Authors: Stoelting, Robert K.; Hillier, Simon C.

Title: Handbook of Pharmacology and Physiology in Anesthetic Practice, 2nd Edition Copyright 2006 Lippincott Williams & Wilkins > Table of Contents > I - Pharmacology > 17 - Cardiac Antidysrhythmic Drugs 17 Cardiac Antidysrhythmic Drugs The use of antidysrhythmic drugs for the treatment and prevention of cardiac dysrhythmias is limited by the potential for these drugs to depress left ventricular contractility and the triggering of new dysrhythmias (Stoelting RK, Hillier SC. Cardiac antidysrhythmic drugs. In: Pharmacology and Physiology in Anesthetic Practice, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2006: 370-386). For these reasons, the pharmacologic treatment of cardiac dysrhythmias is principally used to treat atrial fibrillation and atrial flutter that is not responsive to catheter ablation treatment and for patients with implantable cardioverter-defibrillator devices who are receiving frequent but needed electrical shocks. The pharmacologic treatment of cardiac dysrhythmias and disturbances in the conduction of cardiac impulses using antidysrhythmic drugs is based on an understanding of the electrophysiologic basis of the abnormality and the mechanism of action of the therapeutic drug to be administered. The two major physiologic mechanisms that cause ectopic cardiac dysrhythmias are reentry and enhanced automaticity (Table 17-1). In many patients, the correction of identifiable precipitating events is not sufficient to suppress cardiac ectopic dysrhythmias, and therefore specific cardiac antidysrhythmic drugs may be administered. Drugs administered for the chronic suppression of cardiac dysrhythmias pose little threat to the uneventful course of anesthesia and should be continued P.376 up to the time of anesthesia induction. The majority of cardiac dysrhythmias that occur during anesthesia do not require therapy (Table 17-2). TABLE 17-1. FACTORS UNDERLYING CARDIAC DYSRHYTHMIAS Arterial hypoxemia Electrolyte abnormalities (hypokalemia or hypomagnesemia as produced by diuretics predispose to ventricular dysrhythmias) Acid-base abnormalities (alkalosis more likely than acidosis to trigger cardiac dysrhythmias) Altered autonomic nervous system activity (increased activity predisposes to ventricular fibrillation) Bradycardia (predisposes to ventricular dysrhythmias) Drugs MECHANISM OF ACTION Cardiac antidysrhythmic drugs produce pharmacologic effects by blocking the passage of ions across the sodium, potassium, and calcium ion channels present in the heart. CLASSIFICATION Cardiac antidysrhythmic drugs are most commonly classified into four groups based primarily on the ability of P.377 the drug to control dysrhythmias by blocking specific ion channels and current during the cardiac action potential (Tables 17-3 and 17-4). Antidysrhythmic drugs differ in their pharmacokinetics and efficacy in treating specific types of cardiac dysrhythmias (Tables 17-5 and 17-6). TABLE 17-2. EXAMPLES OF CARDIAC DYSRHYTHMIAS THAT REQUIRE TREATMENT

Persists despite removing the precipitating cause Hemodynamic function is compromised Predisposes to more serious cardiac dysrhythmias TABLE 17-3. CLASSIFICATION OF CARDIAC ANTIDYSRHYTHMIC DRUGS Class I (inhibit fast sodium ion channels) Class IA Quinidine Procainamide Disopyramide Moricizine Class IB Lidocaine Tocainide Mexiletine Class IC Flecainide Propafenone Class II (decrease rate of depolarization) Esmolol Propranolol Acebutolol Class III (inhibit potassium ion channels) Amiodarone Sotalol Ibutilide Dofetilide Bretylium Class IV (inhibit slow calcium channels) Verapamil Diltiazem P.378 TABLE 17-4. ELECTROPHYSIOLOGIC AND ELECTROCARDIOGRAPHIC EFFECTS OF CARDIAC ANTIDYSRHYTHMIC DRUGS Class IA Class IB Class IC Class II Class III Class IV Depolarization rate Decreased No effect Greatly No effect No effect No effect (phase 0) decreased Conduction Decreased No effect Greatly Decreased Decreased No effect velocity decreased Effective Greatly Decreased Increased Decreased Greatly No effect refractory period increased increased Action potential Increased Decreased Increased Increased Greatly Decreased duration increase Automaticity Decreased Decreased Decreased Decreased Decreased No effect P-R duration No effect No effect Increased No effect or Increased No effect Increased QRS duration Increased No effect Greatly No effect Increased No effect

QTc duration

Greatly increased

increased No effect or Increased decreased

Decreased

Greatly increased

No effect

P.379 TABLE 17-5. PHARMACOKINETICS OF CARDIAC ANTIDYSRHYTHMIC DRUGS Principal Clearance Protein Elimination Half- Therapeutic Plasma Mechanism Binding (%) Time (hrs) Concentration Quinidine Hepatic 80-90 5-12 1.2-4.0 g/mL Procainamide Renal/hepatic 15 2.5-5.0 4-8 g/mL DisopyramideRenal/hepatic 15 8-12 2-4 g/mL Lidocaine Hepatic 55 1.4-8.0 1-5 g/mL Tocainide Hepatic/renal 10-30 12-15 4-10 g/mL Mexiletine Hepatic 60-75 6-12 0.75-2.00 g/mL Flecainide Hepatic 30-45 13-30 0.3-1.5 g/mL Propafenone Hepatic >95 5-8 Propranolol Hepatic 90-95 2-4 10-30 ng/mL Amiodarone Hepatic 96 68-107 days 1.5-2.0 g/mL Sotalol Renal Verapamil Hepatic 90 4.5-12.0 100-300 ng/mL P.380 TABLE 17-6. EFFICACY OF CARDIAC ANTIDYSRHYTHMIC DRUGS Conversion of Paroxysmal Premature Atrial Supraventricular Ventricular Ventricular Fibrillation Tachycardia Contractions Tachycardia Quinidine + ++ ++ + Procainamide + ++ ++ ++ Disopyramide+ ++ ++ ++ Lidocaine + 0 ++ ++ Tocainide 0 0 ++ ++ Mexiletine 0 0 ++ ++ Moricizine 0 0 ++ ++ Flecainide 0 + ++ ++ Propafenone 0 + ++ ++ Propranolol + ++ + + Amiodarone + ++ ++ ++ Sotalol ++ + + + Verapamil + ++ 0 0 Diltiazem + ++ 0 0 Digitalis ++ ++ 0 0 Adenosine 0 ++ 0 0 0, no effect; +, effective; ++, highly effective. P.381 PRODYSRHYTHMIC EFFECTS The prodysrhythmic effects of these drugs describe those bradydysrhythmias or tachydysrhythmias that represent new cardiac dysrhythmias associated with chronic antidysrhythmic drug treatment.

Torsade de Pointes Torsade de pointesa polymorphic ventricular tachycardia and ventricular fibrillationis associated with class IA drugs (quinidine, disopyramide) and class III drugs (amiodarone) that prolong the QTc interval by potassium channel blockade. Predisposing factors include hypokalemia, hypomagnesemia, poor left ventricular function, and the concomitant administration of other QTc-prolonging drugs. Incessant Ventricular Tachycardia Incessant ventricular tachycardia may be precipitated by cardiac antidysrhythmic drugs that slow the conduction of cardiac impulses (class IA and class IC drugs) sufficiently to create a continuous ventricular tachycardia reentry circuit. Wide Complex Ventricular Tachycardia Wide complex ventricular tachycardia is usually associated with class IC cardiac antidysrhythmic drugs in the setting of structural heart disease. EFFICACY AND RESULTS OF TREATMENT USING CARDIAC ANTIDYSRHYTHMIC DRUGS Suppression of ventricular ectopy using a cardiac antidysrhythmic drug does not prevent future life-threatening P.382 dysrhythmias and may increase mortality. In fact, patients treated with class IC cardiac antidysrhythmic drugs experienced a higher incidence of sudden cardiac arrest, reflecting the protodysrhythmic effects of these drugs. Survivors of cardiac arrest have a high risk of subsequent ventricular fibrillation, and the treatment of these patients with amiodarone results in fewer life-threatening cardiac events. PROPHYLACTIC ANTIDYSRHYTHMIC THERAPY Lidocaine is not recommended as a prophylactic treatment for patients in the early stages of acute myocardial infarction and without malignant ventricular ectopy. Calcium channel antagonists are not recommended as routine treatment of patients with acute myocardial infarction, because mortality is not decreased by these drugs. Treatment with magnesium is indicated in those patients who, following an acute myocardial infarction, develop torsade de pointes ventricular tachycardia. DECISION TO TREAT CARDIAC DYSRHYTHMIAS The benefit of antidysrhythmic drugs is clearest when it results in the immediate termination of a sustained tachycardia (as in ventricular tachycardia suppressed by lidocaine or supraventricular tachycardia suppressed by adenosine or verapamil). Conversely, it has been difficult to demonstrate that antidysrhythmic drugs alleviate those symptoms related to chronic cardiac dysrhythmias, a situation in which the risk of side effects is greater. The mechanism by which adrenergic antagonists decrease mortality after an acute myocardial infarction is not known. P.383 QUINIDINE Quinidine is a class IA drug that is effective in the treatment of acute and chronic supraventricular dysrhythmias. It slows the atrial rate in the presence of atrial fibrillation and suppresses tachydysrhythmias associated with Wolff-Parkinson-White syndrome. Mechanism of Action Quinidine decreases the slope of phase 4 depolarization, which explains its effectiveness in suppressing the cardiac dysrhythmias caused by enhanced automaticity. Metabolism and Excretion

Quinidine is hydroxylated in the liver to inactive metabolites, which are excreted in the urine. The accumulation of quinidine or its metabolites may occur in the presence of hepatic and/or renal dysfunction. Side Effects Quinidine has a low therapeutic ratio, and its side effects are predictable if the plasma concentration becomes excessive (Table 17-7). PROCAINAMIDE Procainamide is as effective as quinidine for the treatment of ventricular tachydysrhythmias but is not as effective in abolishing atrial tachydysrhythmias. Although procainamide and quinidine have a broader spectrum of antidysrhythmic effects than lidocaine (useful in the treatment of supraventricular and ventricular cardiac dysrhythmias), they are rarely used during anesthesia because of their propensity to produce hypotension. P.384 TABLE 17-7. SIDE EFFECTS OF QUINIDINE Prolongation of the P-R and QTc interval and widening of the QRS complex (heart block may occur) Syncope (may reflect ventricular dysrhythmias) Hypotension (vasodilation especially if administered IV) Atropine-like action Allergic reactions Thrombocytopenia Nausea and vomiting Tinnitus and blurring of vision Accentuate effects of neuromuscular blocking drugs (quinine like effects) Mechanism of Action Procainamide is an analog of the local anesthetic procaine and possesses an electrophysiologic action similar to that of quinidine; however, it produces less prolongation of the QTc interval. Metabolism and Excretion Procainamide is eliminated by renal (unchanged) and hepatic metabolism (acetylated to N-acetyl procainamideactivity of the necessary enzyme is genetically determined). The acetylated metabolite of procainamide is pharmacologically active. Side Effects The incidence of side effects is high when procainamide is used as an antidysrhythmic drug. These effects include hypotension due to direct myocardial depression. P.385 DISOPYRAMIDE Disopyramide is comparable to quinidine in effectively suppressing atrial and ventricular tachydysrhythmias. Prolongation of the QTc interval and paradoxical ventricular tachycardia (similar to quinidine) may occur. The potential for direct myocardial depression, especially in patients with preexisting left ventricular dysfunction, seems to be greater with this drug than with quinidine and procainamide. MORICIZINE Moricizine is a phenothiazine derivative with modest efficacy in the treatment of sustained ventricular dysrhythmias; it is best reserved for the treatment of life-threatening ventricular dysrhythmias, in view of its prodysrhythmic effects. LIDOCAINE

Lidocaine is used principally for the suppression of ventricular dysrhythmias (premature ventricular contractions, ventricular tachycardia), having minimal effects on supraventricular tachydysrhythmias. The efficacy of prophylactic lidocaine therapy for preventing ventricular fibrillation after acute myocardial infarction has not been documented, and its use is no longer recommended. In adult patients with normal cardiac output, hepatic function, and hepatic blood flow, an initial intravenous administration of lidocaine, 2 mg/kg, followed by a continuous infusion of 1 to 4 mg/min should provide therapeutic plasma lidocaine concentrations of 1 to 5 g/mL. Mechanism of Action Lidocaine delays the rate of spontaneous phase 4 depolarization by preventing or diminishing the gradual P.386 decrease in potassium ion permeability that normally occurs during this phase. Metabolism and Excretion Lidocaine is metabolized in the liver, and the resulting metabolites may possess cardiac antidysrhythmic activity. Side Effects Lidocaine is essentially devoid of effects on the ECG or cardiovascular system when the plasma concentration remains <5 g/mL (Table 17-8). TOCAINIDE Tocainide, like mexiletine, is an orally effective amine analog of lidocaine that is used for the chronic suppression of ventricular cardiac tachydysrhythmias. MEXILETINE Mexiletine is an orally effective amine analog of lidocaine that is used for the chronic suppression of ventricular cardiac tachydysrhythmias. TABLE 17-8. SIDE EFFECTS OF LIDOCAINE Hypotension (peripheral vasodilation and myocardial depression when plasma concentrations 5 to 10 g/mL) Bradycardia (slowing of conduction of cardiac impulses, prolonged P-R interval, widened QRS complex) Seizures (plasma concentrations 5 to 10 g/mL) CNS depression, apnea, cardiac arrest (plasma concentrations >10 g/mL) P.387 PHENYTOIN Phenytoin is particularly effective in the suppression of ventricular dysrhythmias associated with digitalis toxicity. Phenytoin may be useful in the treatment of paradoxical ventricular tachycardia or torsade de pointes that is associated with a prolonged QTc. Mechanism of Action The effects of phenytoin on automaticity and velocity of conduction of cardiac impulses resemble those of lidocaine. Metabolism and Excretion Phenytoin is hydroxylated and then conjugated with glucuronic acid for excretion in the urine. Side Effects (Table 17-9) FLECAINIDE

Flecainide is a fluorinated local anesthetic analog of procainamide that is more effective in suppressing ventricular premature beats and ventricular tachycardia than quinidine and disopyramide. Flecainide is also effective in the treatment of atrial tachydysrhythmias. TABLE 17-9. SIDE EFFECTS OF PHENYTOIN Cerebellar disturbances (ataxia, nystagmus, confusion) Hyperglycemia (inhibition of insulin secretion) Thrombocytopenia (bone marrow depression) Skin rash P.388 Side Effects Prodysrhythmic side effects occur in a significant number of treated patients, especially in the presence of left ventricular dysfunction. PROPAFENONE Propafenone, like flecainide, is an effective antidysrhythmic drug for the suppression of ventricular and atrial tachydysrhythmias. Prodysrhythmic effects are more likely to occur in patients with preexisting ventricular dysrhythmias. -ADRENERGIC ANTAGONISTS -Adrenergic antagonists are effective for the treatment of cardiac dysrhythmias related to enhanced activity of the sympathetic nervous system (perioperative stress, thyrotoxicosis, pheochromocytoma). Propranolol and esmolol are effective for controlling the rate of ventricular response in patients with atrial fibrillation and atrial flutter. Multifocal atrial tachycardia may respond to esmolol or metoprolol but is best treated with amiodarone. Acebutolol is effective in the treatment of frequent premature ventricular contractions. -Adrenergic antagonists, especially propranolol, may be effective in controlling torsade de pointes for patients with prolonged QTc intervals. Acebutolol, propranolol, and metoprolol are approved for the prevention of sudden death following myocardial infarction. Mechanism of Action The antidysrhythmic effects of -adrenergic antagonists most likely reflect a blockade of the responses to -receptors in the heart to sympathetic nervous system stimulation, as well as the effects of circulating catecholamines. As a result, the rate of spontaneous phase 4 depolarization is decreased and the rate of sinoatrial node discharge is decreased. P.389 The usual oral dose of propranolol for the chronic suppression of ventricular dysrhythmias is 10 to 80 mg every 6 to 8 hours. Effective -blockade is usually achieved in an otherwise normal person when the resting heart rate is 55 to 60 beats/minute. Metabolism and Excretion Orally administered propranolol is extensively metabolized in the liver, and a hepatic first-pass effect is responsible for the variation in plasma concentration; the therapeutic plasma concentration of propranolol may vary from 10 to 30 ng/mL. Propranolol readily crosses the blood-brain barrier. The principal metabolite of propranolol is 4-hydroxypropranolol, which possesses weak -adrenergic antagonist activity. Side Effects (Table 17-10) TABLE 17-10. SIDE EFFECTS OF BETA-ADRENERGIC ANTAGONISTS Bradycardia Hypotension Myocardial depression

Bronchospasm Congestive heart failure (especially in patients dependent on sympathetic nervous system activity as a compensatory mechanism) Heart block (do not administer these drugs to patients with preexisting heart block) Worsening of Raynaud's disease Mental depression Up-regulation of -adrenergic receptors (manifests as supraventricular tachycardia when treatment is abruptly discontinued) P.390 AMIODARONE Amiodarone is a potent antidysrhythmic drug with a wide spectrum of activity against refractory supraventricular and ventricular tachydysrhythmias. In the presence of ventricular tachycardia or fibrillation that is resistant to electrical defibrillation, amiodarone (300 mgIV) is recommended. Lidocaine or procainamide are recommended during cardiopulmonary resuscitation only when amiodarone has been ineffective. Administered over 2 to 5 minutes, a dose of 5 mg/kg IV produces a prompt antidysrhythmic effect that lasts up to 4 hours. After discontinuation of chronic oral therapy, the pharmacologic effect of amiodarone lasts for a prolonged period (up to 60 days), reflecting the prolonged elimination half-time of this drug. Mechanism of Action Amiodarone, a benzofluorene derivative, is 37% iodine by weight and structurally resembles thyroxine. It prolongs the effective refractory period of all cardiac tissues, including the sinoatrial node, atrium, atrioventricular node, His-Purkinje system, and ventricle. Amiodarone has an antiadrenergic effect (noncompetitive blockade of -and -receptors) and a minor negative inotropic effect. Metabolism and Excretion Amiodarone has a prolonged elimination half-time (29 days) and large volume of distribution (Vd). This drug is minimally dependent on renal excretion. The principal metabolite, desethylamiodarone, is pharmacologically active and has a longer elimination half-time than the parent drug, resulting in an accumulation of this metabolite following chronic therapy. Side Effects Side effects in patients treated chronically with amiodarone are common, especially when the daily maintenance dose exceeds 400 mg (Table 17-11). P.391 TABLE 17-11. SIDE EFFECTS OF CHRONIC AMIODARONE THERAPY Pulmonary toxicity Pulmonary alveolitis (occurs in 5% to 15% of treated patients) Slow insidious onset characterized by dyspnea, cough, and pulmonary infiltrates on x-ray Acute onset of dyspnea, cough, and arterial hypoxemia Cardiotoxicity Prolongation of QTc interval Atrioventricular heart block (potential need for a temporary artificial pacemaker) Ocular, Dermatologic, Neurologic, and Hepatic Corneal micro deposits Photosensitivity Peripheral neuropathy Increases in plasma transaminase concentrations

Pharmacokinetic Inhibition of P-450 enzymes (increased plasma concentrations of digoxin, warfarin) Endocrine Hypothyroidism Hyperthyroidism (as late as 5 months after discontinuing therapy) SOTALOL Sotalol is administered for the treatment of sustained ventricular tachycardia or ventricular fibrillation. Sotalol is a nonselective -adrenergic antagonist drug at low doses, and at higher doses, it prolongs the cardiac action potential in the atria, ventricles, and accessory bypass tracts. Because of its prodysrhythmic effects (torsade de pointes), this drug is usually restricted for patients with life-threatening ventricular dysrhythmias. Excretion is mainly through the kidneys. P.392 IBUTILIDE Ibutilide is effective for the conversion of recent onset atrial fibrillation or atrial flutter to normal sinus rhythm. Hepatic metabolism is extensive. Polymorphic ventricular tachycardia, with or without prolongation of the QTc interval, may occur. DOFETILIDE Dofetilide is effective for the conversion of recent-onset atrial fibrillation or atrial flutter to normal sinus rhythm. This drug is excreted unchanged in the urine. Torsade de pointes occurs, especially in patients with preexisting left ventricular dysfunction. BRETYLIUM Bretylium is no longer recommended for the treatment of ventricular fibrillation during cardiopulmonary resuscitation, because it is less effective than amiodarone and has more side effects. VERAPAMIL AND DILTIAZEM Among the calcium channel blockers, verapamil and diltiazem have the greatest efficacy for the treatment of cardiac dysrhythmias. Intravenous verapamil is highly effective in terminating paroxysmal supraventricular tachycardia (75 to 150 g/kg over 1 to 3 minutes, followed by a continuous infusion of about 5 g/kg per minute to maintain a sustained effect). This drug also effectively controls the ventricular rate in most patients who develop atrial fibrillation or flutter. Verapamil does not have a depressant effect on accessory tracts and thus will not slow the ventricular response rate in patients with Wolff-Parkinson-White syndrome. P.393 Mechanism of Action Verapamil and the other calcium channel blockers inhibit the flux of calcium ions across the slow channels of smooth muscle and cardiac cells. This effect manifests as a decreased rate of spontaneous phase 4 depolarization. Verapamil has a substantial depressant effect on the atrioventricular node and a negative chronotropic effect on the sinoatrial node. Metabolism and Excretion An estimated 70% of an injected dose of verapamil is eliminated by the kidneys. Side Effects (Table 17-12) OTHER CARDIAC ANTIDYSRHYTHMIC DRUGS Digitalis Preparations Digitalis preparations, such as digoxin, are effective cardiac antidysrhythmics for the stabilization of atrial electrical activity and the treatment and prevention of atrial tachydysrhythmias.

Adenosine Adenosine is an endogenous nucleoside that slows the conduction of cardiac impulses through the atrioventricular node, making it an effective alternative to calcium channel blockers (verapamil) for the treatment of paroxysmal supraventricular tachycardia, including that due to conduction through accessory pathways in patients with Wolff-Parkinson-White syndrome. This drug is not effective in the treatment of atrial fibrillation, atrial flutter, or ventricular tachycardia. The usual dose of adenosine is 6 mgIV followed, if necessary, by a repeat injection of 6 to 12 mgIV about 3 minutes later. P.394 TABLE 17-12. SIDE EFFECTS OF CALCIUM CHANNEL BLOCKERS USED TO TREAT CARDIAC DYSRHYTHMIAS Atrioventricular heart block Direct myocardial depression Hypotension (vasodilation) Potentiation of anesthetic-induced myocardial depression Exaggeration of effects of neuromuscular-blocking drugs Mechanism of Action Adenosine stimulates cardiac adenosine1 receptors to increase potassium ion currents, shorten the action potential duration, and hyperpolarize cardiac cell membranes. Short-lived cardiac effects (elimination half-time 10 seconds) are due to carrier-mediated cellular uptake and metabolism to inosine by adenosine deaminase. Side Effects (Table 17-13) TABLE 17-13. SIDE EFFECTS OF ADENOSINE Flushing Headache Dyspnea Chest discomfort Nausea Atrioventricular heart block Bronchospasm