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Nineteen patients with essential hypertension on regular treatment with nifedipine tablets 20 mg twice daily and whose DBP was < 95 mmHg on at least two occasions two weeks apart were entered in a double-blind randomised crossover study of three weeks treatment with nifedipine coat core (new formulation) either as 30 mg one daily or as 60 mg once daily dose. BP and plasma nifedipine levels were measured at 24, two, four and six hours after dosing. The pattern of BP response to both doses was similar over the 24h period. However, a greater BP lowering effect was achieved with 60 mg compared with 30 mg. The BP lowering effect of both doses was less at 24h after the last dose compared with peak effect. Plasma nifedipine levels were significantly associated with the BP lowering effect in the group as a whole (i.e. the higher the nifedipine levels, the lower the BP) and were significantly less at 24 hours compared with peak. Nifedipine in the coat core formulation is effective in lowering BP in patients with essential hypertension. The 60 mg dose is more effective than the 30 mg dose and induces higher nifedipine levels which are associated with greater BP lowering effect. However, the maximum BP lowering effect is not maintained up to 24 hours.

Nifedipine is an effective compound for the treatment of hypertension. However, even as a tablet formulation it is relatively short acting requiring two or three times daily administration. Amlodipine is a long-acting calcium antagonist and effectively lowers BP in patients with essential hypertension. In the present study we compared the BP-lowering effect of nifedipine and amlodipine in patients with essential hypertension. Thirteen patients were studied. They had been on nifedipine tablets for at least four weeks and DBP had been consistently > 95 mmHg. After a further month run-in on nifedipine they entered a randomised double-blind crossover study of one month' treatment with either nifedipine tablet (20 mg twice daily) or amlodipine (5 mg once daily). BP was measured 12 and 2 hours after the last dose of nifedipine and 24 and 2 hours after the last dose of amlodipine. There was a significant peak/trough effect while on nifedipine tablets, the BP being significantly higher at 12 hours than at 2 hours after the last dose (155.2/90.9 +/- 4.6/1.7 vs. 136.1/84.8 +/- 4.3/1.7 mmHg; P < 0.001/P < 0.005). There was no overall difference in BP between nifedipine and amlodipine treatment when BPs were taken at the respective troughs (i.e. 12 hours and 24 hours). If anything, amlodipine tended to be slightly more effective at least on supine SBP (155.2/90.9 +/- 4.6/1.7 vs. 147.6/89.1 +2- 4.3/1.8 mmHg; P < 0.05, NS). In conclusion, amlodipine given once daily is at least as effective as nifedipine tablets given twice daily in patients with essential hypertension.

Purpose: To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine., Patients: Eight patients with uncomplicated mild to moderate essential hypertension were entered in a single-blind, placebo-controlled study of 39 days' duration., Methods: Two 7-day periods while on a fixed sodium intake of 150 mmol/day approximately 3 weeks apart. After 4 days of a placebo and fixed sodium intake, patients were given nifedipine GITS (gastrointestinal therapeutic system) once a day and carefully studied for the following 4 days. Thereafter, patients continued to receive nifedipine GITS, and approximately 3 weeks later they were studied again for a week while on a fixed sodium intake. Nifedipine administration was stopped and changes occurring after withdrawal were studied., Results: Nifedipine caused a significant increase in sodium excretion with a cumulative loss of sodium of 38 mmol per subject within the first 4 days of treatment. The withdrawal of nifedipine treatment caused a significant decrease in sodium excretion and a cumulative retention of sodium of 42 mmol per subject within the first 4 days of withdrawal., Conclusion: Nifedipine causes an acute and a sustained reduction in sodium balance in patients with essential hypertension. This prolonged effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Twelve patients with essential hypertension who were already on treatment with the long-acting calcium antagonist amlodipine (5 mg once daily) were entered into a double-blind, randomized crossover study of the addition of one month's treatment with either bendrofluazide (5 mg once daily) or matching placebo. The addition of bendrofluazide did not cause any statistically significant fall in the supine blood pressure compared to treatment with placebo (147.6/90.1 +/- 4.8/2.8 v 150.8/92.6 +/- 4.3/2.3 mm Hg, respectively). Plasma potassium was significantly lower on bendrofluazide as compared to placebo (3.11 +/- 0.14 v 3.62v +/- 0.13 mmol/L, P less than .001) and 10 of 12 patients had a fall in plasma potassium while on diuretic. The results of this study suggest that a thiazide diuretic has little additive effect on blood pressure in patients already on the long-acting dihydropyridine amlodipine, and may cause hypokalemia.

We studied the effect of amlodipine, a long-acting dihydropyridine calcium antagonist, on blood pressure, urinary sodium excretion, plasma renin activity, aldosterone and atrial natriuretic peptide in six patients (aged 47-63 yrs) with essential hypertension. Patients were placed on a fixed sodium intake of 150 mmol/day. After a control period, amlodipine 10 mg/day was given for two weeks. There was a gradual reduction in supine BP over the first two days of treatment, from 165/103 +/- 5/4 mmHg to 137/92 +/- 6/4 mmHg (P less than 0.001) and BP remained at this level during treatment. Three days after amlodipine was stopped the BP was still reduced at 136/87 +/- 5/4 mmHg but was back to pretreatment levels two weeks later. Plasma amlodipine rose after two weeks of treatment to 29.7 +/- 4.7 ng/ml but had only decreased to 15.0 +/- 3.4 ng/ml three days after the treatment was withdrawn. During the first two days of treatment there was no evidence of an increase in urinary sodium excretion and when amlodipine was withdrawn there was no evidence of sodium retention. Plasma renin activity increased from 1.26 +/- 0.30 to 2.99 +/- 0.68 ng/ml/h (P less than 0.001) and plasma atrial natriuretic peptide fell from 19.3 +/- 7.0 to 11.4 +/- 3.8 pg/ml (P less than 0.03) with two weeks of treatment. This study demonstrates that amlodipine is a long-acting calcium antagonist with a slow onset of action and a slow end of action after withdrawal. This makes it difficult to detect alterations in sodium balance when assessed by changes in urinary sodium excretion. However, one explanation for the increase in plasma renin activity and fall in atrial natriuretic peptide is a small reduction in total body sodium.

Calcium antagonists and converting enzyme inhibitors are now widely used as first line therapy for high blood pressure. This gradual move from the diuretics and beta-blockers is, in part, due to fewer or different side effects and the perceived lack of deleterious metabolic effects. Calcium antagonists may be more effective in elderly and low-renin patients. However, this is likely to be due in part to the finding that calcium antagonists are more effective with a higher initial pressure. The efficacy of converting enzyme inhibitors is related to the initial level of plasma angiotensin II (Ang II) or plasma renin activity. However, patients with low plasma renin activity also have a fall in blood pressure with converting enzyme inhibitors, illustrating the importance of differences in Ang II receptor sensitivity to the prevailing level of Ang II. Many patients require the combination of more than one drug to control their blood pressure. Combining a converting enzyme inhibitor with either a dihydropyridine or a benzothiazepine calcium antagonist is a particularly effective approach to the treatment of patients with more severe essential hypertension.

Objective: To assess the changes in sodium excretion and sodium balance after withdrawal of long term nifedipine., Design: Single blind, placebo controlled study in patients receiving fixed sodium and potassium intakes., Setting: Blood pressure unit of a teaching hospital in south London., Patients: Eight patients with mild to moderate uncomplicated essential hypertension who had been taking nifedipine 20 mg twice daily for at least six weeks., Interventions: Withdrawal of nifedipine and replacement with matching placebo for one week., Main Outcome Measures: Urinary sodium excretion and cumulative sodium balance, body weight, plasma atrial natriuretic peptide concentrations, plasma renin activity and aldosterone concentrations, and blood pressure., Results: During nifedipine withdrawal there was a significant reduction in urinary sodium excretion (day 1: -62.7 mmol/24 h; 95% confidence interval -90.3 to -35.0) and each patient retained a mean of 146 (SEM 26) mmol sodium over the week of replacement with placebo. Body weight and plasma atrial natriuretic peptide concentrations increased during the placebo period and seemed to be associated with the amount of sodium retained. Systolic blood pressure rose from 157 (9) to 165 (9) mmHg (95% confidence interval of difference -7.1 to 22.1) when nifedipine was replaced with matching placebo, and the rise seemed to be related to the amount of sodium that was retained., Conclusions: Nifedipine causes a long term reduction in sodium balance in patients with essential hypertension. This long term effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Nifedipine was given to 15 patients with essential hypertension for 6 weeks and to 8 normotensive subjects for 5 days. In the hypertensives, 30 min after the first dose of nifedipine (5-mg capsule), there was a 13.9% fall in mean blood pressure (p less than 0.001), and, at the 6th week of treatment at the maximum dose of 20 mg t.d.s., a 20.6% fall in mean blood pressure (p less than 0.001). In the normotensive subjects, 30 min after the first dose of 5 mg of nifedipine, there was a 2.3% fall in mean blood pressure (NS), and on the 5th day with the maximum dose of 20 mg t.d.s., the fall was 2.2% (NS). In view of the difference in age between these normotensive and hypertensive subjects, a larger group of patients with essential hypertension and older normotensive subjects were also studied acutely after a single 5-mg capsule of nifedipine. Thirty minutes after the first dose of nifedipine in the larger group of hypertensives, there was a significant fall in mean blood pressure (10.4%; p less than 0.001, n = 33). In the normotensive subjects, there was also a significant fall in mean blood pressure (4.7%; p less than 0.01, n = 29). This was significantly less than in the hypertensives (p less than 0.001). In both the normotensive and hypertensive subjects, there was a significant correlation between pretreatment blood pressure and percentage decrease in blood pressure with nifedipine. Nifedipine, therefore, has a greater blood pressure-lowering effect the higher the initial blood pressure. This finding is compatible with the idea that nifedipine reveals a functional abnormality of vascular smooth muscle that becomes greater the higher the blood pressure.

In a randomised, crossover study of patients with moderate to severe essential hypertension, the effects of the calcium entry antagonist nifedipine and the beta-receptor blocking drug acebutolol were studied on their own, and in combination. After 4 weeks of nifedipine tablets 20 mg twice daily (Adalat, Bayer), mean supine blood pressure (BP) fell by 20 mmHg and after 4 weeks of acebutolol 200 mg twice a day (Sectral, May & Baker) by 11 mmHg. When nifedipine and acebutolol were given in combination in the above doses for 4 weeks, there was a significantly greater fall in BP than with either agent alone, supine mean arterial pressure falling by 27 mmHg. The above BPs were measured 2 h after the last dose of tablets. Measurements 12 h after the last dose showed smaller falls in BP, with a significantly greater fall with combination treatment than with acebutolol alone. The fall in BP 12 h after the last dose of the combination was greater than with nifedipine alone but this difference was not statistically significant. This randomised, controlled study showed that nifedipine and acebutolol have a marked additive effect on BP which is sustained for at least 12 h after treatment.

Nifedipine, given to both normotensive and hypertensive subjects, caused a greater fall in blood pressure the higher the initial blood pressure. Increasing salt intake enhanced the acute blood-pressure-lowering effect of nifedipine in both normotensive and hypertensive subjects. In hypertensive subjects on longer-term treatment with nifedipine tablets, the addition of bendrofluazide caused no further significant fall in blood pressure. These findings provide circumstantial evidence that there may be a link between sodium intake, sodium balance, and inhibitor of sodium transport, and a functional abnormality of the smooth muscle cell to calcium-entry antagonists.

Nifedipine reduces blood pressure predominantly by reducing systemic vascular resistance due to a direct vasodilating action on the arterioles. This peripheral vasodilation appears greater the more severe the hypertension. Nifedipine also causes a long-term loss of sodium, which may be an additive mechanism for the blood pressure fall. In patients who are not controlled on nifedipine alone, studies have demonstrated an additive effect of beta blockers and converting-enzyme inhibitors on blood pressure. There is controversy about whether diuretics have an additive effect on blood pressure in patients already on nifedipine.

The acute blood pressure-lowering effect of nifedipine was studied in patients on high, normal, and low sodium diets. The demonstrated decrease in blood pressure was greatest in those patients receiving the high sodium diet. Studies were then performed with a combination of nifedipine and the diuretic bendrofluazide. When nifedipine was given to patients already on bendrofluazide, there was an additional fall in blood pressure. However, when bendrofluazide was added to the regimen of patients already receiving nifedipine, there was no further reduction in blood pressure. Studies were then performed in patients receiving chronic nifedipine therapy who had their nifedipine treatment stopped while on a fixed sodium intake. All patients retained sodium and there was an increase in weight. This latter study confirms that nifedipine causes a long-term reduction in sodium balance in patients with essential hypertension. It is possible that these long-term changes in sodium balance with nifedipine could partially explain the blunting of the blood pressure-lowering effect seen when the thiazide diuretic was added to the regimen of patients already receiving nifedipine.

The acute response to nifedipine 5 mg was studied in 11 young normotensive subjects and 18 older normotensive subjects who were age matched with 33 patients with uncomplicated essential hypertension. There was an immediate fall in blood pressure which was significantly greater in the hypertensive subjects--10.4%--compared to the normotensive subjects where it was only 4.7%. The best predictor of response both in the hypertensive and normotensive subjects was the pre-treatment mean blood pressure. Multiple regression analysis showed that the addition of age and plasma renin activity made little effect. These results clearly demonstrate that, at least acutely, nifedipine becomes more effective the higher the blood pressure. They are compatible with the idea that nifedipine is partly working on a mechanism which is responsible for the high blood pressure and therefore becomes more effective the higher the blood pressure.

The effects of the addition of a calcium entry antagonist, nifedipine (20-mg tablet twice a day), to an angiotensin converting enzyme inhibitor, captopril (25 mg three times a day), and the addition of captopril to nifedipine were observed in two separate studies in patients with essential hypertension. After 4 weeks of captopril therapy alone, mean arterial pressure fell by 12 mm Hg, and with the addition of nifedipine to captopril for a further month, blood pressure fell by an additional 10 mm Hg. In a separate group of patients treated with the same doses, mean arterial pressure fell by 17 mm Hg with nifedipine treatment alone; when captopril was added to the nifedipine therapy for an additional month, mean arterial pressure fell by a further 11 mm Hg. These blood pressures were measured 2 hours after the last dose; however, there was less of a fall in blood pressure when it was measured 12 hours after the last dose. This study confirms that captopril and nifedipine have a marked additive effect on blood pressure in whichever order they are given, but it shows that the combination is relatively short-acting.

Because captopril alone does not control blood pressure in all patients with essential hypertension, studies were performed to assess the effect of sodium intake and of captopril combined with hydrochlorothiazide, propranolol, and nifedipine. Captopril given for 5 days to normotensive subjects having high, normal, and low sodium intakes reduced blood pressure the most in those on the lowest intake; the fall correlated with that in plasma angiotensin II. When 12 patients with moderate hypertension had hydrochlorothiazide added to captopril their blood pressure fell significantly. When propranolol was added to captopril, however, there was no further fall in blood pressure. When propranolol was added to captopril and a diuretic, pressures measured 4 and 6 h after the last dose of captopril showed reduced values compared with placebo; pressures measured 2 and 12 h after did not. Nifedipine added to captopril reduced blood pressure more than either drug alone. When renin and angiotensin are low, as they may be in essential hypertension, captopril is less effective; its effectiveness should increase if sodium is restricted. Both diuretics and nifedipine increase the effectiveness of captopril; propranolol does not, although it may prolong captopril's action. Experience in patients with resistant hypertension suggests that adding nifedipine to captopril may reduce the need for diuretics, while adding captopril to nifedipine may reduce the need for beta-blockers.

The acute blood pressure lowering effect of nifedipine as a capsule was enhanced by a high-sodium intake in both normotensive and hypertensive subjects. In a double-blind, randomised, placebo-controlled study, the longer-term effect of nifedipine as a tablet in hypertensives was also greater on a high sodium intake than on a normal or low sodium diet. In hypertensive patients who were already on regular treatment with nifedipine, the addition of a thiazide diuretic for 1 month did not cause any significant additional fall in blood pressure despite untoward metabolic side effects. These findings, therefore, strengthen the view that there is a link between the blood pressure lowering activity of calcium entry antagonists and the state of sodium balance.

Twelve hypertensive patients who were already on treatment with atenolol (100 mg once daily) and nifedipine as tablets (20 mg twice daily) were entered into a double-blind, randomized crossover study of the addition of 1 month's treatment with either bendrofluazide (5 mg once daily) or a matching placebo. The addition of bendrofluazide to the combination of atenolol and nifedipine did not cause any statistically significant fall in the blood pressure 2 h after the last dose of nifedipine compared to treatment with placebo [bendrofluazide: 135.2 +/- 5.1/89.8 +/- 2.5 (mean +/- s.e.), versus placebo: 132.1 +/- 4.6/89.9 +/- 3.1 mmHg; P = NS]. However, 12 hours after the last dose of nifedipine blood pressure tended to be lower whilst on bendrofluazide compared with placebo. Plasma urate levels were significantly higher on the diuretic compared to placebo (461 +/- 27 versus 396 +/- 21 mumol P less than 0.001). Plasma potassium was lower on the diuretic compared to placebo (3.59 +/- 0.12 vs 3.76 +/- 0.10) but this difference just failed to reach statistical significance. The results of this study suggest that a thiazide diuretic has little additive effect on blood pressure in patients already on treatment with atenolol and nifedipine, particularly when nifedipine is maximally effective. However, the addition of a diuretic does have potentially deleterious metabolic effects.

The effect of the addition of a diuretic, bendrofluazide, for 1 month was studied in 12 hypertensive patients who were already on treatment with nifedipine tablets (20 mg b.i.d.) When nifedipine was maximally effective, that is, at 2 hours after the last dose, the diuretic had no further blood-pressure-lowering effect. These results suggest that unlike most other blood-pressure-lowering agents, there is little point in giving a diuretic to patients who are already on nifedipine, and if blood pressure is not controlled on nifedipine alone, it may be more effective to add either a beta blocker or a converting enzyme inhibitor. This has the advantage of avoiding the metabolic problems of diuretics.

Nifedipine reduces blood pressure predominantly by reducing systemic vascular resistance due to a direct vasodilating action on the arterioles. This peripheral vasodilation appears greater the more severe the hypertension. Studies have demonstrated an additive effect of beta blockers and converting-enzyme inhibitors in patients not controlled with nifedipine alone. Although there is a controversy about whether diuretics have an additive effect on blood pressure in patients already taking nifedipine, it would appear that the blood pressure-lowering effect of thiazide is blunted. Studies have shown that a high sodium intake may enhance the acute blood pressure-lowering effect of nifedipine. Nifedipine does cause a long-term reduction in sodium balance.

Twelve patients with essential hypertension on no other drug treatment were entered into a randomised crossover study of 5, 10 and 20 mg capsules of nifedipine given 3 times a day and 20 mg tablets given twice a day. Each dose was given for 2 weeks in a random order. All forms of nifedipine were effective in lowering blood pressure. However, 5 mg capsules were less effective than the 10 and 20 mg capsules or 20 mg tablets. There was little to choose between the latter. All doses of nifedipine were more effective 1 and 3 h after the dose compared to subsequent times afterwards. Indeed, as time elapsed after the last dose up to 12 h, there was a gradual increase in blood pressure. However, even at 12 h the 10, 20 mg capsules and 20 mg tablets were still causing an approximate 10% reduction in blood pressure. Nifedipine tablets are as effective as capsules though they might be longer acting, particularly around 6 h after the last dose.

There is controversy about the antihypertensive effect of thiazide diuretics in patients already being treated with nifedipine. Studies that we have conducted suggest that the antihypertensive effect of the thiazide may be blunted in the presence of nifedipine. One possible explanation for this blunted response is that nifedipine has a long-term effect on sodium balance. In a study where long-term nifedipine was withdrawn from hypertensive patients there was evidence that withdrawal of nifedipine was accompanied by sodium retention, as judged by changes in urinary sodium excretion. If these results are confirmed in larger studies, they have important therapeutic implications for the use of nifedipine.

Presents a letter to the editor in response to an article by J. F. Burris et al., on the effects of thiazides plus calcium channel blockers, in a 1990 issue of the 'Journal of the American Medical Association.'