Calcium channel antagonists (also known as calcium channel blockers or calcium antagonists) are widely used to treat hypertension, angina pectoris, coronary spasm, hypertrophic cardiomyopathy, supraventricular cardiac arrhythmias, Raynaud phenomenon, and migraine headache. Toxicity from calcium antagonists may occur with therapeutic use (often owing to underlying cardiac conduction disease or drug interactions) or as a result of accidental or intentional overdose. Overdoses of calcium antagonists are frequently life-threatening and one of the most important sources of drug-induced mortality. As little as one tablet can be potentially life-threatening in a small child.

Calcium antagonists decrease calcium entry through L-type cellular calcium channels, acting on vascular smooth muscle, the heart and pancreas. They can cause coronary and peripheral vasodilation, reduced cardiac contractility, slowed atrioventricular nodal conduction, and depressed sinus node activity. Lowering of blood pressure through a fall in peripheral vascular resistance may be moderated by reflex tachycardia, although this reflex response is often blunted by depressant effects on AV and sinus node activity. In addition, these agents are metabolic poisons causing increased dependence of the heart on carbohydrate metabolism rather than the usual free fatty acids. This toxic effect is compounded by the inhibition of pancreatic insulin release, making it difficult for the heart to use carbohydrates during shock.

1. In therapeutic doses, the dihydropyridines (amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and nisoldipine) act primarily on blood vessels (causing vasodilation), whereas the phenylalkylamines (verapamil) and benzothiazepines (diltiazem) also act on the heart, reducing cardiac contractility and heart rate. Overdoses of verapamil and diltiazem are generally most severe due to cardiogenic shock, while overdoses of dihydropyridines are usually less severe, manifesting as vasodilatory shock, although in massive overdose, this selectivity may be lost.
2. Nimodipine has a greater action on cerebral arteries and is used to reduce vasospasm after recent subarachnoid hemorrhage.
3. Important drug interactions may result in toxicity.
   1. Combined overdoses of dihydropyridines and angiotensin converting enzyme inhibitors or angiotensin receptor blockers are associated with more significant hypotension and need for greater hemodynamic support. Hypotension is also more likely to occur in patients taking beta blockers, nitrates, or both, especially if they are hypovolemic after diuretic therapy. Patients taking disopyramide or other cardiodepressant drugs and those with severe underlying myocardial disease are also at risk for hypotension.
   2. Life-threatening bradyarrhythmias may occur when beta blockers and verapamil are given together, and asystole has occurred after parenteral administration
   3. Macrolide antibiotics, grapefruit juice, and other inhibitors of the cytochrome P450 enzyme CYP3A4 can increase the blood levels of many calcium antagonists. Verapamil and diltiazem can inhibit the metabolism of other drugs by CYP3A4.
   4. Fatal rhabdomyolysis has occurred with concurrent administration of diltiazem and statins.
4. Pharmacokinetics. Absorption is slowed with sustained-release preparations, and the onset of toxicity may be delayed several hours. Most of these agents are highly protein bound and have large volumes of distribution. They are eliminated mainly via extensive hepatic metabolism, and most undergo substantial first-pass removal. Pharmacokinetic parameters with therapeutic doses are shown in Table II-63), but half-lives can be longer with overdoses.

Usual therapeutic daily doses for each agent are listed in Table II-17. The toxic-therapeutic ratio is relatively small, and serious toxicity may occur with therapeutic doses. Any dose greater than the usual therapeutic range should be considered potentially life-threatening. Note that many of the common agents are available in sustained-release formulations, which can result in delayed onset or sustained toxicity.

1. The primary features of calcium antagonist intoxication are hypotension and bradycardia.
   1. Hypotension may be caused by peripheral vasodilation (vasodilatory shock), reduced cardiac contractility and slowed heart rate (cardiogenic shock), or a combination. Dihydropyridines are most likely to cause vasodilatory shock, while verapamil and diltiazem cause combined vasodilatory and cardiogenic shock. Shock from calcium blocker overdoses may be refractory to usual supportive measures.
   2. Bradycardia may result from sinus bradycardia, second- or third-degree AV block, or sinus arrest with junctional rhythm. These are seen most commonly with verapamil and diltiazem overdose.
   3. Most calcium antagonists do not affect intraventricular conduction, so the QRS duration is usually not affected. The PR interval may be prolonged even with therapeutic doses of verapamil.
   4. Noncardiogenic pulmonary edema and ischemic injury to bowel, brain, or kidney may complicate overdose and its management.
2. Noncardiac manifestations of intoxication include nausea and vomiting, metabolic acidosis (resulting from hypotension and/or cardiac metabolic derangements), and hyperglycemia (owing to blockade of insulin release). Hypoinsulinemia impairs myocardial glucose uptake, thereby reducing contractility and contributing to hypotension. In one study, the degree of hyperglycemia was correlated with the severity of the overdose. Mental status is usually normal, but in severe overdoses stupor, confusion and seizures may occur, probably related to cerebral hypoperfusion.

The findings of hypotension and bradycardia, particularly with sinus arrest or AV block, in the absence of QRS interval prolongation should suggest calcium antagonist intoxication. The differential diagnosis should include beta blockers, clonidine, and other sympatholytic drugs. The presence of hyperglycemia in a nondiabetic patient in combination with cardiac toxicity should suggest calcium antagonist toxicity.

1. Specific levels. Serum or blood drug levels are not widely available. Diltiazem and verapamil may be detectable in comprehensive urine toxicology screening.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, arterial blood gases or oximetry, cardiac troponin, and ECG and cardiac monitoring. A bedside echocardiogram may help characterize the hemodynamic physiology and assist with planning therapy.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat coma, hypotension, and bradyarrhythmias if they occur. Consider atropine and cardiac pacing for bradyarrhythmias that are contributing to hypotension (though there is variable efficacy of these interventions).
   3. Monitor the vital signs and ECG for at least 6 hours after ingestion of immediate-release compounds. Sustained-release products, especially verapamil, require a longer observation period (24 hours for verapamil, 18 hours for others). Admit symptomatic patients for at least 24 hours.
2. Specific drugs and antidotes
   1. Calcium reverses the depression of cardiac contractility in some patients, but it does not affect sinus node depression or peripheral vasodilation and has variable effects on AV nodal conduction. Administer calcium chloride 10%, 10 mL (0.1-0.2 mL/kg) IV, or calcium gluconate 10%, 20-30 mL (0.3-0.4 mL/kg) IV. Repeat every 5-10 minutes as needed. In case reports, doses as high as 10-15 g over 1-2 hours and 30 g over 12 hours have been administered without apparent calcium toxicity, however serum calcium concentrations should be monitored closely. Calcium chloride should be given only via a central line or secure peripheral IV line owing to the potential for tissue necrosis.
   2. Hyperinsulinemia/euglycemia therapy (HIET, see Insulin) is effective in animal models of severe verapamil intoxication and has been successful in multiple human case reports. The putative mechanism is enhanced transport of glucose, lactate, and oxygen into myocardial cells, and correction of calcium antagonist-induced hypoinsulinemia, leading to improved cell carbohydrate metabolism and increased myocardial contractility. Like calcium, HIET is not likely to reverse calcium antagonist-induced vasodilation, conduction block, or bradycardia.
   3. Intravenous lipid emulsion (ILE) therapy has shown promise in animal studies and a few case reports of severe verapamil and diltiazem poisoning
   4. Vasopressors are often needed to manage shock from calcium blockers. Extraordinarily high doses may be required for refractory shock; however, ischemia (eg, limb or bowel) is a potential complication. HIET should be used before high-dose pressors. The choice of pressor depends on the pathophysiology. For cardiogenic shock and bradycardia consider epinephrine, glucagon, dobutamine, isoproterenol, and phosphodiesterase inhibitors. For vasodilatory shock consider phenylephrine, norepinephrine and vasopressin.
   5. Glucagon may increase blood pressure in patients with refractory hypotension and with bradyarrhythmias.
   6. Consider mechanical support of the circulation including ECMO (extracorporeal membrane oxygenation) or cardiopulmonary bypass for shock refractory to pharmacotherapy.
   7. Emerging therapies with evidence of benefit in animal studies but unclear efficacy in humans include: levosimendan (sensitizes myocardium to effects of calcium and increases contractility, but is also a vasodilator); methylene blue (inhibits nitric oxide release and may be useful for vasodilatory shock, particularly from amlodipine [see]); cyclodextrins, such as sugammadex (may encapsulate and sequester verapamil from site of action); and 4-aminopyridine (raises intracellular calcium concentrations thereby enhancing contractility).
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). For large ingestions of a sustained-release preparation, consider whole-bowel irrigation in addition to repeated doses of charcoal.
4. Enhanced elimination. Owing to extensive protein binding and large volumes of distribution, dialysis and hemoperfusion are not effective.