Calcium antagonists (slow channel blocking agents) are a very heterogeneous group of agents with dissimilar structural, electrophysiologic and pharmacologic properties. Nifedipine is a potent, long-acting vasodilator that has proved highly efficacious in relieving anginal symptoms caused by coronary vasospasm. In vivo, it exerts no myocardial depressant effects and has no antiarrhythmic properties. Treatment with nifedipine can safely be combined with administration of a beta receptor blocking agent. VErapamil prolongs atrioventricular (A-V) conduction (A-H interval) in a dose-dependent manner. It is the drug of choice for the treatment of reentrant supraventricular arrhythmias, irrespective of whether reentry occurs within the A-V node or through an accessory pathway (the Wolff-Parkinson-White syndrome). Verapamil is only moderately effective as an antianginal agent. Diltiazem is efficacious for the treatment of angiospastic angina, but its value as an antiarrhythmic agent remains to be delineated.

Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem

Calcium ions (Ca++) are vital in many biologic processes, including a variety of enzymatic reactions, activation of excitable cells, coupling of electrical activation to cellular secretion, hemostasis, and the metabolism of bone. The development of drugs that interfere with the entry of Ca++ into cells — variously termed Ca++-channel blockers, Ca++-entry blockers, Ca++ antagonists, and slow-channel blockers — has provided the basic scientist with powerful new tools for the study of the role of this ion in normal as well as pathologic states and has provided the clinician with several important new therapeutic agents for use in . . .

Mechanism of Action of Calcium-Channel-Blocking Agents

Various sections of the manuscript reviewed by: U. Elkayam, Department of Medicine, University of Southern California, Los Angeles, California, USA; H. Emanuelsson, Department of Medicine I, University of Goteborg, Goteborg, Sweden; K. Fox, National Heart Hospital, London, England; W.H. Frishman, Hospital of the Albert Einstein College of Medicine, Bronx, New York, USA; M.D. Gua1.1.i, Cattedra di Cardiologia, U niversita Degli Studi de Milano, Milan, Italy; J.R. Hampton, University Hospital, Queen's Medical Centre, Nottingham, England; CH. Kleinbloesem, Sylvius Laboratories, Leiden, The Netherlands; O. Lederballe Pedersen, Department of Internal Medicine I, Aarhus Amtssygehus, Aarhus, Denmark; P. Lichtlen, Medizinische Hochschule Hannover, Department of Cardiology and Cardiovascular Surgery, Hannover, Federal Republic of Germany; R.G. McAllister, Veterans Administration Medical Center Research Service, Lexington, Kentucky, USA; P. W. Serruys, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands; A.L. Soward, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands.

Nifedipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischaemic heart disease, hypertension and related cardiovascular disorders.

Nifedipine kinetics have not been described in clinically relevant detail because of difficulties in formulating a stable preparation for intravenous use and lack of a specific and sensitive assay for plasma nifedipine. We recently developed a gas-chromatographic method and determined conditions in which nifedipine could be protected from photodegradation. Therefore, we evaluated the kinetics and bioavailability of nifedipine in 12 normal subjects after single intravenous (1 mg/5 min) and oral (10 mg) doses. After intravenous dosing, the drug was eliminated with a half-time of 1.77 +/- 0.25 hour, and total clearance was calculated at 0.62 +/- 0.09 liter/kg/hr. With oral drug administration, the elimination half-time was twice as long for the group; but within these subjects, marked variability in the rate of appearance of the drug in plasma was observed, giving profiles consistent with fast and slow absorption. In the latter group, peak plasma drug concentrations were only one third the level seen in those exhibiting a faster absorption profile, although the extent of drug absorption (as derived from areas under the plasma level-time curves) did not vary. Bioavailability was 0.45 +/- 0.08. Untoward effects resulting from the drug's pharmaco-subjects after intravenous administration (flushing).

Nifedipine Kinetics and Bioavailability After Single Intravenous and Oral Doses in Normal Subjects

In a double-blind clinical trial the antianginal effects of nifedipine (30 and 60 mg/day) and propranolol 240 and 480 mg/day) and a combination of both drugs were compared with those of placebo in 16 patients with severe exertional angina pectoris. Response to treatment was assessed by the objective criteria of 16-point precordial exercise mapping and 48-hour ambulatory electrocardiographic monitoring and subjectively by analysis of patients' daily diaries of episodes of angina and consumption of glyceryl trintrate. The incidence of pain and consumption of glyceryl trinitrate were significantly decreased by each drug compared with placebo, and the combination produced a further significant improvement. Objectively the total area and amount of ST depression on the precordial exercise map and the total number of episodes of ST depression detected on ambulatory monitoring confirmed the efficacy of each treatment regimen; the combination was significantly better than either drug alone (p <0.005). The objective methods permitted greater separation of treatment efficacy and showed reliably that the combination of propranolol and nifedipine was significantly better than either drug alone. Thus this combination is a safe and effective form of treatment for angina.

https://www.bmj.com/content/bmj/281/6234/184.full.pdf

Objective assessment of antianginal treatment: a double-blind comparison of propranolol, nifedipine, and their combination.

Intravenous nifedipine, a powerful calcium antagonist, had no obvious effect on atrioventricular conduction when administered to 11 patients during routine intracardiac electrophysiological studies. Verapamil on the other hand showed potent antiarrhythmic properties, depressing atrioventricular nodal conduction. Nifedipine thus appears safe in patients with angina pectoris who have disorders of atrioventricular nodal conduction, and in those receiving beta-adrenergic blocking drugs. There appear to be differential effects on the slow inward channels of cardiac cells with different 'calcium antagonists'.

https://heart.bmj.com/content/heartjnl/42/2/124.full.pdf

Effect of nifedipine on atrioventricular conduction as compared with verapamil. Intracardiac electrophysiological study.

A 13-yr-old boy presented with atrial flutter 8 yr after surgical correction of tetralogy of Fallot; antiarrhythmic therapy caused depression of the sinoatrial node, with syncope. Disordered sinoatrial function and intraventricular conduction were demonstrated by intracardiac electrography, and appear to have resulted from the operation. Sinoatrial disease may be responsible for supraventricular arrhythmias or syncope long after operative correction of Fallot's tetralogy and may be one of the explanations for the tendency of such patients to die suddenly.

E Rowland

Papers

Effect of nifedipine on atrioventricular conduction as compared with verapamil. Intracardiac electrophysiological study.

'Bradycardia-tachycardia' syndrome 8 yr after correction of Fallot's tetralogy.