibiting renal clearance. It is recommended that procainamide not be combined with captopril therapy because of the potential danger of enhanced immune effects. Disopyramide. Disopyramide is similar but not identical to quinidine. It is equally as effective for treating supraventricular and ventricular arrhythmias and has potent anticholinergic properties but is less likely to produce anorexia, nausea, and vomiting. 1• 12 Although a logical alternative to quinidine and procainamide, disopyramide has a relatively rapid elimination and short half-life in dogs and cats that necessitates dosing every 2 to 4 hours (6 to 12 times per day), making it unacceptable for practical use. 18 Additionally, disopyramide has been demonstrated to produce significant negative inotropic effects in dogs with preexisting heart failure. Disopyramide is ineffective in digitalis toxicity and augments the negative inotropic effects of beta-adrenoceptor- blocking drugs and calcium antagonists. Other toxic manifestations are similar to those of quinidine. Class IB

Lidocaine. Lidocaine is the prototypic class 1B antiarrhythmic drug and varies considerably from quinidine, procainamide, and disopyramide in its electrophysiologic profile. 1· 12 · 18 Lidocaine produces little effect on the sinus node, atrial muscle, or the atrioventricular node but markedly suppresses normal automaticity in Purkinje fibers and delays impulse conduction in the ventricular conduction system and ventricular muscle. Action potential duration is shortened, and the reactivation of tissue excitability is delayed. These electrophysiologic effects are dependent on the plasma potassium concentration and are negligible during hypokale mia (K+ < 2. 7 mEq/L). 15 • 16 Lidocaine is the best first choice antiarrhythmic for


975

most ventricular arrhythmias, including those caused by digitalis toxicity. Clinical studies in dogs suggest that lidocaine may decrease the incidence of sudden death secondary to the acute onset of ventricular fibrillation. 3 Apart from lidocaine's ability to increase the ventricular fibrillation threshold and decrease the potential for sudden death, there is no evidence that lidocaine prolongs life. There are no significant changes in cardiac contractility, cardiac output, arterial blood pressure, or peripheral vascular resistance during lidocaine therapy. Heart rate occasionally increases following large intravenous boluses or during lidocaine infusion, presumably owing to sympathetic activation caused by peripheral vasodilation. Lid0caine is available only for parenteral administration. Intramuscular administration of lidocaine is less effective and more likely to produce toxicity than intravenous therapy and is not recommended. Intravenous bolus dosages of lidocaine range from 2 to 4 mg/kg in dogs and 1 to 2 mg/kg in cats. Lidocaine infusion rates range from 40 to 80 j.Lg/kg/min and are substantially influenced by liver blood flow; decreases in liver blood flow enhance and prolong lidocaine effects. Lidocaine is metabolized by the liver, is not dependent on renal excretion, and is less than 10% protein bound.8 Therapeutic plasma concentrations range from 2.0 to 6.0 j.Lg/mL. Lidocaine toxicity is usually manifested by central nervous system dysfunction, including nystagmus, hypersalivation, nervousness, nausea, vomiting, respiratory arrest, and seizures. Cats are more susceptible to the neurotoxic side effects than dogs, necessitating reduced intravenous bolus dosages. Reflex sinus tachycardia and increased ventricular rates in patients with atrial tachyarrhythmias may occur. Peripheral vasodilation is an unpredictable and occasional side effect. Lidocaine can exacerbate first- and second-degree atrioventricular block and is contraindicated during thirddegree atrioventricular block owing to its ability to suppress Purkinje cell automaticity. Large intravenous boluses of lidocaine can cause sinus arrest, particularly in cats. Proarrhythmic effects are uncommon during lidocaine therapy. Cimetidine, propranolol, and halothane reduce the hepatic clearance of lidocaine. 8 Tocainide, Mexiletine. Tocainide and mexiletine are structural analogs of lidocaine and possess similar electrophysiologic and hemodynamic profiles. Both drugs, like lidocaine, are indicated for the treatment of ventricular arrhythmias of all types, including those induced by digitalis toxicity. Premature ventricular depolarizations, multiform ventricular arrhythmias, and sustained recurrent ventricular tachycardia are suppressed or eliminated.1· 12· 18 Ventricular fibrillatory threshold is increased, suggesting that sudden death due to ventricular fibrillation may be reduced, but neither drug has been demonstrated to prolong life. Tocainide is administered orally three to four times per day at dosages that range from 5 to 10 mg/ kg. A significant portion is metabolized by the liver, but renal elimination and impaired renal function prolong drug effects. Mexiletine is administered orally two to three times per day at dosages ranging from 5 to 10 mg/kg and is entirely metabolized by the liver to inactive metabolites. Both tocainide and mexiletine produce similar and more frequent dose-dependent signs of central nervous system and gastrointestinal toxicity than

976

WILLIAM W.

MuiR III

lidocaine. Nervousness, ataxia, hypersalivation, nausea, vomiting, diarrhea, and seizures can occur following the administration of large oral dosages. Blood dyscrasias including leukopenia and thrombocytopenia have been documented in dogs. Pulmonary fibrosis following tocainide therapy has been reported to occur in humans but not in dogs or cats. Electrophysiologic and electrocardiographic signs of toxicity are similar to those produced by lidocaine. They are contraindicated during bradycardia, AV conduction defects, hypotension, hepatic failure, or severe myocardial failure. Drug interactions are similar to those reported for lidocaine. Interestingly both drugs are noted to produce enhanced antiarrhythmic effects (significantly better than when used alone) when combined with either quinidine or procainamide therapy. Phenytoin. Phenytoin demonstrates a similar electrophysiologic profile to that oflidocaine but is more effective in the treatment of supraventricular arrhythmias than lidocaine, particularly for arrhythmias caused by digitalis toxicity. Unlike lidocaine, phenytoin produces intracellular calcium-blocking activity, which may explain its superior effectiveness in treating supraventricular arrhythmias and suppressing arrhythmias caused by abnormal automaticity. 6 Phenytoin is considered specific therapy for digitalis-induced arrhythmias and is variably effective as therapy for all types of ventricular arrhythmias with or without atrioventricular block. Phenytoin therapy does not prevent sudden death or prolong life. 12 Based on its minimal hemodynamic effects and relatively large safety margin, it is surprising that phenytoin is not used more frequently for the treatment of cardiac arrhythmias. Phenytoin can be administered intravenously or orally and is metabolized by the liver and excreted in the urine. Phenytoin induces liver enzymes and may alter the requirements of other drugs dependent on liver metabolism, including quinidine, propranolol, lidocaine, tocainide, and mexiletine. Intravenous dosages range from 5 to 10 mg/kg administered over a period of 2 to 3 minutes. Oral dosages range from 15 to 30 mg/kg two to three times per day. Toxic manifestations are rare but include lethargy, ataxia, and disorientation. Proarrhythmic effects are believed to be minimal and have not been reported. Rapid intravenous administration has caused asystole, most likely as a result of the effects of the propylene glycol diluent. 18 Drug interactions are a result of liver enzyme induction and reduction of liver blood flow following the administration of large dosages. ClassIC

Flecainide, Encainide, Propafenone. Flecainide, encainide, and propafenone produce electrophysiologic effects that are similar to both class lA and lB antiarrhythmics. They are most noted for their ability to depress the conduction velocity of the cardiac impulse. Propafenone also possesses mild nonspecific beta-adrenoceptor blocking activity (see Table 6). All three drugs are effective in the treatment of both supraventricular and ventricular arrhythmias and are particularly effective in the treatment of arrhythmias caused by accessory pathways (Wolff-Parkinson-White syndrome). 12 These drugs do not decrease the incidence of sudden death or prolong life. 10• 24 All three drugs are not recommended as first choice antiarrhythmic therapy

977


because of their significant hemodynamic effects, which include depression of cardiac contractility, cardiac output, and arterial blood pressure. They are metabolized by the liver and therefore subject to the same changes in plasma concentration as those described for lidocaine. Therapeutic dosage ranges (based on the treatment of spontaneously occurring arrhythmias in dogs and cats) are uncertain for these drugs. They are available as oral preparations only. Toxic manifestations include depression, nausea, vomiting, hypotension, and worsening of congestive heart failure. They are noted for their proarrhythmic and profibrillatory effects and are contrairtdicated during severe heart failure and preexisting atrioventricular or . bundlebranch block abnormalities. 7 They demonstrate drug interactions similar to those for lidocaine, and their elimination is prolonged by liver failure or drugs that impair liver function. CLASS 2 ANTIARRHYTHMIC DRUGS Beta-adrenoceptor Antagonists Increased sympathetic nervous system activity not only augments the force of cardiac contraction but also produces unwanted sinus tachycardia, supraventricular and ventricular arrhythmias, and an acceleration in ventricular rate during atrial flutter or fibrillation. Beta-adrenoceptor antagonists inhibit the effects of increases in sympathetic nervous system activity on the heart by blocking beta1-adrenoceptors. A large number of betaadrenoceptor antagonists are available that vary in their betacblocking specificity, lipophilicity, ability to produce mild beta-receptor stimulation (intrinsic sympathetic activity; ISA), and method of elimin~tion . 17 Labetalol possesses alpha-adrenoceptor blocking activity (Table 11). Propranolol, a nonspecific beta-adrenoceptor blocking drug (blocks both beta 1 and beta2 adrenoceptors) without ISA but with high lipophilicity, is the prototypic class 2 antiarrhythmic drug (see Tables 5-10). Propranolol Indepe ndent of changes in heart rate, propranolol produces electrophysiologic effects in both supraventricular and ventricular tissues that are Table 11. Properties of f>-adrenoceptor Blocking Drugs

DRUG

Propranolol Atenolol Esmolol Labetalolt Metoprolol Nadolol Pindolol Sotalol

~rBLOCKADE POTENCY RATIO*

1.0 1.0 0.01 0.3 1.0 1.0 6.0 0.3

INTRINSIC

MEMBRANE-

RELATIVE~~ SELECTIVITY

SYMPATHOMIMETIC

STABILIZING

ACTIVITY

ACTIVITY

0

0 0 0

++

++ ++ 0

+?

++

0 0

0 0 0 0 0

++

+

0

0

0 0 0

*Propranolol = 1.0. tLabetalol has additional ex-adrenergic blocking activity.

978

WILLIAM W .

MuiR III

similar to those of quinidine. 12· 17· 21 These effects, however, can be attributed to beta1-adrenoceptor blockade and are not due to direct cellular membrane electrophysiologic effects. Normal automatic mechanisms in the sinus node, atrioventricular node, and Purkinje network are depressed by propranolol, as is conduction of the cardiac impulse. This latter effect can be particularly pronounced in the atrioventricular node and is taken advantage of clinically by decreasing ventricular response rates in dogs with atrial fibrillation. Propranolol can be used to decrease sinus rate and treat supraventricular and ventricular arrhythmias. Arguably, propranolol may reduce the incidence of sudden death and prolong life. 10· 24 Hemodynamic depression and, in particular, decreases in cardiac contractility can be pronounced following the initiation of propranolol (beta1-adrenoceptor antagonist) therapy. Titration of the drug until the desired effect is produced and close patient monitoring during initial dosing are mandatory. Propranolol can be administered intravenously (rarely recommended) and orally and is metabolized by the liver to active and inactive metabolites. By contrast, nadolol, another nonspecific beta-adrenoceptor blocking drug, is largely dependent on renal excretion for its elimination. Oral dosages of propranolol rahge from as low as 5 to 10 mg two to four times per day in cats to 40 to 60 mg total two to four times per day in dogs. Signs of toxicity include depression, sinus bradycardia, atrioventricular block, hypotension, and acute heart failure. Proarrhythmic and profibrillatory effects have not been observed. Bronchospasm can occur during propranolol therapy owing to its nonspecific (beta1 and beta2) blocking properties. The use of a more specific beta1-adrenoceptor blocking drug (atenolol, metoprolol) may help to minimize side effects. Gastrointestinal effects (nausea, vomiting) and hypoglycemia may occur during long-term therapy. Diseases or drugs that reduce liver blood flow prolong propranolol elimination. The addition of ultrashort-acting intravenous beta-adrenoceptor blocking drugs (esmolol) has increased the clinical utility of beta-adrenoceptor blocking therapy, particularly for the treatment of the acute onset of ventricular arrhythmias during inhalation anesthesia (halothane) and surgery for hyperthyroidism. Esmolol, an ultrashort-acting cardioselective (beta1) beta-adrenoceptor antagonist, is available for intravenous use only. Infusion dosages range from 10 to 100 J.Lg/kg/min. Beta-adrenoceptor blocking effects gradually disappear within 10 minutes of discontinuing infusion and like all beta-adrenoceptor therapy can be acutely reversed by the administration of catecholamines (dopamine, dobutamine).

CLASS 3 ANTIARRHYTHMIC DRUGS Class 3 antiarrhythmic drugs comprise a relatively diverse group of chemicals that are believed to produce their antiarrhythmic and antifibrillatory effects by prolonging the action potential duration. The three most noted representatives of this group of drugs are amiodarone, bretylium, and sotalol. 3 Almost all drugs categorized as class 3 antiarrhythmics produce antiarrhythmic properties that modify impulse conduction. 12· 18 Amiodarone


979

produces significant sodium channel inhibitory effects, bretylium initially releases catecholamines and blocks adrenergic neurones, and sotalol is a beta-adrenoceptor antagonist. Amiodarone currently serves as the prototypic class 3 antiarrhythmic drug (see Tables 5-10). Amiodarone Amiodarone depresses sinus node automaticity and prolongs action potential duration and the refractoriness of the myocardium. Abnormal automatic mechanisms that are dependent on slow channels are depressed. Amiodarone minimally affects conduction velocity, although it is noted for its ability to produce mild depression of the fast sodium channel.· Cardiac arrhythmias of all types are theoretically susceptible to the antiarrhythmic effects of amiodarone. 12· 18 Clinically, however, amiodarone has demonstrated only moderate effectiveness in the treatment of both supraventricular and ventricular arrhythmias in dogs and cats. Amiodarone' s effectiveness as an antiarrhythmic increases when used in conjunction with class 1A and class 1C antiarrhythmic drugs, although it does not decrease the incidence of sudden death or prolong life. 10· 24 Both alpha1- and nonspecific beta-adrenoceptor blocking activities are produced by amiodarone. Amiodarone decreases the force . of cardiac contraction, cardiac output, and arterial blood pressure following large oral dosages or intravenous administration. Sinus rate usually decreases, atrioventricular conduction is prolonged, and coronary and peripheral vasodilating effects are produced by calcium antagonist effects. Amiodarone is available only for administration by the oral route, is highly lipid-soluble (accumulates in cardiac tissues), and is metabolized by the liver to both active and inactive metabolites. 11 Desmethylamiodarone, a pharmacologically active metabolite, has been identified in the plasma of dogs administered oral amiodarone. Oral dosages in dogs range from 5 to 15 mg/kg administered three to four times per day. Amiodarone produces a wide variety of toxic side effects in humans, which include, but are not limited to, corneal microdeposits, sensitivity to sunlight, abnormalities in liver function, neurotoxicity and ataxia, thyroid function abnormalities, skin discoloration, chronic cough, pulmonary infiltrates, and pulmonary fibrosis. This wide spectrum of toxic side effects has not been reported in dogs. Drug interactions are a potential problem during amiodarone therapy. Quinidine and digoxin blood levels are increased following the initiation of amiodarone therapy. The electrophysiologic and cardiovascular effects of beta-adrenoceptor antagonists and calcium channel blockers are augmented by amiodarone, and proarrhythmic effects are possible, particularly during hypokalemia or when administered in conjunction with class 1A or class 1B antiarrhythmic drugs. 15 · 16 Torsade de pointes has been observed in human patients receiving amiodarone administered alone or in conjunction with class 1A antiarrhythmic drugs. Bretylium tosylate, another class 3 antiarrhythmic drug, is noted for its antiarrhythmic and antifibrillatory effects in humans. It accumulates in sympathetic ne rve terminals, initially releases stored norepinephrine, and then inhibits further release, thereby producing "chemical" sympathectomy. 2 Bretylium is administered intravenously or intramuscularly at dosages that range from 5 to 10 mg/kg and is eliminated by liver metabolism

980

WILLIAM W .

MuiR III

and renal excretion. The clinical use of bretylium in dogs has been disappointing at best, with few or no antiarrhythmic or antifibrillatory effects being reported.

CLASS 4 ANTIARRHYTHMIC DRUGS Drugs that are categorized as class 4 antiarrhythmic drugs produce their antiarrhythmic effects by interfering with or blocking the slow calcium channel. It is for this reason that they are frequently referred to as calcium channel blocking drugs or just simply as calcium antagonists. 12· 18 Chemicals that block calcium channels produce a wide variety of pharmacologic effects in addition to pronounced electrophysiologic and hemodynamic effects. Because of the large number of drugs that produce calcium channel blocking activity and for practical reasons, calcium channel antagonists are categorized into three subgroups based on whether or not their predominant effects are on the myocardium, vasculature, or nodal and conducting tissue (Table 12). Verapamil, diltiaze m, and nifedipine are class 4 antiarrhythmic drugs. Verapamil Verapamil inhibits the passage of calcium ions across the slow calcium channel, thereby depressing both normal and abnormal automatic mechanisms.12· 18 Cardiac arrhythmias caused by oscillatory afterpotentials or triggered activity are particularly susceptible to the antiarrhythmic effects of verapamil. 1 Although theoretically effective for the treatment of either supraventricular or ventricular arrhythmias, calcium channel antagonists have been most effective in terminating premature atrial depolarization, atrial tachyarrhythmias including atrial fibrillation, and junctional arrhythmias. Supraventricular tachyarrhythmias in dogs that are unresponsive to class lA antiarrhythmic drugs frequently respond to verapamil and other calcium antagonists. Verapamil or the other calcium antagonists do not reduce the incidence of sudden death or prolong life. 10· 24 Drugs that inhibit calcium entry into myocardial cells decrease intracellular free calcium concentrations, reduce the force of cardiac contraction, and cause vasodilation. Decreases in cardiac contractile force can be pronounced following intravenous verapamil administration but are of much less concern during Table 12. Myocardial vs. Vascular Selectivity of Calcium Antagonists DRUG

Verapamil Diltiazem Nifedipine Nitrendipine Felodipine Nicardipine Niludipine Nisoldipine

SELECTIVITY FACTOR

j

Decreasing myocardial, increasing vascular effects


981

diltiazem or nifedipine administration. 19 Small reductions in cardiac contractile force and vasodilation may be beneficial in patients with hypertrophic cardiomyopathy because of associated decreases in myocardial oxygen consumption and potential increases in cardiac output due to reduced afterload. Verapamil is available for both oral and intravenous administration but is not recommended for intravenous use because of the potential for cardiac depression and hypotension. Oral dosages range from 1 to 5 mg/kg administered two to three times per day. Verapamil is subject to first pass elimination by the liver, and several metabolites are known to possess reduced antiarrhythmic activity. Drugs that reduce liver biood flow or reduce liver enzyme function prolong verapamil elimination and maintain plasma concentrations. Intravenous dosages range from 0.05 to 0.2 mglkg administered over a period from 2 to 5 minutes. Calcium chloride (1 mLI 10 kg; 10% solution) should be available to counteract hypotension. 18 Toxic side effects include sinus bradycardia, atrioventricular conduction disturbances including complete atrioventricular block hypotension, asystole, and acute cardiovascular collapse. Constipation, diarrhea, vomiting, and nausea may occur following large oral dosages or long-term oral administration. Verapamil increases digoxin plasma concentration and produces additive cardiac depressant effects when combined with beta-adrenoceptor antagonists and class 1 or 3 antiarrhythmic drugs. Calcium channel blocking drugs are recommended as therapy for a variety of medical disorders in addition to their use as antiarrhythmics. Hypertension, myocardial ischemia, cerebral ischemia, congestive heart failure, cardiomyopathy, renal failure, and a variety of neurologic syndromes can be successfully managed with calcium channel blocking drugs. Diltiazem produces electrophysiologic and hemodynamic effects similar to those of verapamil but is less likely to induce side effects. Oral dosages range from 1 to 3 mg/kg administered three times daily.

OTHER ANTIARRHYTHMIC DRUGS The ideal drug that produces both antiarrhythmic and antifibrillatory effects has yet to be developed. Drugs that modify and in particular prolong action potential duration usually demonstrate potent antiarrhythmic effects in experimentally induced arrhythmias and spontaneously occurring rate and rhythm disorders. The prolongation of action potential duration increases refractoriness and reduces the potential for automatic or reentrant arrhythmias. More specifically, drugs that facilitate the continued entry of sodium ion into cells or inhibit the exit of potassium ion from cells have the capability of increasing action potential duration, prolonging refractoriness, and abolishing several of the abnormal mechanisms responsible for cardiac arrhythmias. Drugs that prolong action potential duration would naturally be placed into class 1A (also depress sodium current) or class 3 (little or no sodium current effect) according to current classification schemes (see Table 5). Changes in heart rate also produce correspondingly appropriate changes in action potential duration and refractoriness, which may provide effective antiarrhythmic activity in a variety of clinical situations. Digitalis glycosides, for example, may derive a portion of their effects by

982

WILLIAM W.

MuiR III

slowing heart rate and thereby prolonging action potential duration and refractoriness. The logic of prolonging action potential duration and refractoriness has been verified in both experimental and clinical antiarrhythmic efficacy trials in humans, the natural extension of which has been the combination of antiarrhythmic drugs of more than one class to derive the best possible effects. The combination of class 1A and class 1B, class 2 and class 3, or class 1B and class 3 antiarrhythmic drugs has demonstrated superior antiarrhythmic effects in many spontaneously occurring arrhythmias.

CELLULAR MECHANISMS OF CARDIAC ARRHYTHMIAS AND EFFECTS OF ANTIARRHYTHMIC DRUGS Three fundamental mechanisms for the development of cardiac arrhythmias have been discussed and include arrhythmias caused by normal automatic mechanisms, abnormal automatic mechanisms, and abnormal conduction (see Table 1). Arrhythmias caused by normal automatic mechanisms are for the most part susceptible to the antiarrhythmic effects of most class 1 and class 2 antiarrhythmic drugs . Arrhythmias caused by abnormal automatic mechanisms are resistant to therapeutic concentrations of most class 1 and 2 antiarrhythmic drugs but are suppressed by class 4 antiarrhythmic drugs. Triggered automatic mechanisms are particularly susceptible to the antiarrhythmic effects of class 4 antiarrhythmic drugs. Both class 1 and class 3 antiarrhythmic drugs are effective therapy for the treatment of cardiac arrhythmias caused by conduction disturbances. Class 1C antiarrhythmic drugs produce pronounced depression of conduction and are particularly effective in the treatment of cardiac arrhythmias caused by accessory pathways. Class 1C drugs are also noted for their proarrhythmic and profibrillatory effects.

PROARRHYTHMIC EFFECTS OF ANTIARRHYTHMIC DRUGS Any drug that alters the electrophysiologic properties of the heart (active or passive) has the capability of producing antiarrhythmic or proarrhythmic effects (Table 13). Other pharmacologic reasons for a deterioration in cardiac rate or rhythm are a depression of hemodynamics and alteration in autonomic tone (see Table 5). Naturally only those drugs that produce predominantly antiarrhythmic effects are developed for clinical use. Occasionally, however, drugs administered as antiarrhythmic therapy cause the arrhythmia to become worse. More specifically, the frequency, timing, or location (focus) of the rate or rhythm disturbance suggests that the heart has become electrically less stable (see Table 6). Physical examination findings (capillary refill time, mucous membrane color) may support a deterioration in hemodynamic status. The most common observation is that the frequency or duration of the abnormal events is increased. Antiarrhythmic drugs that depress the conduction of the electrical impulse (class 1C) and prolong action potential duration (class 3) are most noted for their

983


Table 13. Antiarrhythmic Drugs Most Likely to Produce Proarrhythmic Effects in Dogs and Cats Quinidine Procainamide Flecainide

Encainide Propafenone Amiodarone

proarrhythmic effects. Flecainide, encainide, propafenone, and amiodarone are all recognized for their proarrhythmic effects in humans. Few studies exist in the veterinary literature describing the proarrhythmic ~ffects of antiarrhythmic drugs in dogs and cats. The potential for the development of proarrhythmic effects following the administration of antiarrhythmic therapy argues for relatively close patient monitoring following the initiation of this period and for several hours thereafter. If proarrhythmic effects are observed or suspected, the selected therapy must be immediately discontinued and alternative therapy initiated.

ANTIARRHYTHMIC EFFICACY

Far more common than the development of proarrhythmic effects are the absence of an effect or a partial response following the administration of an antiarrhythmic drug. Common reasons for a lack of antiarrhythmic efficacy include the wrong choice of antiarrhythmic drug, inadequate dose or route of administration, deteriorating hemodynamics or poor cardiac function, hypokalemia, and acid- base abnormalities. The administration of an antiarrhythmic drug by constant rate infusion may be the only way that an antiarrhythmic effect can be maintained without producing drug toxicity or causing a deterioration in hemodynamics. There are no studies in the veterinary literature that specifically address the efficacy of antiarrhythmic drugs in the treatment of cardiac arrhythmias. Clinical impression, however, suggests that lidocaine and procainamide are the best first choice therapy for the treatment of all types of ventricular arrhythmias and that betaadrenoceptor blocking drugs, diltiazem, procainamide, and quinidine should all be considered for the treatment of problematic supraventricular arrhythmias (Table 14).

METHODS OF ANTIARRHYTHMIC DRUG ADMINISTRATION

The preferred method of antiarrhythmic drug administration is by the oral route. Although by far the most practical method, the oral administration of antiarrhythmic drugs is also the most likely to result in an inadequate effect or the lack of a sustained effect. The reasons for this include variable absorption of the drug from the gastrointestinal tract, a delayed onset to peak drug effect, immediate metabolism by the liver (first pass effect), variations in drugs' biologic half-life and clearance, and variation in drug plasma conce ntration produced by periodic dosing. The least practical but by far the most efficacious method of antiarrhythmic drug administration is

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WILLIAM

w.

MUIR

III

Table 14. Therapeutic Approach to Arrhythmias ALTERNATIVE ARRHYTHMIA

INITIAL THERAPY

THERAPY

Atrial arrhythmias and atrial fibrillation

Propranolol (betablockers) Diltiazem Quinidine

Digitalis to control ventricular rate Procainamide

Supraventricular tachycardia

Propranolol (betablockers) Diltiazem (calcium antagonists)

Digitalis to slow ventricular rate

Ventricular arrhythmias

Lidocaine Procainamide

Tocainide Mexiletine Propafenone Amiodarone Beta-blockers

Ventricular fibrillation

Cardioversion

Lidocaine Amiodarone Verapamil

REMARKS

Quinidine or procainamide are used for long-term therapy; betablockers slow ventricular rate Initial therapy is dependent on patient status; long-term therapy same as for atrial fibrillation If ventricular rate increases or arrhythmias worsen, discontinue and select alternative therapy; dose carefully if heart failure is present Cardiopulmonary resuscitation may be indicated; lidocaine or procainamide help to prevent arrhythmias; verapamil may preserve the myocardium from the insults of ischemia and hypoxia

by constant rate infusion. There are many instances in which the administration of an antiarrhythmic drug by constant rate infusion is the only method that will sustain an antiarrhythmic effect. The intravenous bolus administration of an antiarrhythmic drug followed by constant infusion avoids the delayed onset and large variations in drug plasma concentration associated with .oral or intramuscular drug administration. The rate of antiarrhythmic drug administration can be determined by selecting a drug dosage, determining the animal's weight in kilograms, and preparing a drug solution of known drug concentration. For example, the administration of 50 J-lg/kg/min of lidocaine to a 20-kg dog requires the administration of 1000 J-lg/min (50 J-lg/kg/min X 20 kg). A solution containing 500 J-lg/mL of lidocaine can be produced by adding 12.5 mL of 2% (20 mg or 20,000 J-lg/mL) lidocaine to a 500-mL bag or bottle of lactated Ringer's solution (500 J-lg/mL X 500 mL -;- 20,000 J-lg/mL = 12.5 mL). Since the dog requires 1000 J-lg/min and the prepared solution contains 500 J-lg/mL, the final solution administration rate will be 2 mL/min (1000 J-lg/min -;- 500 J-lg/mL = 2 mL/min). If a standard solution administration set is used (10 drops/mL), the patient will receive 20 drops/min (10 drops/mL X 2 mLI min = 20 drops/min) of the prepared solution. The rate of fluid adminis-


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Figure 5. Arrhythmias of varying clinical importance. (1) Infrequent premature ventricular depolarizations (benign). (2) Late (escape) ventricular depolarizations (benign). (3) Couplets, and (4) paroxsyms of ventricular depolarizations (potentially lethal). (5) Sustained unifocal ventricular, and (6) multifocal (pleomorphic, polymorphic) tachycardia (lethal).

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WILLIAM W.

MuiR III

Table 15. General Approach to Arrhythmia Evaluation and Therapy STEP

1 2

3 4

5 6

PROCEDURE

Document arrhythmia and correlate with symptoms: Electrocardiogram; 1-min rhythm strip; transtelephonic and event recorder devices Define risk of the arrhythmias (see Tables 3 and 4): Establish type and severity of heart disease Determine specific initiating factors (hypokalemia and magnesemia, pH and blood gas abnormalities, proarrhythmic drugs, neurogenic and endocrine factors) Detect and correct uncompensated ischemia and heart failure Classify ventricular arrhythmia into benign, potentially lethal, or lethal Determine need for therapy Define therapeutic goals and anticipated length of therapy: ? Prevent symptoms ? Reduce sudden death potential Initiate appropriate therapy: Select modality (correction of initiating factors, drugs, pacemaker, surgery) Modify regimen for underlying disease state, using lowest possible drug dose Monitor response to therapy

Modified from Anderson JL: Current clinical perspectives on antiarrhythmic drug therapy. Fed Proc 45(8):2216, 1986; with permission.

tration can be cut to one half by doubling the lidocaine in the prepared lactated Ringer's solution (adding 25 mL of lidocaine to 500 mL of lactated Ringer's solution). The type of arrhythmia (benign, potentially lethal, lethal) should be the principal factor that determines the method of antiarrhythmic therapy selected (Fig. 5; Tables 4 and 15).

REFERENCES 1. Anderson GJ: Relationship between arrhythmogenic mechanisms and drug action. ln Reiser HJ, Horowitz LN (eds): Mechanisms and Treatment of Cardiac Arrhythmias: Relevance of Basic Studies to Clinical Management. Baltimore, Urban and Schwarzenburg, 1985, pp 89- 102 2. Anderson JL: Current clinical perspectives on antiarrhythmic drug therapy. Fed Proc 45(8):2216, 1986 3. Anderson JL, Patterson E, Conlon M, et al: Kinetics of antifibrillatory effects ofbretylium: Correlation with myocardial drug concentrations. Am J Cardiol 46:583, 1980 4. Arnsdorf MF: Basic understanding of electrophysiologic actions of antiarrhythmic drugs. Sources, sinks, and matrices of information. Med Clin North Am 68(5):1247-1280, 1984 5. Badke FR, Walsh RA, Crawford MH, et al: Hemodynamic effects ofN-acetylprocainamide compared with procainamide in conscious dogs. Circulation 6:1142, 1981 6. Bigger JT, Hoffman BF: Antiarrhythmic drugs. ln Gilman AG, Goodman LS, Rail TW, et al (eds): The Pharmacological Basis of Therapeutics, ed 7. New York, 1985, p 748 7. Estes NAM, Garan H, McGovern B, et al: Class I antiarrhythmic agents: Classification, electrophysiologic considerations, and clinical effects. In Reiser HJ, Horowitz IN (eds): Mechanisms and Treatment of Cardiac Arrhythmias: Relevance of Basic Studies to Clinical Management. Baltimore , Urban and Schwarzenburg, 1985, p 183 8. Feely J, Wade D, McAllister CB, et al: Effect of hypotension on liver blood flow and lidocaine disposition. N Eng] J Med 307:866, 1982 9. Harrison DC: Antiarrhythmic drug classification: New science and practical applications. Am J Cardiol 56:185, 1985


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10. Heistracher P: Mechanisms of action of antifibrillatory drugs. Naunyn Schmiedebergs Arch Pharmacol 269:199-211, 1971 11. Latini R, Connolly SJ, Kates RE: Myocardial disposition of amiodarone in the dog. J Pharmacol Exp Ther 224:603, 1983 12. Lucchesi BR, Patterson ES: Antiarrhythmic drugs. In Antonaccio MJ (ed): Cardiovascular Pharmacology, ed 2. New York, Raven Press, 1984, p 329 13. Mason DT, DeMaria AN, Amsterdam EA, et al: Antiarrhythmic agents I: Mechanisms of action and clinical pharmacology. Drugs 5:261, 1973 14. Mason DT, DeMaria AN, Amsterdam EA, et al: Antiarrhythmic agents II: Therapeutic considerations. Drugs 5:292, 1973 15. Materson BJ, Caralis PV: Risk of cardiac arrhythmias in relation to potassium imbalance. · J Cardiovasc Pharmacol 6:S493, 1984 16. McGovern B: Hypokalemia and cardiac arrhythmias. (Editorial views.) Anesthesiology 63:127, 1985 17. Muir WW: Pharmacodynamics of antiarrhythmic and diuretic drugs in dogs and cats. Proceedings of the Ninth Annual Kal Kan Symposium for the Treatment of Small Animal Diseases, Columbus, OH, 1985 18. Muir WW, Sams RA: Clinical pharmacodynamics and pharmacokinetics of beta-adrenoceptor blocking drugs in veterinary medicine. Comp Cont Ed 156:156, 1984 19. Newman RK, Bishop VS, Peterson DF, et al: Effect of verapamil on left ventricular performance in conscious dogs. J Pharmacol Exp Ther 201:723, 1977 20. Papich MG, Davis LE, Davis CA, et al: Pharmacokinetics of procainamide hydrochloride in dogs. Am J Vet Res 47:2351, 1986 21. Resnekov L: Circulatory effects of cardiac dysrhythmias. Cardiovasc Clin 2:24, 1970 22. Rosen MR, Hoffman BF: Mechanisms of action of antiarrhythmic drugs. Circ Res 32:1, 1973 23. Singh BN, Baky S, Nademanee K: Second-generation calcium antagonists: Search for greater selectivity and versatility. Am J Cardiol 55:2148, 1985 24. Szekeres L, Vaughan Williams EM: Antilibrillatory action. J Physiol160:470-482, 1962 25. Williams EMV: A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 24:129, 1984

Address reprint requests to William W. Muir, III, DVM, PhD, ACVA, ACVECC The Ohio State University College of Veterinary Medicine 1935 Coffey Road Columbus, OH 43210

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Block and modulation of cardiac Na+ channels by antiarrhythmic drugs, neurotransmitters and hormones.