Drugs with local anesthetic action block sodium channels and reduce the sodium current, INa. They are the oldest group of antiarrhythmic drugs and are still widely used.
By blocking sodium channels, procainamide slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG. The drug also prolongs the APD (a class 3 action) by nonspecific blockade of potassium channels. The drug may be somewhat less effective than quinidine (see below) in suppressing abnormal ectopic pacemaker activity but more effective in blocking sodium channels in depolarized cells.
Procainamide has direct depressant actions on SA and AV nodes, and these actions are only slightly counterbalanced by drug-induced vagal block.
Procainamide has ganglion-blocking properties. This action reduces peripheral vascular resistance and can cause hypotension, particularly with intravenous use. However, in therapeutic concentrations, its peripheral vascular effects are less prominent than those of quinidine. Hypotension is usually associated with excessively rapid procainamide infusion or the presence of severe underlying left ventricular dysfunction.
Procainamide’s cardiotoxic effects include excessive action potential prolongation, QT-interval prolongation, and induction of torsades de pointes arrhythmia and syncope. Excessive slowing of conduction can also occur. New arrhythmias can be precipitated.
A troublesome adverse effect of long-term procainamide therapy is a syndrome resembling lupus erythematosus and usually consisting of arthralgia and arthritis. In some patients, pleuritis, pericarditis, or parenchymal pulmonary disease also occurs. Renal lupus is rarely induced by procainamide. During long-term therapy, serologic abnormalities (eg, increased antinuclear antibody titer) occur in nearly all patients, and in the absence of symptoms, these are not an indication to stop drug therapy. Approximately one third of patients receiving long-term procainamide therapy develop these reversible lupus-related symptoms.
Other adverse effects include nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (<5%), and agranulocytosis (approximately 0.2%).
Pharmacokinetics & Dosage
Procainamide can be administered safely by intravenous and intramuscular routes and is well absorbed orally. A metabolite (N-acetylprocainamide, NAPA) has class 3 activity. Excessive accumulation of NAPA has been implicated in torsades de pointes during procainamide therapy, especially in patients with renal failure. Some individuals rapidly acetylate procainamide and develop high levels of NAPA. However, the lupus syndrome appears to be less common in these patients.
Procainamide is eliminated by hepatic metabolism to NAPA and by renal elimination. Its half-life is only 3–4 hours, which necessitates frequent dosing or use of a slow-release formulation (the usual practice). NAPA is eliminated by the kidneys. Thus, procainamide dosage must be reduced in patients with renal failure. The reduced volume of distribution and renal clearance associated with heart failure also require reduction in dosage. The half-life of NAPA is considerably longer than that of procainamide, and it therefore accumulates more slowly. Thus, it is important to measure plasma levels of both procainamide and NAPA, especially in patients with circulatory or renal impairment.
If a rapid procainamide effect is needed, an intravenous loading dose of up to 12 mg/kg can be given at a rate of 0.3 mg/kg/min or less rapidly. This dose is followed by a maintenance dosage of 2–5 mg/min, with careful monitoring of plasma levels. The risk of gastrointestinal (GI) or cardiac toxicity rises at plasma concentrations greater than 8 mcg/mL or NAPA concentrations greater than 20 mcg/mL.
To control ventricular arrhythmias, a total procainamide dosage of 2–5 g/d is usually required. In an occasional patient who accumulates high levels of NAPA, less frequent dosing may be possible. This is also possible in renal disease, where procainamide elimination is slowed.
Procainamide is effective against most atrial and ventricular arrhythmias. However, many clinicians attempt to avoid long-term therapy because of the requirement for frequent dosing and the common occurrence of lupus-related effects. Procainamide is the drug of second or third choice (after lidocaine or amiodarone) in most coronary care units for the treatment of sustained ventricular arrhythmias associated with acute myocardial infarction.
Quinidine has actions similar to those of procainamide: it slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT-interval prolongation and induction of torsades de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. It also has modest antimuscarinic actions in the heart.
Adverse GI effects of diarrhea, nausea, and vomiting are observed in one third to one half of patients. A syndrome of headache, dizziness, and tinnitus (cinchonism) is observed at toxic drug concentrations. Idiosyncratic or immunologic reactions, including thrombocytopenia, hepatitis, angioneurotic edema, and fever, are observed rarely.
Pharmacokinetics & Therapeutic Use
Quinidine is readily absorbed from the GI tract and eliminated by hepatic metabolism. It is rarely used because of cardiac and extracardiac adverse effects and the availability of better-tolerated antiarrhythmic drugs.
The effects of disopyramide are very similar to those of procainamide and quinidine. Its cardiac antimuscarinic effects are even more marked than those of quinidine. Therefore, a drug that slows AV conduction should be administered with disopyramide when treating atrial flutter or fibrillation.
Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances described under quinidine. As a result of its negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. Because of this effect, disopyramide is not used as a first-line antiarrhythmic agent in the USA. It should not be used in patients with heart failure.
Disopyramide’s atropine-like activity accounts for most of its symptomatic adverse effects: urinary retention (most often, but not exclusively, in male patients with prostatic hyperplasia), dry mouth, blurred vision, constipation, and worsening of preexisting glaucoma. These effects may require discontinuation of the drug.
Pharmacokinetics & Dosage
In the USA, disopyramide is only available for oral use. The typical oral dosage of disopyramide is 150 mg three times a day, but up to 1 g/d has been used. In patients with renal impairment, dosage must be reduced. Because of the danger of precipitating heart failure, loading doses are not recommended.
Although disopyramide has been shown to be effective in a variety of supraventricular arrhythmias, in the USA, it is approved only for the treatment of ventricular arrhythmias.
Lidocaine has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route.
Lidocaine blocks activated and inactivated sodium channels with rapid kinetics (Figure 14–10); the inactivated state block ensures greater effects on cells with long action potentials such as Purkinje and ventricular cells, compared with atrial cells. The rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction. In depolarized cells, the increased inactivation and slower unbinding kinetics result in the selective depression of conduction. Little effect is seen on the ECG in normal sinus rhythm.
Computer simulation of the effect of resting membrane potential on the blocking and unblocking of sodium channels by lidocaine as the membrane depolarizes. Upper tracing: Action potentials in a ventricular muscle cell. Lower tracing: Percentage of channels blocked by the drug. An 800-ms time segment is shown. Extra passage of time is indicated by breaks in the traces. Left side: At the normal resting potential of −85 mV, the drug combines with open (activated) and inactivated channels during each action potential, but block is rapidly reversed during diastole because the affinity of the drug for its receptor is so low when the channel recovers to the resting state at −85 mV. Middle: Metabolic injury is simulated, eg, ischemia due to coronary occlusion, that causes gradual depolarization over time. With subsequent action potentials arising from more depolarized potentials, the fraction of channels blocked increases because more channels remain in the inactivated state at less negative potentials (Figure 14–4, left), and the time constant for unblocking during diastole rapidly increases at less negative resting potentials (Figure 14–4, right). Right: Because of marked drug binding, conduction block and loss of excitability in this tissue result; that is, the “sick” (depolarized) tissue is selectively suppressed.
Lidocaine is one of the least cardiotoxic of the currently used sodium channel blockers. Proarrhythmic effects, including SA node arrest, worsening of impaired conduction, and ventricular arrhythmias, are uncommon with lidocaine use. In large doses, especially in patients with preexisting heart failure, lidocaine may cause hypotension—partly by depressing myocardial contractility.
Lidocaine’s most common adverse effects—like those of other local anesthetics—are neurologic: paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions. These occur most commonly in elderly or otherwise vulnerable patients or when a bolus of the drug is given too rapidly. The effects are dose-related and usually short-lived; seizures respond to intravenous diazepam. In general, if plasma levels above 9 mcg/mL are avoided, lidocaine is well tolerated.
Pharmacokinetics & Dosage
Because of its extensive first-pass hepatic metabolism, only 3% of orally administered lidocaine appears in the plasma. Thus, lidocaine must be given parenterally. Lidocaine has a half-life of 1–2 hours. In adults, a loading dose of 150–200 mg administered over about 15 minutes (as a single infusion or as a series of slow boluses) should be followed by a maintenance infusion of 2–4 mg/min to achieve a therapeutic plasma level of 2–6 mcg/mL. Determination of lidocaine plasma levels is of great value in adjusting the infusion rate. Occasional patients with myocardial infarction or other acute illness require (and tolerate) higher concentrations. This may be due to increased plasma α1-acid glycoprotein, an acute-phase reactant protein that binds lidocaine, making less free drug available to exert its pharmacologic effects.
In patients with heart failure, lidocaine’s volume of distribution and total body clearance may both be decreased. Therefore, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased; the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Although steady-state concentrations may be achieved in 8–10 hours in normal patients and patients with heart failure, 24–36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition.
Lidocaine is the agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia. However, routine prophylactic use of lidocaine in this setting may actually increase total mortality, possibly by increasing the incidence of asystole, and is not the standard of care. Most physicians administer IV lidocaine only to patients with arrhythmias.
Mexiletine is an orally active congener of lidocaine. Its electrophysiologic and antiarrhythmic actions are similar to those of lidocaine. (The anticonvulsant phenytoin [see Chapter 24] exerts similar electrophysiologic effects and has been used as an antiarrhythmic.) Mexiletine is used in the treatment of ventricular arrhythmias. The elimination half-life is 8–20 hours and permits administration two or three times per day. The usual daily dosage of mexiletine is 600–1200 mg/d. Dose-related adverse effects are seen frequently at therapeutic dosage. These are predominantly neurologic, including tremor, blurred vision, and lethargy. Nausea is also a common effect.
Mexiletine has also shown significant efficacy in relieving chronic pain, especially pain due to diabetic neuropathy and nerve injury. The usual dosage is 450–750 mg/d orally. This application is off label.
Flecainide is a potent blocker of sodium and potassium channels with slow unblocking kinetics. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval.) It is currently used for patients with otherwise normal hearts who have supraventricular arrhythmias. It has no antimuscarinic effects.
Flecainide is very effective in suppressing premature ventricular contractions. However, it may cause severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmias and those with a previous myocardial infarction and ventricular ectopy. This was dramatically demonstrated in the Cardiac Arrhythmia Suppression Trial (CAST), which was terminated prematurely because of a two and one-half-fold increase in mortality rate in the patients receiving flecainide and similar group 1C drugs. Flecainide is well absorbed and has a half-life of approximately 20 hours. Elimination is both by hepatic metabolism and by the kidney. The usual dosage of flecainide is 100–200 mg twice a day.
Propafenone has some structural similarities to propranolol and possesses weak β-blocking activity. Its spectrum of action is very similar to that of quinidine, but it does not prolong the action potential. Its sodium channel-blocking kinetics are similar to those of flecainide. Propafenone is metabolized in the liver, with an average half-life of 5–7 hours. The usual daily dosage of propafenone is 450–900 mg/d in three divided doses. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation; arrhythmia exacerbation can also occur.
Moricizine is an antiarrhythmic phenothiazine derivative that was used for treatment of ventricular arrhythmias. It is a relatively potent sodium channel blocker that does not prolong action potential duration. Moricizine has been withdrawn from the US market.