Calcium channel blockers (CCBs) are commonly used for the treatment of hypertension and angina pectoris and for ventricular rate control in supraventricular dysrhythmias. Less common uses include prophylactic treatment of migraine headaches, treatment of arterial vasospasm due to Raynaud’s disease, esophageal spasm, and pulmonary hypertension.¹ For the last 50 years, CCBs have accounted for more poisoning deaths than any other cardiovascular drug and are the second most common cause of prescription drug poisoning death.

Intracellular calcium is the primary stimulus for smooth and cardiac muscle contraction and for impulse formation in sinoatrial pacemaker cells. At therapeutic concentrations, CCBs bind to the subunit of the L-type calcium channel, causing the channel to favor the closed state and thereby decreasing calcium entry during the plateau phase (phase 2) of the transmembrane action potential. At very high concentrations, some CCBs (notably verapamil) may occupy the channel canal and completely block calcium entry. The result is profound smooth muscle relaxation, weakened cardiac contraction, blunted cardiac automaticity, and intracardiac conduction delay.¹ Clinically, these effects produce hypotension and bradycardia. Animal data suggest that verapamil overdose also impairs myocardial carbohydrate intake, which contributes to the negative cardiac inotropy.²

The three main pharmacologic classes of CCBs are phenylalkylamines (verapamil and gallopamil), benzothiazepines (diltiazem), and dihydropyridines (nifedipine, amlodipine, and most newer agents—aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine).

All of these drugs relax vascular smooth muscle, reduce pacemaker activity, and decrease cardiac contractility; however, these effects occur at different dose ranges for each drug. In addition, all three classes increase coronary blood flow in a dose-dependent fashion.³ Each group binds a different region of the calcium channel and has different affinities for calcium channels in various tissues. Verapamil is the most potent negative inotrope of all CCBs, causing at least equal depression of heart contraction and vascular smooth muscle dilatation at any concentration.⁴ This combined cardiovascular effect may be one reason that verapamil overdose causes more deaths than all other CCBs combined.

Dihydropyridines bind more selectively to vascular smooth muscle calcium channels than to cardiac calcium channels and therefore relax smooth muscle at concentrations that produce almost no negative inotropy. The differences in the effects of these agents is the reason for preferential use of specific agents in particular clinical situations.⁵ For example, verapamil and diltiazem are used to manage hypertension, to achieve rate control in atrial flutter and atrial fibrillation, and to abolish supraventricular reentrant tachycardias. Dihydropyridines are typically used to treat diseases with increased peripheral vascular tone such as hypertension, Prinzmetal’s angina, and vasospasm after subarachnoid hemorrhage.¹

The original three CCBs—verapamil, nifedipine, and diltiazem—all have relatively short serum half-lives (Table 195-1). Consequently, extended-release formulations have been developed for all of these agents. Because extended-release formulations prolong drug absorption, onset of symptoms may be delayed and toxicity may be prolonged following overdose.^6,7 Several of the newer dihydropyridines have prolonged duration of action, and therefore are generally not formulated as extended-release products. Because newer formulations are released frequently, it is helpful to contact a regional poison control center for help in determining if a given product ingested in an overdose is formulated as an extended-release preparation.

The most prominent and life-threatening effects are an extension of the therapeutic effects on the cardiovascular system, particularly myocardial depression and peripheral vasodilation. Hypotension is the most common physiologic abnormality after overdose.^8,9 Patients with moderate verapamil or diltiazem poisoning often have sinus bradycardia, varying degrees of atrioventricular block, and hypotension. Atrioventricular block occurs more often with verapamil than with diltiazem or nifedipine.¹⁰ Mild or moderate dihydropyridine overdoses usually cause peripheral vasodilatation with resultant hypotension and reflex tachycardia.¹⁰ In severe overdose, any of these agents may cause complete heart block, depressed myocardial contractility, and vasodilatation that ultimately results in cardiovascular collapse.

Pulmonary and CNS effects are generally secondary to decreased myocardial function and impaired organ perfusion. Cardiogenic pulmonary edema is sometimes observed in severe overdoses, especially if large volumes of crystalloid are infused during resuscitation. Acute lung injury (noncardiogenic pulmonary edema) has also been reported.^11,12 Seizures, delirium, and coma have been described and are presumed to be secondary to cerebral hypoperfusion. Alteration in consciousness in the absence of hypotension should not be attributed to CCB toxicity; prompting an evaluation for other causes. GI symptoms, such as nausea and vomiting, are uncommon.¹³

POTENTIAL TOXICITY

Estimations have been made of the lowest doses and mean doses ingested that produce toxicity (Table 195-2).⁷ A history of ingestion that is near these doses should be considered potentially toxic, and doses in excess of the lowest toxic dose reported should be expected to produce toxicity.⁷ Adults receiving long-term therapy with CCBs can develop hypotension, bradycardia, or cardiac conduction abnormalities if they ingest twice their regular daily dose.¹⁴ It is hypothesized that patients receiving long-term CCB therapy have comorbidities and may be taking additional medications, such as other antihypertensives, that render these patients sensitive to the adverse effects of an additional amount of their CCB. Children may be sensitive to CCB toxicity, and deaths have been reported after ingestion of a single tablet: nifedipine, 10 milligrams, in a 14-month-old child¹⁵ and verapamil, 25 milligrams, in a 7-day-old infant.¹⁶ Therefore, all pediatric CCB ingestions should be referred for medical attention and observation.

Extended-release preparations are increasingly used for patient convenience and enhancing patient adherence to the drug regimen. These preparations complicate the management of overdosed patients by delaying the onset of toxicity. Therefore, it is important to determine the exact formulation of the ingested agent to guide management decisions. If the history cannot identify the exact formulation, the clinician should assume it is extended-release and modify treatment in a conservative way. In a review of CCB overdose cases, 52% of patients ingested extended-release preparations, and of these, 8% had no evidence of toxicity on initial evaluation but developed delayed toxicity 6 hours or later after ingestion.¹⁰ In addition to the exact formulation ingested, other important aspects in the history are the time of ingestion and the possibility of co-ingestants that may contribute to toxicity.

ECG findings include sinus bradycardia, varying degrees of atrioventricular block, and slowing of intraventricular conduction. Reflex tachycardia is commonly seen with low to moderate toxic ingestions of dihydropyridines, whereas junctional rhythms and ventricular escape rhythms are frequently noted in severe overdoses with verapamil or diltiazem.

Laboratory testing is done to assess the overall metabolic state of the patient; none is crucial in the acute management of CCB toxicity. Hyperglycemia is often noted after CCB ingestion, which differentiates it from β-blocker ingestion, which is typically euglycemic or sometimes hypoglycemic.¹⁷ CCBs inhibit calcium-mediated insulin secretion from the beta islet cells in the pancreas, impeding the use of carbohydrates, and also increase insulin resistance by unclear mechanisms.¹⁸

Systemic hypoperfusion may cause a lactate acidosis with an elevated anion gap and low serum bicarbonate level. Hypokalemia may be observed in severe overdoses. Serum calcium levels are usually normal. Ionized serum calcium levels may be followed during treatment with intravenous calcium preparations, but the optimum serum calcium level for patients with severe CCB poisoning is unknown. CCB serum concentrations are not routinely available and are not used in management. Screen blood and urine for other potential toxins after suicidal overdose.

DIFFERENTIAL DIAGNOSIS

A few conditions and other drug toxicities can produce bradycardia, atrioventricular block, and hypotension (Table 195-3). Hypothermia should be detected during vital sign assessment. Myocardial infarction may be evident on the initial or subsequent ECG. Suspect hyperkalemia in patients with renal failure.

It may be difficult to distinguish CCB toxicity from cardiac glycoside toxicity; patients may be taking these drugs for the same indications and at the same time (see chapter 193, “Digitalis Glycosides”). In general, patients with chronic digoxin poisoning have greater ventricular excitation, including rate and ectopy, than patients with CCB toxicity. In acute overdose, digoxin toxicity may be distinguished by hyperkalemia. However, because the main manifestation of acute cardiac glycoside poisoning is heart block and bradycardia, bedside differentiation may be difficult.

Toxicity from β-adrenergic antagonists may be clinically indistinguishable from CCB toxicity (see chapter 194, “Beta-Blockers”). In general, β-blocker toxicity is not as severe, and patients tend to have low to normal glucose and normal to elevated serum potassium levels. However, these findings are not consistent enough to have diagnostic value. Fortunately, the treatment for these two poisonings is similar, with calcium, adrenergic agonists, glucagon, insulin, and pacing considered useful therapy for both.¹⁹