Adverse Reactions to Calcium Antagonists

Summary

The calcium antagonists are a chemically heterogeneous group, so it might be expected that they could have their own particular side effects and problems. They do, however, possess certain side effects in common which can be related to their pharmacological properties, but the intensity and frequency varies between the individual agents. Vasodilatory features are more likely with nifedipine, namely flushing, sensation of heat, palpitation, tachycardia, dizziness and vertigo. Oedema around the shins and ankles is also common with nifedipine but the mechanism is uncertain, although it may be related to precapillary vasodilatation. Deterioration of cardiac function has been most often reported with verapamil, although in the clinical situation the negative inotropic effect is rarely a problem if selection is careful and, when β-blockers are prescribed concomitantly, supervision and follow-up are meticulous. Patients with aortic stenosis should not receive calcium antagonists.

Some of the calcium antagonists interfere with impulse generation and atrioventricular conduction at therapeutic concentrations — this effect being most likely with verapamil and diltiazem. Local gastrointestinal symptoms such as nausea occur and constipation is very frequent with verapamil. Prenylamine is little used and is associated with sedation, tremor and cardiac arrhythmias. Use of perhexiline is also much restricted by its liability to cause liver and neurological sequelae.

Many of the available reports of the effects of the calcium antagonists are single dose, short, or medium term formal studies supplemented by individual case reports of adverse reactions. Recent studies have utilised sophisticated techniques including echocardiography, cardiac catheterisation, radionuclides (for ejection fraction), computerised treadmill evaluation as well as conventional and ambulatory ECG monitoring. Biochemical evaluation has included possible changes in sodium and water balance (e.g. sodium excretion while on nifedipine), altered regulation of the renin-angiotensin system, and serial measurement of lipid fractions for disturbances while on therapy. Plasma concentrations and metabolites can be measured and have helped in the study of altered drug kinetics in various pathophysiological states and significant drug-drug interactions. Drug-host interactions resulting in altered kinetics can take place during absorption, metabolism and excretion. For instance, with lipophilic drugs such as verapamil, bioavailability is low due to high first-pass hepatic extraction and thus decreased liver blood flow, and hepatic disease can lead to higher blood levels. Also, increasing age and renal impairment are associated with delayed elimination of verapamil, while long term use is itself associated with accumulation of the drug.

The pharmacodynamic effects of the calcium antagonists can also be related to the diseases being treated, since indications range from otherwise healthy patients with hypertension and good left ventricular function, to those with compromised function from ischaemia (associated with angina or myocardial infarction) or from cardiomyopathy. Obviously, the more compromised is heart function, the greater the risks.

Depending on the type of patient being treated and the agent, side effects may be very common — up to 50% in some series. While frequent, they are usually trivial, or transient, and can be lessened by skill in administering the drug, with appropriately staged increments up to the effective or maximum dose and attempts at decrements when the condition is stable. At other times, side effects can be managed by adding a β-blocker. When a calcium antagonist is ineffective or poorly tolerated and has to be withdrawn in patients with ischaemic heart disease, the dosage should be gradually tapered so as to avoid rebound angina which may be of a different kind from the original type, and occur at rest. As with all new drugs one danger of early and premature marketing of a calcium antagonist is that an adequate number of patients may not have been treated for long enough in the various indications in an ‘ordinary’ environment. The true incidence of toxicity consequent on long term administration of the calcium antagonists is still awaited. These drugs are being increasingly prescribed and the wider exposure of patients to nifedipine, verapamil and diltiazem has followed confidence in their efficacy, familiarity with their use, and also widening indications. Patients of all ages, often with coexisting diseases and medications, now receive calcium antagonists. Overall safety is improved when the indications are appropriate and contraindications such as heart block, sick sinus syndrome, severe heart failure and hypotension not due to arrhythmia are adhered to. The route of administration is also important; intravenous use is more hazardous and full resuscitative facilities should be at hand. To date, deliberate or accidental overdosage has been rare, but guidelines are available; use is made of the antagonistic action of calcium.

With increasing numbers of patients receiving calcium antagonists it is to be expected that further idiosyncratic reactions will be encountered. So far they have been reported in the liver and skin.