All antidysrhythmics in Vaughan-Williams class I (A, B, and C) alter Na+ conductance through cardiac voltage-gated, fast inward Na+ channels (Table 64–1). These medications bind to the Na+ channels and slow their recovery from the open or inactivated state to the resting state (Fig. 64–1). This conversion must occur before the channel can reopen and participate in another depolarization. Consequently, as the proportion of medication bound Na+ channels increases, fewer of these channels are capable of reactivation on the arrival of the next depolarizing impulse. As a result, by reducing the excitability of the myocardium, abnormal rhythms are both prevented and terminated.
Blockade of these Na+ channels slows the rise of phase 0 of the cellular action potential, which correlates with a reduction in the rate of depolarization of the myocardial cell (or Vmax). Similarly, conduction through the myocardium is slowed, producing a measurable prolongation of the QRS complex on the surface electrocardiogram. Correspondingly, slowed intra-myocardial conduction is associated with reduced contractility, manifesting as negative inotropy. Myocardial depression also results from effects of reduced intracellular Na+ on Na+-Ca2+ exchange.61 This, in turn, reduces the intracellular Ca2+ concentration, which is required for adequate contractility.
The differences among class I antidysrhythmics are directly related to their pharmacologic relationships with the Na+ channel. However, it is noteworthy that the original subdivision of class I antidysrhythmics was based on clinical observations, not current pharmacologic awareness, accounting for the somewhat illogical ordering of the class I subdivisions.97 Type IB antidysrhythmics have their highest affinity for inactivated Na+ channels. This occurs at the end of depolarization, during early repolarization, and during periods of myocardial ischemia, all situations in which the myocardium is partially depolarized. These medications also have rapid “on–off” binding kinetics (rapid τrecovery) and are thus bound only briefly, during late electrical systole, the period during which the Na+ channels are predominantly in the inactivated form. They are almost exclusively unbound during electrical diastole, which is the major portion of the cardiac cycle at normal heart rates. However, the degree of binding increases as the heart rate accelerates, because the duration of diastole decreases and the relative proportion of time spent in systole increases; this is termed use dependence. Because all IB antidysrhythmics do not bind to activated Na+ channels, in therapeutic doses they do not affect the rate of rise of phase 0 of the action potential, or Vmax, and have no effect on the electrocardiogram. Alternatively, the class IC antidysrhythmics preferentially act on activated Na+ channels or they release from the Na+ channels very slowly (slow τrecovery), and, thus, are still bound during the next cardiac cycle. This prolonged channel blockade and reduced channel reactivation result in both greater pharmacologic effects and toxicity, even at slow heart rates. These medications reduce Vmax and prolong the QRS complex. Class IA antidysrhythmics fall between the other two subclasses.
Although in the Vaughan-Williams classification all class I antidysrhythmics are considered primarily Na+ channel blockers, many, particularly those in class IA, have important effects on cardiac K+ channels. These channels are critical to maintenance of the cardiac action potential and repolarization of the myocardial cell. Slowing of K+ efflux prolongs the duration of the action potential and accounts for the persistence of refractoriness, or the time during which the cell is incapable of redepolarization. This effect produces QT prolongation and predisposes to the triggering of polymorphic ventricular tachycardia.43 Because class IB antidysrhythmics have no effect on myocardial K+ channels, they do not alter refractoriness or the QT interval. In fact, class IB antidysrhythmics often reduce the action potential duration, shortening refractoriness. Further discussion of K+ channel blockade is found in Chap. 16 and in the discussion of class III antidysrhythmics below.
See Table 64–1 for a description of the pharmacokinetics and clinical properties of the various antidysrhythmics.
Class IA Antidysrhythmics: Procainamide, Quinidine, and Disopyramide
Procainamide can be used to suppress either atrial or ventricular tachydysrhythmias. Importantly, procainamide undergoes hepatic biotransformation by acetylation to N-acetylprocainamide (NAPA), the rate of which is genetically determined.64 Although NAPA lacks the Na+ channel-blocking activity of procainamide, it prolongs the action potential duration through blockade of the K+ rectifier currents, and for this reason is available as the class III antidysrhythmic acecainide.38
Rapid intravenous dosing of procainamide is potentially dangerous because its initial volume of distribution is smaller than its final volume of distribution. Because this initial compartment includes the heart, adverse myocardial effects may be unexpectedly pronounced. Thus, to prevent toxicity during medication infusion, the intravenous loading dose is generally administered by slow infusion with electrocardiographic monitoring. Both procainamide and NAPA are renally eliminated and may accumulate in patients with chronic kidney disease (CKD).55
Although the chronic use of procainamide is commonly accompanied by the development of antinuclear antibodies or medication-induced systemic lupus erythematosis,39 this syndrome is not associated with acute poisoning. Furthermore, NAPA has less propensity than procainamide to produce this syndrome.38 Other reported adverse effects include seizures and antimuscarinic effects with acute overdose and myopathic pain, thrombocytopenia, and agranulocytosis following long-term use.
Serum concentrations of both procainamide and NAPA serum concentrations should be determined as part of therapeutic drug monitoring (therapeutic: 5–20 µg/mL) and in patients with procainamide overdose. Because the elimination half-life of procainamide is 3 to 4 hours, which is substantially shorter than that of NAPA (6–10 hours), chronic overdosing typically results in NAPA toxicity.4 In this situation, the QT interval, a reflection of K+ channel blockade, correlates directly, and blood pressure correlates inversely, with the degree of poisoning. Severe effects usually do not occur until total (procainamide plus NAPA) serum concentrations are greater than 60 µg/mL. Because of its structural similarity with amphetamine, patients with procainamide overdose may have a false-positive urine enzyme-multiplied immunoassay test (EMIT) for amphetamines.98
Quinidine, the d-isomer of quinine, is derived from the bark of the cinchona tree. Because it is a weak base, it is typically formulated as the sulfate or gluconate salt. Quinidine undergoes hydroxylation by the liver, and both active and inactive metabolites are renally eliminated.
Quinidine was once widely used for the management of atrial or ventricular dysrhythmias, but has largely fallen out of favor due to its adverse effects. Quinidine has substantial cardiotoxicity that includes intraventricular conduction abnormalities and an increased QT interval. “Quinidine syncope,” in which patients on therapeutic doses of quinidine experience paroxysmal, transient loss of consciousness, is most frequently a result of torsade de pointes.41
Because quinidine shares many pharmacologic properties with quinine (Chap. 59), patients may occasionally experience cinchonism following either chronic or acute quinidine overdose. This syndrome includes abdominal symptoms, tinnitus, and altered mental status. Quinidine also produces both peripheral and cardiac antimuscarinic effects, which enhance conduction via the atrioventricular (AV) node. Furthermore, as with quinine, quinidine-induced blockade of K+ channels in pancreatic islet cells may cause uncontrolled insulin release, leading to hypoglycemia.69
Serum quinidine concentrations greater than 14 µg/mL are associated with cardiotoxicity,47 as evidenced by a 50% increase in either the QRS or QT interval.
Disopyramide (Fig. 64–2) is more likely than other class IA antidysrhythmics to produce negative inotropy and congestive heart failure. This effect may be noted both in patients receiving therapeutic dosing,88 and in those who overdose, and may be related to the blockade of myocardial Ca++ channels caused by disopyramide. The current use of disopyramide for the treatment of patients with hypertrophic cardiomyopathy capitalize on this clinical effect.25 The mono-N-dealkylated metabolite of disopyramide produces the most pronounced anticholinergic effects of the class,95 accounting for the occasional, though unproven, use of disopyramide to treat neurocardiogenic syncope.77 Lethargy, confusion, or hallucinations may be prominent in overdose.
Structures of class IA antidysrhythmics and quinine.
Electrophysiologic abnormalities similar to those associated with poisoning from other class IA antidysrhythmics can occur, including intraventricular conduction abnormalities, torsade de pointes, and other ventricular dysrhythmias. Disopyramide may cause hyperinsulinemic hypoglycemia through its antagonism of K+ channels in the pancreatic islet cells.1
Management of Class IA Antidysrhythmic Toxicity.
Management concentrates on assessment and correction of cardiovascular dysfunction. Following airway evaluation and intravenous line placement, 12-lead electrocardiography (ECG) and continuous ECG monitoring are of paramount importance. Appropriate gastrointestinal decontamination is recommended when the patient is sufficiently stabilized and should include whole-bowel irrigation if a sustained-release preparation is involved (Chap. 8 and Antidotes in Depth: A2).
For patients who have widening of the QRS complex duration, bolus administration of intravenous hypertonic sodium bicarbonate is indicated (Antidotes in Depth: A5). Depolarization is accelerated and the QRS complex duration is reduced, by enhancing rapid Na+ ion influx through the myocardial Na+ channels.8 However, hypokalemia from the use of sodium bicarbonate may further prolong the QT interval, requiring careful monitoring of the serum K+ and ECG. Class IA antidysrhythmic-induced hypotension is treated primarily with rapid infusion of 0.9% NaCl to expand intravascular volume and to simultaneously increase myocardial contractility by enhancing the Starling force. Hypotension in the setting of QRS complex duration prolongation may respond favorably to hypertonic sodium bicarbonate, which enhances inotropy by both accelerating depolarization and raising intravascular volume. Dobutamine (an inotrope) or norepinephrine (an inotrope and pressor), and intraaortic balloon pump insertion may also be required, but their use has not been systematically evaluated. Because disopyramide also blocks Ca2+ channels, Ca2+ administration is reportedly beneficial,2 although evidence to support this antidotal effect is lacking. Glucagon effectively reversed myocardial depression in canine models, but it has not been evaluated in humans.63
Patients with stable ventricular dysrhythmias occurring in the setting of class IA antidysrhythmic poisoning are usually treated with hypertonic sodium bicarbonate or lidocaine. Although it may seem counterintuitive to administer another class I antidysrhythmic to a patient already poisoned by a class I antidysrhythmic, there is sound theoretical and experimental literature to support the use of lidocaine in this setting.99 Because lidocaine is a class IB antidysrhythmic with rapid on–off receptor kinetics, it may displace the “slower” class IA antidysrhythmic from the binding site on the Na+ channel, effectively reducing channel blockade. Sodium bicarbonate enhances conduction through the myocardium, promoting spontaneous termination of the ventricular dysrhythmia. Magnesium sulfate and overdrive pacing may be helpful in preventing recurrent torsade de pointes. Medications that must be avoided in treating patients with dysrhythmias associated with class IA poisoning include other class IA and IC antidysrhythmics, as well as the β-adrenergic antagonists and Ca2+ channel blockers, all of which may exacerbate conduction abnormalities or produce hypotension.
The roles of charcoal hemoperfusion, hemofiltration, and continuous arteriovenous hemodiafiltration are inadequately defined, but may be most beneficial for removing NAPA.55 There is no clinical evidence to support the use of hemodialysis or hemoperfusion for quinidine or disopyramide poisoning.1
Class IB Antidysrhythmics: Lidocaine, Tocainide, Mexiletine, and Moricizine
Lidocaine (Fig. 64-3) is an aminoacyl amide that is a synthetic derivative of cocaine. Its predominant clinical uses are as a local anesthetic and, for mechanistically similar reasons, to control ventricular dysrhythmias. The high frequency of lidocaine-related medication errors relates in part to its wide use in the past as well as the availability of “amps” of varying quantities, designed for specific uses such as preparation of intravenous infusions or for local anesthesia.44 Lidocaine may prevent myocardial reentry and subsequent dysrhythmia (Chap. 16) by preferentially suppressing conduction in compromised tissue.89 Following an intravenous bolus, lidocaine rapidly enters the central nervous system but quickly redistributes into the peripheral tissue with a distribution half-life of approximately 8 minutes.9 Lidocaine is 95% dealkylated by hepatic CYP3A4 to an active metabolite, monoethylglycylxylidide (MEGX) and, subsequently, to the inactive glycine xylidide (GX). GX is further metabolized to monoethylglycine and xylidide. MEGX, although less potent as a Na+ channel blocker than lidocaine, may bioaccumulate because of its substantially longer half-life.6
Structures of the class IB antidysrhythmics lidocaine (and metabolite monoethylglycylxylidide), tocainide, mexiletine, and moricizine.
Patients with massive lidocaine toxicity develop both central nervous system and cardiovascular effects, generally in that order. Because of its rapid entry into the brain, acute lidocaine poisoning typically produces central nervous system dysfunction, with paresthesias or convulsion, as the initial manifestation.28,74,84 Concomitant respiratory arrest generally occurs. Shortly following the central nervous system effects, depression in the intrinsic cardiac pacemakers leads to sinus arrest, AV block, intraventricular conduction delay, hypotension, and/or cardiac arrest. If the patient is supported through this period, then the medication rapidly distributes away from the heart, and spontaneous cardiac function returns.
Acute submassive lidocaine toxicity is generally related to excessive or inappropriate parenteral therapeutic dosing. Common settings include inadvertent intravenous administration instead of the intended route and excessive subcutaneous administration during laceration repair. Acute lidocaine toxicity may occur also with topical tracheal application of lidocaine used for bronchoscopy,101 during cirumcision,74 as well as ureteral application during ureteroscopic stone extraction.66 The typical central nervous system (CNS) manifestations of submassive lidocaine poisoning include drowsiness, weakness, a sensation of “drifting away,” euphoria, diplopia, decreased hearing, paresthesias, muscle fasciculations, and seizures. The more severe of these effects develop when serum lidocaine concentrations exceed 5 µg/mL and are often preceded by paresthesias or somnolence. Therefore, any of these symptoms should prompt the health care professional to examine the patient’s medication administration history or medication-infusion rate. Apnea and seizures, as well as hypotonia in neonates, are reported to result from submassive acute lidocaine toxicity.73
A related form of toxicity and death results from subcutaneous and adipose administration of lidocaine during tumescent liposuction.71 In this technique, a large volume of dilute lidocaine is used to distend subcutaneous fat prior to liposuction.7 Although in some reports the cause of death was controversial,70 postmortem lidocaine concentrations were commonly elevated, and it is likely that lidocaine metabolites were also involved in the adverse events.45 Interestingly, proponents of this procedure suggest that lidocaine doses up to a maximum of 55 mg/kg are safe,7 whereas the conventional recommended limit for subcutaneous lidocaine with epinephrine is only 5 to 7 mg/kg. Of significant concern is that the recommended doses used for liposuction procedures do not consider the ability of lidocaine to saturate the CYP3A4 enzymes. When saturation occurs, elimination lags behind absorption and lidocaine toxicity may result.
Numerous publications unequivocally demonstrate the toxicity associated with orally administered lidocaine despite its poor bioavailability.16,102 Some of the toxicity may be due to MEGX. Because of the relatively high concentration of viscous lidocaine (typically 4%), this preparation is overrepresented in reports of oral lidocaine poisoning.102 As little as 15 mL of 2% viscous lidocaine in a 3 year-old child (estimate, 300 mg or 21.4 mg/kg/dose) may cause seizures.
Chronic lidocaine toxicity most commonly occurs as a result of therapeutic misadventure in patients on lidocaine infusions, generally in a critical care unit. Toxicity following appropriate dosing is most likely to occur in patients with reduced hepatic blood flow as occurs with congestive heart failure, liver disease, or concomitant therapy with CYP3A4 and CYP1A2 inhibitors (Chap. 9).94 Adverse reactions to lidocaine also increase with advancing age, decreasing body weight, and increasing infusion rate. Chronic lidocaine toxicity occurs in 6% to 15% of patients receiving infusions at 3 mg/min for several days.82 Partly for this reason, lidocaine is no longer routinely used to prevent dysrhythmias in the immediate postmyocardial infarction period. The clearance of lidocaine falls after approximately 24 hours of the start of an infusion, and this effect may be due to competition for hepatic metabolism between lidocaine and its metabolites.
Mexiletine, originally developed as an anorectic, was found to have antidysrhythmic, local anesthetic, and anticonvulsant activity.13 It is currently available in oral form for the management of ventricular dysrhythmias and is also used for the management of chronic neuropathic pain. Its chemical structure and electrophysiologic properties are similar to those of lidocaine. Mexiletine, a base, is absorbed in the small intestine; therefore, its absorption is increased when the gastric contents are alkalinized. Congestive heart failure and cirrhosis, as well as therapy with cimetidine or disulfiram, decrease the clearance of mexiletine.51 Its metabolism, predominantly through CYP2D6, is accelerated by concomitant use of phenobarbital, rifampin, and phenytoin.
Adverse therapeutic effects are primarily neurologic and are similar to those that occur with lidocaine. The few reported cases of mexiletine overdose describe prominent cardiovascular effects such as complete heart block, torsade de pointes, and asystole.18,31 Neurotoxicity resulting from overdose includes self-limited seizures, generally in the setting of cardiotoxicity. Moreover, a single case report described a patient with mexiletine poisoning who experienced status epilepticus without any hemodynamic or electrocardiographic abnormalities.60 Mexiletine may produce a false-positive result on the amphetamine immunoassay of the urine.18,48
Moricizine possesses the general qualities of class I antidysrhythmics, but is difficult to specifically subclassify as it has properties that place it in both classes IB or IC.17 Historically it is discussed as a class IB antidysrhythmic, as it is here. The parent medication undergoes extensive and rapid metabolism. Dose-related lengthening of PR and QRS intervals are expected, as are hemiblocks, bundle blocks, and sustained ventricular tachydysrhythmias. Experience in the setting of myocardial infarction during CAST II suggests that it is a prodysrhythmic.92 Clinical experience with overdose is limited, but is expected to be similar to that of other class I antidysrhythmics.
Management of Class IB Antidysrhythmic Toxicity.
The focus of the initial management for intravenous lidocaine-induced cardiac arrest is continuous cardiopulmonary resuscitation to allow lidocaine to redistribute away from the heart. Apart from this setting, management of hemodynamic compromise includes fluid replacement and other conventional strategies. Resistant hypotension may require norepinephrine administration, insertion of an intraaortic balloon assist pump, or bypass.33 Cardiopulmonary bypass, which does not directly enhance elimination, maintains hepatic perfusion, thereby allowing the lidocaine to be metabolized.33 Bradydysrhythmias typically do not respond to atropine, requiring the administration of a chronotrope such as norepinephrine or isoproterenol. External pacing or insertion of a transvenous pacemaker may be useful, but the myocardium is often refractory to electrical capture. Lidocaine-induced seizures, and those related to lidocaine analogs, are generally brief in nature and do not require specific therapy. For patients requiring treatment, an intravenous benzodiazepine generally suffices; rarely, a barbiturate is required. Similarly, although intravenous fat emulsion is often described as useful for the resuscitation of patients with life threatening local anesthetic overdose, its use for lidocaine poisoned patients is limited to case reports and likely unnecessary given the rapid time course of recovery (Antidotes in Depth: A20). Enhanced elimination techniques are limited following intravenous poisoning because of the rapid time course of poisoning.33
Following oral poisoning by a class IB antidysrhythmic, activated charcoal should be administered as appropriate. Lidocaine and its metabolites are not well cleared by hemodialysis,22 and there are no adequate data to support the use of extracorporeal removal for mexiletine or moricizine.
Class IC Antidysrhythmics: Flecainide and Propafenone
Flecainide, a derivative of procainamide, is orally administered to maintain sinus rhythm in patients with structurally normal hearts who have atrial fibrillation or supraventricular tachycardia.90 Kidney disease, medication interactions, and congestive heart failure all decrease the clearance of flecainide and its active metabolite. Additionally, alkaluria reduces its clearance, presumably by enhanced tubular reuptake of nonionized medication. Therapeutic doses may produce left ventricular dysfunction with worsening congestive heart failure. This is presumably a result of the negative inotropic effect of flecainide, which itself may relate to its antagonistic effects on Ca2+ channels. Furthermore, sudden dysrhythmic death may occur, particularly in patients with underlying ischemic heart disease.90
A 50% increase in QRS complex duration, a 30% prolongation of the PR interval, or a 15% prolongation of the QT interval occurs with flecainide toxicity.87 The expected consequences of these electrophysiologic disturbances include bradycardia, premature ventricular contractions, and ventricular fibrillation. The combination of marked QRS and PR interval changes, associated with minimal QT interval prolongation, is characteristic of flecainide toxicity and contrasts with those described with other antidysrhythmics.
Propafenone bears a structural resemblance to propranolol,30 as well as similar qualitative, but not quantitative, electrophysiologic properties.27 Propafenone blocks fast inward Na+ channels, is a weak β-adrenergic antagonist, and is an L-type Ca2+ channel blocker.27 Its long half-life allows the accumulation of parent compound, particularly in patients with the slow metabolizer pharmacogenetic variant of CYP2D6, which may cause excessive β-adrenergic antagonism.52 Propafenone overdose produces sinus bradycardia, ventricular dysrhythmias, and negative inotropy. The electrocardiogram often shows right bundle-branch block, first-degree AV block, and prolongation of the QT interval. Generalized seizures may also occur.65
Management of Class IC Antidysrhythmic Toxicity.
Initial stabilization should include standard management strategies for hypotension and seizures. Additionally, therapy for hypotension, and the electrocardiographic manifestations of class IC poisoning, includes intravenous hypertonic sodium bicarbonate to overcome the Na+ channel blockade.60 Several reports of overdose in humans verify QRS complex narrowing in response to hypertonic sodium bicarbonate administration for flecainide10,40,54 and propafenone.65 Although sodium loading with hypertonic saline may be similarly effective, it remains unproven. The renal elimination of flecainide is reduced by urinary alkalinization, suggesting that sodium chloride, in equimolar doses, may ultimately prove superior to sodium bicarbonate.58 The administration of other class IC or IA antidysrhythmics is contraindicated because of their additive blockade of the Na+ channel. Similarly, the administration of phenytoin to a child with propafenone poisoning was associated with a prolongation of the QRS interval, which initially responded to sodium bicarbonate, but the patient subsequently developed bradyasystolic arrest.57 However, amiodarone was successful in the setting of flecainide-induced ventricular fibrillation refractory to other therapy.85 As with β-adrenergic antagonists, an animal model suggests that hyperinsulinemic euglycemic therapy may be beneficial following propafenone poisoning.103 The efficacy of an external or internal pacemaker may be limited because of the medication-induced increased electrical pacing threshold of the ventricle. Successful therapy with cardiopulmonary bypass or extracorporeal membrane oxygenation is reported and should be considered if available.5,20 Intravenous fat therapy was reportedly successful in patients with severe flecainide poisoning24 and propafenone poisoning,96 although the safety and efficacy of this therapy remain undefined.
Extracorporeal removal is not expected to be beneficial for patients with flecainide poisoning. Although hemodialysis was successful in removing propafenone following overdose, additional studies are needed to determine its clinical benefit.11