Calcium Channel Antagonists

Calcium channel antagonists (also known as calcium channel blockers or calcium antagonists) are widely used to treat angina pectoris, coronary spasm, hypertension, 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 an important source of drug-induced mortality. As little as one tablet can be potentially life-threatening in a small child.

Mechanism of toxicity. Calcium antagonists decrease calcium entry through L-type cellular calcium channels, acting primarily on vascular smooth muscle and the heart. They 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 offset 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 these carbohydrates during shock.
1. In therapeutic doses, the dihydropyridines (amlodipine, felodipine, isradipine, nicardipine, nifedipine, 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. In overdose, this selectivity may be lost.
2. Bepridil and mibefradil have verapamil-like effects on the heart, inhibit the fast sodium channel, and have type III antiarrhythmic activity. They have proarrhythmic effects, especially in the presence of hypokalemia. They are no longer sold in the United States.
3. Nimodipine has a greater action on cerebral arteries and is used to reduce vasospasm after recent subarachnoid hemorrhage.
4. Important drug interactions may result in toxicity. Hypotension is 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 depressant cardioactive drugs and those with severe underlying myocardial disease are also at risk for hypotension. Macrolide antibiotics, grapefruit juice, and other inhibitors of the cytochrome P-450 enzyme CYP3A4 can increase the blood levels of many calcium antagonists. Life-threatening bradyarrhythmias may occur when beta blockers and verapamil are given together, and asystole has occurred after parenteral administration. Propranolol also inhibits the metabolism of verapamil. Fatal rhabdomyolysis has occurred with concurrent administration of diltiazem and statins.
5. 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. In a report on two patients with verapamil overdoses (serum levels, 2200 and 2700 ng/mL), the elimination half-lives were 7.8 and 15.2 hours (see also Table II–61).

Toxic dose. 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.

Table II-17 Calcium Antagonists