Introduction to Antidysrhythmic Drugs

Friday, January 10, 2003 8:00 a.m. - 8:50 a.m. L.S. Satin, PhD E-mail: lssatin@vcu.edu Post a question to the bulletin board

Lecture Outline:
Objectives | Brief Review of Physiological Concepts | Mechanisms of Dysrhythmias General Strategy of Antidysrhythmic Drugs | Classification of Antidysrhythmic Drugs Key Aspects of Antidysrhythmic Drugs Action and Therapy | Learning Resources

OBJECTIVES: After studying the material presented, the student will understand the following concepts: 1. Distinguish how, in general, antidysrhythmic drugs suppress electrical disorders due to impairments of impulse generation or conduction. 2. Recognize how drugs differentially suppress firing in abnormal vs. normal cardiac tissue. 3. State-dependent drug action and its significance for antidysrhythmic action. 4. Recall the current Vaughan-Williams scheme for classifying antidysrhythmic drugs and its limitations. 5. Recognize the Sicilian Gambit classification of antidysrhythmic agents.

I.

Brief Review of Physiological Concepts: A. The response of cells to excitatory electrical stimuli is a function of the number of available sodium (Na) channels. An index of the number of open Na channels is dV/dt (of Phase 0) of the cardiac action potential (AP). B. Steady membrane depolarization decreases dV/dt, decreases Na current (INa) and slows conduction velocity. C. Abnormal heart tissue is usually depolarized, which reduces Na current, decreases dV/dt and decreases conduction velocity.

Chart 1

D. Voltage-dependent Na channel availability results from Voltage (Vm) -dependent Na channel states. Recovery time of Na channels from excitation/depolarization strongly contributes to the refractory period and is increased by many drugs (See chart 1). II. Mechanisms of dysrhythmias Dysrhythmias can occur because of: A. Abnormal impulse generation 1. abnormal automaticity of normally automatic cells (sinus, A-V, His-Purkinje cells) 2. abnormal generation of impulses in normally nonautomatic cells 3. Abnormal firing may result from: a. development of a phase 4 depolarization in normally nonautomatic cells b. "triggered activity" due to early or delayed afterdepolarizations (EADs, DADS) B. Abnormal impulse conduction 1. AV block: allows ventricle to fire at its own pacemaker rhythm 2. Re-entry: reexcitation around a conducting loop, which produces tachycardia requires:

a. unidirectional conduction block b. establishment of a new loop of excitation c. conduction time that outlasts refractory period Re-entry can occur in many sites in heart. III. General strategy of antidysrhythmic drugs Suppression of dysrhythmias A. Suppression of cells firing at high frequency at ectopic foci by blocking Na channels, eliminating phase 4 depolarization or increasing maximum diastolic potential B. Increase conduction block from unidirectional to bidirectional to prevent re-entry C. Alter timing or increase refractory period so that re-entered tissue becomes refractory to re-excitation IV. Classification of Antidysrhythmic Drugs A. Vaughan-Williams classification (1970), subsequently modified by Harrison. 1. based on the pattern of electrophysiological actions in normal tissue 2. presumes a mechanism of action of antidysrhythmic drugs 3. consists of four main classes and three subclasses Class I- directly block Na channels. All behave like local anaesthetics. Largest class of antidysrhythmics. Subclasses based on differing effects on AP duration (APD) and degree of Na channel block (Phase 0).

Table 1

Table 2

Table 3

B. Shortcomings of Vaughan-Williams system (V-W): 1. V-W is a hybrid in that Class I and Class IV agents block ion channels, Class II block receptors, Class III change an electrophysiological variable APD). In addition, a single class effect can come about by multiple mechanisms. Some drugs have properties of several classes (amiodarone, for example, has properties of classes I-IV ) and cannot be pigeonholed.

2. V-W describes antidysrhythmic drugs that block ion channels and does not consider drugs that activate channels or receptors. 3. V-W is incomplete, and does not include adenosine, digitalis, cholinergic agonists, alpha adrenergic blockers or agents that modulate gap junctions, ion pumps or exchangers. 4. The classification (excluding Class II) is mainly based on drugs which modify the electrophysiological characteristics of normal cardiac tissue. In diseased tissue, where dysrhythmias are more likely to occur, channels and receptors, and their responses to drugs, are modified. 5. Does not incorporate the idea that antidysrhythmic drugs may be effective in various ways: slowing tachycardias, terminating dysrhythmias, or preventing them. C. Sicilian Gambit (S-G) classification (1991) 1. S-G approach assumes that an alteration in one or more electrophysiological parameters will terminate or prevent a given type of dysrhythmia ("vulnerable parameters") See Tables 4 and 5. 2. Usually one of the vulnerable parameters can be changed with a minimum of undesireable effects. 3. Example: abnormal automaticity at an ectopic atrial focus yields an atrial tachycardia. The vunerable parameter here is the maximum diastolic potential. Thus, increasing the diastolic potential with a drug known to hyperpolarize atrial cells (such as an M2 muscarinic agonist) would be therapeutic. V. Key aspects of antidysrhythmic drug action and therapy A. Antidysrhythmic drug action is state-dependent; drug effects depend on the molecular states of the channel (i.e. open, closed, or inactivated). Two current models: 1. modulated receptor hypothesis: different states have different affinities 2. guarded receptor hypothesis: channel gate limits drug access to site

B. Antidysrhythmic drugs selectively affect firing and conduction in abnormal/depolarized cells. See Table 3. C. Since transitions between different states are dependent on membrane voltage and cell firing frequency, drug action is also dependent on membrane voltage and spike frequency. In addition, by binding to inactivated states and slowing recovery from inactivation, some drugs can increase the time needed for recovery from inactivation. Figure 1

D. Antidysrhythmic drugs also selectively affect different parts of the heart (See Table 2) 1. Ca channel blockers (Class IV) are selective for AV and S-A node, where Ca APs predominate. This explains why Class IV drugs are useful for treating A-V re-entrant tachycardias 2. Lidocaine (Class IB) is useful for treating PVCs in Purkinje fibers, since longer APDs in Purkinje yield more inactivated Na channels. Lidocaine selectively blocks inactivated state Na channels. Lidocaine has little effect on atrial tissue. 3. Quinidine affects both atrial and ventricular dysrhythmias (but usually used to treat atrial fibrillation). Other aspects of antidysrhythmic drugs: E. usually have more than one action, which can hinder understanding their major mechanism of action. F. can be prodysrhythmic under certain circumstances G. often affect the autonomic nervous system, and have hemodynamic effects and effects on cardiovascular reflexes

H. may have significant cardiac and extracardiac toxicity; many Class 1A drugs, for example, can seriously depress cardiac contractility directly by acting on heart muscle I. can interact with other drugs. Useful interactions as well as deleterious interactions occur, with the former exploited in combination therapy (e.g. quinidine and digoxin to treat supraventricular tachycardias). Combinations of antidysrhythmics are used to increase the efficacy of therapy and to avoid the necessity of using higher doses of any particular drug alone. Table 4

Table 5

Learning Resources: Recommended Reading: Books 1. Basic and Clinical Pharmacology, Katzung (Eighth Ed.), Chapter 14, p.219-244 2. The Pharmacological Basis of Therapeutics, Goodman & Gilman (9th Ed.), Chapter 35, p.839 3. Cardiovascular Drug Therapy, Messerli, F.H., p. 1150-1181. W.B. Saunders Press, 1990. Articles 1. The Sicilian Gambit, European Society of Cardiology (1991), Circulation 84: 1831-1851 2. Antiarrhythmic Drugs, Woosley, R.L. (1991). Ann. Rev. Pharm. Tox. 31:427-455 Instructional Interactive CD-ROM

1. The Sicilian Gambit, Knoll Pharmaceuticals, 1992. In the LRC, Hunton Hall. Highly recommended.