Antidysrhythmics modify impulse generation and conduction by interacting with various membrane sodium, potassium, and calcium ion channels. Generally, antidysrhythmics affect electrophysiologic effects either through alteration of the channel pore or, more commonly, by modification of its gating mechanism (Fig. 63–1).56 Unfortunately, given their exceedingly complex mechanisms of action, the descriptive terms used to explain their molecular actions are not always completely accurate. For example, the description of an antidysrhythmic as a specific "channel blocker," although representative of the conceptual action of that drug, is inaccurate because in most cases, the molecule does not actually block the channel but rather prevents the channel from opening properly. Furthermore, many of these drugs are active nonspecifically at other channels or on other cells, resulting in divergent clinical actions of similarly classified drugs.
The Vaughan-Williams classification of antidysrhythmics by electrophysiologic properties emphasizes the connection between the basic electrophysiologic actions and the antidysrhythmic effects.115 Although initially proposed as a descriptive model for electrophysiologic actions and not for clinical effects, the Vaughan-Williams classification is commonly invoked as a user-friendly guide to clinical therapy. In 1991, a competing system known as "the Sicilian Gambit" was constructed by a task force of European cardiologists based on the mechanisms by which antidysrhythmics modify dysrhythmogenic mechanisms.2 Although perhaps more contemporary in theory, this latter classification system is complex and is therefore not widely implemented. An even more rational classification would match the electrophysiologic effects of the antidysrhythmics with their molecular interactions on different regions of the various ion channels, such as channel gating and pore conductance.56
This discussion of antidysrhythmics uses the Vaughan-Williams classification, recognizing the shortcomings delineated above.113 The pharmacokinetic properties of the various drugs are summarized in Table 63–1.
All antidysrhythmics in Vaughan-Williams class I (A, B, and C) alter Na+ conductance through cardiac voltage-gated, fast inward Na+ channels (see Table 63–1). These drugs bind to the Na+ channels and slow their recovery from the open or inactivated state to the resting, or closed, state (see Fig. 63–1). This conversion must occur before the channel can reopen and participate in another depolarization. Consequently, as the proportion of drug-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 sodium 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 (ECG). Correspondingly, slowed intramyocardial conduction is associated with reduced contractility, manifesting as negative inotropy. Myocardial depression also results from effects of reduced intracellular Na+ on Na+-Ca2+ exchange.76 This in turn reduces the intracellular Ca2+ concentration, normal concentrations of which are required for adequate contractility.
The differences among class I drugs are directly related to their pharmacologic relationships with the Na+ channel. However, it is noteworthy that the original subdivision of class I drugs was based on clinical observations, not current pharmacologic awareness, accounting for the somewhat illogical ordering of the class I subdivisions.113 Type IB drugs 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 drugs 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 drugs do not bind to activated sodium 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 ECG.114 Alternatively, the class IC drugs either act preferentially 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 results in both greater pharmacologic effects and toxicity, even at slow heart rates. These drugs reduce Vmax and prolong the QRS complex. Class IA drugs fall between the other two subclasses.
Although in the Vaughan-Williams classification, class I drugs are considered primarily sodium channel blockers, many, particularly those in class IA, have important effects on cardiac potassium channels. These channels are critical to maintenance of the cardiac action potential and repolarization of the myocardial cell. Slowing of potassium 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 re-depolarization. This effect produces QT prolongation on the surface ECG, and predisposes to the triggering of polymorphic ventricular tachycardia.94 Because class IB drugs have no effect on myocardial potassium channels, they do not alter refractoriness or the QT interval. In fact, class IB drugs often reduce the action potential duration, shortening refractoriness. Further discussion of potassium channel blockade is found in Chapter 22 and below in the discussion of class III antidysrhythmics.
Class IA Antidysrhythmics: Procainamide, Quinidine, and Disopyramide
Procainamide (Fig. 63–2) 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.79 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, it is available as the class III antidysrhythmic acecainide.47
Structures of class IA antidysrhythmics and quinine.
Rapid intravenous (IV) 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 drug infusion, the IV loading dose is generally administered by slow infusion with ECG monitoring. Both procainamide and NAPA are renally eliminated and may accumulate in patients with renal insufficiency.28,69
Although the chronic use of procainamide may be accompanied by the development of antinuclear antibodies or drug-induced systemic lupus erythematosis,50 this syndrome is not associated with acute poisoning. Furthermore, NAPA has less propensity than procainamide to produce this syndrome.47 Other reported adverse effects include seizures and antimuscarinic effects with acute overdose and myopathic pain, thrombocytopenia, and agranulocytosis after long-term use.
Serum concentrations of both procainamide and NAPA should be determined as part of therapeutic drug monitoring (therapeutic dose, 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.7 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.8 Because of its structural similarity with amphetamine, patients with procainamide overdose may have a false-positive urine enzyme-multiplied immunoassay test (EMIT) result for amphetamines.116
Quinidine (see Fig. 63–2), 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 patients with atrial or ventricular dysrhythmias but has largely fallen out of favor because of its adverse effects. Quinidine has substantial cardiotoxicity that includes intraventricular conduction abnormalities and an increased QT interval. Many of the ECG changes mimic those of hypokalemia. "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.54
Because quinidine shares many pharmacologic properties with quinine (see Chap. 58), patients may occasionally experience cinchonism after 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 enhances 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.86
Serum quinidine concentrations greater than 14 μg/mL are associated with cardiotoxicity,61 as evidenced by a 50% increase in either the QRS or QT interval.
Disopyramide (see Fig. 63–2) 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 dosing108 and in those who overdose, and may be related to the blockade of myocardial calcium channels caused by disopyramide.51 The mono-N-dealkylated metabolite of disopyramide produces the most pronounced anticholinergic effects of the class,88,100 accounting for the occasional use of disopyramide to treat patients with neurocardiogenic syncope. Lethargy, confusion, or hallucinations may be prominent in overdose.
Electrophysiologic abnormalities similar to those associated with poisoning from other class IA drugs can occur, including intraventricular conduction abnormalities, torsades de pointes, and other ventricular dysrhythmias. Disopyramide frequently causes hyperinsulinemic hypoglycemia through its antagonism of K+ channels in the pancreatic islet cells.48
Management of Class IA Antidysrhythmic Toxicity
Management centers on assessment and correction of cardiovascular dysfunction. Following airway evaluation and IV line placement, 12-lead 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.
For patients who have widening of the QRS complex duration, bolus administration of IV hypertonic sodium bicarbonate is indicated. [see Antidotes In Depth A5, Sodium Bicarbonate] Depolarization is accelerated and the QRS complex duration is reduced, by enhancing rapid sodium ion influx through the myocardial sodium channels.14 However, hypokalemia from the use of sodium bicarbonate may further prolong the QT interval, requiring careful monitoring of the serum K+ concentration and ECG. Class IA antidysrhythmic-induced hypotension is treated primarily with rapid infusion of 0.9% NaCl, in order to expand the patient's intravascular volume and to simultaneously increase myocardial contractility (i.e., enhanced 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. Dopamine, dobutamine, isoproterenol, norepinephrine, and intraaortic balloon pump insertion may also be required, but their use has not been systematically evaluated. Because disopyramide also blocks calcium channels, calcium administration is reportedly beneficial,4 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.78
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.118 Because lidocaine is a class IB drug with rapid on-off receptor kinetics, it may displace the "slower" class IA drug from the binding site on the sodium 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 treating torsades de pointes. Xenobiotics 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 calcium channel blockers, all of which may exacerbate conduction abnormalities or produce hypotension.
The roles of activated charcoal hemoperfusion, hemofiltration, and continuous arteriovenous hemodiafiltration are inadequately defined, but may be most beneficial for removing NAPA.8,16,69 There is no clinical evidence to support the use of hemodialysis or hemoperfusion for quinidine or disopyramide poisoning.55
Class IB Antidysrhythmics: Lidocaine, Tocainide, Mexiletine, and Moricizine
Lidocaine (Fig. 63–3) 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 as well as the availability of multiple diverse "amps" of lidocaine designed for varying indications including resuscitation, preparation of infusions, and local anesthesia.57 Lidocaine may prevent myocardial reentry by preferentially suppressing conduction in compromised tissue.109 Following an IV bolus, lidocaine rapidly enters the central nervous system but quickly redistributes into the peripheral tissue with a distribution half-life of approximately 8 minutes.15, 71 Lidocaine is 95% dealkylated by hepatic CYP 3A4 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 the parent drug, may bioaccumulate because of its substantially longer half-life.12
Structures of the class IB antidysrhythmics lidocaine (and metabolite [MEGX]), tocainide, mexiletine, and moricizine.
Patients with 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, particularly seizures, as its initial manifestation.34,93,103 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.23 If the patient is supported through this period, the drug rapidly distributes away from the heart, and spontaneous cardiac function returns.
Acute lidocaine toxicity from nonmassive amounts is generally related to excessive or inappropriate therapeutic dosing. Common settings include inadvertent IV 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,120 during cirumcision,93 as well as intraureteral application during ureteroscopic stone extraction.83 The typical CNS manifestations of nonmassive acute 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. Any of these symptoms should, therefore, prompt the clinician to examine the patient's medication administration history or drug-infusion rate. Apnea and seizures, as well as hypotonia in neonates, are reported to result from nonmassive acute lidocaine toxicity.92
A related form of toxicity and death results from subcutaneous and adipose administration of lidocaine during tumescent liposuction.90 In this technique, a large volume of dilute lidocaine is used to distend subcutaneous fat prior to liposuction. Although in some reports the cause of death was controversial,87 postmortem lidocaine concentrations were commonly elevated, and it is likely that lidocaine metabolites were also involved in the adverse events.58,90 Interestingly, proponents of this procedure suggest that lidocaine doses up to a maximum of 55 mg/kg are safe,81 whereas the conventional recommended limit for subcutaneous lidocaine with epinephrine is only 5–7 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.23, 121 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.49 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 receiving lidocaine infusions, generally in a critical care unit. Toxicity following appropriate dosing is most likely to occur in patients with reduced hepatic blood flow (e.g., congestive heart failure), liver disease, or concomitant therapy with CYP3A4 and CYP1A2 inhibitors (see Chap. 12 Appendix).80,111 Adverse reactions to lidocaine also increase with advancing age, decreasing body weight, and increasing infusion rate. Chronic lidocaine toxicity occurs in 6–15% of patients receiving infusions at 3 mg/min for several days.101 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.
Tocainide is indicated for the oral treatment of ventricular dysrhythmias; it is no longer available in the US. Although a lidocaine analog, it does not undergo first-pass metabolism and is therefore almost 100% orally bioavailable.65 Both renal failure and congestive heart failure prolong its half-life considerably. The few overdoses reported with tocainide are associated with CNS and cardiovascular complications similar to those that occur with lidocaine overdose.10,107 Therapeutic dosing is associated with rash, hepatotoxicity and blood dyscrasias, which, although rare, have limited its widespread use.
Mexiletine, originally developed as an anorectic agent, was found to have antidysrhythmic, local anesthetic, and anticonvulsant activity.20 It is currently available in oral form for the management of ventricular dysrhythmias. 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.64 Its metabolism, predominantly through CYP2D6, is accelerated by concomitant use of phenobarbital, rifampin, and phenytoin.64
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.26,38 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.77 Mexiletine may produce a false-positive result on the amphetamine immunoassay of the urine.26,62
Moricizine possesses the general qualities of class I drugs but is difficult to specifically subclassify because it has properties that place the drug in either classes IB or IC.25 Historically, it has been discussed as a class IB drug, as it is here. The parent drug 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 with moricizine during the CAST II trial in the setting of myocardial infarction suggests that it is a prodysrhythmic.1 Clinical experience with overdose is limited, but it 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 IV 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 dopamine or norepinephrine administration, insertion of an intraaortic balloon assist pump, or bypass.40 Cardiopulmonary bypass, which does not directly enhance elimination, maintains hepatic perfusion, thereby allowing the lidocaine to be metabolized.40 Bradydysrhythmias typically do not respond to atropine, requiring the administration of a chronotrope such as dopamine, 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 IV benzodiazepine generally suffices; rarely, a barbiturate is required. Similarly, although IV lipid emulsion is often described as useful for the resuscitation of patients with life-threatening local anesthetic overdose, its use for lidocaine-poisoned patients is unstudied and likely unnecessary given the rapid time course of recovery (see Antidotes in Depth: A21: Intravenous Fat Emulsion). Enhanced elimination techniques are limited after IV poisoning because of the rapid time course of poisoning.
After oral poisoning by a class IB drug, activated charcoal should be administered as appropriate. Hemoperfusion or hemodialysis may increase the clearance of tocainide, but its indications remain unclear, and its benefit is likely very limited.117 The extensive distribution and rapid metabolism of mexiletine make it a poor candidate for extracorporeal drug removal.
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.11 Renal insufficiency, drug 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 drug. Patients using therapeutic doses may develop 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 calcium channels. Furthermore, sudden dysrhythmic death may occur, particularly in patients with underlying ischemic heart disease.89
A 50% increase in QRS duration, a 30% prolongation of the PR interval, or a 15% prolongation of the QT interval occurs with flecainide toxicity, a combined complex that may mimic Brugada syndrome.45,52 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 antidysrhythmic agents.24
Propafenone bears a structural resemblance to propranolol,36 as well as similar qualitative, but not quantitative, electrophysiologic properties.73 Propafenone blocks fast inward sodium channels, is a weak β-adrenergic antagonist, and is an L-type calcium channel blocker.33,104 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.66 Propafenone overdose produces sinus bradycardia, as well as ventricular dysrhythmias and negative inotropy.36
Acute overdose of propafenone typically produces wide complex tachycardia, right bundle-branch block, first-degree AV block, and prolongation of the QT interval, as well as generalized seizures.59 Massive overdose in a young adult may be related to the subsequent development of a mild cardiomyopathy and a left bundle-branch block.59
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 IV hypertonic sodium bicarbonate to overcome the Na+ channel blockade.60 An animal study documented the beneficial effects of hypertonic sodium bicarbonate on flecainide-induced ventricular dysrhythmias, and three reports of human overdose verify QRS complex narrowing in response to hypertonic sodium bicarbonate administration.17,42,68 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.74 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 a bradyasystolic arrest.72 However, amiodarone has been successful in the setting of flecainide-induced ventricular fibrillation refractory to other therapy.105 The efficacy of an external or internal pacemaker may be limited because of the drug-induced increased electrical pacing threshold of the ventricle.31 Successful therapy with cardiopulmonary bypass or extracorporeal membrane oxygenation (ECMO) has been reported and should be considered if available.9,27
Extracorporeal removal is not expected to be beneficial for patients with flecainide poisoning. Although hemodialysis was successful in removing propafenone after overdose, additional studies are needed to determine its clinical benefit.18
Class III Antidysrhythmics: Amiodarone, Dofetilide, and Ibutilide
The class III antidysrhythmics prevent and terminate reentrant dysrhythmias by prolonging the action potential duration and effective refractory period without slowing conduction velocity during phase 0 or 1 of the action potential. This drug-induced effect on the action potential is generally caused by blockade of the rapidly activating component of the delayed rectifier potassium current, which is responsible for repolarization.
The class III antidysrhythmics in use today prolong repolarization of both the atria and the ventricles. Thus, common electrocardiographic effects at therapeutic doses include prolongation of the PR and QT intervals and abnormal T and U waves. Chapters 22 and 23 contain a detailed discussion of the pharmacologic mechanisms of class III antidysrhythmics. Also, Chapters 23 and 61 discuss sotalol.
Amiodarone (Fig. 63–4) is an iodinated benzofuran derivative that is structurally similar to both thyroxine and procainamide. Forty percent of its molecular weight is iodine. The 2005 revision of the Advanced Cardiac Life Support (ACLS) guidelines placed tremendous emphasis on the early IV administration of amiodarone. This, along with the ability of amiodarone to terminate or prevent atrial fibrillation, has lead to the increased use of this drug despite its association with potentially severe adverse effects.112
Structures of amiodarone (A) compared with triiodothyronine (T3) (B). Amiodarone is nearly 40% iodine (I) by weight.
Although amiodarone has multiple pharmacologic effects, its efficacy as an antidysrhythmic agent is primarily the result of its class III antidysrhythmic effects. It also has weak α- and β-adrenergic antagonist activity and can block both l-type calcium channels and inactivated sodium channels. Amiodarone is slowly absorbed by the oral route and concentrates in the liver, lung, and adipose tissue. Steady-state pharmacokinetics may not occur until after 1 month of use.
The ECG effects of amiodarone differ based on the route of drug administration. Therapeutic oral doses prolong PR and QT intervals but not the QRS complex. IV dosing may produce a prolongation of the PR interval but has few other ECG manifestations. Ventricular dysrhythmias and sinus bradycardia are the most serious cardiac complications of therapeutic doses of amiodarone.119 Monomorphic and polymorphic ventricular tachycardias may be resistant to cardioversion and pharmacologic interventions13,35 but are surprisingly uncommon, given the frequency and extent to which the QT interval prolongation occurs. The ability of amiodarone to compete for P-glycoprotein is responsible for several consequential drug effects, including elevated digoxin and cyclosporin concentrations and an enhanced anticoagulation effectiveness of warfarin63,122 (see Chap. 8 and 12).
The diverse complications associated with long-term therapy do not occur after short-term IV use. Chronic therapy with oral amiodarone is associated with substantial pulmonary, thyroid, corneal, hepatic, and cutaneous toxicity because of bioaccumulation in these organs. Many of these effects appear to be dose related, but because of the wide range of bioavailabilities and metabolic patterns among different patients, as well as the overlap between therapeutic and toxic serum concentrations, therapeutic drug monitoring is of limited benefit.43 Pneumonitis, the most consequential extracardiac adverse effect, affects up to 5% of patients taking amiodarone therapeutically. Amiodarone pneumonitis may develop within days of initiating therapy but typically occurs only after years of therapy. Its occurrence may be dose related: a daily dose of more than 400 mg is a risk factor, and pneumonitis is rare in those taking less than 200 mg daily. The recent focus on using the minimal effective dose has reduced the incidence of pneumonitis.32,82 Oxygen supplementation may speed the development of pneumonitis, which may explain the initial belief that patients with chronic lung disease are at increased risk for amiodarone pneumonitis. Manifestations of pneumonitis include dyspnea, cough, hemoptysis, crackles, hypoxia, and radiographic changes.21 Computed tomography scanning is the most helpful initial diagnostic test for pneumonitis, but is not useful for monitoring purposes (monitoring is often done with diffusing capacity of CO).43 Bronchoalveolar lavage typically reveals interstitial pneumonitis with many macrophages and a characteristic finely vacuolated foamy cytoplasm, but confirmation of the diagnosis requires open lung biopsy.
Thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH), occurs in approximately 4% of patients.22 AIH is more common than AIT when iodine intake is sufficient.43 AIH is likely caused by an exaggerated Wolff-Chaikoff effect, in which iodine, in this case from amiodarone, inhibits the organification and release of thyroid hormone. AIT appears to exist in two distinct forms: type I AIT, which occurs in patients with abnormal thyroid glands and iodine-induced excessive thyroid hormone synthesis and release, and type II AIT, in which destructive thyroiditis leads to release of thyroid hormone from the damaged follicular cells. The relative prevalence of the two forms of AIT is unknown, but it may depend on the ambient iodine intake. Amiodarone may also reduce the effect of thyroid hormone on peripheral tissue.37 The diagnosis is confirmed with standard thyroid function testing110 (see Chap. 49).
Corneal microdeposits are extremely common during chronic therapy and may lead to vision loss.70 Abnormal elevation of hepatic enzymes occurs in more than 30% of those on long-term therapy, and hepatotoxicity may be associated with progression to cirrhosis. Periodic monitoring of aminotransferases is typically recommended.43 Hepatotoxicity may occur after initial loading of amiodarone.91 Slate gray or bluish discoloration of the skin is common, particularly in sun-exposed portions of the body.97
Dofetilide is approved for conversion of atrial fibrillation or atrial flutter to a normal sinus rhythm. Dofetilide increases the effective refractory period more substantially in atrial tissue than in ventricular fibers, accounting for this clinical indication.98 Unlike many of the other antidysrhythmics, it may reduce the morbidity of atrial fibrillation in patients with congestive heart failure, and it is still used despite the emphasis on rate control instead of rhythm control in treating atrial fibrillation. Dofetilide has no known effect on calcium or sodium channels, nor does it result in β-adrenergic antagonism. Dofetilide increases the QT interval but does not change either the PR interval or the QRS complex in humans. Heart rate and blood pressure are also not appreciably affected.
Although limited data are available, the expected and reported adverse cardiac events include ventricular tachycardia, particularly torsade de pointes.119 The approximate incidence of torsade de pointes in patients receiving high therapeutic doses of the drug is 3%.5 For this reason, the Food and Drug Administration has in place strict requirements for the use of dofetilide, such as an individualized dose initiation algorithm and mandatory hospitalization for initial therapy.6,85
Overdose data reported by the manufacturer include two cases. Whereas one patient reportedly ingested 28 capsules and experienced no events, a second patient inadvertently received two supratherapeutic doses 1 hour apart and experienced fatal ventricular fibrillation after the second dose.85 A 33-year-old man ingested 5 mg (20 capsules) and developed QT prolongation within 1 hour of ingestion but had no dysrhythmia during his 4-day hospital stay.
Ibutilide is an antidysrhythmic with predominant class III activity used for the rapid conversion of atrial fibrillation and flutter to normal sinus rhythm. Because of its extensive first-pass metabolism, ibutilide can only be administered parenterally. Its metabolic pathways are not well understood but do not involve the isoenzymes CYP3A4 or CYP2D6. Pharmacokinetic data thus far do not indicate that age, gender, hepatic, or renal dysfunction necessitates adjustment of recommended dosage of ibutilide. In addition to its effects on the delayed rectifier current, ibutilide activates a slow inward sodium current.75
Ibutilide may increase the QT interval and cause torsades de pointes, especially in patients with congenital long-QT syndrome and in women.44 Although ibutilide may enhance the efficacy of transthoracic cardioversion for atrial fibrillation, its use in patients with ejection fractions below 20% is associated with an increased incidence of sustained polymorphic ventricular tachycardia. Acute renal failure, including biopsy-identified crystals, has been reported in association with ibutilide cardioversion, but a causal relationship is not yet definitive.39 Acute overdose information, only available in limited form (four patients) through the manufacturer, suggests that ventricular dysrhythmias and high-degree AV conduction abnormalities should be expected.84
Management of Class III Antidysrhythmic Toxicity
Treatment experience with class III drug overdose is limited. Isoproterenol and overdrive pacing have been used successfully to treat patients with amiodarone-induced torsades de pointes.102 Administration of class IB antidysrhythmics or propranolol for the control of monomorphic ventricular tachycardia cannot be recommended on theoretical grounds. Paradoxically, amiodarone may reduce the "torsadogenic" effects of the other class III antidysrhythmics.106 This effect is likely mediated by the beneficial effects of amiodarone on the dispersion of myocardial repolarization and its calcium channel—blocking activity.
Multiple-dose activated charcoal may be helpful if used shortly after overdose. Hemodialysis is not expected to be beneficial in general, either because of extensive protein binding or because of large volumes of distribution (see Table 63–1). A neonate survived cardiovascular collapse with the use of ECMO after an iatrogenic IV amiodarone overdose.46
Adenosine, a nucleoside found in all cells, is released from myocardial cells under physiologic and pathophysiologic conditions. It is administered as a rapid IV bolus to terminate reentrant supraventricular tachycardia. The effects of adenosine are mediated by its interaction with specific G protein—coupled adenosine (A1) receptors that activate acetylcholine-sensitive outward K+ current in the atrium, sinus nodes, and AV nodes. The resultant hyperpolarization reduces the rate of cellular firing. Adenosine also reduces the Ca2+ currents, and its antidysrhythmic activity results from its effect in increasing AV nodal refractoriness and from inhibiting delayed afterdepolarizations elicited by sympathetic stimulation.67
The adverse effects of adenosine administration are very common and include transient asystole, dyspnea, chest tightness, flushing, hypotension, and atrial fibrillation. Although bronchospasm occurs after intrapulmonary administration, it has not been reported after IV use. Dyspnea, and probably chest tightness, is related to adenosine stimulation of the pulmonary vagal C fibers.19 Fortunately, most of the adverse effects of adenosine are transient because of its rapid metabolism to inosine by both extracellular and intracellular deaminases. The clinical effects are potentiated by dipyridamole, an adenosine uptake inhibitor,41 and by denervation hypersensitivity in cardiac transplant recipients. Methylxanthines may produce adenosine receptor blockade (see Chap. 65). In this setting, larger-than-usual doses of adenosine are required to produce an antidysrhythmic effect. Overdose of adenosine has not been reported. Treatment is supportive because of the rapid elimination of the drug.