Quinidine is a class IA drug that is effective in the treatment of acute and chronic supraventricular arrhythmia (rarely used because of its side effects). Supraventricular tachyarrhythmias associated with Wolff-Parkinson-White syndrome are effectively suppressed by quinidine.

1. Mechanism of Action. Quinidine decreases the slope of phase 4 depolarization, which explains its effectiveness in suppressing cardiac arrhythmias caused by enhanced automaticity.

2. Metabolism and Excretion

   1. Quinidine is hydroxylated in the liver to inactive metabolites, which are excreted in the urine.

   2. The concurrent administration of phenytoin or rifampin may lower blood levels of quinidine by enhancing liver clearance.

3. Side Effects. Quinidine has a low therapeutic ratio, with heart block, hypotension, and proarrhythmia being potential adverse side effects.

Procainamide is as effective as quinidine for the treatment of ventricular tachyarrhythmias but less effective in abolishing atrial tachyarrhythmias. Premature ventricular contractions and paroxysmal ventricular tachycardia are suppressed in most patients within a few minutes after intravenous (IV) administration, which is better tolerated than IV quinidine but may still cause hypotension.

1. Mechanism of Action

   1. Procainamide is an analogue of the local anesthetic procaine.

   2. Procainamide possesses an electrophysiologic action similar to that of quinidine but produces less prolongation of the QTc interval on the ECG (paradoxical ventricular tachycardia is a rare feature of procainamide therapy).

   3. Procainamide has no vagolytic effect and can be used in patients with atrial fibrillation to suppress ventricular irritability without increasing the ventricular rate.

2. Metabolism and Excretion

   1. Procainamide is eliminated by renal excretion and hepatic metabolism (dose of procainamide must be decreased when renal function is abnormal).

   2. The activity of the N-acetyltransferase enzyme response for the acetylation of procainamide is genetically determined (in patients who are rapid acetylators, the elimination half-time of procainamide is 2.5 hours compared with 5 hours in slow acetylators).

3. Side Effects

   1. Similar to quinidine, use of procainamide has dramatically decreased due to its side effect profile and availability of newer agents.

   2. Hypotension that results from procainamide is more likely to be caused by direct myocardial depression than peripheral vasodilation.

   3. Chronic administration of procainamide may be associated with a syndrome that resembles systemic lupus erythematosus.

Disopyramide is comparable to quinidine in effectively suppressing atrial and ventricular tachyarrhythmias. About 50% of the drug is excreted unchanged by the kidneys.

1. Side Effects

   1. The most common side effects of disopyramide are dry mouth and urinary hesitancy, both of which are caused by the drug’s anticholinergic activity.

   2. Prolongation of the QTc interval on the ECG and paradoxical ventricular tachycardia (similar to quinidine) may occur.

   3. Disopyramide has significant myocardial depressant effects and can precipitate congestive heart failure and hypotension.

Moricizine is a phenothiazine derivative that is reserved for the treatment of life-threatening ventricular arrhythmias when other drugs such as amiodarone are not available or contraindicated (e.g., allergy).

1. Side Effects. Proarrhythmic effects occur in 3% to 15% of patients treated chronically with moricizine.

Lidocaine is used principally for suppression of ventricular arrhythmias, having minimal if any effect on supraventricular tachyarrhythmias. The efficacy of prophylactic lidocaine therapy for preventing early ventricular fibrillation after acute myocardial infarction has not been documented and is no longer recommended. Advantages of lidocaine over quinidine or procainamide are the more rapid onset and prompt disappearance of effects when the continuous infusion is terminated, greater therapeutic index, and a much reduced side effect profile. Lidocaine for IV administration differs from that used for local anesthesia because it does not contain a preservative.

1. Mechanism of Action

   1. The effectiveness of lidocaine in suppressing premature ventricular contractions reflects its ability to decrease the rate of spontaneous phase 4 depolarization.

   2. The ineffectiveness of lidocaine against supraventricular tachyarrhythmias presumably reflects its inability to alter the rate of spontaneous phase 4 depolarization in atrial cardiac cells.

2. Metabolism and Excretion. Lidocaine is metabolized in the liver, and resulting metabolites may possess cardiac antiarrhythmic activity.

3. Side Effects

   1. Lidocaine is essentially devoid of effects on the ECG or cardiovascular system when the plasma concentration remains less than 5 μg/mL (does not alter the duration of the QRS complex on the ECG, and activity of the sympathetic nervous system is not changed).

   2. Toxic plasma concentrations of lidocaine (>5 to 10 μg/mL) produce peripheral vasodilation and direct myocardial depression, resulting in hypotension.

   3. Stimulation of the central nervous system (CNS) occurs in a dose-related manner, with symptoms appearing when plasma concentrations of lidocaine are greater than 5 μg/mL. Seizures are possible at plasma concentrations of 5 to 10 μg/mL.

   4. CNS depression, apnea, and cardiac arrest are possible when plasma lidocaine concentrations are greater than 10 μg/mL.

   5. The convulsive threshold for lidocaine is decreased during arterial hypoxemia, hyperkalemia, or acidosis (importance of monitoring these parameters during continuous infusion of lidocaine to patients for suppression of ventricular arrhythmias).

Mexiletine is an orally effective amine analogue of lidocaine that is used for the chronic suppression of ventricular cardiac tachyarrhythmias. As it is a lidocaine analog, mexiletine may be effective in decreasing neuropathic pain for patients in whom alternative pain medications have been unsatisfactory.

1. Side Effects

   1. Neurologic side effects include tremulousness, diplopia, vertigo, and occasionally slurred speech.

   2. Increases in liver enzymes may occur especially in patients manifesting congestive heart failure.

Tocainide is an orally effective amine analogue of lidocaine that is used for the chronic suppression of ventricular cardiac tachyarrhythmias.

Phenytoin is particularly effective in suppression of ventricular arrhythmias associated with digitalis toxicity and may be useful in the treatment of paradoxical ventricular tachycardia or torsades de pointes. The IV dose is 100 mg (1.5 mg/kg) every 5 minutes until the cardiac arrhythmia is controlled or 10 to 15 mg/kg (maximum 1,000 mg) has been administered. Because phenytoin can precipitate in 5% dextrose in water, it is preferable to give the drug via a delivery tubing containing normal saline.

1. Mechanism of Action

   1. Phenytoin exerts a greater effect on the electrocardiographic QTc interval than does lidocaine and shortens the QTc interval more than any of the other antiarrhythmic drugs.

   2. The ability of some volatile anesthetics to depress the sinoatrial node is a consideration if administration of phenytoin during general anesthesia is planned.

2. Metabolism and Excretion

   1. Phenytoin is hydroxylated and then conjugated with glucuronic acid for excretion in the urine (impaired hepatic function may result in higher than normal blood levels of the drug).

   2. Warfarin, phenylbutazone, and isoniazid may inhibit metabolism and increase phenytoin blood levels.

3. Side Effects

   1. Phenytoin toxicity most commonly manifests as CNS disturbances, especially cerebellar disturbances (ataxia, nystagmus, vertigo, slurred speech, sedation, mental confusion).

   2. Phenytoin partially inhibits insulin secretion and may lead to increased blood glucose levels in patients who are hyperglycemic.

   3. Leukopenia, granulocytopenia, and thrombocytopenia may occur as a manifestation of drug-induced bone marrow depression.

Flecainide is a fluorinated local anesthetic analogue of procainamide that is more effective in suppressing ventricular premature beats and ventricular tachycardia than quinidine and disopyramide. Flecainide is also effective for the treatment of atrial tachyarrhythmias (effective for the treatment of tachyarrhythmias).

1. Metabolism and Excretion

   1. Oral absorption of flecainide is excellent, and a prolonged elimination half-time (about 20 hours) makes a twice daily dose of 100 to 200 mg acceptable (not available in an IV formulation).

   2. Elimination of flecainide is decreased in patients with congestive heart failure or renal failure and decreased left ventricular function.

2. Side Effects

   1. Proarrhythmic effects occur in a significant number of treated patients especially in the presence of left ventricular dysfunction.

   2. Flecainide prolongs the QRS complex and may depress sinoatrial node function as do -adrenergic antagonists and calcium channel blockers (not administered to patients with second- and third-degree atrioventricular heart block).

   3. The most common noncardiac adverse effect of flecainide is dose-related blurred vision.

   4. Flecainide increases the capture thresholds of pacemakers.

Propafenone, like flecainide, is an effective oral antiarrhythmic drug for suppression of ventricular and atrial tachyarrhythmias. The rate of metabolism is genetically determined with about 90% of patients able to metabolize propafenone efficiently in the liver (availability of propafenone increases significantly in the presence of liver disease).

1. Side Effects

   1. Propafenone depresses the myocardium and may cause conduction abnormalities such as sinoatrial node slowing, atrioventricular block, and bundle branch block.

   2. Propafenone interferes with the metabolism of propranolol and metoprolol resulting in increased plasma concentrations of these blockers. This drug also increases the plasma concentration of warfarin and may prolong the prothrombin time.

-Adrenergic antagonists are effective for treatment of cardiac arrhythmias related to enhanced activity of the sympathetic nervous system (perioperative stress). 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 torsades de pointes for patients with prolonged QTc intervals. Acebutolol, propranolol, and metoprolol are approved for prevention of sudden death following myocardial infarction.

1. Mechanism of Action

   1. The antiarrhythmic effects of -adrenergic antagonists most likely reflect blockade of the responses of receptors in the heart to sympathetic nervous system stimulation, as well as the effects of circulating catecholamines (rate of spontaneous phase 4 depolarization is decreased and the rate of sinoatrial node discharge is decreased).

   2. -Adrenergic antagonists can depress the myocardium not only by blockade but also by direct depressant effects on cardiac muscle.

   3. The usual oral dose of propranolol for chronic suppression of ventricular arrhythmias 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 per minute. For emergency suppression of cardiac arrhythmias in an adult, propranolol may be administered IV in a dose of 1 mg per minute (3 to 6 mg).

2. Metabolism and Excretion

   1. Orally administered propranolol is extensively metabolized in the liver, and a hepatic first-pass effect is responsible for the variation in plasma concentration.

   2. Propranolol readily crosses the blood-brain barrier.

   3. The principal metabolite of propranolol is 4-hydroxypropranolol, which possesses weak -adrenergic antagonist activity.

3. Side Effects

   1. Bradycardia, hypotension, myocardial depression, and bronchospasm are side effects of -adrenergic antagonists that reflect the ability of these drugs to inhibit sympathetic nervous system activity. The use of propranolol in patients with preexisting atrioventricular heart block is not recommended.

   2. Interference with glucose metabolism may manifest as hypoglycemia in patients being treated for diabetes mellitus.

   3. Upregulation of -adrenergic receptors occurs with chronic administration of -adrenergic antagonists such that abrupt discontinuation of treatment may lead to supraventricular tachycardia.

Amiodarone is a potent antiarrhythmic drug with a wide spectrum of activity against refractory supraventricular and ventricular tachyarrhythmias. In the presence of ventricular tachycardia or fibrillation that is resistant to electrical defibrillation, amiodarone 300 mg IV is recommended. Preoperative oral administration of amiodarone decreases the incidence of atrial fibrillation after cardiac surgery. It is also effective for suppression of tachyarrhythmias associated with Wolff-Parkinson-White syndrome. Similar to blockers and unlike class I drugs, amiodarone decreases mortality after myocardial infarction. After initiation of oral therapy, a decrease in ventricular tachyarrhythmias occurs within 72 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 (Fig. 21-2).

Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been developed as an alternative for the treatment of atrial fibrillation and atrial flutter. The clinical use of dronedarone is limited by its contraindication in patients with permanent atrial fibrillation or patients with advanced or recent congestive heart failure exacerbations.

1. Mechanism of Action. Dronedarone has the pharmacologic ability to block multiple ion channels. It also has sympatholytic effects.

2. Metabolism and Excretion

   1. Dronedarone is well absorbed after oral administration undergoes significant first-pass metabolism that reduces its net bioavailability to 15%.

   2. Dronedarone is a substrate for and a moderate inhibitor of CYP3A4 (should not be coadministered with other CYP3A4 inhibitors such as antifungals, macrolide antibiotics, or protease inhibitors). When coadministered with moderate CYP3A4 inhibitors (verapamil, diltiazem), lower doses of concomitant drugs should be used to avoid severe bradycardia and conduction block.

3. Side Effects. The most frequently reported adverse effect of dronedarone is nausea and diarrhea. Treated patients do not have an increased rate of interstitial lung disease, hyperthyroid, or hypothyroidism.

Sotalol is a nonselective -adrenergic antagonist drug that is usually restricted for use in patients with life-threatening ventricular tachycardia or fibrillation.

1. Side Effects. The most dangerous side effect of sotalol is torsades de pointes. The blocking effects of sotalol result in decreased myocardial contractility, bradycardia, and delayed conduction of cardiac impulses through the atrioventricular node.

Ibutilide is effective for the conversion of recent onset atrial fibrillation or atrial flutter to normal sinus rhythm. Polymorphic ventricular tachycardia may occur during ibutilide treatment, especially in patients with predisposing factors (impaired left ventricular function, preexisting prolonged QTc intervals, hypokalemia, hypomagnesemia).

Bretylium is no longer recommended for treatment of ventricular fibrillation during cardiopulmonary resuscitation as it is less effective than amiodarone.

Verapamil and Diltiazem. Verapamil is highly effective in terminating paroxysmal supraventricular tachycardia, controls reentrant tachycardia, and 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. Verapamil has little efficacy in the therapy for ventricular ectopic beats. The usual dose of verapamil for suppression of paroxysmal supraventricular tachycardia is 5 to 10 mg IV (75 to 150 μg/kg) over 1 to 3 minutes followed by a continuous infusion of about 5 μg/kg/minute to maintain a sustained effect. The administration of calcium gluconate, 1 g IV, approximately 5 minutes before administration of verapamil may decrease verapamil-induced hypotension without altering the drug’s antiarrhythmic effects. Diltiazem, 20 mg IV, produces antiarrhythmic effects similar to those of diazepam, and the potential side effects are similar.

1. Mechanism of Action

   1. Verapamil and the other calcium channel blockers inhibit the flux of calcium ions across the slow channels of vascular smooth muscle and cardiac cells (manifests as a decreased rate of spontaneous phase 4 depolarization).

   2. Verapamil has a substantial depressant effect on the atrioventricular node and a negative chronotropic effect on the sinoatrial node. This drug exerts a negative inotropic effect on cardiac muscle and produces a moderate degree of vasodilation of the coronary arteries and systemic arteries.

2. Metabolism and Excretion

   1. An estimated 70% of an injected dose of verapamil is eliminated by the kidneys, whereas up to 15% may be present in the bile.

   2. The need for a large oral dose is related to the extensive hepatic first-pass effect that occurs with the oral route of administration.

3. Side Effects

   1. Atrioventricular heart block is more likely in patients with preexisting defects in the conduction of cardiac impulses.

   2. Direct myocardial depression and decreased cardiac output are likely to be exaggerated in patients with poor left ventricular function.

   3. Peripheral vasodilation may contribute to hypotension.

   4. There may be potentiation of anesthetic-produced myocardial depression, and the effects of neuromuscular blocking drugs may be exaggerated.