Modified-Release Nifedipine

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Abstract
Nifedipine is a dihydropyridine calcium channel antagonist with predominantly vasodilatory activity. Modified-release formulations of nifedipine are effective antihypertensive and antianginal therapies and are generally well tolerated. Among the available formulations, those that produce a gradual increase in plasma nifedipine concentration, which is then sustained over a 24-hour period, are preferred, as they cause a gradual onset of vasodilatation and avoid baroreflex sympathetic activation (for example, nifedipine gastrointestinal therapeutic system [GITS] and a Japanese controlled-release formulation). Modified-release nifedipine had beneficial effects on a number of markers of vascular function, and nifedipine GITS reduced the need for coronary procedures in patients with coronary artery disease. In patients with hypertension, nifedipine GITS and nifedipine retard had beneficial effects on the overall incidence of major cardiovascular events, as did nifedipine retard in patients with concurrent hypertension and coronary artery disease. The primary pharmacodynamic effect of nifedipine is the dilatation of both large and small arteries, through a reduction in smooth muscle contraction in the arterial wall. Nifedipine has little effect on cardiac contractility or conduction. In addition to its vasodilatory actions, it also demonstrates antiatherosclerotic activity. Nifedipine is almost completely absorbed from the gastrointestinal tract after oral administration, undergoes first-pass metabolism in the liver and gut wall, and has oral bioavailability of 43–77%. It is highly plasma protein-bound. Nifedipine is metabolised in the liver to inactive metabolites, which are eliminated primarily in the urine; <1% of a dose is excreted unchanged in the urine. The haemodynamic response with nifedipine correlates with plasma concentration and the rate of change in plasma concentration. Rapid increases in plasma concentrations with the original immediate-release (short-acting) capsule, which was administered three times daily, led to an abrupt onset of vasodilatation that was associated with baroreflex sympathetic activation, commonly manifested as tachycardia. Modified-release formulations of nifedipine that provide a gradual increase to a moderate peak plasma level (accompanied by a gradual onset of vasodilatation) that is sustained over a 24-hour period, are not associated with baroreflex sympathetic activation. Examples include the once-daily nifedipine GITS formulation and a controlled-release formulation available in Japan. A number of other once-daily formulations of nifedipine are available, with different drug-release and plasma-concentration profiles. In addition, a marked food interaction occurs with some formulations but not others. Consequently, different once-daily formulations of nifedipine may have different effects on blood pressure (BP) and heart rate over a 24-hour period and, unless adequate data demonstrating similar profiles are available, they cannot be assumed to be equivalent in terms of their clinical effects. In patients with chronic stable angina pectoris, modified-release nifedipine (irrespective of formulation) significantly increased the time to onset of 0.1mV ST-segment depression during exercise testing compared with baseline. Improvements were similar to those seen with atenolol, carvedilol or diltiazem, although not as great as those seen with controlled-release metoprolol. In patients with an inadequate response to β-adrenoceptor antagonists, the addition of modified-release nifedipine significantly increased the time to 0.1mV ST-segment depression compared with atenolol monotherapy and increased it to a greater extent than seen with the addition of modified-release isosorbide mono- or dinitrate. Modified-release nifedipine was as effective as modified-release isosorbide dinitrate or nisoldipine coat-core in patients with variant angina. In adults with essential hypertension, monotherapy with modified-release nifedipine (irrespective of formulation) for ≥8 weeks led to similar reductions in systolic and diastolic BP, and achieved similar response rates, to those seen with comparator agents, including amlodipine, lacidipine, extended-release verapamil, enalapril, lisinopril, losartan (with or without hydrochlorothiazide) and nebivolol. In one trial, nifedipine retard reduced systolic, but not diastolic, BP more than atenolol. In INSIGHT, nifedipine GITS and hydrochlorothiazide/amiloride (co-amilozide) reduced mean 24-hour BP to a similar extent. The antihypertensive efficacy of modified-release nifedipine formulations was similar to that of lercanidipine, fosinopril, losartan (with or without hydrochlorothiazide) and amlodipine in elderly patients; to that of amlodipine and captopril plus hydrochlorothiazide in Black patients; and to that of telmisartan or lisinopril in diabetic patients. The combination of nifedipine GITS plus losartan reduced systolic and diastolic BP more than losartan monotherapy and reduced systolic (but not diastolic) BP more than nifedipine GITS monotherapy. In patients with an inadequate response to candesartan, atenolol or diuretic monotherapy, the addition of modified-release nifedipine formulations led to significant reductions in BP. Several studies have assessed the effects of modified-release nifedipine on end organs. When considering vascular function, substudies of INSIGHT and the ENCORE trials showed that nifedipine GITS slowed the progression of carotid intima-media thickening and coronary calcification and improved endothelial function in patients with cardiovascular disease. Nifedipine retard slowed the angiographic progression of atherosclerosis, particularly in mild to moderate stenosis, in a JMIC-B substudy. In patients with left ventricular (LV) hypertrophy, nifedipine GITS reduced LV mass index to a similar extent as an ACE inhibitor in the PRESERVE trial. Renal function was better preserved with...

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