Nifedipine Gastrointestinal Therapeutic System (GITS)

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Abstract
Nifedipine ‘gastrointestinal therapeutic system’ (GITS) is a recently developed formulation that slowly releases the drug into the intestinal tract over a 24-hour period. When administered once daily, it is of similar efficacy to sustained release formulations of felodipine, verapamil, and diltiazem and at least as effective as standard formulations of lisinopril and enalapril, and long-acting propranolol and atenolol in the treatment of patients with mild to moderate essential hypertension. Substitution of nifedipine GITS for conventional formulations of nifedipine, diltiazem or verapamil, maintained adequate control of anginal symptoms in patients with stable angina pectoris. Nifedipine GITS appears to maintain quality of life and is apparently better tolerated than those formulations of nifedipine which require 2 or 3 times daily administration in both elderly and younger patients. In addition, it has minimal effect on lipid and glucose metabolism and reverses left ventricular hypertrophy, and is thus suitable for treatment of the majority of patients with mild to moderate hypertension or angina pectoris. The primary action of nifedipine is inhibition of the influx of calcium through cardiac and smooth muscle cell membranes by blockade of L-type voltage-operated and possibly receptor-operated calcium channels. In patients with mild to moderate essential hypertension, repeated administration of nifedipine GITS decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 8 to 14% and 7 to 15%, respectively, while having minimal effect on heart rate. Principally, as a result of peripheral arterial dilatation, nifedipine causes a reduction in systemic vascular resistance and therefore, afterload. The drug has a direct negative inotropic effect (in vitro and following intracoronary administration), although this is usually not observed following oral administration. Long term treatment with nifedipine GITS reversed left ventricular hypertrophy and was associated with improved left ventricular filling and diastolic performance. The drug also increased renal blood flow and glomerular filtration rate, induced natriuresis during increased dietary sodium intake and blunted the response of the renin-aldosterone axis to changes in dietary sodium intake. Treatment with nifedipine GITS for periods of up to 12 weeks had no consistent effect on either lipid or glucose metabolism. The nifedipine GITS two-layered tablet utilises an osmotically driven ‘push-pull’ mechanism whereby nifedipine particles contained in an osmotic drug core become suspended in solution and are pushed into the intestinal tract by expanding active polymers. The oral bioavailability, relative to that of conventional nifedipine formulations, is 75 to 85% at steady-state and the formulation has linear pharmacokinetic behaviour. Mean maximum plasma concentrations (Cmax) were similar in healthy elderly (67 μg/L) and younger volunteers (62 μg/L) following repeated administration of nifedipine GITS 60mg once daily. Compared with the twice daily sustained release formulation of nifedipine, the GITS formulation had a lower Cmax, a longer time to Cmax, a higher trough concentration and a smaller peak-trough fluctuation. However, the area under the plasma concentration-time curve was similar with both formulations, indicating that the rate, but not the extent, of drag absorption differed between the 2 formulations. The mean steady-state volume of distribution of nifedipine is 1.3 L/kg and protein binding, principally to albumin, is about 98% at therapeutic plasma concentrations. Nifedipine is extensively metabolised in the liver to inactive oxidation products and undergoes extensive first-pass metabolism. Although earlier studies with conventional nifedipine formulations suggested that there were differences in the pharmacokinetic profile of the drug in elderly and younger volunteers, recent studies with the nifedipine GITS formulation reported no significant age-related differences. There was no significant correlation between nifedipine bioavailability and creatinine clearance after single or repeated doses. The suitability of nifedipine GITS for once daily administration for the treatment of mild to moderate essential hypertension is demonstrated by its trough: peak ratio (ratio of the antihypertensive effect at the end of the dose interval and that at the time of peak effect). A once daily dose of 30mg resulted in an individual trough: peak ratio of 0.5 in 61 to 79% of all patients studied, and in 73 to 87% and 87 to 93% of responders assessed by clinic blood pressure measurements and ambulatory monitoring, respectively. The efficacy of the GITS formulation was similar whether administered at night or in the morning. Following substitution of once daily nifedipine GITS for an equal daily dosage of twice daily sustained release nifedipine, DBP was maintained at <90mm Hg in 89% of patients with mild to moderate hypertension. This same degree of blood pressure control was achieved in 78% of patients after substitution of conventional release nifedipine for nifedipine GITS. Tolerability and compliance improved on switching to the GITS formulation. In comparisons with other calcium antagonists also administered once daily, nifedipine GITS was of similar efficacy to sustained release felodipine, verapamil and diltiazem. Nifedipine GITS was at least as effective as lisinopril and enalapril and tended to be more effective than long-acting propranolol or atenolol. Results from the Modern Approach to the Treatment of Hypertension (MATH) trial, indicated that the response rate (sitting DBPdecreasedto <90mmHgandby≥10mmHg) to nifedipine GITS 30 to 180mg once daily was similar in Black and Caucasian patients, and in males and females, although it was higher in elderly (≥65 years) compared with younger patients. Nifedipine GITS monotherapy maintained DBP at <95mm Hg in 73% of patients with initially severe refractory hypertension after 18 months of therapy. The small number of studies that have compared the effects of nifedipine GITS with those of sustained release verapamil or atenolol on quality of life of patients with mild to moderate essential hypertension indicated that nifedipine GITS generally maintains quality of life in such patients. In comparison, sexual function tended to deteriorate during treatment with atenolol. In a small study recipients of sustained release verapamil were more satisfied with their current antihypertensive treatment than those receiving nifedipine GITS, probably because of the higher incidence of vasodilatory adverse effects reported by patients treated with nifedipine. When added to existing β-blocker treatment in patients with stable angina pectoris, nifedipine GITS was more effective than placebo and similar in efficacy to a conventional formulation of diltiazem or atenolol in increasing time to angina, and decreasing nitroglycerin (glyceryl trinitrate) consumption, the total number and duration of ischaemic episodes during ambulatory monitoring, and the extent of ST-segment depression. Substitution of nifedipine GITS for conventional release formulations of nifedipine, diltiazem or verapamil resulted in continued control of exercise-induced symptoms in 89% of patients and a further reduction in overall frequency of anginal symptoms and nitroglycerin consumption and improved quality of life in over one-third of patients. The majority of adverse events associated with nifedipine GITS in clinical trials of patients with essential hypertension or coronary heart disease were related to the vasodilatory action of the drug and included peripheral oedema, headache, dizziness and flushing. Only oedema was clearly dose-related, reaching an incidence of 10.4 to 15.6% and 15.8 to 30.8% during administration of 150 and 180mg once daily, respectively. The incidence of adverse events with nifedipine GITS was lower than with conventional release formulations of nifedipine, diltiazem or verapamil, or sustained release (twice daily) formulations of nifedipine, and similar to that with sustained release diltiazem, felodipine, long-acting propranolol and atenolol. In a limited number of trials involving small numbers of patients, sustained release verapamil was better tolerated than nifedipine GITS, while enalapril was the better tolerated drug in a single trial comparing the ACE inhibitor with nifedipine GITS. The initial dosage of nifedipine GITS in the treatment of essential hypertension or stable angina pectoris is 30mg once daily. Dosage should be titrated at weekly intervals according to response up to a maximum of 120mg once daily.

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