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Nifedipine

A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy, in Ischaemic Heart Disease, Hypertension and Related Cardiovascular Disorders

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Summary

Synopsis: Nifedipine1 is an antagonist of calcium influx through the slow channel of the cell membrane and has been shown to be an effective and relatively well-tolerated treatment for stable, variant and unstable angina, mild to severe hypertension and Raynaud’s phenomenon. Although its exact mechanism of action in these various diseases has not been precisely described, the potent coronary and peripheral arterial dilator properties of nifedipine, with concomitant improvements in oxygen supply/demand and reductions in systemic vascular resistance, are of major importance.

Clinical trials support the view that nifedipine can be considered a first-line choice in all grades of angina, especially when coronary vasospasm is the underlying cause or when hypertension and/or congestive heart failure are added complications. Nifedipine also appears to be particularly useful in clinical situations when a rapid lowering of elevated blood pressure is needed, and there is growing evidence that it is an effective and safe choice for the longer term management of patients with mild to moderate hypertension. However, the majority of data have been from medium term studies, and confirmation of its long term usefulness in well-designed trials is still required. Additionally, nifedipine has convincingly been shown to be a useful adjunct for controlling blood pressure in patients refractory to conventional treatment with β-blockers, diuretics and various vasodilators. Nifedipine reduces the number, duration and severity of vasospastic attacks in more than 60% of patients with Raynaud’s phenomenon of varying aetiology, and in individual cases it apparently facilitates the healing of digital ulcers.

Side effects appear to be dose related and occur in approximately 20% of patients. These effects, most of which are manifestations of the drug’s potent vasodilating activity, include headache, flushing and dizziness.

Thus, nifedipine is a worthwhile alternative to other drugs available for the treatment of the various forms of angina, acute episodes of hypertension, mild to severe hypertension (alone or in combination) and Raynaud’s phenomenon. While further well-designed clinical trials are needed to clarify its relative place in the long term management of mild to moderate hypertension, it is clear that nifedipine is now a well established agent in cardiovascular therapeutics.

Pharmacodynamic Properties: Nifedipine inhibits the slow inward current of calcium in normal cardiac tissues, its major effects being on the sinoatrial and atrioventricular nodes. In contrast to diltiazem or verapamil, nifedipine in vivo either has no effect on, or enhances, sinus or paced atrioventricular nodal conduction. Nifedipine also reduces atrioventricular nodal functional and effective refractory periods and atrioventricular nodal Wenckebach cycle lengths, and may be preferable to diltiazem or verapamil in patients with symptomatic ischaemic heart disease and depressed atrioventricular nodal function.

Sublingual or oral administration of nifedipine may lower mean arterial blood pressure at rest and after exercise by 20% or more. The onset of this reduction after both oral and sublingual administration occurs within 30 minutes and may last up to 5 hours. Intravenous nifedipine 1 to 4mg has produced significant decreases in blood pressure of up to 34% in patients with various cardiac disorders, with greater reductions in blood pressure seen in patients with hypertension than in normotensive individuals.

The effect of nifedipine on heart rate depends on its rate of input into the body. Oral capsule administration has not been associated with significant increases in heart rate, while sublingual, intravenous and intracoronary administration increase heart rate by up to 28%.

The reduction in systemic vascular resistance produced by sublingual nifedipine causes significant increases in cardiac output and decreases in left ventricular filling pressure due to afterload reduction, especially in patients with impaired left ventricular function. Intravenous nifedipine may produce decreases in left ventricular end-diastolic pressure and increases in cardiac index; however, intracoronary nifedipine may increase left ventricular end-diastolic pressure while decreasing systolic blood pressure. Thus, in contrast to intracoronary administration, the direct negative inotropic effect of intravenous nifedipine is overridden by reflex increases in heart rate and contractility that result from lowered blood pressure. In addition, both pulmonary vascular resistance and mean pulmonary arterial pressures decrease after nifedipine administration. Concomitant increases in cardiac index that are associated with these pulmonary effects further indicate that nifedipine has a selective effect on arterial resistance vessels.

By virtue of its strong arterial dilating ability, in patients with angina pectoris nifedipine produces favourable haemodynamic effects such as decreases in systemic vascular resistance and left ventricular afterload, and also decreases in systolic, diastolic and mean arterial pressure while maintaining cardiac inotropy and chronotropy in patients with left ventricular dysfunction. In such patients nifedipine is comparable to diltiazem, verapamil, β-blockers or nitrates in improving clinical status and reducing electrocardiographic signs of myocardial ischaemia on exercise or atrial pacing.

Greater reductions in blood pressure are achieved with the combination of nifedipine and β-blockers than result from either drug used separately in volunteers and patients with angina pectoris and hypertension. Reflex increases in heart rate and acute increases in plasma renin activity produced by nifedipine are blocked by β-blockade, and increases in total peripheral resistance produced by β-blockers are decreased by nifedipine.

Although hydralazine may be more suitable than nifedipine in patients with severe congestive heart failure when left ventricular afterload reduction is required, nifedipine produces more pulmonary vasodilatation than hydralazine and has a more balanced overall vasodilating effect. The combinations of nifedipine and Captopril, and nifedipine and digoxin or dobutamine, produce greater decreases in blood pressure and increases in cardiac index, respectively, than when these drugs are used alone. Nifedipine may also produce comparable improvements in cardiac performance as nitrates in patients with heart failure secondary to acute myocardial infarction, and in combination with nitrates may produce greater decreases in systemic vascular resistance and increases in cardiac index than sole nitrate therapy. Nitroprusside may be preferable to nifedipine in the single-dose treatment of severe congestive heart failure because it produces less reduction in blood pressure and greater increases in cardiac index.

The administration of nifedipine to patients with coronary artery disease results in an increase in coronary blood flow, especially to myocardial tissue served by stenotic coronary arteries, with little change in myocardial oxygen consumption. Nifedipine may protect the myocardium during subsequent reperfusion after cardiac surgery, and may also limit the extent of ischaemic injury after myocardial infarction, although further studies in humans are needed to define the exact degree of benefit that may be obtained in such patients.

Other pharmacodynamic effects of nifedipine include increased peripheral blood flow and decreased peripheral vascular resistance (especially in hypertensive subjects), inhibition of platelet aggregation, decreased lower oesophageal sphincter pressure and inhibition of peristalsis. In short term studies a reduction in glucose tolerance has been reported, but no such effects occurred in longer studies.

Nifedipine produces little effect on renal blood flow but its effect on renovascular resistance and glomerular filtration rate has been varied. Angiotensin II and acute plasma renin activity concentrations increase after nifedipine administration, possibly due to increases in sympathetic discharge induced by the drug; however, plasma aldosterone concentrations do not appear to be affected. Varying increases in hepatic blood flow have been reported with nifedipine use, possibly due to arterial vasodilatation produced by the drug.

Pharmacokinetic Properties: Close to 100% of a single oral dose of nifedipine is absorbed, although only about 45 to 68% of the drug reaches the systemic circulation. Considerable variations in peak plasma nifedipine concentrations after oral and sublingual administration, and the time required to reach these peaks, have been measured, presumably due to interindividual differences in the rate of drug absorption and/or variability in the extent of first-pass hepatic extraction and metabolism.

The steady-state volume of distribution of nifedipine in man after oral and intravenous administration is 1.32 and 0.62 to 1.12 L/kg, respectively. Nifedipine protein binding to albumin is concentration dependent and has ranged from 92 to 98%. Nifedipine undergoes almost complete (95%) hepatic oxidation to 3 pharmacologically inactive metabolites which are excreted in the urine.

The elimination half-life of nifedipine is apparently dependent upon the dosage form in which it is administered, with half-lives of 6 to 11 hours, 2 to 3.4 hours and 1.3 to 1.8 hours measured after oral tablet, oral capsule and intravenous administration, respectively. The total systemic and intrinsic clearances of nifedipine from plasma have ranged from 27 to 66 L/h and 33 to 37 L/h, respectively. Renal impairment does not significantly alter nifedipine pharmacokinetics.

Despite the difficulties involved in establishing a direct relationship between nifedipine plasma concentrations and clinical effects, some studies have shown plasma nifedipine concentrations to correlate significantly with changes in blood pressure, heart rate and lower oesophageal sphincter pressure. In addition, improved exercise tolerance and decreases in the frequency and occurrence of ischaemic attacks in patients with angina pectoris have also been shown to be directly related to nifedipine plasma concentrations.

Therapeutic Trials: Nifedipine has been shown to be effective in stable exercise-induced angina as assessed by decreases in anginal frequency and glyceryl trinitrate (nitroglycerin) consumption, and improvements in objective parameters such as work performance and time to onset of ST segment changes during exercise. Comparative trials in patients with stable angina have generally been of short duration in small numbers of patients and have failed to identify any consistent differences in efficacy between nifedipine and alternative first-line drugs such as β-blockers or other calcium antagonists. In those studies where nifedipine and a β-blocker were used together, the combination produced more favourable results without any significant deterioration of left ventricular function.

Approximately 80% of patients with variant (Prinzmetal’s) angina had a greater than 50% reduction in angina frequency (almost half gained complete remission from anginal attacks) when treated with nifedipine. Similar response rates were reported during short and long term (up to 6 years) trials, although some authors cited the need for additional antianginal drugs such as nitrates and β-blockers to help control symptoms. Comparative studies in patients with variant angina have not identified any consistent advantages or disadvantages for nifedipine over other drugs used, such as isosorbide dinitrate, diltiazem or verapamil.

Open trials in patients with unstable angina refractory to conventional therapy have shown that addition of nifedipine to their treatment regimen produced a favourable response in 47 to 89% of those treated. In comparative studies in patients with unstable angina, nifedipine was significantly superior to placebo and of equivalent efficacy as propranolol — alone, or combined with isosorbide dinitrate. Combination of nifedipine with propranolol in patients who did not benefit from monotherapy greatly increased the rate of successful responses. In terms of mortality, incidence of infarction, infarct size or extent of myocardial necrosis, nifedipine did not offer any advantages over placebo when administered to patients threatened by an acute myocardial infarction. In contrast, nifedipine was extremely useful for reducing or eliminating recurring episodes of ischaemic pain immediately after myocardial infarction.

A number of case studies have demonstrated the efficacy of sublingual or intracoronary nifedipine, alone or in combination with glyceryl trinitrate for preventing coronary artery spasm during coronary artery bypass surgery.

Nifedipine, administered by various routes, has been shown to be a relatively safe and effective drug for rapidly lowering elevated blood pressure in a number of clinical settings such as during or after surgery, in haemodialysis patients, and in hypertensive crises. In a comparative single-dose trial, nifedipine produced a faster reduction of blood pressure than prazosin in patients with uncontrolled hypertension. Prazosin, on the other hand, lowered blood pressure by a greater amount 2 to 3 hours after administration, although this was associated with a high incidence of postural hypotension.

In numerous therapeutic trials in patients with mild to severe hypertension, the antihypertensive efficacy of nifedipine has been maintained for periods of up to 3 or 4 years. Comparative medium term studies in patients with mild to moderate hypertension have shown nifedipine to be of equivalent efficacy as traditional first-line agents such as β-blockers and diuretics. Nifedipine has also been found to be an extremely useful adjunct for controlling blood pressure in patients refractory to conventional 2- or 3-drug regimens. Recently, a sustained release formulation of nifedipine, allowing twice daily administration, has been introduced to improve compliance. Therapeutic trials to date demonstrate that this preparation maintains 24-hour control of blood pressure at least as well as the conventional capsule formulation of nifedipine.

Nifedipine has been used in patients with Raynaud’s phenomenon of varying aetiology and has produced subjective improvement in the number, duration and severity of vasospastic attacks in more than 60% of patients. In some individuals nifedipine apparently facilitated the healing of cutaneous ulceration and relieved the frequency and severity of migraine associated with Raynaud’s phenomenon. Clinical evaluation of nifedipine in other therapeutic areas such as congestive heart failure, pulmonary hypertension and hypertrophic cardiomyopathy have been of a preliminary nature. Firm conclusions regarding its relative efficacy awaits further research, although some encouraging individual results have been reported.

Side Effects: Side effects from nifedipine are dose related and occur in approximately 20% of patients. The most common side effects occur secondary to the vasodilating properties of nifedipine and include headache (7%), flushing (5 to 7%) and dizziness (3 to 12%). The character, severity and incidence of side effects with nifedipine use is no greater during long term (> 6 months) treatment with the drug than during shorter courses of therapy. These side effects may be mitigated by reducing the nifedipine dose or by combining the drug with a β-blocker. This combination of nifedipine and β-blockers has not been found to place patients at greater risk than sole nifedipine therapy and thus may be advantageous in the treatment of angina pectoris or hypertension in patients with compromised cardiovascular function. Discontinuance of the drug due to side effects has been necessary in 2 to 6% of patients, while the occurrence of a true ‘withdrawal syndrome’ has not been noted.

Drug Interactions: Most studies suggest that nifedipine has no effect on plasma digoxin concentrations, although some studies have reported increased concentrations and clinical effects of digoxin. Nifedipine does not alter the pharmacokinetics of metoprolol, atenolol, nadolol or propranolol, but a few case reports have described severe hypotension or cardiac failure associated with nifedipine/β-blocker use in high risk patients with severe angina pectoris, triple-vessel disease, impaired left ventricular function and a prior history of myocardial infarction.

Dosage and Administration: for the clinical management of patients with angina pectoris, hypertension or Raynaud’s phenomenon, nifedipine dosage should be individualised. The current recommendation is for a starting dosage of one 10mg capsule 3 times daily, during or after meals, and this can be carefully titrated up to 20mg 3 times daily in patients with hypertension or Raynaud’s phenomenon and up to 90 to 120 mg/day (in divided doses) in patients with angina. If an immediate effect is required the capsules should be bitten open and the liquid contents allowed to remain in the mouth for faster sublingual absorption. A sustained release tablet formulation of nifedipine is now available for the treatment of hypertension, the recommended dosage of which is 20mg twice daily, after food, increased if necessary to 40mg twice daily. Recently, injectable (intravenous injection or infusion) preparations of nifedipine have been introduced for treating coronary vasospasm and/or acute hypertensive episodes. An intracoronary formulation is also available for treating coronary vasospasm that occurs during diagnostic or therapeutic interventions. It is imperative that these products are protected from light.

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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 Göteborg, Göteborg, 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. Guazzi, Cattedra di Cardiologia, Università Degli Studi de Milano, Milan, Italy; J.R. Hampton, University Hospital, Queen’s Medical Centre, Nottingham, England; C.H. 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.

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Sorkin, E.M., Clissold, S.P. & Brogden, R.N. Nifedipine. Drugs 30, 182–274 (1985). https://doi.org/10.2165/00003495-198530030-00002

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