Overdoses Involving Cardiovascular Drugs

By Lewis Nelson, MD

A 56-year-old man was brought to the emergency department two hours after he ingested an unknown quantity of verapamil during a suicide attempt. On arrival, his heart rate was 50, blood pressure 90/60 mm Hg, and his mental status was good. An electrocardiogram revealed junctional bradycardia.

 
DIFFERENTIAL DIAGNOSIS

In the absence of evidence pointing to an overdose of verapamil, the most likely cause of this patient's symptoms would be myocardial infarction. Unless the history clearly implicates such an ingestion, the possibility of myocardial ischemia must be investigated and ruled out. That done, the differential diagnosis would shift to the myriad possible cardiotoxins.

The differential diagnosis of drug-induced bradycardia and hypotension is broad and complicated by the fact that the clinical findings described may be triggered by agents that are not directly cardiotoxic. For example, clonidine causes bradycardia through a reduction in centrally mediated sympathetic stimulation. Similarly, the alpha1-adrenergic agonist phenylpropanolamine produces a reflex response that occurs after a rapid increase in blood pressure.

Cholinesterase inhibitors such as organophosphorous compounds and carbamates can cause bradycardia, because inhibition of acetylcholine metabolism enhances vagal tone in the conduction system. Despite the inability of acetylcholine to be cleared from the vagus nerve of patients who have organophosphate poisoning, however, many such patients present with tachycardia, perhaps because sympathetic tone is enhanced by either bronchorrhea-induced hypoxemia or the action of acetylcholine on nicotinic receptors in the autonomic ganglia.

Digoxin and other cardiac steroids also slow conduction through the heart by enhancing vagal tone. Both the positive inotropic effects of digoxin and its potentially life-threatening toxicity are mediated by its direct effects on the myocardium--namely, inhibition of the normal exchange of sodium and potassium during repolarization, resulting in an increase in intracellular calcium. Although small increases in intracellular calcium enhance myocardial contractility, large elevations affect the electrical stability of the heart by increasing its resting potential.

Many agents cause bradycardia through sodium-channel blockade with subsequent slowing of myocardial depolarization and prolongation of the action potential. Aside from type I and III antiarrhythmic drugs, important examples include tricyclic antidepressants, thioridazine, and cocaine. It is worth noting, however, that in mildly poisoned patients the anticholinergic effects of the tricyclic agents and of quinidine and the sympathomimetic effects of cocaine more commonly produce tachycardia. In severe poisoning, the degree of sodium-channel blockade surpasses the capacity of the cells to depolarize and repolarize, and bradycardia ensues.

Beta-adrenergic antagonists can cause bradycardia not only during an overdose but also at therapeutic dosages. The effects of beta-blockade may not be overwhelming in previously healthy patients who do not require significant sympathetic stimulation at rest. The risk of a severe response is high, however, in patients with congestive heart failure, who may require significant sympathetic nervous system stimulation to maintain cardiac contractility and heart rate even at rest. However, because several of the beta-blockers, such as pindolol, actually produce intrinsic sympathomimetic activity, someone who has overdosed on one of these agents may present with a normal or elevated heart rate.

Calcium-channel blocker overdose may cause profound bradycardia, often accompanied by various degrees of atrioventricular heart block. For the sake of simplicity, patients who have taken overdose amounts of calcium-channel blocker and beta-blocker agents are often classified together, but the subtle differences in presentation and management should be noted. For example, whereas patients with calcium-channel blocker poisoning more often remain conscious--even with profound alterations in vital signs--the opposite is true of patients who have taken an overdose of beta-blockers. Whether this difference occurs because calcium-channel blockers promote neuronal stability by inhibiting the influx of calcium or because most beta-blockers are highly lipophilic is not known.

Electrocardiographic abnormalities also tend to differ between the two groups. Ventricular conduction disturbances are more likely to occur in patients who have beta-blocker poisoning, because the drugs are able to block myocardial sodium channels, whereas high-degree atrioventricular blocks are more likely to occur in patients who have calcium-channel blocker poisoning. In addition, seizures are more common after beta-blocker overdose than after calcium-channel blocker poisoning. Finally, although hyperglycemia can occur with either type of overdose, only beta-blockers cause hypoglycemia.

 
TREATMENT

The advanced cardiac life support algorithm for treating bradydysrhythmia is a useful starting point for the empiric management of poisoned patients who have bradycardia. Atropine is virtually always safe when given in an appropriate dose—as much as 3 mg for an adult—but its efficacy may be limited in patients who do not have bradycardia caused by organophosphate or cardiac-glycoside exposure. The major disadvantage is smooth muscle atony, which could impair attempts to achieve adequate gastrointestinal decontamination.

If digoxin poisoning is confirmed or strongly suspected, antidotal therapy with digoxin immune Fab must be administered as soon as symptomatic or progressive bradycardia appears. If a sodium-channel blocker is involved, an intravenous bolus of hypertonic sodium bicarbonate, 1 to 2 mEq/kg, or hypertonic saline must be administered initially in an attempt to overwhelm the sodium-channel blockade.

The first step in managing patients poisoned by either a calcium-channel blocker or beta-adrenergic antagonist is to aggressively support the vital signs. External pacemakers should be employed early, but capture or acceleration may be difficult. Fluid therapy—limited only by the presence of congestive heart failure—should precede administration of vasopressor or inotropic agents. For patients undergoing calcium channel blockade, calcium is clearly the therapeutic agent of choice, and its nonspecific cardiac effects may also be beneficial for patients with beta-blocker poisoning. The recommended dose is approximately 1 gm of calcium chloride or 3 gm of calcium gluconate, each of which contains approximately 13 mEq.

Invasive monitoring is ideal but not always practical. In its stead, pressor or inotropic agents are largely empiric, with the dose titrated to the response. Because paradoxical reactions to these medications often occur, vital signs must be closely monitored after any medication or dosage change. Some patients, for example, may have a decrease in blood pressure after administration of norepinephrine, a result that occurs because the impaired myocardium cannot overcome the increase in systemic vascular resistance caused by the alpha-adrenergic effects of the drug.

Hypotension and bradycardia caused by beta-blocker poisoning may respond more predictably to glucagon than to catecholamine therapy. The inotropic effects of glucagon are qualitatively similar to those of catecholamine agents but are not mediated by the beta-receptors. As a result, glucagon can work in patients undergoing beta-blockade therapy, but catecholamines cannot gain access to the receptors.

Recently, intravenous insulin in doses of 0.1 U/kg with sufficient glucose to maintain euglycemia has been found to produce excellent results in experimental models and actual patients who have ingested an overdose of beta-blockers. Although the mechanism is undefined, the benefit is probably related to improved energy handling by the myocytes, and the result is enhanced inotropism.

When necessary, heroic measures may entail the use of an intraaortic balloon pump or extracorporeal circulation; hemodialysis, however, has no known role.

One of the most important, and often neglected, aspects of treatment is aggressive gastrointestinal decontamination. Stabilization of vital signs is undoubtedly paramount, but removing the toxic source will presumably limit the duration and extent of the problem. The choice of which decontamination procedure to use depends on several factors. If an ingested toxin is not likely to cause death, activated charcoal usually will suffice. On the other hand, a more aggressive approach is indicated for patients who have taken an overdose of a high-risk medication, such as verapamil, or who have life-threatening vital sign abnormalities.

Sustained-release preparations can be given once or twice a day, a dosage that helps enhance compliance with therapy, and the improved pharmacokinetic profiles of these formulations indicate fewer peaks and troughs. The disadvantage associated with these preparations, however, is the severe and prolonged toxic effects that often occur when the retarded release of a drug is combined with the large gastrointestinal burden that occurs after an overdose. Fortunately, the stability of the pills makes whole bowel irrigation possible. The procedure entails administering a large volume (2 to 3 L/hr for an adult) of a polyethylene glycol electrolyte solution orally or via nasogastric tube. No significant systemic absorption occurs, and the entire gastrointestinal tract is cleared in three to six hours.

 
PATIENT OUTCOME

Because the patient in this case ingested a sustained-release formulation of verapamil, he underwent whole bowel irrigation with a polyethylene glycol electrolyte solution and received early supportive care, antidotal therapy with a total of 8 gm of intravenous calcium chloride, and norepinephrine. Although beneficial, those measures failed to increase his heart rate and blood pressure sufficiently. Early application of a balloon pump, however, significantly improved systemic perfusion. The patient's cardiac rhythm improved progressively and he recovered fully by the third hospital day.