CHAPTER 35 Overdose of Cardiotoxic Drugs
We begin with a review of poisoning due to calcium channel antagonists and β-adrenergic receptor antagonists (β-blockers). These two primary cardiovascular drug classes account for well more than half of the life-threatening events and deaths due to cardiovascular agents reported to the American Association of Poison Control Centers each year.1 Digitalis poisoning is also discussed. Finally, agents that produce cardiotoxicity primarily through sodium channel blockade and those with prominent sympathomimetic toxicity are also reviewed.
Calcium Channel Antagonists
Pharmacology
The calcium channel blocking drugs are a heterogeneous class of drugs that block the inward movement of calcium into cells from extracellular sites through “slow channels.”2 There are three major classes of these agents: phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), and dihydropyridines (e.g., nifedipine, amlodipine, nicardipine, nimodipine, felodipine). They are used in the treatment of coronary vasospasm, supraventricular dysrhythmias, hypertension, migraine headache, Raynaud phenomenon, subarachnoid hemorrhage, and many other disease states.3 In general, calcium channel antagonists are rapidly and completely absorbed from the gastrointestinal tract and, with the exception of nifedipine, undergo extensive first-pass hepatic metabolism yielding low systemic bioavailability. The volume of distribution is large for all but nifedipine, and protein binding is high (>90% for all but diltiazem). Elimination is almost entirely by the liver; impaired renal function does not affect clearance with the exception of a somewhat pharmacologically active metabolite of verapamil that is renally excreted.4 Terminal half-lives are generally from 3 to 10 hours, but all three classes of calcium channel antagonists are available in sustained-release preparations, which can result in greatly prolonged half-lives.
Pathophysiology
Electrophysiologic effects are most prominent for verapamil and diltiazem and are seen much less often with nifedipine and other dihydropyridines, which work primarily on the peripheral vasculature. Sinus node function may be significantly altered by verapamil and diltiazem in patients with underlying sinus node disease; in excess, these agents may prolong AV nodal conduction sufficient to produce advanced heart block. Depression of myocardial contractility by impeding phase 2 calcium influx is most pronounced in overdose or in patients who already have depressed myocardial function from underlying disease or concomitant drugs. Contraction of vascular smooth muscle, particularly arterial smooth muscle, is also mediated by calcium influx that is inhibited by calcium antagonists. In overdose, the effect of vasodilation on systemic blood pressure may be profound. However, in some cases, especially those involving the dihydropyridines, vasodilation may be ameliorated by a reflex increase in sympathetic activity, with increased heart rate and cardiac output.
Clinical Manifestations
The most serious consequences of calcium antagonist toxicity result from their effects on the cardiovascular system. Generally, these effects are an extension of the pharmacodynamic effects of the specific agent, although unique features of the different agents’ specificity profiles may be lost in overdose.5 Clinical features are summarized in Table 35-1. Bradycardia and conduction defects are among the most frequent findings in overdose of verapamil or diltiazem. Additionally, hypotension is present in most significant exposures to any calcium antagonist. These features generally develop within 1 to 2 hours of exposure, but the onset of moderate to severe cardiovascular manifestations may be delayed for more than 12 hours when a sustained release preparation has been ingested.6
Table 35–1 Clinical Features of Calcium Antagonist and β-Blocker Overdose
| Cardiovascular |
| Hypotension, shock |
| Dysrhythmias |
Patients at particular risk for toxicity from calcium antagonists include those with sinus node dysfunction, AV nodal conduction disease, severe myocardial dysfunction, obstructive valvular disease, hypertrophic cardiomyopathy, hepatic failure (leading to impaired elimination), and combined treatment of a calcium antagonist with β-blockers or digoxin.7 In addition, verapamil may dangerously accelerate conduction through accessory pathways when administered intravenously to patients with accessory or anomalous AV connections such as in Wolff-Parkinson-White syndrome.8 It should not be given to patients with atrial fibrillation and evidence of pre-excitation on electrocardiography.
Profound hypotension is the major manifestation of overdose with nifedipine and may produce reflex tachycardia, flushing, and palpitations. Conduction defects are rare unless there is an underlying conduction disease, a very large ingestion, or the presence of coingestants such as β-blockers.5,7
Management
Hypotension should be addressed based on the pathophysiology discussed earlier. Intravenous fluids and vasoconstriction with agents such as norepinephrine, epinephrine, phenylephrine, or dopamine may be successful in hypotension primarily due to peripheral vasodilation. Hypotension due to depressed myocardial contractility may be responsive to intravenous administration of calcium salts (calcium chloride 10% solution, 10 to 20 mL, or calcium gluconate 10% solution, 30 mL, followed by continuous infusion). The optimal dose of calcium is unclear from the available literature, and the danger of hypercalcemia-induced impairment of myocardial contractility and vascular tone must be kept in mind.10 However, calcium levels have been elevated to as high as 15 to 20 mg/dL in previous case reports without any adverse effects, and with an improvement in blood pressure.11
Glucagon has had some anecdotal success in cases of calcium antagonist overdose, and several animal models have shown its efficacy in this setting.12 Its use is discussed further in the section on treatment of β-blocker toxicity. Calcium antagonists are generally both highly protein bound and extensively distributed in tissue. Therefore, enhanced elimination techniques such as hemodialysis and hemoperfusion are unlikely to be of benefit, and clinical reports have failed to support a role in either therapeutic or overdose settings.13,14
Finally, a newer treatment using a hyperinsulinemia/euglycemia protocol has shown impressive results in case reports of calcium antagonist poisoning.15 Laboratory research in this area has also been promising.16 Numerous reports of the success of this treatment, along with published reviews of the management of calcium channel blocker toxicity, support its use early in the management of these poisonings. Insulin is thought to improve ionotropy and increase peripheral vascular resistance. Although the mechanisms are not completely known, it is thought to have a direct ionotropic effect on cells and to improve calcium pumps in myocardial cells.16,17,19 The most common insulin dosing regimen is 0.5 to 1 unit/kg/hr, along with 0.5 g/kg/hr of glucose using D5, D10, D25, or D50 (the latter two typically require central venous access due to their vascular irritant effects). In general, however, these patients are often already hyperglycemic and may not require the glucose component of the regimen while they remain toxic from the poisoning. Serum glucose concentrations should be checked hourly while the patient is on this therapy.
In severe refractory cases, cardiovascular bypass remains a viable option. Implementation has revealed successful results in previous reports, as patients are supported through the toxic effects of their poisoning.20,21 If patients can survive through the metabolism of the medication, they can often demonstrate a full recovery, both cardiovascularly and neurologically.
β-Adrenergic Antagonists
Clinical Manifestations
β-blocker toxicity is most commonly due either to administration to patients with underlying cardiac disease or to acute massive overdose. In the setting of acute overdose with a nonsustained release product, the onset of symptoms can be expected to occur within 6 hours of ingestion.22
Generally, poisoning due to β-blockers shares many features of clinical presentation with poisoning due to calcium channel antagonists (see Table 35-1), but the hallmark of β-blocker poisoning is hypotension, due predominantly to impaired contractility. Sinus node depression and conduction abnormalities are also common. As noted earlier, membrane-stabilizing properties seen most prominently with propranolol may lead to impaired conduction, QRS prolongation, and ventricular dysrhythmias23,24 Highly β-selective agents (atenolol, nadolol) may produce hypotension with a normal heart rate, but selectivity is frequently lost in large overdose. Overdose of agents with intrinsic sympathomimetic activity, most notably pindolol, may actually manifest with hypertension and tachycardia due to a stimulation. Sotalol is a unique agent that possesses some class III antiarrhythmic properties and therefore may produce Q–T interval prolongation, ventricular tachycardia, and torsades de pointes.25
Lethargy and coma may be present in patients with β-blocker poisoning. Seizures are rare manifestations of β-blocker poisoning, except for propranolol. This appears to correspond with CNS effects of the drug rather than to hypoperfusion of the CNS.23,24 Bronchospasm and respiratory depression may occur from overdose with β-blockers, but are infrequent. Hypoglycemia may also occur in contradistinction to calcium channel antagonists that result in hyperglycemia.26
Management
Glucagon is the mainstay of antidotal therapy for symptomatic β-blocker toxicity. Glucagon is a polypeptide hormone that appears to bypass the β-adrenergic receptor on a cardiac myocyte and increases intracellular levels of cyclic AMP by stimulating a distinct glucagon receptor on the membrane. The resultant promotion of transmembrane calcium flux and intracellular calcium release leads to restoration of chronotropy and inotropy.27 Although not universally effective, glucagon is of benefit in the majority of β-blocker overdoses. The initial dose of glucagon for a symptomatic β-blocker poisoning in the average adult is 3 to 5 mg bolused intravenously. The bolus may be repeated, and a continuous infusion of 2 to 5 mg/hr or higher may be necessary to maintain conduction and contractility. Mild nausea and vomiting, along with mild hyperglycemia, may occur with these doses, but otherwise the use of glucagon is without significant side effects.
As with calcium channel antagonist toxicity, calcium salts have been reported to be useful in β-blocker toxicity. In studies, calcium infusion can increase blood pressure in hypotensive β-blocker poisonings without any concomitant effect on heart rate.28 Thus calcium therapy may augment glucagon treatment in these cases. Recommended starting doses are 1 to 3 grams of calcium chloride 10% solution (10 to 30 mL) given intravenously. If central line access is not available, calcium gluconate should be used, as calcium chloride can be irritating to peripheral veins.
Some β-blocking agents, such as propranolol and acebutolol, can also act as membrane-stabilizing drugs, and can cause QRS prolongation in overdose. When the QRS duration is widened to greater than 120 milliseconds, treatment with sodium bicarbonate boluses may be required (see later). Some animal models and case reports have shown proven benefit with sodium bicarbonate in such circumstances.29
Phosphodiesterase inhibitors such as amrinone have not been shown to be of any additional benefit when compared with glucagon for management of β-blocker overdose, but their use might be considered if other therapy is failing.30,31 These agents may vasodilate and should be discontinued if blood pressure does not immediately respond.
Successful use of an intra-aortic balloon pump support in patients in whom other measures were unsuccessful has been reported.32 This may allow sufficient time for elimination of the toxicant and should be considered when the patient remains profoundly hypotensive despite glucagon and high-dose vasopressors.
Digoxin
Clinical Manifestations
There are no dysrhythmias diagnostic of digoxin toxicity. Several rare dysrhythmias, such as ventricular bigeminy and bidirectional ventricular tachycardia, are highly suggestive of poisoning by this agent. The classic early cardiac presentation of chronic toxicity is the appearance of premature ventricular contractions in a patient with atrial fibrillation whose ventricular response rate had been previously well controlled. Most patients with chronic, unintentional toxicity will complain first of anorexia and fatigue and will often have nausea and vomiting. Neurologic symptoms can begin subtly as visual changes, described as blurred vision, decreased visual acuity, or yellow halos, and progress on to confusion, hallucinations, seizures, or coma.33,34
Management
Digoxin-specific Fab fragments (Fab) are ovine IgG antibodies to digoxin that have had the Fc portion removed by papain digestion to reduce immunogenicity. When administered intravenously into a victim with digoxin toxicity, Fab fragments reverse conduction disturbances, restore contractility, and re-establish sodium-potassium ATPase activity by removing digoxin off receptor sites.35 Hyperkalemia is also reversed after Fab administration. Signs and symptoms of toxicity should resolve in less than an hour but are often gone within 10 minutes. Patients with severe hypotension or cardiac arrest may not be able to circulate the antibody fragments and may therefore be refractory to treatment.36
The dose of Fab fragment recommended to reverse digoxin toxicity is an equimolar dose to that of the ingested cardiac glycoside. A dose of 50 to 100 mg will neutralize 1 mg of digoxin. One vial contains 40 mg, and the manufacturer recommends a starting dose of 10 vials when the amount ingested or the level is unknown. Tables are available in the Fab package insert or through regional poison control centers to relate the dose of Fab to the measured serum digoxin concentration. Allergic reactions to Fab are extremely rare, and skin testing is unnecessary.35 Fab has also been shown to be effective in the treatment of severe cardiac glycoside cardiotoxicity from plants such as oleander containing similar compounds, but larger doses of the Fab may be required.37
Sodium Channel Blocking Agents
Of all categories of cardiotoxic drugs, perhaps the most heterogeneous contains those that impair sodium conduction through membrane channels (Table 35-2). These substances are commonly described as having “quinidine-like” or “membrane stabilizing” effects on the myocardial cell. Substances exhibiting these properties include analgesics, antihistamines, psychotropics, antidepressants, antidysrhythmics, anticonvulsants, and local anesthetics. Many of these medications have unique clinical effects at therapeutic doses, but in overdose, each can produce similar cardiotoxicity. The most common group of sodium channel blocking drugs, and the one to which all others are compared, is the class I antiarrhythmic agents.
| Class Ia antiarrhythmics |
| Class Ib antiarrhythmics |
| Class Ic antiarrhythmics |
| Chloroquine |
| Quinine |
| Propoxyphene |
| Cyclic antidepressants |
| Phenothiazines |
| Antihistamines (sedating and nonsedating H, antagonists) |
| Cocaine |
| Propranolol |
| Carbamazepine |
Pathophysiology
The subclassification of class I agents is partly based on the effect of these agents on potassium channels during cell repolarization. Blockade of potassium channels, most commonly displayed by class Ia drugs, leads to prolongation of repolarization and a subsequent increase in Q–T interval duration.39 As the duration of repolarization and therefore the Q–T interval lengthens, the opportunity for early afterpolarizations during this relative refractory period increases. Episodes of polymorphic ventricular tachycardia (torsades de pointes) can occur in this situation, especially in the presence of low potassium or magnesium concentrations.40 Class Ib agents shorten repolarization and reduce the duration of the action potential, while leaving potassium channels open and the Q–T intervals unaffected.39 Class Ic drugs are the most potent sodium channel blockers38 but have little effect on the repolarization phase of the action potential.
Pharmacology and Clinical Manifestations
Class Ia Antiarrhythmics
As noted earlier, all drugs in this class inhibit fast sodium channels in a dose-dependent manner. Generally, class Ia drugs are high potency sodium channel blockers.38 Depression of slow inward calcium and outward potassium movement may account for reduced action potential plateau and prolonged repolarization. The result is prolongation of the relative refractory period, decreased pacemaker automaticity, and a generalized slowing of conduction through the heart.
Quinidine
Quinidine, the prototype of class Ia antiarrhythmics, was released in the United States in the early 1900s. Orally ingested quinidine has good bioavailability. The sulfate reaches peak plasma concentrations within 90 minutes, while the absorption of gluconate and polygalacturonate salts may be delayed 3 to 6 hours.41 Quinidine is highly protein-bound, with a large volume of distribution throughout the body (3.0 L/kg).41 Up to 40% of an ingested dose of quinidine may be eliminated by the kidneys, but the remainder is metabolized to inactive products in the liver. High “therapeutic” plasma concentrations of quinidine were found in some individuals that developed both QRS and Q–T interval prolongation, and a sudden loss of consciousness associated with its use was soon described.41 These symptoms, referred to as “quinidine syncope,” were found to be caused by ventricular tachydysrhythmias.38 The incidence of these attacks is estimated to be 2% to 4%, and they are usually associated with polymorphic ventricular tachycardia.38 This dysrhythmia is often related to a prolonged Q–T interval, but some studies have determined that quinidine-associated ventricular tachycardia often does not present as torsades de pointes and may not be associated with a prolonged Q–T interval.42 Studies have also demonstrated little relationship between quinidine concentrations and the incidence of this dysrhythmia.44,48 Hypokalemia, however, is frequently found in patients with quinidine-associated syncope.40,45
As quinidine serum concentrations increase, Q–T interval prolongation is the earliest and most predictable electrocardiographic effect, 46 followed closely by QRS widening. In overdose, QRS widening is almost always present, with bundle branch blocks, sinoatrial and AV blocks, sinus arrest, and junctional or ventricular escape rhythms noted at high concentrations.39,40
Hypotension from quinidine, like many other of the drugs discussed in this section, is multifactorial. Unlike quinidine syncope, quinidine-induced generalized myocardial depression is dose-dependent.40,47 At low doses, especially when administered intravenously, quinidine exerts little negative inotropic effect but is an antagonist of peripheral α-receptors, leading to vasodilation.40 This effect can result in orthostatic syncope in some patients. At toxic concentrations, quinidine causes circulatory collapse due to a profound negative inotropic effect.47 In addition to shock, severely poisoned patients can have recurrent dysrhythmias, central nervous system depression, and renal failure.
The optical isomer of quinidine is quinine, and this compound has the capability to produce the same signs and symptoms in overdose.48,49 Toxic doses of either of these agents can also lead to cinchonism, a condition named after the tree from which these compounds are derived.49 This syndrome results in tinnitus, blurred vision, photophobia, confusion, delirium, and abdominal pain.49 Quinine amblyopia may result from large ingestions of these compounds, and the visual loss may be complete and sudden. Although vision returns in some patients as toxicity resolves, the loss may be permanent.50 Coma and seizures can occur with toxic concentrations of these drugs, even in hemodynamically stable individuals.40 Cinchonism is not reported with poisonings of the other class Ia agents.
Quinidine also has antimuscarinic effects and it may exacerbate the ventricular response to atrial flutter via enhanced conduction of the atrioventricular (AV) node. Furthermore, its potassium channel blockade may cause increased insulin release in the pancreatic islet cells, leading to hypoglycemia.51
Procainamide
A therapeutic oral dose of procainamide reaches peak plasma concentration within an hour, but massive ingestions can greatly delay absorption and prolong toxicity.49 Like quinidine, up to 40% of a given dose of procainamide may be eliminated unchanged in the urine. Unlike quinidine, procainamide is metabolized to a compound with cardiac activity similar to that of the parent drug, N-acetylprocainamide (NAPA), which may complicate the correlation of plasma levels of the parent compound with clinical effects.49 The therapeutic volume of distribution of procainamide is 2.0 L/kg, with a plasma half-life of 3 to 4 hours. The plasma half-life in overdose may increase significantly.49
Cardiotoxicity from procainamide is mechanistically similar to that described from quinidine. Myocardial depression, polymorphic ventricular tachycardia, and other cardiac dysrhythmias are all expected at high serum concentrations of procainamide.49 However, procainamide exerts a less negative inotropic effect, and a lower incidence of ventricular dysrhythmia than quinidine.52,53 Hypotension is mostly seen with intravenous use and usually only during infusions faster than 20 mg/min.40 Procainamide overdose can result in severe hypotension and dysrhythmias identical to those described with quinidine. Inability to electrically pace the heart of a procainamide-intoxicated patient due to high pacing thresholds has been described.54 Serious toxicity from procainamide includes lethargy, confusion, and depressed mentation along with the cardiotoxicity.39–41 Other adverse events in acute overdoses include seizures and antimuscarinic effects.55 Hematologic abnormalities such as agranulocytosis, thrombocytopenia, and hemolytic anemia have been reported in long-term use of procainamide.56 Procainamide may also produce a lupus-like syndrome.
Disopyramide
Peak serum concentrations of disopyramide may be delayed up to several hours in toxic ingestions owing to its antimuscarinic effects on intestinal motility.40 The protein binding (50% to 60%) and volume of distribution (<1 L/kg) of disopyramide are less than those of quinidine or procainamide and suggest the possibility that hemodialysis could be effective in removing toxic concentrations.40,57 A therapeutic dose of disopyramide has a mean plasma half-life of 6 to 8 hours and is 40% to 60% eliminated by the kidneys.49 The main hepatic metabolite, mono-N-dealkylated disopyramide, has little cardiac activity, but produces more antimuscarinic effects than the parent compound.
Disopyramide is the newest of the Class Ia antiarrhythmic agents and demonstrates electrophysiologic effects similar to quinidine and procainamide. Although Q–T interval prolongation does not usually occur with therapeutic concentrations of disopyramide, syncopal episodes have been reported.58 Of all class Ia agents, the negative inotropic effects of disopyramide are most pronounced, and hypotension can be seen in disopyramide poisoning without concomitant electrocardiographic changes.40,59,60 This may in part be related to its ability to block myocardial calcium channels.61 Although mild antimuscarinic effects can be noted in poisonings of all class Ia agents, those following disopyramide toxicity are the most clinically significant40 and can result in sinus tachycardia, blurred vision, altered mental status, seizures, urinary retention, and ileus, at times without accompanying serious cardiotoxicity.40 Overdose experience with disopyramide is limited in the United States.
Class Ib Antiarrhythmics
Drugs in this class suppress automaticity similarly to the class Ia agents but shorten the action potential refractory phase and increase conduction through hypoxic myocardial tissue.62 Class Ib drugs have rapid “on-off” binding kinetics for myocardial sodium channels and possess the highest affinity for sodium channels that are in the inactivated state.49 At therapeutic concentrations, these compounds moderately depress phase 0 of the myocyte action potential. The resultant effects on the electrocardiogram include a normal or shortened Q–T interval and an unchanged QRS duration.63
Lidocaine
A large first-pass effect is seen with oral dosing of lidocaine, and only 30% to 35% of an ingested dose is bioavailable.64 However, large ingestions have resulted in significant absorption, resulting in toxicity.65 Lidocaine is well absorbed topically through abraded epithelium and from the trachea and bronchi after endotracheal administration.66 The apparent volume of distribution of lidocaine is 1.3 L/kg, but it is significantly reduced in the presence of congestive heart failure.67 The liver metabolizes virtually all of a lidocaine dose, with an elimination half-life in therapeutic concentrations of about 2 hours.49 The most significantly active metabolite is monoethylglycinexylidide (MEGX), with a half-life also of 2 hours.68
Lidocaine is the prototype of class Ib antiarrhythmics, and in poisoning it causes cardiovascular and CNS toxicity. Lidocaine is primarily metabolized in the liver to MEGX. Both compounds are neurotoxic at high concentrations and can cause seizures and apnea.63
