Calcium channel antagonists (CCA) effectively treat a variety of medical conditions. Yet, accidental and intentional overdoses of theses agents can be life threatening. CCAs consistently top the list of cardiovascular medications with the greatest proportion of deaths per exposure [1,2,3]. Severely poisoned patients demonstrate cardiovascular collapse as well as metabolic derangements similar to diabetic acidosis. Cardiovascular instability is often refractory to typical cardiotonic therapies and medication doses. There is no antidote for CCAs, and no controlled clinical studies to guide therapy. Treatment recommendations are therefore based on case series, case reports, animal
studies, and extrapolation. Simultaneous use of multiple therapies is often required and should be tailored to the patient’s cardiovascular and metabolic responses. Overall goals of treatment are to provide supportive care, optimize cardiovascular and metabolic function, and decrease drug absorption. If vital signs can be supported until the drug is metabolized or eliminated, most patients will survive without sequelae.

Available CCAs antagonize calcium influx through L-type voltage sensitive channels [4], a specific type of calcium channel found in the heart, vascular smooth muscle, and pancreatic β-islet cells. Multiple physiologic functions are dependent on this calcium influx.

In the cardiovascular system, calcium influx through L-type channels is responsible for the spontaneous pacemaker activity of the sinoatrial (SA) node and depolarization of the atrioventricular (AV) node [4,5]. Other myocardial cells rely on sodium influx for initial depolarization [5,6], but calcium entry via L-type channels contributes to the plateau phase of their action potential [5,7]. Calcium entering during the plateau phase signals the release of additional calcium from the sarcoplasmic reticulum into the cytosol, allowing contraction to occur [5,8,9]. The magnitude and duration of sarcoplasmic calcium release and myocardial contraction is proportional to the magnitude and duration of calcium entry via L-type channels [8]. Vascular smooth muscle tone is also maintained by a similar mechanism [8]. Thus, therapeutic clinical effects of CCAs arise from blockade of L-type channels resulting in decreased cytosolic calcium levels. Depending on the class of CCA administered (see Pharmacology section), the clinical result is depression of SA node automaticity, AV node conduction, myocardial contractility, and vasodilation. The pathophysiologic effects of CCA overdose are essentially an exaggeration of pharmacologic effects that lead to cardiovascular shock. In canines, shock ensues despite a 14-fold or greater increase in endogenous catecholamine concentrations [10,11,12].

In addition to cardiovascular effects, CCA poisoning also produces a diabetogenic effect of hyperglycemia and acidosis. Insulin secretion is dependent on calcium influx into pancreatic β-islet cells. Although generally not a concern at therapeutic doses, CCBs decrease insulin secretion [13,14,15,16]. In canine models of verapamil-induced shock, systemic insulin levels fail to increase in response to an intact glucogenic response and hyperglycemia [10,12,17]. Experimentally, verapamil toxicity also produces systemic [12,18] and myocardial [10] resistance to insulin-mediated carbohydrate uptake. The cause of this resistance may be multifactorial involving decreased substrate delivery from poor perfusion, interference with calcium-dependent cellular insulin responsiveness and glucose uptake, and inhibition of calcium-stimulated mitochondrial dehydrogenases (i.e., pyruvate dehydrogenase) and glucose catabolism [12]. More recent evidence suggests CCAs interfere with cellular signaling, specifically recruitment of glucose transporter proteins (GLUTs) from the intracellular space to cell membranes [19]. These GLUTs are responsible for normal cellular uptake of glucose.

Verapamil toxicity also produces a state of hyperlacticacidemia due to a combination of tissue hypoperfusion and probably a defect in carbohydrate metabolism [12]. In stressed states such as CCA toxicity, the heart switches from preferentially using free fatty acids to carbohydrates (glucose and lactate) for energy production [10,11,17]. Although there is an abundance of circulating carbohydrates (e.g., glucose and lactate), they are essentially unavailable for use because of insulin resistance and decreased insulin availability.

In essence, CCAs decrease cytosolic calcium levels resulting in desirable cardiovascular effects at therapeutic doses, and at toxic doses an exaggeration of those effects. Additionally, toxicity produces a vicious cycle where the myocardium is preferentially metabolizing carbohydrates yet carbohydrate utilization is hindered by impaired insulin release and insulin resistance.

In the United States, available CCAs fall into one of three classes: phenylalkylamine (verapamil), benzothiazepine (diltiazem), and dihydropyridines (nifedipine and all other agents). At therapeutic doses, each class has differing affinities for myocardial tissues and vascular smooth muscle. Verapamil and diltiazem are potent inhibitors SA node automaticity, AV node conduction, myocardial contractility, and cause modest vasodilation [20,21]. Verapamil affects the SA node, contractility, and vasodilation more than diltiazem [20,21]. This is probably why verapamil generally causes more deaths than other CCAs [1,2,3]. Dihydropyridines are far more selective for vascular smooth muscle, and at therapeutic doses have very little effect on cardiac pacemaker cells or contractility [9,20,21]. In significant poisoning this selectivity is lost however.

Pharmacologic properties of CCAs make extracorporeal removal of limited or no value as demonstrated in several cases [22,23,24], although plasmapheresis was believed to be beneficial in several cases [25,26,27]. Therapeutic half-lives of CCBs are variable, but in overdose can be prolonged [22,28,29,30,31]. The duration of toxicity in most cases is less than 24 hours, but has been reported to last 48 hours with sustained release (SR) verapamil [32] and for more than 5 days with amlodipine [33].

Verapamil, diltiazem, nifedipine, and several of the newer dihydropyridines are available in both immediate release (IR) and SR formulations. This information becomes important when considering how long to observe asymptomatic patients after an overdose. Immediate-release preparations produce signs or symptoms of toxicity within 6 hours of ingestion [34] whereas toxicity with SR products may be delayed 6 to 12 hours [34,35,36,37] or rarely longer [38]. Amlodipine, a dihydropyridine, has unique pharmacokinetics however. It is not a sustained release product, but has a late onset of peak effect and long half-life allowing for delayed and prolonged toxicity.

There is no accurate definition of a toxic dose, and patients have demonstrated significantly different effects at similar doses. Unintentional overdoses are common, but uncommonly result in significant effect. However, several adult patients have developed toxicity and death at doses less than maximum recommended daily doses [39]. Factors that could have contributed to this are advanced age, underlying medical conditions, additional medications, and chewing and swallowing SR preparations—essentially changing the pharmacokinetics into an IR formulation [39]. In general, the most significant poisonings are large intentional ingestions, but patients with significant underlying medical diseases, or advanced age can have significant effects at lower doses.

Cardiovascular effects are the primary manifestation of CCA poisoning. Alterations in mental status without significant hypotension should not be attributed to CCA ingestion. Minimally intoxicated patients, or those who present soon after ingestion, may demonstrate no signs of toxicity. All CCAs can cause hypotension in overdose. However, the cause of the hypotension is typically an extension of the drugs’ therapeutic effects. (i.e., dihydropyridines causing significant vasodilation with reflex tachycardia where verapamil and diltiazem slow
SA and AV node conduction, decrease contractility, and cause vasodilation) Thus, in overdose normal sinus rhythm or reflex tachycardia is commonly seen with nifedipine [34,37,40], where sinus bradycardia, AV nodal blocks, and junctional rhythm are common with verapamil and diltiazem [34,37,41]. This selectivity may be lost in large overdoses so that dihydropyridine poisoning results in bradycardia and/or impaired cardiac conduction [33,34,37,42,43,44,45,46,47]. Although overdose experience with dihydropyridines other than nifedipine is limited [33,45,46,47,48], they would be expected to have effects similar to nifedipine. The exception may be amlodipine where toxic effects may be delayed [46].

Severe poisoning is characterized by hypotension and bradycardia [34,37,40,49,50], hyperglycemia [37,38,40,42,45,46,47,49,50,51,52,53,54,55,56,57,58,59] and metabolic acidosis [17,33,42,46,47,49,52,53,56,59]. Hyperglycemia is due to aforementioned alterations in insulin and carbohydrate homeostasis (see Physiology and Pathophysiology section). In fact, in a recent review of 40 CCA overdoses the degree of hyperglycemia was the best predictor of the composite end points of death, pacemaker requirement, or vasopressor requirement [60]. Dysfunctional carbohydrate metabolism and tissue hypoperfusion result in hyperlacticacidemia. In addition, tissue hypoperfusion can result in cerebrovascular accidents, seizures, renal failure, myocardial infarction, and noncardiogenic pulmonary edema [61].