Overdose of Cardiotoxic Drugs

Pharmacology

The calcium channel blocking drugs (CCBs) are a heterogeneous class of drugs that block the movement of calcium from extracellular sites through “slow channels” into cells. There are two major categories of these agents: nondihydropyridines, which include phenylalkylamines (e.g., verapamil) and benzothiazapines (e.g., diltiazem); and dihydropyridines (e.g., nifedipine, amlodipine, nicardipine, nimodipine). They are used in a variety of disease states and clinical settings, including coronary vasospasm, supraventricular arrhythmias, hypertension, migraine headache, Raynaud phenomenon, and subarachnoid hemorrhage. In general, CCBs are rapidly absorbed from the gastrointestinal tract and, while the majority undergo extensive first-pass hepatic metabolism yielding low systemic bioavailability, taken in overdose, hepatic enzymes are saturated, reducing the first-pass effect. The volume of distribution of these agents is large, except for nifedipine, and protein binding is high (>90% for all but diltiazem). Additionally, interactions through CYP3A4 or inhibition of P-glycoprotein–mediated drug transport may change clearance or bioavailability. Impaired renal function does not affect clearance of CCBs with the exception of a somewhat pharmacologically active metabolite of verapamil that is renally excreted. Terminal half-lives are generally from 3 to 10 hours, but all three classes of CCBs are available in sustained-release preparations, which can result in greatly prolonged half-lives and clinical effects.

Pathophysiology

CCBs can exert profound effects on the cardiovascular system, particularly in overdose. They work by antagonizing L-type or long-acting voltage-gated ion channels in the cardiac pacemaker cells and decreasing phase 2 calcium ion flux in smooth muscle cells of blood vessels. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocardial contractility, and peripheral vasodilation may result.

Electrophysiologic effects are most prominent with nondihydropyridines and are seen much less often with the dihydropyridines, which work primarily on peripheral vasculature. Sinus node function may be significantly altered by nondihydropyridines in patients with underlying sinus node disease; in excess, these agents may prolong AV nodal conduction sufficient to produce high-grade heart block. The effect of decreased myocardial contractility 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, can also be affected by CCBs through inhibition of calcium influx. 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 the pharmacodynamic effects of the specific agent on the cardiovascular system, although unique features of the different agents’ specificity profiles may be lost in overdose. Clinical features are summarized in Box 34.1 . Bradycardia and conduction defects are among the most frequent electrocardiogram (ECG) findings in overdose of the nondihydropyridines. Additionally, hypotension is present in most significant exposures to any CCB. 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.

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 concomitant use of β-blockers or digoxin. 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. It should not be given to patients with atrial fibrillation and evidence of preexcitation on ECG.

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 underlying conduction disease, a very large ingestion with loss of receptor specificity, or the presence of coingestants such as β-blockers.

Lethargy, confusion, dizziness, and slurred speech are common in CCB poisoning. Coma usually occurs in the setting of cardiovascular collapse with profound hypotension. Seizures are rare. Nausea and vomiting may occur. Metabolic acidosis is common in severely poisoned patients and is likely due to hypoperfusion. Hyperglycemia is also common in overdose with calcium antagonists and is an important diagnostic clue to differentiate poisoning with these medications from others with similar clinical effects. CCBs inhibit calcium-mediated insulin secretion from β-islet cells in the pancreas, impeding the use of carbohydrates, and also increase insulin resistance by unclear mechanisms.

Management

Initial management of poisoning due to calcium antagonists is similar to that for other toxic drug exposures, with initial support of the airway, adequate ventilation, and attention to circulatory status, followed by gastrointestinal decontamination, if appropriate. If accidental or intentional oral overdose has occurred, the administration of activated charcoal orally or through a nasogastric tube is indicated when the patient's airway is not at risk of compromise by potential aspiration. Gastric lavage is not now routinely advocated in the management of overdose patients, except perhaps in recent massive ingestions that present within the first hour. Repeated doses of activated charcoal and the use of whole-bowel irrigation with an iso-osmotic, isotonic lavage solution, such as polyethylene glycol (Go-Lytely) should be considered early in cases involving a slow-release preparation. Recommended rates of whole-bowel irrigation are 2 L/h in adults and 500 mL/h in children via nasogastric tube. Acute changes in the clinical picture can occur rapidly in these ingestions, which should be factored into the decision to decontaminate the patient. Continuous cardiac monitoring should be instituted in anticipation of cardiovascular collapse.

Specific therapy for sinus node depression or AV nodal conduction abnormalities is necessary only when there are signs of hemodynamic compromise or instability. Atropine may be administered but is often ineffective. Temporary cardiac pacing may be considered when severe conduction blocks are present, but because these agents can decrease contractility and peripherally vasodilate, hypotension may persist despite correction of electrical activity and conduction.

Hypotension should be addressed based on the pathophysiology discussed earlier. Treatment should begin with intravenous administration of calcium salts (calcium chloride 10% solution, 10 to 20 mL, or calcium gluconate 10% solution, 30 to 60 mL, followed by either repeat doses or a continuous infusion of 0.2–0.5 mL/kg per hour of calcium chloride or 0.6–1.5 mL/kg per hour of calcium gluconate) though improvement, if observed, may be transient. 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. 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.

Intravenous fluids and vasoconstriction with agents such as norepinephrine, epinephrine, phenylephrine, or dopamine may be successful in correcting hypotension due to peripheral vasodilation. In fact, one study suggests that higher than usual rates of vasopressor administration may be used as the only treatment for hypotension and shock related to CCB toxicity.

Glucagon has had reported successes and failures in cases of calcium antagonist overdose. Its use is discussed further in the section on treatment of β-blocker toxicity. As previously noted, 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; clinical reports have failed to support a role for them in either therapeutic or overdose settings.

More recently, use of a hyperinsulinemia/euglycemia therapy (HIT) has gained widespread acceptance as the mainstay of therapy in CCB toxicity. Although there are no controlled studies to support its use, animal studies have demonstrated survival benefit with this treatment as well as many case reports of success with HIT in patients with calcium antagonist poisoning. There is also one human observational study that showed a transient improvement in hemodynamics with HIT in patients that had ingested diltiazem. The proposed mechanisms include exerting a direct inotropic effect on cells without effecting chronotropy, improving calcium pumps in myocardial cells or reversing insulin resistance, allowing for glucose utilization by the heart. The most recognized insulin dosing regimen is 1 U/kg per hour, along with 0.5 g/kg per hour of glucose using D5, D10, D25, or D50 (the latter two typically require central venous access owing to their vascular irritant effects). In general, serum glucose concentrations should be checked hourly while the patient is on this therapy; however, patients with severe CCB toxicity are typically hyperglycemic and may not even need glucose supplementation. As their toxicity resolves, the glucose levels begin to normalize and glucose supplementation may be added or the insulin infusion may be weaned.

Intravenous fat emulsion (IFE) has been touted as a possible treatment for life-threatening CCB toxicity or for those presenting in cardiac arrest. The majority of studies examining the use of fat emulsion as an antidote dealt specifically with toxicity from local anesthetic agents, such as lidocaine. However, the lipophilicity of CCBs have led many to consider its use during toxicity. The proposed mechanism of action of IFE is that it creates a pharmacologic sink for fat-soluble drugs. Animal studies of CCB toxicity have shown improved survival when treated with fat emulsion; however, there are only a few human case reports of fat emulsion use in CCB toxicity. The dose of fat emulsion is 1.5 mg/kg bolus, which may be repeated several times, followed by an infusion of 0.25 mL/kg per minute over 30 to 60 minutes. In addition to interference with laboratory parameters, there are rare adverse effects, such as hypertriglyceridemia, hypoxemia (with high doses), and hyponatremia.

In severe refractory cases of CCB poisoning, cardiovascular bypass remains a viable option, allowing patients to be supported through the toxic effects of their poisoning as the drug metabolizes. Additionally, the successful use of methylene blue has been reported in cases of refractory shock in sepsis and there are case reports of its use in CCB toxicity. The mechanism is thought to be related to nitric oxide scavenging and inhibition of nitric oxide synthase. If patients survive long enough for the medication to be metabolized, they often achieve a complete cardiovascular and neurologic recovery.

Pharmacology

Many β-adrenergic antagonists (β-blockers) are available that vary in their pharmacodynamic properties of receptor selectivity, intrinsic sympathomimetic activity, membrane stabilization, bioavailability, lipid solubility, protein binding, elimination route, and half-life. β-Blockers are generally rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations achieved after 1 to 2 hours and with elimination half-lives of 2 to 12 hours for nonsustained-release preparations. Reduced first-pass hepatic extraction and impaired hepatic metabolism in liver disease or in massive overdose may contribute to toxicity by prolonging the half-life of the primary agent or an active metabolite.

Pathophysiology

Poisoning from β-blockers primarily affects the cardiovascular system, disrupting normal coupling of excitation-contraction and impairing ion transport in myocardial and vascular tissue. The mechanism of toxicity from β-blocker poisoning is difficult to fully explain but appears to be related to impaired response to catecholamine stimulation of β-receptors, to disturbances of sodium and calcium ion homeostasis, and to membrane stabilization. Receptor subtype (β1 vs. β2) selectivity may suggest the predominant effect of toxicity due to a given agent; in large overdoses, however, this selectivity is often lost. Membrane stabilizing effects, especially seen in propranolol poisoning—and, to a lesser extent, with acebutolol, betaxolol, carvedilol, and oxprenolol—may result in impaired conduction, prolonged QRS duration, and ventricular ectopy or tachycardia. The lipophilicity of propranolol facilitates central nervous system (CNS) penetration, frequently leading to seizures.

Clinical Manifestations

β-Blocker toxicity is most commonly owing to therapeutic dosing in patients with underlying cardiac disease or to acute 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.

Generally, poisoning owing to β-blockers shares many clinical features with poisoning owing to CCB (see Box 34.1 ), but the hallmark of β-blocker poisoning is hypotension, predominantly due 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 arrhythmias. 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 manifest with hypertension and tachycardia owing to α-stimulation. Sotalol is a unique agent that possesses some class III antidysrhythmic properties and therefore may cause QT prolongation, ventricular tachycardia, and torsades de pointes.

Lethargy and coma may be present in patients with β-blocker poisoning. Seizures are a rare manifestation of β-blocker poisoning, except for propranolol. This appears to be owing to the CNS effects of the drug rather than to hypoperfusion of the CNS. Bronchospasm and respiratory depression may occur from overdose with β-blockers but are infrequent. Hypoglycemia may also occur in contradistinction to the hyperglycemia seen in CCB poisoning.

Management

The initial approach to managing a patient with β-blocker overdose is similar to that for CCB overdose. However, β-blockers are receptor antagonists as opposed to CCBs, which block ion channels and movement of calcium into the cell. This may explain why β-blocker poisoning is more responsive than CCB poisoning to therapeutic approaches that either competitively overcome the agent at the blocked receptor (high-dose norepinephrine or epinephrine) or bypass the receptor to achieve a common physiologic endpoint (glucagon).

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. Although not universally effective, glucagon is of benefit in the majority of β-blocker overdoses. The initial dose of glucagon for symptomatic β-blocker poisoning in the average adult is 3 to 5 mg bolus intravenously. The bolus may be repeated; a continuous infusion of 2 to 5 mg/h or higher may be necessary to maintain conduction and contractility. Nausea and vomiting as well as mild hyperglycemia may occur with these doses; otherwise, the use of glucagon is without significant side effects.

As with CCB toxicity, calcium salts have been reported to be useful in β-blocker toxicity. Calcium infusion can increase blood pressure in hypotensive β-blocker poisonings without any concomitant effect on heart rate. Thus calcium therapy may augment glucagon treatment in these cases. Recommended starting doses are 1 to 3 g 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. The target of therapy should be a calcium level of 13 to 15 mg/dL.

Similar to CCB poisoning, insulin/euglycemia (HIE) should be considered for severe β-blocker poisoning when patients have not responded to glucagon, calcium, and atropine. A bolus of 1 U/kg is given along with a 0.5 g/kg dose of dextrose. The patient is then started on an infusion of 1 U/kg per hour, which can be increased by 0.5 to 1 U/kg per hour up to 10 U/kg per hour every 10 to 15 minutes when reassessing cardiac function. The patient should be concomitantly started on a dextrose infusion of 0.5 g/kg per hour as these patients are not typically hyperglycemic. When initially started on these infusions, the patient should have blood glucose level monitored every 15 to 30 minutes until stable and then every 1 to 2 hours while therapy is continued. The blood glucose should be targeted to between 100 and 250 mg/dL. Serum electrolytes should be monitored frequently, as hypokalemia may occur. Since there is often a delay in effect from insulin (15 to 60 minutes), a vasopressor will frequently have to be started while insulin takes effect.

Some β-blockers, 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 ms, treatment with sodium bicarbonate boluses may be required (discussed later). Some animal models and case reports have shown proven benefit with sodium bicarbonate in such circumstances.

Phosphodiesterase inhibitors such as amrinone have not been shown to be of any additional benefit when compared to glucagon for management of β-blocker overdose, but their use might be considered if other therapy is failing. These agents may vasodilate and should be discontinued if blood pressure does not immediately respond.

There is no clear advantage to a specific β-adrenergic agonist in the treatment of β-blocker poisoning, although many toxicologists prefer epinephrine and norepinephrine. Isoproterenol was commonly used in the treatment of these poisonings in the past but may not be available at many hospitals. Dose should be titrated to effect with restored perfusion or return of an appropriate heart rate. Successful use of intraaortic balloon pump support in patients in whom other measures were unsuccessful has been reported. Extracorporeal membrane oxygenation (ECMO) is also gaining popularity as a treatment for cardiovascular collapse if other aforementioned treatments have failed. There is currently significant interest in the use of ECMO in poisoning with cardiotoxic drugs such as β-blockers; at this time, however, the data are limited to a small number of case reports. ECMO may allow sufficient time for elimination of the toxicant and should be considered when the patient remains profoundly hypotensive despite glucagon, high-dose vasopressors, and HIE.

The use of IFE for β-blocker toxicity is controversial. There is theoretical benefit for medications that are significantly lipid soluble (LogD > 2). This has been supported by a small number of case reports but has shown no benefit in others. IFE should only be used in the sickest of patients who remain hypotensive or in cardiac arrest despite other therapies. It must be noted that use of IFE can increase the adverse effects (machine failure, blood clots, fat agglutination in lines) of ECMO and must be considered before starting treatment. The β-blockers that have shown some benefit with IFE include atenolol, carvedilol, nebivolol, and propranolol.

Enhanced elimination measures, such as hemodialysis, are unlikely to be of benefit for most of these medications. Exceptions include those patients with impaired renal function or in the setting of toxicity by a renally excreted agent such as atenolol, acebutolol, nadolol, or sotalol.

Pharmacology

Cardiac glycosides, such as digoxin, have been used for centuries in the treatment of a variety of heart diseases. Poisonings, both accidental and intentional, from these agents were once among the most difficult to manage and fatalities were common. With advances in the management of congestive heart failure using newer classes of drugs and the development of digoxin-specific Fab antibody fragments, the incidence of severe digoxin toxicity has declined.

Digoxin is well absorbed after ingestion and, although intravascular concentrations may rise rapidly after oral overdose, tissue distribution may be delayed. The estimated volume of distribution in adults is 7 to 8 L/kg. The kidney excretes over 60% of digoxin unchanged, while digitoxin is metabolized by hepatic enzymes.

Pathophysiology

Cardiac glycosides inhibit the sodium-potassium ATPase pump on cell membranes. As a result, in acute toxic exposures, extracellular and serum potassium concentrations rise along with intracellular sodium and calcium concentrations. Both conduction and contractility are impaired by the drug's effect on cardiac myocytes, but enzyme inhibition occurs throughout the body. There is an increase in automaticity as well as a decrease in depolarization and conduction velocity that are mediated by an increase in vagal tone.

Clinical Manifestations

There are no arrhythmias diagnostic of digoxin toxicity. Several uncommon arrhythmias, such as ventricular bigeminy and bidirectional ventricular tachycardia, are highly suggestive of poisoning by this agent or other cardiac glycosides. The characteristic 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 present with 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.

Fatalities from digoxin poisoning result most often from cardiovascular collapse. Ventricular dysrhythmias, severe AV block, and depression of myocardial contractility are seen in massive overdose and may be refractory to most conventional therapies. Hyperkalemia can also be significant, especially in acute poisonings, and may contribute to arrhythmias. There was discussion in the past about not treating this hyperkalemia with calcium owing to concern for causing a phenomenon known as “stone heart.” However, this concern was not supported in a recent case series.