Lisinopril versus slow-release nifedipine in the treatment of mild to moderate hypertension: a multicentre study. The Cooperative Study Group.
ABSTRACT The antihypertensive effects of lisinopril 20 mg once daily and slow-release nifedipine 20 mg twice daily were compared in a double-blind, parallel group, 10-week study involving 274 patients with mild to moderate hypertension. During the first 6 weeks of treatment, slow-release nifedipine and lisinopril produced similar reductions in lying and standing blood pressure (BP), except for lying systolic BP (SBP) which was reduced to a greater extent by lisinopril. After 6 weeks of double-blind treatment, hydrochlorothiazide 25 mg once daily was added if BP remained uncontrolled (lying DBP greater than or equal to 95 mmHg); a significantly greater proportion of patients in the nifedipine group than in the lisinopril group required additional diuretic treatment (29% versus 14%, respectively; P = 0.005). Moreover, after a further 4 weeks of treatment BP was adequately controlled (lying DBP less than 95 mmHg) in significantly more lisinopril-treated patients than in the nifedipine group (91.4% versus 78.3%, respectively; P = 0.006). Lisinopril was better tolerated than slow-release nifedipine. The frequency of drug-related events was significantly lower (threefold) for lisinopril than for nifedipine (P = 0.001) and the number of withdrawals from treatment with nifedipine was more than three times that in the lisinopril treatment group (P = 0.009). Lisinopril appears to provide an effective once-daily antihypertensive treatment which is at least as effective as, and better tolerated than, slow-release nifedipine.
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ABSTRACT: Synopsis Nifedipine antagonises influx of calcium through cell membrane slow channels, and sustained release formulations of the calcium channel blocker have been shown to be effective in the treatment of mild to moderate hypertension and both stable and variant angina pectoris. Preliminary findings also indicate that these formulations are effective in the treatment of Ray naud’s phenomenon and hypertension in pregnancy, and that they reduce the frequency of ischaemic episodes in some patients with silent myocardial ischaemia. The exact mechanism of action of nifedipine in all of these disorders has not been defined. However, its potent peripheral and coronary arterial dilator properties, together with improvements in oxygen supply/demand, are of particular importance. A major goal of sustained release therapy is to permit reductions in the frequency of nifedipine administration, preferably to once daily, and thus improve patient compliance. Two new once-daily formulations — the nifedipine gastrointestinal therapeutic system (GITS) and a fixed combination capsule comprising sustained release nifedipine 20mg and atenolol 50mg — have exhibited marked antihypertensive efficacy. The GITS preparation has also been used effectively in the treatment of stable angina pectoris, and both formulations appear to be well tolerated. Sustained release nifedipine formulations are generally better tolerated than their conventionally formulated counterparts, particularly with regard to reflex tachycardia. Adverse effects seem to be dose related, are mainly associated with the drug’s potent vasodilatory action, and include headache, flushing and dizziness. Generally, these effects are mild to moderate in severity and transient, usually diminishing with continued treatment. Thus, sustained release nifedipine formulations are useful and established cardiovascular therapeutic agents which have demonstrable efficacy in various forms of angina, mild to moderate hypertension and Raynaud’s phenomenon. Further, promising results shown by the nifedipine GITS formulation, with its advantage of once daily administration suggest that it is likely to become one of the preferred nifedipine formulations for the treatment of hypertension and the various forms of angina. Pharmacodynamic Properties Nifedipine inhibits influx of calcium through cardiac muscle and vascular smooth muscle cell membranes. It differs from diltiazem and verapamil, particularly with regard to sinoatrial and atrioventricular node function, where it may enhance conduction. Repeated administration of sustained release nifedipine reduces systolic and diastolic blood pressure by about 10 to 20%, whereas a fixed combination sustained release nifedipine/atenolol capsule and nifedipine gastrointestinal therapeutic system (GITS) reduce blood pressure by approximately 20%. Administered once daily, the latter formulation effectively controls blood pressure in a dose-dependent manner throughout a 24-hour dosing interval. Single doses of conventional nifedipine formulations increase heart rate by 12 to 17%, but these increases range from only 6 to 9% during longer term (1 to 6 weeks) administration. In contrast to conventional nifedipine formulations, sustained release preparations are generally not associated with postdose tachycardia. The main haemodynamic actions of nifedipine are peripheral arterial vasodilation with subsequent reductions in systemic vascular resistance and afterload, and an increase in cardiac index. Nifedipine has a small, direct negative inotropic effect in vitro and after intracoronary administration to humans. This is usually not observed after oral administration. Sustained release nifedipine may increase cardiac output, and it increased cardiac efficiency and reduced cardiac power in patients with hypertension. Further, the fixed combination sustained release nifedipine/ atenolol formulation caused a marked regression of left ventricular hypertrophy after 1 year’s treatment. Nifedipine has antianginal effects which parallel those of diltiazem, verapamil,β-blockers and nitrates. It improves clinical status and reduces ECG signs of myocardial ischaemia on exercise or atrial pacing. In addition, it increases coronary blood flow, particularly to myocardial areas supplied by stenotic arteries, without significantly altering myocardial oxygen consumption. Nifedipine also relieves coronary vasospasm in variant (Prinzmetal) angina, and improves exercise performance by reducing myocardial oxygen demand in patients with effort angina. Generally, the vasocdlating action of nifedipine is greater in hypertensive patients than in normotensive volunteers. Nifedipine significantly increases forearm blood flow and brachial artery compliance, while significantly reducing forearm vascular resistance and characteristic impedance. Nifedipine reduces plasma levels of β-thromboglobulin, a protein released during platelet activation, in patients with Raynaud’s phenomenon, and reverses thrombocytopenia in women with pre-eclampsia. Data regarding the effect of nifedipine on serum lipids are conflicting with reports of no significant effects, increases in high density lipoprotein (HDL), HDL2 and apolipoprotein A-I and A-II, and significant decreases in apolipoprotein E, and low density lipoprotein (LDL): HDL and apolipoprotein B: A-I ratios. However, animal experiments have indicated that nifedipine may slow the progression of new atherosclerotic lesions. This was confirmed in the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) in which nifedipine (formulation not stated) significantly reduced the progression of new atherosclerotic lesions in patients with mild to moderate coronary artery disease. Administration of sustained release nifedipine for 6 to 52 weeks had no effect on glucose tolerance in hypertensive patients with or without concomitant diabetes. In a large number of single-dose studies involving healthy volunteers and subjects with impaired glucose tolerance or diabetes, nifedipine also had no significant effect on glucose tolerance. Thus, the weight of evidence indicates that nifedipine has no real diabetogenic potential. Nifedipine rarely has marked renal effects. However, renal blood flow increases significantly and renovascular resistance decreases significantly after 4 weeks’ nifedipine administration to patients with essential hypertension. Nifedipine increases glomerular filtration rate (+11 to +46%) in hypertensive patients with or without concomitant glomerulonephritis, but usually does not alter this parameter in healthy volunteers. Increases in plasma renin activity are noted after the acute administration of nifedipine, whereas during longer term administration both increases and decreases in plasma renin activity have been recorded. Plasma aldosterone levels do not change in parallel with alterations in plasma renin activity. However, angiotensin II levels increase, particularly in younger normotensive and hypertensive subjects. Nifedipine has significant diuretic and natriuretic actions, may also significantly increase urinary potassium excretion, and has a significant uricosuric action. Pharmacokinetic Properties Nifedipine is almost completely absorbed from the jejunum after the administration of an oral dose. However, as a result of extensive and variable first-pass hepatic extraction, it has a relatively low bioavailability ranging from 43 to 77%. Absorption of nifedipine from sustained release oral tablets is prolonged (tmax=1.2 to 4.0 hours) in comparison with immediate release capsules (tmax=0.5 to 1.9 hours). Food increases the bioavailability of a sustained release nifedipine tablet and may also delay gastric emptying, thereby increasing the dissolution of a ‘biphasic’ nifedipine formulation in the stomach. Nifedipine’s absorption from the gastrointestinal therapeutic system (GITS) is unaffected by gastrointestinal pH or motility. This formulation has an oral bioavailability of 55 to 65% after a single dose, and 75 to 85% at steady-state. As with other nifedipine formulations, the GITS tablet exhibits a linear pharmacokinetic profile and plasma nifedipine concentrations begin to rise 2 hours after, and plateau approximately 6 hours after, GITS administration. ‘Dose-dumping’ does not occur with this sustained release formulation, and although food increases the rate of absorption of nifedipine from the GITS this is not associated with alterations in bioavailability. The mean steady-state apparent volume of distribution of nifedipine is 1.32 L/kg after oral administration. Nifedipine is highly bound to plasma proteins (92 to 98%), in particular albumin. Assuming complete absorption of an orally administered nifedipine dose, about 30 to 40% of the drug is eliminated by first-pass metabolism. Nifedipine undergoes oxidation to 3 pharmacologically inactive metabolites which are subsequently excreted in the urine together with traces of unchanged nifedipine. Two types of nifedipine metaboliser — fast and slow — have been postulated. These may arise because of oxidation polymorphism with a genetic basis. Mexican populations may have a prevalence of slow metabolisers, whereas fast metabolisers may be found more frequently in European populations. After oral administration of radiolabelled nifedipine approximately 70 to 80% of the total administered radioactivity appears in the urine in the form of metabolites, along with trace amounts of unchanged nifedipine. The remaining radioactivity is recovered in the faeces, also in the form of metabolites. The intrinsic clearance of nifedipine from the plasma ranges from 21 to 37 L/h and the rate of nifedipine elimination is probably dependent on drug metabolising activity and hepatic blood flow. Elimination half-life values of sustained release nifedipine (3.8 to 16.9 hours) are about 2 to 6 times greater than those of immediate release nifedipine capsules. In elderly volunteers, administration of sustained release nifedipine results in greater values for Cmax, AUC, mean residence time and elimination half-life than in younger volunteers. Although Cmax values may be significantly reduced in patients with severe renal impairment, the pharmacokinetic profile of nifedipine is usually not altered in such patients. Therapeutic Efficacy Sustained release nifedipine (20 to 80 mg/day) has produced statistically significant blood pressure reductions of about 20% in patients with essential hypertension in noncomparative as well as in placebo-controlled trials. Generally, response rates (usually the percentage of patients attaining a goal diastolic blood pressure of ≤ 95mm Hg) have ranged from about 80 to 85%. Sustained release nifedipine is also an effective antihypertensive agent when used in combination with β-blockers, ACE inhibitors and/or diuretics, and Black patients have responded well to the drug. Unlike conventionally formulated nifedipine, reflex tachycardia is usually not a feature of sustained release nifedipine therapy. The majority of comparative trials suggest that sustained release nifedipine has an antihypertensive efficacy which is generally similar to that of β-blockers, ACE inhibitors and other calcium antagonists, although marked tolerability differences exist between these agents. Combined sustained release nifedipine and atenolol regimens have been extensively studied and such combinations cause significantly greater blood pressure reductions than either agent alone. The nifedipine GITS (30 to 180mg administered once daily) produces mean blood pressure reductions ranging from 8 to 22% and associated response rates of about 60 to 80% in patients with hypertension. Preliminary studies suggest that nifedipine GITS is at least as effective as hydrochlorothiazide in elderly and Caucasian patients, more effective than hydrochlorothiazide in Blacks, and more effective than propranolol in Caucasians. Ambulatory blood pressure monitoring has confirmed the antihypertensive efficacy of nifedipine GITS throughout a 24-hour dosage interval. The efficacy of sustained release nifedipine in elderly patients (> 60 years of age) with hypertension is similar to that of ACE inhibitors, although the latter agents appear to have slightly better tolerability profiles in this population. The fixed sustained release nifedipine/atenolol combination appears to be effective and well tolerated in elderly patients. In addition, preliminary results suggest that sustained release nifedipine is effective when used alone and in combination with atenolol or methyldopa in hypertension during pregnancy although its effects, if any, on the fetus remain undefined. Sustained release nifedipine also appears to be effective and suitable for use in patients with malignant hypertension and in hypertensive patients with severe concomitant diseases (e.g. renal, cardiovascular and cerebrovascular disease, diabetes, asthma and systemic lupus erythematosus). In patients with stable angina pectoris, sustained release nifedipine has significantly improved both subjective and objective symptoms of angina. Its antianginal efficacy parallels that of nisoldipine, and sustained release and conventional formulations of isosorbide mononitrate. However, in contrast to nitrate regimens, tolerance usually does not occur during long term therapy with sustained release nifedipine. Nifedipine GITS and other sustained release nifedipine formulations have shown superior antianginal efficacy to conventional nifedipine formulations. In the treatment of patients with variant angina pectoris, sustained release formulations of nifedipine and isosorbide dinitrate are similarly effective, although headache has occurred in significantly more nitrate recipients. The Nifedipine-Total Ischemia Awareness Program has assessed the efficacy of nifedipine (formulation not stated) in the management of silent myocardial ischaemia. In this study, 83% (113/136) of patients had silent and/or symptomatic episodes of myocardial ischaemia. Addition of nifedipine to previous antianginal regimens significantly reduced the mean frequency of ST segment depression. Preliminary findings with sustained release nifedipine in the treatment of silent myocardial ischaemia have been promising and the results of INTACT have shown that nifedipine significantly reduces the progression of new atherosclerotic lesions in patients with mild to moderate coronary artery disease. However, the effect of nifedipine on cardiac mortality in these patients remains unclear. Initial findings suggest that sustained release nifedipine is effective in the treatment of Raynaud’s phenomenon. Indeed, both ‘biphasic’ (5mg immediate release and 15mg sustained release) and sustained release nifedipine have improved subjective and objective symptoms of the disorder. Other studies indicate that sustained release nifedipine may be a useful agent in the treatment of perniosis (chilblains). Sustained release nifedipine has also been used successfully, both pre- and postoperatively, in the management of labile high blood pressure due to phaeochromocytoma. Tolerability In worldwide use, nifedipine is associated with an overall incidence of adverse effects of about 20%. These effects are usually related to its vasodilatory action, are mild to moderate in severity and transient; they include headache (about 7%), flushing (5.3 to 7.4%), dizziness (3.1 to 12.1%) and lower leg oedema (0.6 to 7.7%) and usually necessitate treatment cessation in 2 to 6% of patients. Other adverse effects associated with nifedipine therapy include gastrointestinal symptoms (occurring with an incidence of 5.2 to 7.5%) and transient hypotension (about 5%). Nifedipine has also been reported to cause nocturia and joint pain, and there are several reports of gingival hyperplasia, but the latter reaction is relatively uncommon and readily resolves after treatment withdrawal. Some cases of increasing angina frequency, and paradoxical worsening of cardiac ischaemia, have occurred during nifedipine treatment. In addition, the abrupt cessation of nifedipine therapy has led to isolated instances of coronary artery spasm, hypertensive crisis, and a worsening of asthma symptoms. Sustained release nifedipine and nifedipine GITS tablets are generally better tolerated than conventional nifedipine formulations because of a slower absorption, a more gradual onset of action and lower peak plasma concentrations. Atenolol reduces the vasodilator adverse effects of nifedipine, and conversely, nifedipine may decrease the incidence of adverse effects resulting from β-blockade. In comparative trials, the use of a fixed sustained release nifedipine/atenolol combination has been associated with a better tolerability profile than either agent alone. Dosage and Administration For the treatment of hypertension and Raynaud’s phenomenon and for the prophylaxis of the various forms of angina pectoris, sustained release nifedipine tablets are administered at an initial oral dosage of 20mg twice daily, increasing to 40mg twice daily if necessary. For these indications, the nifedipine GITS starting dosage is 30mg once daily, titrated at weekly intervals to a maximum of 150mg once daily if necessary. A sustained release nifedipine/atenolol fixed combination capsule (20/50mg) may be administered once daily for the treatment of essential hypertension.Drugs 05/1991; 41(5):737-779. DOI:10.2165/00003495-199141050-00006 · 4.13 Impact Factor
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ABSTRACT: Nifedipine antagonises influx of calcium through cell membrane slow channels, and sustained release formulations of the calcium channel blocker have been shown to be effective in the treatment of mild to moderate hypertension and both stable and variant angina pectoris. Preliminary findings also indicate that these formulations are effective in the treatment of Raynaud's phenomenon and hypertension in pregnancy, and that they reduce the frequency of ischaemic episodes in some patients with silent myocardial ischaemia. The exact mechanism of action of nifedipine in all of these disorders has not been defined. However, its potent peripheral and coronary arterial dilator properties, together with improvements in oxygen supply/demand, are of particular importance. A major goal of sustained release therapy is to permit reductions in the frequency of nifedipine administration, preferably to once daily, and thus improve patient compliance. Two new once-daily formulations--the nifedipine gastrointestinal therapeutic system (GITS) and a fixed combination capsule comprising sustained release nifedipine 20 mg and atenolol 50 mg--have exhibited marked antihypertensive efficacy. The GITS preparation has also been used effectively in the treatment of stable angina pectoris, and both formulations appear to be well tolerated. Sustained release nifedipine formulations are generally better tolerated than their conventionally formulated counterparts, particularly with regard to reflex tachycardia. Adverse effects seem to be dose related, are mainly associated with the drug's potent vasodilatory action, and include headache, flushing and dizziness. Generally, these effects are mild to moderate in severity and transient, usually diminishing with continued treatment. Thus, sustained release nifedipine formulations are useful and established cardiovascular therapeutic agents which have demonstrable efficacy in various forms of angina, mild to moderate hypertension and Raynaud's phenomenon. Further, promising results shown by the nifedipine GITS formulation, with its advantage of once daily administration suggest that it is likely to become one of the preferred nifedipine formulations for the treatment of hypertension and the various forms of angina.Drugs 06/1991; 41(5):737-79. · 4.13 Impact Factor
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ABSTRACT: For several reasons, increasing numbers of patients with hypertension are treated with angiotensin-converting enzyme inhibitors and calcium channel blockers. In a twenty-four week, double-blind, randomized, parallel study, the antihypertensive effect of lisinopril (20 to 80 mg qd) and nifedipine (20 to 80 mg bid) were compared in 21 patients. Fourteen patients received lisinopril (mean dose 35 mg), and 7 patients received nifedipine (mean dose 54 mg). By the end of week 12, 8 patients had responded (supine diastolic pressure less than or equal to 90 mg) to lisinopril and 5 to nifedipine. At the end of the study supine systolic/diastolic blood pressure was reduced from 172/104 to 149/92 mmHg with lisinopril and from 171/102 to 158/94 mmHg with nifedipine. No significant difference between the two treatments was detected. Three patients were reported to have at least one clinical adverse experience during the active treatment period, 1 in the lisinopril group and 2 in the nifedipine group. No serious clinical adverse experiences were recorded. In conclusion, lisinopril and nifedipine are both effective in reducing blood pressure in patients with mild to severe hypertension. Lisinopril qd and nifedipine slow release bid produce similar decreases in blood pressure after twelve weeks of therapy and the safety profiles of the two drugs are similar.Angiology 07/1992; 43(6):482-9. DOI:10.1177/000331979204300605 · 2.37 Impact Factor