Poisoning Due to Calcium Antagonists

Abstract

The calcium antagonists are a heterogeneous class of drugs which block the inward movement of calcium into cells through 'slow channels' from extracellular sites. By inhibiting phase 0 depolarisation in cardiac pacemaker cells and phase 2 plateau in myocardium, and by depressing calcium ion flux in smooth muscle cells of blood vessels, these agents may exert profound effects on the cardiovascular system, particularly in susceptible individuals or in overdose. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocardial contractility, and peripheral vasodilatation may result. Pharmacokinetic features of calcium antagonists include rapid and complete absorption from the gastrointestinal tract, with extensive first-pass hepatic metabolism yielding generally low bioavailability. The volume of distribution is generally large and protein binding is high. Elimination is almost entirely by the liver. Impaired renal function does not affect pharmacokinetics. Verapamil is the most potent inhibitor of cardiac conduction and contractility, with diltiazem also showing such effects. Nifedipine is the most potent vasodilator, but only occasionally impairs the sinus node or AV conduction. Significant pharmacodynamic effects are common during combination therapy with calcium antagonists, especially verapamil and beta-blockers. Verapamil may significantly elevate serum digoxin concentrations and may exert additive negative effects on chronotropism and dromotropism when this combination is used. Overdoses of calcium entry blockers are becoming more frequent and reflect an extension of the known pharmacodynamic profile of these agents. Typical features include confusion or lethargy, hypotension, sinus node depression and cardiac conduction defects. Onset of symptoms may be delayed if a sustained release preparation is ingested. Management of calcium antagonist overdose includes gut decontamination with lavage and activated charcoal. All symptomatic patients and patients with a history of ingesting a sustained release preparation should be admitted for ECG monitoring. If bradycardia and/or conduction defects contribute to hypotension, atropine or isoprenaline (isoproterenol) may accelerate the ventricular rate. Transvenous pacing may be required. Depressed myocardial contractility usually responds well to calcium chloride or calcium gluconate administration, but further inotropic support may be required. Peripheral vasodilation should be managed with intravenous fluids and a pressor agent such as dopamine or norepinephrine (noradrenaline).

Third‐generation antidepressants

“…464 Most of the interest has centered upon verapamil in mania, and there are only two small uncontrolled studies of other representative calcium antagonists like nifedipine and diltiazem (Fig. 18).…”

Quantitation of verapamil and norverapamil in postmortem and clinical samples using liquid-liquid extraction, solid phase extraction, and HPLC

“…Physicians often prescribe verapamil for hypertension because a calcium channel blocking drug can prevent the intracellular accumulation of calcium and therefore protect myocardial ceils from necrosis [2]. Other therapeutic uses for verapamil include the management of angina and cardiac arrhythmia.…”

“…Patients with hepatic or cardiovascular disorders show an increase in verapamil halflife from 3.7 to 14.2 hours [1,5,6]. Verapamil and its metabolites are excreted mainly in the urine, however, only three percent is unchanged verapamil [2].…”

Overdose of diltiazem

“…Roper suggests that there is a correlation between clinical sequelae and the diltiazem concentration after overdose. Concentrations of the calcium antagonists do not, however, usually correlate well with clinical outcome after overdose,2 and routine measurements would be of little value. For example, death has been reported with diltiazem concentrations as low as 1500 µg/l and survival with concentrations as high as 6090 µg/l.…”

“…For example, death has been reported with diltiazem concentrations as low as 1500 µg/l and survival with concentrations as high as 6090 µg/l. 34 Similarly, verapamil concentrations have been as low as 1500 µg/l in patients who have died and as high as 4000 µg/l in survivors 2. Nifedipine is technically difficult to measure as the compound is photosensitive.…”