Cardiac Intensive Care || Overdose of Cardiotoxic Drugs

Calcium Channel Antagonists

β-Adrenergic Antagonists

Digoxin

Sodium Channel Blocking Agents

Cyclic Antidepressants

Antipsychotics (Phenothiazines, Butyrophenones, and Atypical Agents)

Antihistamines

Propoxyphene

Carbamazepine

Chloroquine

Management of Sodium Channel Blocking Drug Toxicity

Illicit Drugs

Conclusion

Overdose of Cardiotoxic DrugsMegan DeMott, Michael Young, Saralyn R. Williams,

Richard F. Clark CHAPTER 35

CardiaC dysrhythmias, myocardial depression, and vasodilation are the major cardiovascular effects observed in poisonings. A large number of therapeutic and nontherapeutic agents pos-sess toxicity directed toward the cardiovascular system, whether in the setting of actual overdose or merely therapeutic misad-venture. In this chapter we address some of the most significant and most common cardiovascular toxins. We describe these toxicants briefly, review their relevant pharmacology, delineate their known pathophysiology, describe clinical manifestations of their poisonings, and discuss their current management rec-ommendations. In all such cases, consultation with a medical toxicologist or a certified regional poison control center should be considered.

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.

Not included in this chapter are a number of other cardiotoxic agents that are less commonly encountered or that demonstrate unique mechanisms of toxicity that are beyond the scope of this general discussion. The reader is referred elsewhere for review of these agents, which include clonidine and other antihyper-tensive agents, antidysrhythmics not noted earlier, cyclosporine, colchicine, chemotherapeutic agents (doxorubicin; anthracy-clines such as daunorubicin, and idarubicin), and certain metals (notably selenium, cobalt, copper, and arsenic).

Calcium Channel AntagonistsPharmacologyThe 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 dihydro-pyridines (e.g., nifedipine, amlodipine, nicardipine, nimodipine, felodipine). They are used in the treatment of coronary vaso-spasm, 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 gas-trointestinal 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 nife-dipine, and protein binding is high (>90% for all but diltiazem). Elimination is almost entirely by the liver; impaired renal func-tion 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.

PathophysiologyIn susceptible individuals or in overdose, these agents can exert profound effects on the cardiovascular system. They work by antagonizing L-type voltage gated ion channels in the cardiac pacemaker cells, and through depression of calcium ion flux in smooth muscle cells of blood vessels. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocar-dial contractility, and peripheral vasodilation may result.

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 conduc-tion 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

Noncoronary Diseases: Diagnosis and Management

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 pro-found. 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 ManifestationsThe 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 fea-tures are summarized in Table 35-1. Bradycardia and conduc-tion 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

Patients at particular risk for toxicity from calcium antago-nists include those with sinus node dysfunction, AV nodal conduction disease, severe myocardial dysfunction, obstruc-tive valvular disease, hypertrophic cardiomyopathy, hepatic failure (leading to impaired elimination), and combined treat-ment 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

Lethargy, confusion, dizziness, and slurred speech are com-mon in calcium channel antagonist 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 likely represents hypoperfusion. Hyperglycemia is also com-mon in overdose with calcium antagonists, and can serve as an important diagnostic clue to differentiate poisoning with these medications from others with similar clinical effects.

ManagementInitial management of poisoning due to calcium antagonists is similar to that for other toxic drug exposures with initial sup-port of the airway, adequate ventilation, and attention to cir-culatory status, followed by gastrointestinal decontamination when 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. In general, gastric lavage is no longer routinely advocated in the manage-ment 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 involv-ing a slow-release preparation. Recommended rates of whole bowel irrigation are 2 L/hr in adults and 500 mL/hr in children, via nasogastric tube. Continuous cardiac monitoring should be instituted in anticipation of cardiovascular collapse.

Specific therapy for sinus node depression or AV nodal con-duction abnormalities is only necessary when hemodynamic status is compromised. Calcium salts may be administered, but routine doses are often ineffective at improving conduction. Atropine may be given, but is often ineffective at reversal of con-duction defects, and pacing may need to be employed. Because of the effects of calcium antagonists on the myocardium and on the peripheral vasculature, hypotension may persist despite cor-rection of electrical activity and conduction.

Hypotension should be addressed based on the pathophysi-ology 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 myocar-dial contractility may be responsive to intravenous administra-tion of calcium salts (calcium chloride 10% solution, 10 to 20 mL, or calcium gluconate 10% solution, 30 mL, followed by continu-ous 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

Table 35–1. Clinical Features of Calcium Antagonist and β-Blocker Overdose

Cardiovascular

Hypotension, shock

Dysrhythmias

Sinus bradycardiaSecond- and third-degree atrioventricular block with nodal or

ventricular escapeSinus arrest with atrioventricular nodal escapeAsystoleProlonged QRS, ventricular ectopy/tachycardia (propranolol)

Hypertension, tachycardia (pindolol)

Central Nervous System

Lethargy, confusion, coma

Respiratory arrest

Seizures (especially from propranolol)

Gastrointestinal

Nausea, vomiting

Metabolic

Hyperglycemia (verapamil, diltiazem)

Hypoglycemia (β-blockers)

Lactic acidosis

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35Overdose of Cardiotoxic Drugs

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 sec-tion 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 thera-peutic or overdose settings.13,14

Finally, a newer treatment using a hyperinsulinemia/eugly-cemia 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 reg-imen 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 concen-trations 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 AntagonistsPharmacologyMany β-adrenergic antagonists (β-blockers) are available, with profiles varying to greater or lesser degrees in the pharmaco-dynamic properties of receptor selectivity, intrinsic sympatho-mimetic activity, membrane stabilization, bioavailability, lipid solubility, protein binding, elimination route, and half-life. β-blockers are generally rapidly absorbed from the gastroin-testinal 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.

PathophysiologyPoisoning 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 sta-bilization. Receptor subtype (β1 versus β2) selectivity may sug-gest the predominant effect of toxicity due to a given agent, but

in large overdoses this selectivity is often lost. Quinidine-like (membrane-stabilizing) effects, especially seen in propranolol poisoning, and to a lesser extent with acebutolol, oxprenolol, and betaxolol, may result in impaired conduction, prolonged QRS duration, and ventricular ectopy or tachycardia. The lipo-philicity of propranolol also facilitates CNS penetration, fre-quently leading to seizures.

Clinical Manifestationsβ-blocker toxicity is most commonly due either to adminis-tration 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 chan-nel antagonists (see Table 35-1), but the hallmark of β-blocker poisoning is hypotension, due predominantly to impaired con-tractility. Sinus node depression and conduction abnormali-ties are also common. As noted earlier, membrane-stabilizing properties seen most prominently with propranolol may lead to impaired conduction, QRS prolongation, and ventricular dys-rhythmias23,24 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 poison-ing, 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. Hypogly-cemia may also occur in contradistinction to calcium channel antagonists that result in hyperglycemia.26

ManagementThe initial approach to managing a patient with β-blocker over-dose is similar to that for calcium channel antagonist overdose. However, β-blockers are receptor antagonists as opposed to cal-cium channel antagonists, which block ion channels and move-ment of calcium into the cell. This may explain why β-blocker poisoning is more responsive than calcium channel antagonist poisoning to therapeutic approaches that either competitively overcome the agent at the blocked receptor (high-dose norepi-nephrine, epinephrine) or bypass the receptor to achieve a com-mon physiologic end point (glucagon).

Glucagon is the mainstay of antidotal therapy for symptom-atic β-blocker toxicity. Glucagon is a polypeptide hormone that appears to bypass the β-adrenergic receptor on a cardiac myo-cyte and increases intracellular levels of cyclic AMP by stimulat-ing a distinct glucagon receptor on the membrane. The resultant promotion of transmembrane calcium flux and intracellular cal-cium 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

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5 mg bolused intravenously. The bolus may be repeated, and a continuous infusion of 2 to 5 mg/hr or higher may be neces-sary 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 stud-ies, 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 bicarbon-ate boluses may be required (see later). Some animal models and case reports have shown proven benefit with sodium bicarbon-ate 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.

There is no clear advantage to a specific β-adrenergic agonist in the treatment of β-blocker poisoning, although many toxi-cologists prefer epinephrine, norepinephrine, or their combi-nation. Isoproterenol was commonly used in the treatment of these poisonings in the past, but may not be available at some hospitals. Dose should be titrated to effect with restored perfu-sion or return of an appropriate heart rate.

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 vaso-pressors.

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

DigoxinPharmacologyCardiac 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 recent 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 intra-vascular concentrations may rise rapidly and dramatically 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.

PathophysiologyCardiac glycosides inhibit the sodium-potassium ATPase pump on cell membranes. As a result, in acute toxic exposures, extra-cellular and serum potassium concentrations rise, along with intracellular sodium and calcium concentrations. Both con-duction 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 and a decrease in depolarization and conduction velocity, which is mediated by an increase in vagal tone.

Clinical ManifestationsThere are no dysrhythmias diagnostic of digoxin toxicity. Several rare dysrhythmias, such as ventricular bigeminy and bidirec-tional 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. Neuro-logic 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

Fatalities from digoxin poisoning result most often from car-diovascular 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 poison-ings, and may contribute to dysrhythmias.

ManagementBefore digoxin-specific Fab fragments, the treatment of severe digoxin poisoning consisted of the administration of large doses of atropine and vasopressors, along with the early use of external or transvenous cardiac pacemakers. These therapies are often of little benefit in significantly toxic victims. The development of digoxin-specific Fab antibody fragments has revolutionized the management of these poisonings.

Digoxin-specific Fab fragments (Fab) are ovine IgG antibod-ies 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 frag-ments reverse conduction disturbances, restore contractility, and re-establish sodium-potassium ATPase activity by remov-ing 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 min-utes. 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 gly-coside. 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

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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 AgentsOf all categories of cardiotoxic drugs, perhaps the most hetero-geneous contains those that impair sodium conduction through membrane channels (Table 35-2). These substances are com-monly described as having “quinidine-like” or “membrane sta-bilizing” effects on the myocardial cell. Substances exhibiting these properties include analgesics, antihistamines, psychotro-pics, antidepressants, antidysrhythmics, anticonvulsants, and local anesthetics. Many of these medications have unique clini-cal effects at therapeutic doses, but in overdose, each can pro-duce similar cardiotoxicity. The most common group of sodium channel blocking drugs, and the one to which all others are com-pared, is the class I antiarrhythmic agents.

PathophysiologyAll sodium channel blocking substances affect conduction of impulses throughout the myocardium by influencing the move-ment of ions through the cell membrane. Sodium, potassium, and calcium ion exchange through channels in the myocardial cell membrane is responsible for the various phases of the action potential. All class I antiarrhythmics block fast sodium channels, decreasing the slope of phase 0 of the action potential. In over-dose, this effect leads to a gradual widening of the QRS complex, eventually culminating in heart block or ventricular dysrhyth-mias. Depression of myocardial contractility contributes to the hypotension produced by these agents.

The subclassification of class I agents is partly based on the effect of these agents on potassium channels during cell repo-larization. Blockade of potassium channels, most commonly displayed by class Ia drugs, leads to prolongation of repolariza-tion 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 polymor-phic 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 repolar-ization and reduce the duration of the action potential, while leaving potassium channels open and the Q–T intervals unaf-fected.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 ManifestationsClass Ia AntiarrhythmicsAs noted earlier, all drugs in this class inhibit fast sodium chan-nels 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 repolariza-tion. The result is prolongation of the relative refractory period, decreased pacemaker automaticity, and a generalized slowing of conduction through the heart.

QuinidineQuinidine, 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 tachy-cardia 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 electrocardio-graphic 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 syn-cope, 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 vaso-dilation.40 This effect can result in orthostatic syncope in some

Table 35–2. Common Sodium Channel Blocking Drugs

Class Ia antiarrhythmics

Class Ib antiarrhythmics

Class Ic antiarrhythmics

Chloroquine

Quinine

Propoxyphene

Cyclic antidepressants

Phenothiazines

Antihistamines (sedating and nonsedating H, antagonists)

Cocaine

Propranolol

Carbamazepine

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patients. At toxic concentrations, quinidine causes circulatory collapse due to a profound negative inotropic effect.47 In addi-tion 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 com-pound has the capability to produce the same signs and symp-toms 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 com-plete and sudden. Although vision returns in some patients as toxicity resolves, the loss may be permanent.50 Coma and sei-zures 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 exac-erbate 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

ProcainamideA 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 clini-cal effects.49 The therapeutic volume of distribution of procain-amide 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 simi-lar to that described from quinidine. Myocardial depression, polymorphic ventricular tachycardia, and other cardiac dys-rhythmias are all expected at high serum concentrations of procainamide.49 However, procainamide exerts a less negative inotropic effect, and a lower incidence of ventricular dysrhyth-mia than quinidine.52,53 Hypotension is mostly seen with intra-venous 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 leth-argy, confusion, and depressed mentation along with the car-diotoxicity.39-41 Other adverse events in acute overdoses include seizures and antimuscarinic effects.55 Hematologic abnormali-ties 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.

DisopyramidePeak serum concentrations of disopyramide may be delayed up to several hours in toxic ingestions owing to its antimusca-rinic 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 remov-ing toxic concentrations.40,57 A therapeutic dose of disopyra-mide 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 prolonga-tion 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 diso-pyramide 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 fol-lowing disopyramide toxicity are the most clinically significant40 and can result in sinus tachycardia, blurred vision, altered men-tal 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 AntiarrhythmicsDrugs 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 con-centrations, these compounds moderately depress phase 0 of the myocyte action potential. The resultant effects on the electro-cardiogram include a normal or shortened Q–T interval and an unchanged QRS duration.63

LidocaineA 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, result-ing 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 distri-bution 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 signifi-cantly 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. Lido-caine is primarily metabolized in the liver to MEGX. Both compounds are neurotoxic at high concentrations and can cause seizures and apnea.63 Some individuals experience mild neurologic symptoms at therapeutic plasma concentrations.63 Since lidocaine rapidly passes through the blood-brain bar-rier, patients with toxicity usually manifest CNS dysfunction as initial symptoms.69 Early signs of CNS toxicity from lidocaine include lightheadedness, agitation, confusion, hallucinations, and dysarthria. Some individuals initially complain of tongue or

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perioral numbness. Progression to convulsions or coma can be rapid. Cardiovascular toxicity occurs primarily in massive over-dose. Following central nervous system dysfunctions, intrinsic cardiac pacemakers are depressed, conduction is delayed, and myocardial contractility is impaired.70,71 Large intravenous lido-caine doses greater than 1 g have resulted in asystole, complete heart block, and refractory hypotension.63,70,72

PhenytoinPhenytoin absorption from the gastrointestinal tract can be erratic, and peak levels after an oral overdose can be delayed up to 24 hours or more.73 Phenytoin is 90% protein bound, and the volume of distribution of the free drug is 0.5 L/kg.49,73 Signs of toxicity correlate better with free phenytoin levels, but most laboratories still assay for both bound and unbound fractions. Phenytoin is metabolized to nontoxic metabolites by the liver. At high concentrations, these enzymes become saturated, and the half-life may increase to several days as elimination kinetics change from first order to zero order.74 Patients with low serum albumin concentrations may be particularly prone to chronic phenytoin toxicity, owing to the higher relative fraction of free drug.49

Like lidocaine, phenytoin is classified as a class Ib agent. Poi-soning with phenytoin occurs most often during long-term therapy for epilepsy when a medication inhibiting phenytoin metabolism is added, or when the patient develops a disease state impairing hepatic mixed function oxidase activity. Acute overdoses occur less frequently, but the resulting clinical pre-sentation is similar.

Phenytoin poisoning primarily causes neurotoxicity, mani-fested as drowsiness, ataxia, dysarthria, and nystagmus. In mas-sive poisonings, coma and seizures can be seen, but respiratory depression is infrequent. Cardiac dysrhythmias and hypoten-sion are rarely reported with toxic phenytoin ingestions but are often encountered during rapid intravenous infusions.75 Although phenytoin does have sodium channel blocking effects on myocardial tissue, the diluent of the intravenous solution, propylene glycol, has been implicated as the source of myocar-dial depression and dysrhythmias associated with intravenous infusion.76 Slowing the rate of infusion prevents the majority of these complications.

Tocainide, MexilitineOverdose experience with other class Ib drugs has been lim-ited. Tocainide toxicity has resulted in gastrointestinal symp-toms, seizures, and cardiac dysrhythmias similar to other class I agents.77 Therapeutic use of tocainide resulting in blood dyscra-sias78 and pulmonary fibrosis79 has also been reported. Mexili-tine poisoning has caused seizures, ventricular dysrhythmias, and impaired myocardial conduction.80 Other adverse effects of mexilitine are primarily neurologic and comparable to symp-toms that occurred with lidocaine.

Class Ic AntiarrhythmicsClass Ic drugs (encainide, flecainide, propafenone) bind to sodium channels in the activated state and have the most potent sodium channel blocking effects of all class I antiarrhythmics.49 Therapeutic concentrations of class Ic agents produce little effect on myocyte repolarization compared to other class I antiarrhyth-mics.81 At higher concentrations, these agents exert a significant negative inotropic effect.82 Overdose experience with these

drugs is limited, but they would be expected to produce similar cardiovascular effects as other class I compounds, with no anti-muscarinic features. Seizures, hypotension, and dysrhythmias have been reported after a 3- to 4-g overdose of encainide.82

Class III AntiarrhythmicsClass III agents (amiodarone, ibutilide, dofetilide) block the rapidly activating component of the delayed rectifier potassium channels.49 These potassium channels are responsible for phase 3 repolarization in cardiac action potentials. Therefore Class III drugs delay repolarization and cause an increase in duration of the action potential and an increase in the effective refrac-tory period. On the electrocardiogram, this results in prolonged Q–T intervals. By increasing the refractory period, these drugs are very useful in terminating re-entrant dysrhythmias.

AmiodaroneAmiodarone is an antidysrhythmic with a multitude of pharma-cologic effects. It undergoes hepatic metabolism through cyto-chrome oxidase systems to produce another pharmacologically active but less potent metabolite, desethylamiodarone.83 The main mechanism of action of amiodarone is prolongation of cardiac myocyte repolarization through blockade of the rapidly activating delayed rectifier potassium channel. Collectively this represents a class III antidysrhythmic effect. However, amio-darone is also a weak α- and β-adrenergic receptor antagonist and may block inactivated sodium channels and L-type calcium channels.84 Expected electrocardiographic outcomes are pro-longed Q–T intervals, ventricular dysrhythmias, and conduc-tion blocks. Amiodarone is used to terminate re-entrant atrial or ventricular dysrhythmias and it has recently been added to the Advanced Cardiac Life Support (ACLS) tachydysrhyth-mia guidelines.85 Despite its more frequent use today, there are few reported cases of oral amiodarone overdose resulting in significant cardiac toxicity. The low toxicity is likely due to its low and unpredictable oral bioavailability (22% to 86%) and large volume of distribution (>6.0 L/kg).86 Intravenous overdose of amiodarone has not been reported although hypotension, bronchospasms, and hepatitis from therapeutic doses have been described. Most of the toxic effects reported from amiodarone in the literature are from long-term treatment and appear to be dose-related. Chronic use of amiodarone has been associated with pneumonitis, hypothyroidism, thyrotoxicosis, hepatitis, skin discoloration, and corneal damage.87 Although not well studied, cholestyramine has been suggested as treatment for both acute and chronic amiodarone toxicity by its gastrointesti-nal binding of unabsorbed amiodarone and blockade of entero-hepatic circulation of the drug.88

Ibutilide, DofetilideBoth ibutilide and dofetilide are newer class III antiarrhythmics used for chemical cardioversion of atrial fibrillation or flutter. Because of their effect on the rapidly activating delayed recti-fier potassium channels, both drugs can delay action potentials and prolong Q–T intervals.49 Experiences with overdoses of either drug are limited but expected toxicity would be induc-tion of ventricular dysrhythmias. Toxic effect of either drug occurs within 60 minutes of administration and therapeutic use has resulted in torsades de pointes.84,89 Therefore a reason-able observational period of 4 to 6 hours is recommended in all patients who received ibutilide or dofetilide.

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Cyclic AntidepressantsToxicity from cyclic antidepressants is perhaps the most well-described of all fast sodium channel blocking compounds. These substances are responsible for more fatalities each year than any of the other drugs in this group.90 After being originally studied for their antihistaminic properties in the 1940s, cyclic antide-pressants were introduced into the pharmaceutical market in the United States in the 1960s, rapidly replacing electroshock therapy as a more “humane” treatment for severe depression.

PharmacologyThe “first generation” of cyclic antidepressant compounds, known as the tertiary amines, includes amitriptyline, imipra-mine, doxepine, and trimipramine. All are potent inhibitors of myocyte sodium channels. Each undergoes metabolism in the liver. Amitriptyline and imipramine are hepatically converted to the active secondary amines nortriptyline and desipramine, respectively, and these latter compounds were soon marketed as second-generation therapies for depression.49 The membrane-stabilizing effects of these second-generation agents were soon appreciated as being similar to that of their parent compounds.49

Newer marketed antidepressants, categorized as serotonin or norepinephrine reuptake inhibitors (i.e., trazodone, fluoxetine, sertraline, buproprion, paroxetine, and others) have so far dem-onstrated far less sodium and potassium channel impedance. Although each of these drugs may cause adverse reactions in overdose, their cardiotoxicity appears to be minimal in compari-son to the first- and second-generation cyclic drugs.

In therapeutic doses, cyclic antidepressant drugs are rapidly absorbed. Although one might expect delayed gastric emptying as a result of an antimuscarinic effect in large ingestions, clini-cal signs of cyclic antidepressant toxicity usually appear within 6 hours.91 Asymptomatic patients without concomitant inges-tions should not develop toxicity after 6 hours. Antimuscarinic effects on the central and peripheral nervous systems usually precede cardiotoxicity, but large ingestions of agents with less muscarinic receptor activity, such as imipramine, may pre-sent initially with hypotension and dysrhythmias. Cardiotoxic-ity, mental status depression, and seizures resulting from these agents can proceed rapidly, necessitating continuous monitoring.

Cyclic antidepressants are significantly protein bound in cir-culation and widely distributed in the body (40 L/kg).49 Hepatic metabolism is the major route of elimination for these com-pounds, with some, such as amitriptyline and imipramine, producing active metabolites. Elimination half-life can be pro-longed in overdose due to enzyme saturation.

PathophysiologyThe pathophysiology of cyclic antidepressant cardiotoxicity results from four main properties: (1) fast sodium channel or membrane-stabilizing effects, (2) muscarinic receptor block-ade, (3) α-receptor blockade, and (4) norepinephrine reuptake blockade. Animal data also suggest blockade of delayed rectifier potassium channel and the γ-aminobutyric acid (GABA) recep-tor complex in the brain.92,93

Cyclic antidepressants block fast sodium channels in a man-ner similar to quinidine and other class Ia antiarrhythmics, markedly decreasing the slope of phase 0 of the action poten-tial.49 Prolongation of both the QRS and Q–T interval dura-tions have been demonstrated clinically in overdose, but in vitro

experiments show that cyclic antidepressants block primarily fast depolarizing sodium currents and actually shorten repolar-ization.94,95 The Q–T prolongation resulting from cyclic antide-pressant toxicity is mainly attributed to the result of progressive QRS widening with globally impaired myocardial conduction.95 However, the potential blockade of the delayed rectifier potas-sium channels may also contribute to the Q–T prolongation.93 The cardiotoxic effects include ventricular dysrhythmias and depressed myocardial contractility.95

Cyclic antidepressants block several receptor sites in both the central and peripheral nervous system, including H1 and H2 receptors, dopamine receptors, and muscarinic receptors.96 This effect on the autonomic nervous system produces a clini-cal syndrome of dry mouth, blurred vision, sinus tachycardia, altered mental status (ranging from confusion and hallucination to seizures and coma), ileus, urinary retention, and anhidrosis. These signs and symptoms frequently precede the sodium chan-nel blocking effects and are more common with doxepin and amitriptyline than imipramine.49,96

Cyclic antidepressants are potent α-receptor antagonists. This effect is responsible for the orthostatic hypotension often expe-rienced by patients at the initiation of therapy with these com-pounds.49 The resulting vasodilation can be severe in overdose and combined with the impaired cardiac output from myocar-dial depression can lead to refractory hypotension and cardio-vascular collapse.97 α-Receptor blockade of the pupil in patients with cyclic antidepressant toxicity can prevent the anticipated antimuscarinic mydriasis, resulting in an unanticipated miotic pupillary effect.

The hypothesized mechanism of antidepressant action of cyclic antidepressants lies in their ability to block the catechol-amine reuptake pump on the presynaptic terminal of neurons.96 In overdose, this effect can deplete presynaptic catecholamine concentrations, thought to contribute to dysrhythmias and hypotension.49

Hypotension can be present in cyclic antidepressant poison-ing without significant dysrhythmias. Sinus tachycardia is usually present before the development of ventricular dysrhythmias or heart block.98 Several studies have evaluated the electrocardio-graphic abnormalities predictive of toxicity from these agents. One review found that 33% of patients with QRS intervals greater than 100 ms developed seizures and 14% developed ventricular dysrhythmias.99 There was also a 50% incidence of ventricular dysrhythmias in patients with QRS duration exceeding 160 ms.99 Unfortunately, up to 25% of normal individuals may have a QRS duration greater than 0.10 second.49 Another study suggested that a rightward terminal vector, best seen in the R wave of lead aVR, may correlate with the degree of cyclic antidepressant tox-icity.100,101 In this study, an R wave of lead aVR greater than 3 mm notably predicted toxicity. Although having electrocardiographic abnormalities can be useful in assessing potential toxicity, none of the findings is 100% sensitive. Absence of these concerning findings is more indicative that cardiac toxicity is not developing.

Antipsychotics (Phenothiazines, Butyrophenones, and Atypical Agents)Phenothiazine derivative compounds such as Thorazine, thiorid-azine, and prochlorperazine may have clinical effects similar to the cyclic antidepressants. Antimuscarinic toxicity is frequently

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more pronounced in poisonings from these drugs, rather than their membrane-stabilizing cardiac effects. However, heart block and wide complex tachycardias and refractory hypoten-sion are occasionally reported in overdoses of these agents.102,103 Fatalities are rare, even in massive ingestions of these drugs. The most common clinical presentation of phenothiazine overdose is neurotoxicity, manifesting as delirium, agitation, coma, sei-zures, and other antimuscarinic effects.

Haloperidol and droperidol are butyrophenone antipsy-chotic and antiemetic compounds available in the United States. Although these drugs share the potent dopamine receptor blocking properties of the phenothiazines, overdoses of these agents lack the prolonged sedation and antimuscarinic effects most often seen with phenothiazines. Torsades de pointes has been reported with the butyrophenones but usually follows large parenteral dosing.104

Newer, atypical antipsychotics, such as quetiapine, olanza-pine, risperidone, and ziprasidone, seem to have fewer effects on cardiac conduction. Most atypical antipsychotics have inhib-itory functions at serotonin receptors, in addition to antimusca-rinic and dopamine receptor blocking properties. Retrospective data and case reports have demonstrated the ability of some of these drugs to block fast sodium channels and potassium chan-nels, resulting in QRS and Q–Tc prolongation, respectively. In general, these effects are much less common than with the older “typical” antipsychotic agents.

AntihistaminesMany H1 receptor antagonists have been found to exert similar effects on the myocardial action potential as the class Ia antidys-rhythmic compounds. The most commonly used medication in this class, diphenhydramine, has been shown to effectively block fast sodium channels at high concentrations.105

In mild to moderate poisonings with these agents, patients most often exhibit a classic antimuscarinic syndrome, with sinus tachycardia, dry mouth, and confusion, often marked by hallu-cinations and psychotic behavior. The toxic syndrome may also include seizures, urinary retention, decreased gastric motility, and coma. Respiratory depression can occur in some severe cases, necessitating ventilator support.

In massive poisonings, antihistamines can impair fast sodium channel conduction, resulting in dysrhythmias and hypoten-sion similar to that seen with other sodium channel blocking agents.105, 106 Dysrhythmias and cardiovascular collapse from these drugs are exacerbated by acidosis and, therefore, often occur after seizures, which frequently cause a sudden decline in the serum pH.105, 106

PropoxyphenePropoxyphene is an opioid analgesic found in combination with acetaminophen in Darvocet, and with salicylates in Dar-von. Hepatic metabolism of propoxyphene produces an active metabolite known as norpropoxyphene. Both agents block fast sodium channels, causing QRS prolongation in toxic serum concentrations.107 Overdoses of propoxyphene can result in hypotension and widening of the QRS complex, which can lead to ventricular dysrhythmias.108 It is this membrane-stabilizing effect that is also thought to be responsible for the greater inci-dence of seizures from propoxyphene poisonings than from

other opioids. As with other sodium channel blocking agents, widening of the QRS complex with propoxyphene poisoning has been shown to respond to therapy with sodium bicarbonate (see later discussion).109 Propoxyphene-induced seizures can be refractory to conventional anticonvulsants, such as phenytoin, necessitating use of benzodiazepines and phenobarbital for control.

CarbamazepineCarbamazepine is an anticonvulsant with structural similarity to the cyclic antidepressants. In vitro, carbamazepine cardio-toxicity resembles that of the class Ia antiarrhythmics. However, carbamazepine rarely causes significant quinidine-like effects in poisoning, even with massive ingestions.110,111 Carbamazepine toxicity often results in mental status changes and occasionally respiratory depression.110,111 In addition, toxic carbamazepine concentrations may produce blockade of muscarinic receptors, resulting in the classic antimuscarinic syndrome with effects such as sinus tachycardia, dry mouth, and mydriasis.

ChloroquineChloroquine is a common antimalarial agent that often results in severe toxicity when taken in overdose. Chloroquine is structur-ally related to quinine and quinidine, and cardiotoxicity result-ing from any of these agents can be indistinguishable.111 The toxic to therapeutic ratio of chloroquine is low, and ingestions of as little as 300 mg by children have been fatal.112 Seizures com-monly and rapidly accompany the cardiotoxicity of this drug and appear to be unrelated to hypoxia.111 A combination of inten-sive supportive care, intravenous boluses of benzodiazepines for convulsions, and vasopressor use for cardiovascular support has been shown to decrease mortality in animal models and human case reports of chloroquine poisoning.113

Management of Sodium Channel Blocking Drug ToxicityAs in the treatment of other cardiotoxic drug overdoses dis-cussed in this chapter, the initial management of poisonings involving sodium channel blocking medications should begin with airway and circulatory support (Table 35-3). Any patient who is not breathing or in whom a patent airway is of question should receive endotracheal intubation and mechanical venti-lation. Combative patients may require sedation and paralysis before an endotracheal tube can be placed.

Resuscitating the patient poisoned with sodium channel blocking drugs can be challenging. The hypotension resulting from massive ingestions of these agents is multifactorial and often refractory to intravenous fluid boluses. Vasopressors may be necessary in some situations, and vasopressor choice may be important. Although dopamine is employed with success in many cases of poisoning-related hypotension, it may be ineffec-tive or even exacerbate the hypotension associated with cyclic antidepressants, phenothiazines, and other α-receptor block-ing agents.114 Dopamine is the precursor of norepinephrine and requires uptake into the presynaptic terminals for activation; thus it may be ineffective with these agents, which block the cate-cholamine reuptake pump. At higher doses, the vasoconstrictive

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effects of dopamine are antagonized by the α-blocking effects of some of these drugs, leading to unopposed β-receptor stimula-tion of blood vessels and worsening of hypotension. For these reasons, vasopressors with more direct α-receptor stimulation, such as norepinephrine or phenylephrine, may be required for consistent blood pressure support.

The most helpful adjunct in the management of sodium channel blockade from drug poisoning has proved to be sodium bicarbonate. Sodium bicarbonate has been shown to be effective in raising the blood pressure and treating dysrhythmias associ-ated with cyclic antidepressants, cocaine, flecainide, quinidine, chloroquine, and diphenhydramine.115-121 Sodium bicarbon-ate has been shown in both animal models and human cases of toxicity from these agents to increase blood pressure and improve conduction through the heart. Studies suggest that this is the result of the concomitant effects of both the bicarbonate and sodium components because they offer a synergistic ben-efit together when compared to each alone. Thus the beneficial effects are likely secondary to both an increase in the blood pH and an increase in the extracellular sodium concentration.

Although controlled studies do not exist to support the use of sodium bicarbonate for every drug in this category, its empirical administration to patients with evidence of toxicity from impaired sodium conduction seems prudent. The degree of alkalinization that one must achieve to be of benefit has not been well defined. Maintaining serum pH in normal ranges has been sufficient in our practice, but many authors recom-mend bolus injections of sodium bicarbonate to keep serum pH between 7.45 and 7.50. One common practice is the addition of 50 to 100 mmol sodium bicarbonate (1 to 2 ampules) to 1000 mL of 5% dextrose and water, titrating the infusion to an alkaline pH. This exercise may require frequent analyses of serum pH and sodium, and may lead to hypernatremia if not monitored closely. Intermittent boluses of sodium bicarbonate, at 1-2 meq/kg are equally effective. The bolus method is preferred by many toxi-cologists for the ability to more precisely titrate sodium bicar-bonate doses to the effect of a narrowed QRS.

In some severe cases of sodium channel blocking drug toxic-ity, ventricular dysrhythmias may be refractory to the aforemen-tioned management. Oxygenation should be maintained and resuscitative efforts continued as long as cardiac activity is pres-ent. Patients have survived neurologically intact after over an hour of advanced cardiac life support following massive cyclic antidepressant poisoning.122 Prolonged resuscitation may allow enough drug redistribution from cardiac receptors to restore conduction. The use of lidocaine has been effective in improving cardiac performance after overdose of membrane-stabilizing drugs,116 and can be administered in cases refractory to sodium bicarbonate.

Several therapeutic considerations should be addressed with regard to the antimuscarinic toxicity resulting from agents such as cyclic antidepressants, antihistamines, and phenothiazines. The antimuscarinic signs and symptoms that usually predomi-nate are seldom life-threatening. Seizures from these agents, in the absence of severe hypotension or hypoxia, are most likely related to blockade of muscarinic receptors in the brain. They are usually self-limited and easily controlled with benzodiaz-epines or barbiturates. Sinus tachycardia produced by reduced vagal tone does not require specific treatment. Physostigmine, a short-acting carbamate cholinesterase inhibitor, can reverse the CNS toxicity and the sinus tachycardia associated with these agents, but may exacerbate impaired conduction throughout the heart, occasionally resulting in asystole.123 For this reason, phy-sostigmine is best reserved for cases with altered mental status in whom no cardiac conduction delays are present.

All patients with severe antimuscarinic signs and symptoms will need a urinary catheter if urinary retention occurs. Mul-tiple doses of activated charcoal, and food and beverages, should be avoided in those individuals with evidence of impaired gas-tric motility. Soft restraints may be necessary and are usually adequate in individuals with agitation due to the CNS effects of these drugs. They are also usually preferred over pharma-cologic restraints so as not to further impair the neurologic examination.

Gut decontamination may prevent absorption after inges-tions of any of the agents discussed earlier. If benefit is to be derived from gastric decontamination, it should be undertaken soon after ingestion. The longer the delay, the more the drug escapes into the small intestine where most absorption occurs. Gastric decontamination more than 1 hour after ingestion may be of little benefit unless drugs that delay gastric emptying are involved in the poisoning. Large studies have found no effect on outcome when gastric decontamination is avoided altogether.124 Syrup of ipecac is no longer recommended as a method of decontamination. Furthermore, gastric lavage is no longer rou-tinely advocated, with the exception of life-threatening poison-ings that present within 1 hour of ingestion.

Activated charcoal has been found to bind most cardiotoxic drugs and may be of benefit in limiting absorption. The timing of activated charcoal administration is also important, but char-coal administration may still be effective in binding a drug that has entered the duodenum. It is therefore rational to administer a dose of activated charcoal to most patients with a history or clinical evidence of ingesting a cardiotoxic substance. The rec-ommended dose of activated charcoal is 1 g/kg, and patients may either drink the aqueous charcoal suspension (which has no taste) or have the dose administered through a nasogastric tube when intubated or uncooperative. Caution should be used

Table 35–3. Outline of General Management of Sodium Channel Blocking Agent Toxicity

1. Stabilize airway. 2. Control breathing and hyperventilate patient if head injury is

possible, or if cardiotoxicity is present and intravenous access is not established.

3. Resuscitate blood pressure and treat dysrhythmias. a. Start intravenous normal saline or Ringer's lactate. b. Normalize serum pH. (1) Intravenous sodium bicarbonate (2) Hyperventilation c. Vasopressors (1) Norepinephrine (2) Phenylephrine (3) Dopamine d. Administer lidocaine for refractory ventricular dysrhythmias

in cyclic antidepressant or class Ia antiarrhythmic poisoning. 4. Decontamination a. Consider gastric lavage if less than 1 hour after massive

poisoning. b. Administer 1 g/kg oral activated charcoal

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when using activated charcoal in obtunded patients or in those who are unable to protect their airway because this poses a risk of aspiration. Multiple doses of activated charcoal have been found to be of benefit in poisonings with agents such as theoph-ylline and phenobarbital, but this therapy is not likely to benefit humans poisoned with any of the cardiotoxic agents listed in this chapter. In addition, those drugs that slow gastrointestinal motility may predispose the patient to charcoal bezoar forma-tion when multiple doses are administered.125

Extracorporeal removal of drugs using techniques such as hemodialysis or hemoperfusion has proved beneficial in over-doses of compounds such as theophylline, salicylates, and phenobarbital. Most other drugs, including those listed in this chapter, have not been found to be well removed by these modalities.

Illicit DrugsPsychostimulant toxicity is a common cause of emergency department visits. Deaths have been described as a result of the multiorgan effects of these drugs. Although only cocaine and amphetamine derivatives are discussed here in detail, other agents such as ephedrine, pseudoephedrine, and phenylpropa-nolamine may cause similar clinical effects in toxic concentra-tions.

CocaineCocaine is an alkaloid derived from the leaves of Erythroxylon coca and other trees indigenous to Peru and Bolivia. The alka-loid is dissolved in hydrochloric acid to form a water-soluble salt termed cocaine hydrochloride (chemical name, benzoyl-methylecgonine). Cocaine hydrochloride is sold as crystals, granules, or white powder. “Crack” (cocaine freebase) is the basic, nonsalt form that is created by the organic esterification of cocaine hydrochloride from a basic solution with ether. When crack is heated, it melts and forms a fat-soluble vapor that can be smoked and rapidly absorbed through the lungs. The name crack is derived from the popping sound made by the drug when it is heated. Therapeutically, cocaine is classified as an ester type of local anesthetic and currently limited to use as a mucosal anesthetic.

PharmacologyCocaine is well absorbed from the mucous membranes of the nose, lung, genitourinary, and gastrointestinal tract. Administra-tion can occur through the intravenous, respiratory, intramus-cular, and rectal routes. The method and dose of administration determine the onset of action. The “high” from intravenous administration of cocaine peaks within a few minutes after injection. Inhalation of the drug will produce effects within 1 to 3 minutes, but oral ingestion may delay symptoms up to 60 to 90 minutes. Plasma concentrations after intranasal use peak within 20 to 30 minutes and gradually decline over the next 60 minutes.126

Cocaine is metabolized by nonenzymatic hydrolysis and liver esterases, including plasma cholinesterase. The two major metabolites include benzoylecgonine and ecgonine methyl ester, neither of which crosses the blood-brain barrier. Both of these compounds are water-soluble and are excreted in urine. Cocaine metabolites may be detected in urine up to 72 hours after an exposure, although heavy users may have positive urine screens

for up to 3 weeks.127 When a user of cocaine also coingests ethanol, hepatic transesterification will create another pharma-cologically active metabolite, cocaethylene. Cocaethylene is not on routine urine screens for cocaine metabolites.

PathophysiologyThe pharmacologic effects of cocaine in humans include the ability to stabilize membranes and block nerve conduction. The resulting effects on myocardial tissue cause blockade of fast sodium channels, leading to widening of the QRS complex with subsequent dysrhythmias. The sympathomimetic effects of cocaine are caused by impaired catecholamine reuptake and enhanced catecholamine release at nerve terminals.126 The increased synaptic concentrations of neurotransmitters stimu-late α- and β-receptors throughout the autonomic nervous sys-tem resulting in a cascade of clinical effects. Cocaine may also enhance the release of norepinephrine and dopamine in the CNS.128 The unique ability of cocaine to inhibit nerve conduc-tion while enhancing vasoconstriction is primarily responsible for its cardiovascular toxicity.126

Cocaethylene is also a potent sodium channel blocking agent and appears to prolong the recovery time for the channel com-pared with cocaine.129 In animal models, cocaine plus ethanol depressed myocardial contractility more than either agent given alone.130,131 Once formed, cocaethylene has a longer half-life than cocaine.

The mechanism of cocaine-induced myocardial ischemia is thought to be multifactorial. Cocaine increases myocardial oxygen demand while increasing heart rate and blood pressure. Usually, myocardial oxygen demand results in coronary vasodi-lation; however, cocaine taken by some routes can induce coro-nary vasospasm.132 Coronary artery thrombus formation has also been implicated as a cause of cocaine-induced myocardial ischemia. Thrombus formation leading to myocardial infarc-tion has been associated with coronary artery vasospasm.133 The vasospasm may damage the endothelium and cause release of vasoactive substances precipitating platelet aggregation. Cocaine may enhance this effect because in vitro studies have demonstrated that cocaine alone may directly stimulate platelet aggregation and platelet thromboxane production.134 Cocaine activates platelets in whole blood by inducing the release of platelet granule contents and by promoting the binding of fibrinogen to the surface of the platelet.134

Clinical ManifestationsThe clinical effects of cocaine result from diffuse hyperadrener-gic stimulation both centrally and peripherally. The peripheral sympathomimetic effects include tremor, mydriasis, urinary retention, and ileus. Adrenergic stimulation of the CNS leads to agitation, hallucinations, seizures, and coma.135 Patients may experience psychosis, paranoia, and anxiety due to increased dopaminergic transmission.136 Cerebrovascular complications from cocaine-induced vasospasm and a hyperadrenergic state include cerebral infarctions, transient ischemic attacks, and sub-arachnoid and intracranial hemorrhages.135,136

Myocardial ischemia and infarction are well-documented complications of cocaine use. Ischemia of the myocardium does not require a massive exposure to cocaine and occurs com-monly in the young adult with no history of cardiac risk fac-tors. Symptoms of chest pain may be typical, atypical, or absent. A delay of several hours in the onset of chest discomfort may

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occur after exposure to the drug.137-139 Electrocardiograms from patients with cocaine-associated chest pain may demon-strate a variety of abnormalities, including classic findings of myocardial injury such as ST segment elevation but may also be normal or have only nonspecific findings. A study of 42 cocaine users with chest pain and normal or nondiagnostic electro-cardiograms documented 8 of these patients as having acute myocardial infarctions, defined by total creatinine kinase and myocardial isoenzyme levels.140 Thus single or even serial elec-trocardiograms may not be useful in ruling out cocaine-induced ischemia.

Cocaine has been associated with a variety of dysrhythmias. Sinus tachycardia is common owing to the sympathomimetic effects. Atrial fibrillation, premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation have all been described.141 Dysrhythmias may occur with or without underly-ing ischemia. Since cocaine can cause sodium channel blockade, this can lead to widening of the QRS complex and can precipi-tate associated dysrhythmias. Sodium channel blockade should be treated with sodium bicarbonate, as previously discussed.

Hypertension is also common with cocaine poisoning. The elevation in blood pressure combined with tachycardia may increase shear forces on the great vessels, resulting in aortic dissection,142 and coronary artery dissection.143 The intestinal vasculature is susceptible to α-stimulating effects of catechol-amines, and ischemic colitis has been described in adults144 and in neonates after in utero exposure to cocaine.145 The uteropla-cental vasculature may also respond to cocaine exposure with diminished uterine blood flow after maternal cocaine use.146

Extreme hyperthermia is often documented in cocaine over-dose. Temperatures are frequently reported in excess of 106° F and are thought to result from a disturbance in thermoregula-tion due to excess dopaminergic stimulation, combined with excessive musculoskeletal activity and agitation.147,148 Although cocaine-induced hyperthermia may occur independent of sei-zure activity, it can be exacerbated by concomitant convul-sions.149 An acute rise in the central body temperature has also occurred after rupture of bags of cocaine ingested by body packers.150

Rhabdomyolysis also contributes to the morbidity and mor-tality of cocaine poisoning. All routes of cocaine exposure have been associated with a rise in serum creatinine phosphokinase level from direct myotoxicity.150-152 An association has been made between drug-induced hyperthermia and rhabdomy-olysis, but observations suggest that cocaine can also induce rhabdomyolysis independently of hyperthermia.150 Cocaine-induced rhabdomyolysis is associated with myoglobinuric renal failure.152 Cocaine is not known to be directly toxic to the renal tubules; however, the effects of cocaine on renal blood flow may exacerbate the effects of myoglobinuria.

Amphetamine DerivativesAmphetamine derivatives, such as methamphetamine, are pop-ular agents of abuse available as many different “designer” drugs in the phenylethylamine family (Table 35-4). Substitutions of the phenylethylene ring can result in many compounds with simi-lar effects. The only approved uses of phenylethylamines in the United States at this time are for treatment of narcolepsy, atten-tion deficit disorder, and short-term use for weight loss.

Amphetamines have been recognized for their stimulant properties for centuries and continue to be abused by various

routes including intravenous and oral administration. “Ice” is a pure preparation of methamphetamine and is marketed in a solid form, hence its nickname. This preparation is volatile and can be smoked, resulting in rapid absorption and effect. This form of methamphetamine rapidly became one of the leading drugs of abuse in Hawaii and California in the 1980s.153,154 Illicit laboratories are able to produce large quantities of methamphet-amines because of easy availability of most reagents.

Abuse of the phenylethylamines results in euphoria with increased self-confidence and well-being. Persistent use with repetitive doses over several days is common. During this “speed run,” the user may not sleep or eat owing to the stimulant and anorectic effects of the drug. Chronic use of amphetamines leads to tachyphylaxis, and increasing doses are usually required to maintain euphoria.

PharmacologyThe volume of distribution of amphetamines tends to be large, and the half-life ranges from 8 to 30 hours.155 Elimination is primarily through hepatic transformation, but renal excretion results in significant elimination of certain members of the amphetamine family, such as methamphetamine.156 Although acidification of the urine may enhance the excretion of some amphetamine derivatives, it may also exacerbate renal toxicity in the presence of rhabdomyolysis and is therefore not recom-mended.157

PathophysiologyThe pharmacologic mechanisms of action of amphetamines are diverse but are thought to rely on indirect effects on catechol-amine receptors. These compounds act by entering presynaptic neurons and stimulating the release of endogenous catechol-amines such as norepinephrine and dopamine. Amphetamines also inhibit the reuptake of catecholamines and their breakdown by the monoamine oxidase enzyme system. These effects may last for hours, whereas those of cocaine may resolve within sev-eral minutes.155

Increased catecholamine release results in stimulation of α- and β-receptors, both peripherally and centrally. Dopaminergic and serotonergic receptor stimulation may contribute to the behavioral disturbances and hyperthermic effects that are com-mon with these poisonings.158 The release of dopamine may be responsible for the pleasurable effects reported with these drugs. Although all members of the amphetamine family may produce a generalized hyperadrenergic state, the pattern of effects with these compounds differs with modification of the parent phenyl-ethylamine molecule, resulting in different anorectic, cardiovas-cular, and hallucinogenic properties.159

Table 35–4. Designer Amphetamines

Chemical Name Nickname

3,4-Methylenedioxymethamphetamine MDMA, Adam, Ecstasy, XTC

3,4-Methylenedioxyethamphetamine MDEA, Eve

3,4-Methylenedioxyamphetamine MDA, Love Drug

4-Methyl-2,5-dimethoxyamphetamine DOM/STP, Serenity, Tranquility

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Clinical ManifestationsPhysical findings in amphetamine poisoning are similar to those seen with other sympathomimetic drugs. The cardiovascular toxicity of amphetamines manifests most commonly as tachy-cardia and hypertension. Dysrhythmias are a common cause of death and can include ventricular tachycardia and ventricu-lar fibrillation.160 Hypertensive emergencies with intracranial hemorrhages and cerebrovascular accidents may be more com-mon with amphetamine and methamphetamine than cocaine abuse.161 Acute myocardial ischemia, infarction, aortic dissec-tion, and dilated cardiomyopathy are also known to occur in the setting of amphetamine use.162 Diffuse vascular spasm has also been reported with amphetamine poisoning, and may result in death.163,164

CNS toxicity is the most common reason for amphetamine-poisoned patients to present to a hospital. Most victims are agitated, anxious, and can become volatile and violent. Tactile and visual hallucinations may contribute to patient agitation, and psychoses similar to paranoid schizophrenia are frequently observed in these patients. Mydriasis and diaphoresis are com-mon. Seizures often complicate amphetamine poisoning.164

As in acute cocaine intoxication, hyperthermia is well doc-umented in amphetamine poisoning and is associated with increased morbidity and mortality. Hyperthermia may occur independent of seizures and has been associated with rhabdo-myolysis, coagulopathy, renal failure, and death.164-166

ManagementSuccessful treatment of sympathomimetic poisoning begins with aggressive supportive care. Management of airway, breath-ing, and circulation are initial priorities. Placement of the patient in a quiet setting may reduce the amount of stimulation and reduce patient agitation; however, the victim must be continu-ously monitored for potential complications. Vital signs should be obtained frequently and body temperature verified by rectal thermometer if hyperthermia is suspected. Rapid cooling mea-sures should be instituted as soon as hyperthermia is discovered, and neuromuscular paralysis may be required in severe cases of hyperthermia.

Decontamination of the patient who ingested sympathomi-metics or bags containing these drugs begins with the adminis-tration of activated charcoal as described earlier. Whole-bowel irrigation with an iso-osmotic, isoelectric lavage solution (e.g., Go-Lytely) may enhance the removal of bags from the gastroin-testinal tract.167 Due to the large volume of distribution of these agents, hemodialysis and hemoperfusion are not effective in their removal; however, hemodialysis may be required if acute renal failure develops as a complication of rhabdomyolysis.

Rapid and effective control of hypertension from sympa-thomimetic poisoning is imperative. The use of β-blockers to control the hypertension associated with sympathomimetics is controversial because these compounds may potentiate both coronary and peripheral vasoconstriction due to unopposed α-agonist activity.168,169 Case reports have suggested the use of labetalol as an alternative to nonselective β-blocking agents,170 but labetalol is a more potent β than α antagonist. One study of patients given intranasal cocaine while undergoing angiography demonstrated that labetalol reduced the mean arterial pressure but had no effect on coronary artery vasoconstriction.171 Use of direct vasodilators such as nitroglycerin, nitroprusside, or phen-tolamine is optimal.172,173

Cocaine or amphetamine-related chest pain must be consid-ered to represent active myocardial ischemia. Therapy should initially include the application of oxygen and the reduction of central sympathomimetic effects with the liberal use of benzo-diazepines. Nitroglycerin has been demonstrated to be effective in alleviating cocaine-induced vasoconstriction in diseased and nondiseased coronary arteries.173 An antiplatelet drug such as aspirin may be administered because platelets are activated by cocaine. Heparin or thrombolytics may be considered when ischemia is refractory to more conservative management.

Treatment of sympathomimetic-induced dysrhythmias begins with the administration of benzodiazepines to sedate the patient and reduce catecholamine release.174 Wide complex tachydysrhythmias from cocaine have been effectively treated by administering intravenous sodium bicarbonate.175 Lidocaine may be considered for treatment of dysrhythmias secondary to ischemia or refractory to sodium bicarbonate but should be used with caution because it has potentiated cocaine-induced seizures and death in rats.176

Benzodiazepines are the mainstay of treatment for CNS effects of sympathomimetic poisonings. These sedative- hypnotics have been demonstrated to reduce the lethality of both cocaine and amphetamines.174,177 Butyrophenones have also been effective in reducing the dopaminergic-based delir-ium associated with amphetamine use.178 Butyrophenones must be administered cautiously to patients with either cocaine or amphetamine toxicity because most antipsychotic medica-tions may lower seizure thresholds, alter temperature regula-tion, and cause acute dystonias.

ConclusionMany drugs possess the ability to cause life-threatening cardio-toxicity in overdose. In this chapter we have outlined some of the most significant and most common agents in this regard, with emphasis on clinical presentation and management. Although primary resuscitative efforts in all disease states should focus on airway and circulation, the varied mechanisms of action of cardio-toxic compounds may require specific therapeutic interventions. Early consultation with a certified regional poison control center or a medical toxicologist may assist in the care of these patients.

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