Fig. 22.1
Ia lengthens the action potential (right shift); Ic does not significantly affect the action potential (no; Ib shortens the action potential (left shift) shift)
Class I anti-arrhythmic agents are subdivided into three groups: (1) Class IA drugs slow the rate of rise of phase 0 (V max) of the action potential and prolong the refractory period; (2) Class IB drugs have a minimal effect on V max and the refractory period of healthy myocardium while causing conduction block in diseased myocardium; and (3) Class IC drugs cause a marked depression in the conduction velocity with minimal effects on refractoriness in all cardiac tissue. Many Class I anti-arrhythmic drugs have effects on other ion channels and membrane receptors (Table 22.1).
Table 22.1
Properties of Class I anti-arrhythmic drugs
Drug | Recovery from Na channel block | K+ channels | Other receptor effects | ECG changes | Elimination | Bio-availability (%) | Time to peak concentration after oral dose (h) | Elimination half life (h) | Dose modification |
|---|---|---|---|---|---|---|---|---|---|
Class IA | |||||||||
Procainamide | Intermediate | ↓I Kr | Inhibits β-adrenergic and muscarinic receptors | ↑QT | Hepatic (40–70 %), renal (30–60 %) | 100 | 1 | 2–4 | ↓RD |
Quinidine | Intermediate | ↓I TO, ↓I Kr, ↓I Ks | ↑QT | Hepatic (50–90 %), renal (10–30 %) | 70 | 1.5–3 | 3–19 | ↓HD | |
Disopyramide | Intermediate | ↓I TO, ↓I Kr, ↓I KAch | Inhibits muscarinic receptors | ↑QT | Hepatic (20–30 %), renal (40–50 %) | 80–90 | 1–2 | 6–8 | ↓RD, ↓HD |
Class IB | |||||||||
Lidocaine | Rapid | Hepatic | 1.5–4 | ↓HD, ↓CHF | |||||
Mexiletine | Rapid | Hepatic | 90 | 2–4 | 8–20 | ↓HD, ↓CHF | |||
Class IC | |||||||||
Propafenone | Slow | ↓I Kr, ↓I Kur | Inhibits β-adrenergic receptors | ↑PR, ↑QRS | Hepatic | 10–50 | 2–3 | 2–24 | |
Flecainide | Slow | ↓I Kr, ↓I Kur | Inhibits β-adrenergic receptors | ↑PR, ↑QRS, slight ↑QT | Hepatic (70 %), renal (30 %) | 90–95 | 2 | 14–20 | ↓RD, ↓HD |
Class IA
Quinidine
Quinidine (Quinidex) is the dextro-isomer of quinine and was one of the first clinically used anti-arrhythmic agents (Tables 22.1 and 22.2). Due to the high incidence of ventricular pro-arrhythmia (Table 22.3) and numerous equally efficacious agents, quinidine is now used sparingly. Quinidine shares all of the pharmacological properties of quinine, including anti-malarial, antipyretic, oxytocic, and skeletal muscle relaxant actions.
Table 22.2
Class I drugs
Drug | Class | Dose | T 1/2 | Route of elimination | Therapeutic serum levels | ECG changes | ||
|---|---|---|---|---|---|---|---|---|
PR | QRS | QTc | ||||||
Quinidine gluconate | Ia | PO: 10–30 mg/kg/d ÷ bid–tid | 6 h | H | 26 mg/mL | ± | ↑↑ | ↑↑↑ |
Procainamide | Ia | PO: 15–50 mg/kg/d ÷ tid–qid | 2.5–4.5 h (68 h for SR) | HR | 48 μg/ml | ± | ↑ | ↑↑ |
IV: load: 7–15 mg/kg over 1 h | NAPA: 48 μg/mL | |||||||
Infusion: 20–100 μg/kg/min | ||||||||
Lidocaine | Ib | IV: load = 1 mg/kg (may repeat × 3), infusion = 20–50 μg/kg/min | 12 h | H | 1.5–6.0 μg/mL | ± | ± | ± |
Mexiletine | Ib | PO: 6–15 mg/kg/d ÷ tid | 10–12 h | HB | 0.5–2.0 μg/mL | ± | ± | ± |
Flecainide | Ic | PO: 4–6 mg/kg/d ÷ bid–tid or 50–200 mg/m2 ÷ bid–tid | 12–30 h | HR | 0.2–1.0 μg/mL | ↑↑ | ↑↑ | ↑ |
Propafenone | Ic | PO: 8–10 mg/kg/d ÷ tid, may increase dose slowly to 20 mg/kg/d with careful monitoring | 2–10 h | HR, 1/3 unchanged in urine | 0.06–0.1 μg/mL | ↑↑ | ↑↑ | ± |
Table 22.3
Pro-arrhythmia syndromes and their management
Syndrome | Mechanism | Clinical presentations | |
|---|---|---|---|
Digitalis intoxication | Na+-K+ATPase inhibition → intracellular calcium overload | Ectopic activity, with suppressed sinus and AV nodal function | Mild: observe; possible temporary pacing |
Atrial or junctional tachycardia | Serious: anti-digoxin antibody | ||
Bidirectional VT | |||
Torsades de pointes | I Kr block | Pause-dependent polymorphic VT, with QT prolongation and deformity | Mild: magnesium |
Serious: pacing, isoproterenol | |||
Sodium channel blocker toxicity | Block of cardiac sodium channels, often exacerbated by underlying tachycardia or ischemia | Atrial flutter slowing with 1:1 AV conduction | Mild: no therapy or heart rate slowing (β-blocker) |
Frequent or difficult to cardiovert monomorphic or polymorphic VT | |||
Incessant SVT | Serious: intravenous sodium bicarbonate | ||
Increase death rate during long-term therapy after myocardial infarction | |||
β-Blocker withdrawal | Up regulation of receptor number with chronic therapy; withdrawal → more receptors available for agonist | Sinus tachycardia, other sympathetically mediated arrhythmia, hypertension | β-Blocker |
Ventricular fibrillation | Three drug-related mechanisms: | VF | No specific therapy beyond drug withdrawal and resuscitation |
Digitalis in manifest preexcitation with atrial fibrillation | |||
Coronary vasoconstriction (many drugs: cocaine, ergot) | |||
Inappropriate use of verapamil for sustained VT | |||
Calcium channel blocker toxicity | Calcium channel blocker excess, often in overdose | Hypotension, bradycardia, AV block | Temporary pacing, IV calcium |
Electrophysiological actions. Quinidine’s effect depends on the parasympathetic tone and the dose. The anticholinergic actions of quinidine predominate at lower plasma concentrations and direct electrophysiological actions predominate at higher serum levels.
SA node and atrial tissue: At low concentrations a slight increase in heart rate results from the anticholinergic effects while at higher concentrations spontaneous diastolic depolarization is slowed. Quinidine slows the V max of phase 0 slowing conduction through all tissues. Quinidine also has “local anesthetic” properties.
AV node: The anticholinergic effect of quinidine enhances conduction through the AV node. Quinidine’s direct electrophysiological actions on the AV node decreases conduction velocity and increases the ERP.
His–Purkinje system and ventricular muscle: Quinidine decreases the slope of phase 4 depolarization, inhibiting automaticity. Depression of automaticity in the His–Purkinje system is more pronounced than depression of SA node pacemaker cells. Quinidine also prolongs repolarization in ventricular muscle resulting in an increase in the duration of the action potential and QT interval on ECG a result of blocking the delayed rectifier potassium channel (I Kr).
Electrocardiographic changes. Quinidine prolongs the PR, QRS, and QT intervals. QRS and QT prolongation is more pronounced than with other anti-arrhythmic agents. The magnitude of prolongation is directly related to the plasma concentration.
Hemodynamic effects. Myocardial depression is not a problem in patients with normal cardiac function while patients with compromised myocardial function may experience a decrease in cardiac function. Quinidine relaxes vascular smooth muscle directly as well as indirectly by inhibition of alpha-1-adrenoceptors.
Pharmacokinetics. Quinidine has nearly complete oral bioavailability with an onset of action within 1–3 h, and peak effect within 1–2 h. The plasma half-life is 6 h with primarily hepatic metabolism. Therapeutic serum concentrations are 2–4 μg/mL.
Clinical uses. The use of quinidine is limited by the poor side effect profile and the availability of equally or more efficacious agents. Quinidine may be used in combination with other agents such as mexiletine for the control of ventricular arrhythmias. Since the CAST study, the use of quinidine has declined. Currently, the inclusion of quinidine should be limited to patients with ICDs due to the significant risk of pro-arrhythmia. More recently, it may be useful in patients with short QT syndrome (Chap. 19).
Adverse effects. The most common adverse effects are diarrhea, upper gastrointestinal distress, and light-headedness. Other relatively common adverse effects include fatigue, palpitations, headache, angina-like pain, and rash. These adverse effects are dose related and reversible with cessation of therapy. Thrombocytopenia may also occur.
The cardiac toxicity of quinidine includes AV and intraventricular block, ventricular tachyarrhythmias, and depression of myocardial contractility. Ventricular pro-arrhythmia with loss of consciousness, referred to as “quinidine syncope,” is more common in women and may occur at therapeutic or subtherapeutic plasma concentrations.
Large doses of quinidine can produce a syndrome known as cinchonism, which is characterized by ringing in the ears, headache, nausea, visual disturbances or blurred vision, disturbed auditory acuity, and vertigo. Larger doses can produce confusion, delirium, hallucinations, or psychoses. Quinidine can also cause hypoglycemia.
Contraindications. One absolute contraindication is complete AV block with a junctional or idioventricular escape rhythm that may be suppressed leading to cardiac arrest. Persons with congenital QT prolongation may develop torsades de pointes and should not be exposed to quinidine. Owing to the negative inotropic action of quinidine, the drug is contraindicated in congestive heart failure and hypotension. Digitalis intoxication and hyperkalemia accentuate the effect of quinidine on conduction velocity. The use of quinidine and quinine should be avoided in patients who have previously shown evidence of quinidine-induced thrombocytopenia.
Drug interactions. Quinidine increases the plasma concentrations of digoxin, requiring a downward adjustment in the digoxin dose. Drugs that inhibit the hepatic metabolism of quinidine and increase the serum concentration include acetazolamide, certain antacids (magnesium hydroxide and calcium carbonate), and cimetidine. Phenytoin, rifampin, and barbiturates increase the hepatic metabolism of quinidine and reduce its plasma concentrations.
Procainamide
Procainamide (Pronestyl, Procan SR) is a derivative of the local anesthetic agent procaine (Tables 22.1 and 22.2). Procainamide compared with procaine has a longer half-life, does not cause CNS toxicity at therapeutic plasma concentrations, and is effective orally. Procainamide is effective in the treatment of supraventricular, ventricular, and digitalis-induced arrhythmias. Its use is limited by its short serum half-life and frequent side effects when used chronically.
Electrophysiological actions. Procainamide’s direct electrophysiological effects are nearly identical to quinidine’s, although it has a significantly weaker anticholinergic effect. The ECG changes are similar to quinidine.
Hemodynamic effects. Hemodynamic compromise is less profound than with quinidine and seldom occurs after oral administration.
Pharmacokinetics. Procainamide is highly bio-available (75–95 %) with an onset of action of 5–10 min. The peak response following an oral dose is 60–90 min with a plasma half-life of 2.5–4.5 h (6–8 h for the sustained release preparation). The drug is metabolized hepatically and 50–60 % is excreted unchanged in the urine. The primary metabolite N-acetylprocainamide (NAPA) is cardioactive with Class III properties and is eliminated unchanged in the urine. In patients who are rapid acetylators or have renal dysfunction, NAPA may accumulate more rapidly than procainamide. Therapeutic levels range from 4 to 8 μg/mL and may need to be slightly higher in neonates. NAPA levels should be considered separately from procainamide levels rather than combined and are also in the range of 4–8 μg/mL.
Clinical uses. Procainamide is useful in the treatment of accessory pathway-mediated tachycardia, atrial fibrillation of recent onset, all types of ventricular dysrhythmias, and combined with patient cooling for the treatment of postoperative junctional ectopic tachycardia.
Care should be used when initiating therapy in patients with atrial flutter or IART as procainamide may slow conduction in the flutter circuit allowing for 1:1 AV conduction and an increase in the ventricular rate. Additionally, procainamide may slow conduction velocity in other macroreentrant circuits (such as AVRT) and convert self-limited tachycardia into slower incessant tachycardia.
Intravenous administration for Brugada syndrome has emerged as a possible diagnostic test.
Adverse effects. Acute cardiovascular reactions to procainamide administration include hypotension, AV block, intraventricular block, ventricular tachyarrhythmias, and complete heart block. The drug dosage must be reduced, or even stopped, if severe depression of conduction (severe prolongation of the QRS interval) or repolarization (severe prolongation of the QT interval) occurs. Long-term drug use may result in a clinical lupus-like syndrome. The symptoms disappear within a few days of cessation of therapy.
Procainamide, unlike procaine, has little potential to produce CNS toxicity. Rarely, patients may experience mental confusion or hallucinations. Procainamide, along with other class 1 drugs may produce lupus erythematosus-like picture; it resolves after withdrawal of the drug.
Contraindications. Contraindications are similar to those for quinidine. Procainamide should be administered with caution to patients with second-degree AV block and bundle branch block. The drug should not be administered to patients who have shown previous procaine or procainamide hypersensitivity. Prolonged administration should be accompanied by hematologic studies, since agranulocytosis may occur. Because of a potential hypotensive effect, intravenous administration should be titrated carefully monitoring blood pressure at no faster rate than 10–15 mg/kg/over 5–10 min. Procainamide currently is difficult to obtain in the United States.
Drug interactions. Cimetidine inhibits the metabolism of procainamide. Simultaneous use of alcohol will increase the hepatic clearance of procainamide. The simultaneous administration of quinidine or amiodarone may increase the plasma concentration of procainamide.
Class IB
Lidocaine
Electrophysiological Actions
SA node and atrium: At therapeutic doses (1–5 mg/kg), lidocaine has no effect on the sinus rate and weak effects on atrial tissue.
AV node: Lidocaine has minimal effects on the conduction velocity and ERP of the AV node.
His–Purkinje system and ventricular muscle: Lidocaine reduces membrane responsiveness and decreases automaticity. Lidocaine in very low concentrations slows phase 4 depolarization in Purkinje fibers. In higher concentrations, automaticity may be suppressed, and phase 4 depolarization eliminated.
Electrocardiographic changes. The PR, QRS, and QT intervals are usually unchanged, although the QT interval may be shortened in some patients. The paucity of electrocardiographic changes reflects lidocaine’s lack of effect on healthy myocardium and conducting tissue.
Hemodynamic effects. At usual doses, lidocaine does not depress myocardial function, even in the patient with heart failure.
Pharmacokinetics. Due to extensive first pass metabolism, lidocaine is not used orally. The onset of action is immediate when given intravenously with a plasma half-life of 1–2 h. Elimination is primarily via the liver (90 %) with the rest unchanged in the urine. Therapeutic serum levels range from 1.5 to 6.0 μg/mL. Lidocaine clearance is reduced by CHF, hepatic dysfunction, and concomitant treatment with cimetidine or beta-blockers.
Clinical uses. Lidocaine is useful in the control of ventricular arrhythmias. It is not useful for the treatment of supraventricular arrhythmias. Lidocaine’s use has decreased as amiodarone is frequently being used primarily for postoperative ventricular ectopy.
Adverse effects. CNS toxicity is the most frequent adverse effect. Paresthesias, disorientation, and muscle twitching may forewarn of more serious deleterious effects, including psychosis, respiratory depression, and seizures. Myocardial depression may occur at very high doses.
Contraindications. Contraindications include hypersensitivity to local anesthetics of the amide type (a very rare occurrence), severe hepatic dysfunction, or a previous history of grand mal seizures due to lidocaine. Care must be used in the presence of second- or third-degree heart block as it may increase the degree of block and abolish all idioventricular pacemakers.
Drug interactions. The concurrent administration of lidocaine with cimetidine, but not ranitidine, may cause an increase in the plasma concentration of lidocaine. The myocardial depressant effect of lidocaine is enhanced by phenytoin administration.
Mexiletine
Mexiletine (Mexitil) is a structural analog of lidocaine altered to prevent first pass metabolism. Mexiletine has properties similar to lidocaine and is frequently combined with quinidine to increase efficacy while decreasing the risk of pro-arrhythmia (Tables 22.1 and 22.2).
Electrophysiological actions. Mexiletine slows conduction velocity with a negligible effect on repolarization. Mexiletine demonstrates a rate-dependent blocking action on the sodium channel with rapid onset and recovery kinetics.
Hemodynamic effects. Although its cardiovascular toxicity is minimal, the drug should be used with caution in patients who are hypotensive or who exhibit severe left ventricular dysfunction.
Pharmacokinetics. Mexiletine has an oral bioavailability of 90 %. Its onset of action is 0.5–2.0 h with a plasma half-life of 10–12 h. Mexiletine is metabolized in the liver and excreted in the bile with 10 % renal excretion. Therapeutic serum concentrations range from 0.5 to 2.0 μg/mL.
Clinical uses. Mexiletine is useful in the management of both acute and chronic ventricular arrhythmias. While not currently an indication for use, there is interest in using mexiletine to treat the congenital long QT syndrome caused by a mutation in the SCN5A gene (LQTS 3).
Adverse effects. A very narrow therapeutic window limits mexiletine use. The first signs of toxicity are a fine tremor of the hands, followed by dizziness and blurred vision. Side effects include upper gastrointestinal distress, tremor, light-headedness, and coordination difficulties. These effects generally are not serious and can be reduced by downward dose adjustment or administering the drug with meals. Cardiovascular-related adverse effects are less common and include palpitations, chest pain, and angina or angina-like pain.
Contraindications. Mexiletine is contraindicated in the presence of cardiogenic shock or preexisting second- or third-degree heart block in the absence of a cardiac pacemaker. Caution must be exercised in administration of the drug to patients with sinus node dysfunction or disturbances of intraventricular conduction.
Drug interactions. An upward adjustment in dose may be required when mexiletine is administered with phenytoin or rifampin, due to increased hepatic metabolism of mexiletine.
In the search for new anti-arrhythmic drugs, single enantiomers of existing drugs that are racemic mixtures are being developed. One such drug is Mexiletine-m-Hydroxymexiletine (MHM), a minor metabolite of the Class IB anti-arrhythmic drug mexiletine. It is approximately twofold more potent than the parent compound on human cardiac voltage-gated sodium channels (hNav1.5), and equipotent to mexiletine on human skeletal muscle voltage-gated sodium channels (hNav1.4). An alternative and simplified synthesis of this promising compound has been accomplished avoiding the use of oxidizing agents, such as the meta-chloroperoxybenzoic acid. At the time of publication, this medication has not been put into clinical trials.
Class IC
Flecainide
Electrophysiological Actions
SA node and atrium: Flecainide causes a clinically insignificant decrease in heart rate. In the atrium, flecainide decreases the conduction velocity, shifts the membrane responsiveness curve to the right, and prolongs the action potential in a use-dependent fashion.
AV node: Atrioventricular conduction is prolonged.
His–Purkinje system and ventricular muscle: Flecainide slows conduction in the His–Purkinje system and ventricular muscle to a greater degree than in the atrium. Flecainide may also cause block in accessory AV connections, which is the principal mechanism for its effectiveness in treating atrioventricular reentrant tachycardia.
Electrocardiographic changes. Flecainide increases the PR, QRS, and to a lesser extent, the QTc intervals. The rate of ventricular repolarization is not affected and the QT interval prolongation is caused by the increase in the QRS duration.
Hemodynamic effects. Flecainide produces modest negative inotropic effects that may become significant in the subset of patients with compromised left ventricular function.
Pharmacokinetics. Flecainide is well absorbed with a bioavailability of 90–95 %. Oral absorption may be inhibited by milk and milk-based formulas. The onset of action is 1–2 h with a serum half-life of 12–30 h. The drug is primarily metabolized in the liver and excreted in the urine. Therapeutic serum concentrations are 0.2–1.0 μg/mL. The dose should be halved in patients with severe renal impairment.
Clinical uses. Flecainide is effective in treating atrial arrhythmias, particularly those supported by reentrant mechanisms, and is also used for life-threatening ventricular arrhythmias. Based on the results of the CAST study in adults with ischemic heart disease, and several reports of pro-arrhythmia in patients with repaired congenital heart disease, flecainide should be used with caution in patients with acquired or congenital structural heart disease. Flecainide crosses the placenta with fetal levels approximately 70 % of maternal levels and in many centers is the second-line drug after digoxin for therapy of fetal arrhythmias. Flecainide is also the second-line drug for SVT in children who are not well controlled on beta-blockers in many centers. Due to the possibility of pro-arrhythmia (Table 22.3), initiation of therapy or significant increases in dosing may be performed as an inpatient. Based on murine studies and a retrospective clinical report, flecainide may have selective properties for the management of catecholaminergic polymorphic ventricular tachycardia; a randomized trial is underway.
Adverse effects. Most adverse effects are observed within a few days of initial drug administration and include dizziness, visual disturbances, nausea, headache, and dyspnea. Worsening of heart failure and prolongation of the PR and QRS intervals may occur. The risk of pro-arrhythmia appears to be less than that observed in the adult population. The most frequent pro-arrhythmic effect is the occurrence of slow incessant SVT. Ventricular arrhythmias have been observed in patients following repair of congenital heart disease.
Contraindications. Flecainide is contraindicated in patients with preexisting second- or third-degree heart block unless a pacemaker is present to maintain ventricular rhythm. The drug should not be used in patients with cardiogenic shock.
Drug interactions. Cimetidine may reduce the rate of flecainide’s hepatic metabolism, thereby increasing the potential for toxicity. Flecainide may increase digoxin concentrations.
Propafenone
Propafenone (Rythmol) blocks the sodium channel, and like flecainide, propafenone weakly blocks potassium channels. Additionally propafenone is a weak β-receptor antagonist and L-type calcium channel blocker (Tables 22.1 and 22.2).
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