Nifedipine Capsules Research Articles

Usefulness of nifedipine for myocardial ischemia and the nifedipine gastrointestinal therapeutic system

Although conventional treatment of angina pectoris with nifedipine capsules involves frequent daily dosing, a new vehicle for the once-daily delivery of this potent but insoluble calcium channel blocking agent has been developed. With the gastrointestinal therapeutic system (GITS) formulation, constant effective drug levels of nifedipine are delivered for a full 24-hour period. When nifedipine GITS 30, 60 or 90 mg was administered once daily to patients with stable angina pectoris taking β blockers, clinical effectiveness was demonstrated both by an increase in time to angina and by exercise time compared with placebo. Improvement was noted to be more significant with the higher doses of nifedipine administered once daily. This study indicates that nifedipine GITS provides additional antianginal protection in patients with exercise-induced angina secondary to coronary artery disease who are receiving a fixed dose of β blocker.

Cardiac and hemodynamic adjustments to rapid and sustained blood pressure reduction.

The most effective strategies for achieving immediate and long-term control of blood pressure and reversal of left ventricular (LV) hypertrophy and dysfunction in severe hypertensives is not known. In this preliminary communication, we report our experience with long-term blood pressure control in severe hypertensives who were treated with up to 150 mg of nifedipine gastrointestinal therapeutic system (GITS)--a once daily nifedipine formulation. In 23 subjects with diastolic blood pressures greater than 120 mm Hg, treatment was begun with nifedipine capsules for immediate reduction of diastolic blood pressure to less than 110 mm Hg. Doppler echocardiography was used to measure LV mass, percent LV fractional shortening (%FS), and cardiac output (CO). To achieve a goal diastolic blood pressure of less than 95 mm Hg, the 22 subjects who responded to nifedipine capsules were titrated up to 150 mg of nifedipine GITS. To date, 12 subjects completed two months of goal blood pressure with nifedipine GITS. CO, heart rate (HR), and %FS were elevated following nifedipine capsules. During long-term therapy with nifedipine GITS, CO and HR returned to baseline, while %FS remained elevated. These preliminary data suggest that in patients with severe hypertension, effective long-term control of BP with a once-a-day dosage of nifedipine in the GITS formulation may be achieved without adverse hemodynamic effects.

Effect of oral administration of nifedipine on neuropeptide Y- and noradrenaline-induced vasoconstriction in the human forearm.

Neuropeptide Y (NPY) has recently been shown be co-released with noradrenaline (NA) from sympathetic nerves and to cause arterial vasoconstriction in experimental animals and man. The effect of a single oral dose (10 mg capsule) of nifedipine on NPY- and NA-induced reductions of forearm blood flow (FBF) was studied in seven healthy volunteers. Intra-arterial infusions of NPY and NA into the brachial artery before nifedipine caused dose-dependent reductions in FBF with threshold doses of 0.2 and 0.03 nmol x min-1, respectively. The response to NPY was slower in onset and more long lasting than that to NA. Forty-five min after administration of nifedipine, FBF and heart rate had increased significantly (by 49% and seven beats x min-1, respectively, P less than 0.001), while no significant change was observed in systemic blood pressure. The NPY-induced decrease in FBF was slightly but significantly attenuated after compared to before nifedipine (19 +/- 6 vs. 28 +/- 5% at 1.0 nmol NPY x min-1; P less than 0.01). The response to NA was, however, not significantly altered by nifedipine. In conclusion, the NPY-induced reduction in FBF in man was only slightly prevented and the NA response not significantly affected by oral nifedipine administration in a clinically used dose. This suggests that this calcium antagonist, in the present dosage, does not, to any major extent, inhibit the vasoconstrictor effect of NPY or NA in man in vivo.

Once-daily therapy for angina pectoris with nifedipine gastrointestinal therapeutic system: Dosing and clinical efficacy

The nifedipine gastrointestinal therapeutic system (GITS) is a promising new formulation that provides continuous release of nifedipine over the course of 24 hours with once-daily dosing. Results from a 14-week, open-label, crossover multicenter trial completed by 91 patients with chronic stable angina pectoris demonstrate that patients treated with standard nifedipine capsules may be switched to equivalent total 24-hour doses of nifedipine GITS and achieve comparable or improved efficacy (due to improved compliance) with a more favorable side-effects profile. Furthermore, in a subset of 10 patients who underwent sequential exercise testing, exercise responses obtained throughout 12 weeks of treatment with nifedipine GITS were comparable to measurements obtained during treatment with nifedipine capsules and demonstrated that tolerance did not occur. These patients also experienced significantly fewer vasodilatory side effects during treatment with nifedipine GITS compared with nifedipine capsules. Thus, nifedipine GITS represents a sound pharmacologic approach to the management of ischemic disease; and with once-daily dosing and a favorable side-effect profile this agent affords the potential for better patient compliance and efficacy without concern about the development of tolerance.

Gas chromatographic-mass spectrometric analysis of plasma nifedipine

A gas chromatographic-mass spectrometric assay is described for the determination of plasma nifedipine using nitrendipine as an internal standard. Chromatographic separation was performed on a dimethylsilicone capillary column, and detection was by selected ion monitoring of electron impact-generated base peak ions. The lower limit of quantifiable detection of nifedipine was 2 ng/ml. The method was applied to plasma samples obtained from a human subject who had been dosed with a 10-mg nifedipine capsule every 8 h for eight doses.

Nifedipine gastrointestinal therapeutic system in stable angina pectoris: Results of a multicenter open-label crossover comparison with standard nifedipine

To compare the clinical efficacy and dose equivalency of standard nifedipine versus a new gastrointestinal therapeutic system (GITS) formulation of nifedipine, 98 patients with chronic stable angina pectoris participated in a 14-week, multicenter, open-label, cross-over trial. All patients were administered nifedipine capsules for one month prior to study entry and continued receiving other antianginal, non-calcium blocker medications. Ninety-one patients (93 percent), 80 men and 11 women, mean age 62 ± 1 years, completed the trial, which included two weeks receiving standard nifedipine followed by 12 weeks receiving nifedipine GITS starting at a dosage equal to the 24-hour total dose of nifedipine capsules and titrated upward as necessary. However, throughout the trial, mean nifedipine dosage was similar on nifedipine GITS compared with standard nifedipine. Angina frequency was significantly less with nifedipine GITS at Weeks 6, 10, and 14 (0.8 episodes/week) compared with baseline with standard nifedipine (1.3 episodes/week, p <0.05). Likewise, nitroglycerin consumption was also less at Weeks 6, 10, and 14, but only significantly less at Week 6 (nifedipine 1.2/week versus nifedipine GITS at six weeks, 0.7/week; p <0.05). Resting hemodynamic parameters, including systolic and diastolic blood pressure and heart rate, were not significantly different with standard nifedipine versus nifedipine GITS during the 12-week study. Total incidences of side effects were similar for both treatments (standard nifedipine, 16; nifedipine GITS, 17). However, incidence of vasodilator side effects (flushing, dizziness, and light-headedness) was significantly less frequent with nifedipine GITS (standard nifedipine, 12; nifedipine GITS, six; p <0.05). Thus, results from this open-label, crossover trial suggest that nifedipine GITS dosing is similar to multidose standard nifedipine with equivalent 24-hour efficacy for nifedipine GITS.

Multicenter comparison of the nifedipine gastrointestinal therapeutic system and long-acting propranolol in patients with mild to moderate systemic hypertension receiving diuretics: A preliminary experience

The efficacy and safety of nifedipine in a gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation was compared with long-acting propranolol in 49 patients with mild to moderate hypertension already receiving diuretics. Using a two-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 24) in doses of 30 mg, 60 mg, or 90 mg once daily; or long-acting propranolol (n = 25) in doses of 80, 160, or 240 mg once daily. Previous diuretic therapy was continued. Sitting and five-minute standing blood pressure and heart rate measurements were made 24 hours after dosing. At the endpoint of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p <0.001) in the sitting and standing positions. Nifedipine GITS was more effective in lowering standing systolic blood pressure than was propranolol (p <0.02). Propranolol caused a greater reduction in resting heart rate than did nifedipine GITS (p <0.003). Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension who are already receiving diuretics, may be more effective than sustained-release propranolol, and may be better tolerated than conventional nifedipine capsules.

To the Editor.—

In response to the article by Wachter in the March issue of theArchives,¹"Symptomatic Hypotension Induced by Nifedipine in the Acute Treatment of Severe Hypertension," the adverse effects noted are at variance with the results of studies conducted by Pfizer Pharmaceuticals, New York. To investigate the action of nifedipine capsules in the treatment of severe hypertension, we carefully monitored over 250 patients for at least four hours and showed no hypotensive "overshoot" (data on file, Pfizer Pharmaceuticals). Furthermore, as stated by the author, no significant hypotension has been noted in the over 400 patients with severe hypertension treated with nifedipine (some of whom comprise our patient population) described in the literature. Although this is not a US Food and Drug Administration—approved indication for nifedipine, the prior excellent results in this situation reflect careful titration with consideration to pharmacokinetics. As has been well documented and noted by the

Factors affecting the pharmacokinetics of nifedipine.

The plasma pharmacokinetics of nifedipine and the formation of its metabolites have been studied in volunteers under conditions which would affect the activity of the cytochrome P-450 system. The pharmacokinetics of a 10-mg capsule of nifedipine were not significantly different between smokers and non-smokers of similar age. After pretreatment with cimetidine, which inhibits the activity of cytochrome P-450, the peak plasma concentration and area under the plasma-time concentration curve for nifedipine were increased by a mean 84%. In contrast, pre-treatment with ranitidine which has little effect on cytochrome P-450, did not significantly alter nifedipine pharmacokinetics. Smoking does not contribute significantly to the variability in nifedipine pharmacokinetics. However, the interaction between nifedipine and cimetidine, but not ranitidine, may be of clinical importance.

Comparative Pharmacokinetics and Antihypertensive Effects of the Nifedipine Tablet and Capsule

The pharmacokinetics and antihypertensive effects of the nifedipine tablet and capsule have been examined in six male patients with diastolic pressure greater than 95 mm Hg despite metoprolol therapy. On two separate mornings, a 20 mg nifedipine tablet or 2 X 10 mg nifedipine capsules were administered with metoprolol 100 mg following a 12-h fast. Both capsule and tablet significantly reduced blood pressure (BP), with the maximum fall occurring at 45 min for the capsule and 4 h for the tablet. Two patients developed postural hypotension after the capsule and a third experienced flushing and palpitations. The maximum nifedipine plasma concentration after the capsule was 257 ng/ml compared with 50 ng/ml for the tablet, and the time of maximum concentration was significantly earlier for the capsule. Although the nifedipine capsule results in a fivefold higher maximum plasma concentration and is associated with a more rapid reduction in blood pressure than the tablet, its use may be limited by postural hypotension and other untoward symptoms.

Comparative Pharmacokinetics and Antihypertensive Effects of the Nifedipine Tablet and Capsule

Comparative Pharmacokinetics and Antihypertensive Effects of the Nifedipine Tablet and Capsule

Kinetics and dynamics of nifedipine after oral and sublingual doses

Nifedipine is frequently administered by the sublingual route to provide rapid onset of intense effect, especially in patients in whom urgent reduction of elevated blood pressure is indicated. Previously available data, however, suggest that peak levels of nifedipine are higher and occur earlier when the drug is administered orally. Results of pharmacodynamic studies show that maximal hypotensive effects occur between 30 and 60 minutes after administration by either route, but that such effects are often achieved earlier when the drug is given orally. Recent work implies that the absorption of nifedipine through the buccal mucosa is poor, if it occurs at all, and that the appearance of nifedipine in plasma requires delivery of the drug to the stomach for active absorption. The small time lag in absorption that may be attributed to the dissolution of the nifedipine capsule may be obviated by biting through the capsule and swallowing the contents; this bite-and-swallow approach to dosing provides the most rapid rise in plasma nifedipine concentrations, and produces peak levels well above those achieved with sublingual administration.

Rectal administration of perforated nifedipine capsules to maintain an effective level of longer duration

Masamichi Ishikawa, M.D., Naji Yokota, M.D., Akio Sawazaki, M.D., Shuji Kashiro, M.D., Shunkichi Hirata, M.D., Michio Okada, M.D., and Kyozo Ishikawa, M.D. Tokyo, Japan longitudinally with an l&gauge injection needle (Fig. 1). In both groups, the plasma level of nifedipine was measured at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after drug administration. The blood pressure and heart rate were monitored for 6 hours after drug administration. Based on the results obtained in the healthy volunteers, similar investigations were undertaken in the patients with angina pectoris. Each patient was given 10 mg nifedipine orally four times a day (after every meal plus at 9:00 P.M.). The plasma level of nifedipine was measured at 5:00 and 7:00 A.M. the next morning. In addition, under the same conditions, the nighttime dose was administered rectally instead of orally, and the plasma level of nifedipine was measured similarly. The plasma nifedipine levels were determined by gas chromatography using a non-radioactive electron capture detector (Yanaco G 2800-EN, Tokyo, Japan). The minimum detectable concentration was 0.5 rig/ml. Statistical analysis was performed by the paired t test. All values are expressed as the mean + 1 standard deviation.

Use of the calcium-channel blocker nifedipine in the management of hypertensive emergency.

Nifedipine, a well-tolerated calcium-channel blocking drug, is known to produce a rapid and vigorous vasodilating effect on the peripheral vasculature. In order to determine its effectiveness in rapidly treating moderately severe hypertension, nifedipine was administered buccally to 63 patients. Ten-milligram capsules, perforated ten times with a 26-gauge needle, were chewed by patients to expel the viscous drug within them. If one capsule was not sufficiently effective within 20 to 30 minutes, a second capsule was administered similarly. The drug was administered to 63 patients with diastolic blood pressure of 120 mm Hg or greater, or systolic blood pressure of 200 mm Hg or greater with a diastolic blood pressure in excess of 90 mm Hg. Forty-two patients responded to 10 mg of nifedipine, with a drop in blood pressure from a mean (+/- SD) of 205.5 +/- 24.4/127.7 +/- 11.7 mm Hg to 158.6 +/- 24.7/88.8 +/- 10 mm Hg in 39.9 +/- 13.0 minutes. Nineteen patients responded to two doses of nifedipine (20 mg), with a drop in blood pressure from 212.1 +/- 27.1/128.2 +/- 17.3 mm Hg to 165.4 +/- 24.5/93.8 +/- 10.7 mm Hg after 66.0 +/- 17.8 minutes. There were no side effects and no hypotension, even among the 38 patients who had recently received other medications, including beta blockers, diuretics, hydralazine, methyldopa, captopril, and clonidine. It is our conclusion that the chewing of nifedipine capsules is a safe and effective method to lower blood pressure promptly without the use of parenteral medications.

Chewing Nifedipine to Rapidly Treat Hypertension

Nifedipine, a calcium channel-blocking agent, was administered buccally to 63 patients who had a diastolic BP of 120 mm Hg or higher (51 patients) or a systolic BP of 200 mm Hg or higher (46 patients). Forty-two patients responded to one dose of 10 mg of nifedipine with a drop in BP from 205.5 +/- 24.4/127.7 +/- 11.7 (mean systolic BP +/- SD/mean diastolic BP +/- SD) to 158.6 +/- 24.7/88.8 +/- 10 mm Hg in 39.9 +/- 13.0 minutes (mean +/- SD). Nineteen patients responded to two doses of 10 mg of nifedipine with a drop in BP from 212.1 +/- 27.1/128.2 +/- 17.3 to 165.4 +/- 24.5/93.8 +/- 10.7 mm Hg after 66.0 +/- 17.8 minutes. There were no side effects and no hypotension even among the 38 patients who had recently received other medications. Chewing perforated nifedipine capsules is a safe and effective method to lower BP promptly without parenteral medications.

Nifedipine tablets for systemic hypertension: A study using continuous ambulatory intraarterial recording

The action of nifedipine tablets was examined in 17 patients with essential hypertension focusing particularly on the profile of blood pressure (BP) reduction over 24 hours resulting from both twice-daily and once-daily therapy (dose range 40 to 120 mg daily). This new formulation of nifedipine has a more prolonged and lower peak plasma level than an equivalent dose of nifedipine capsules. Our patients were fully ambulant and studied by continuous intraarterial recording techniques. BP responses during isometric and dynamic exercise testing were also observed. Within-patient comparisons of consecutive mean hourly systolic and diastolic BP showed a highly significant effect from twice-daily therapy (p < 0.001) for nearly the entire day. Also, significantly lower BP was maintained during isometric and dynamic exercise. Mean hourly heart rates were not significantly altered. The profile of action of the single morning dose was initially similar, but its efficacy diminished from 6 p.m. to 8 a.m. on the following day. Side effects were not unduly troublesome and did not cause any patient withdrawals. Four patients developed mild ankle edema. Two others had facial flushing.Nifedipine given twice daily in tablet form, therefore, is an effective antihypertensive drug capable of lowering BP consistently over 24 hours in ambulant patients and during formal exercise testing. We suggest that this agent may be useful as initial therapy for systemic hypertension, although the tablets are not as yet widely available.

Contrasting Effects of Nifedipine, Captopril, and Propranolol in Normotensive and Hypertensive Subjects

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.

Pathophysiological mechanisms in essential hypertension

As the number of antihypertensive agents increases, the choice of optimal therapy becomes more difficult. Certainly, hemodynamic derangements caused by the disease state as well as therapy must be considered. Patient convenience and quality of life are also issues that must be addressed. Preliminary experience suggests that the gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation of nifedipine is safe and efficacious in the treatment of hypertension. In 1 study, nifedipine GITS was compared with sustained-release propranolol in patients with mild to moderate hypertension already receiving diuretics. Using a 2-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 31) in doses of 30, 60 or 90 mg once daily, or sustained-release propranolol (n = 32) in doses of 80, 160 or 240 mg once daily. Previous diuretic therapy was continued. Sitting and 5-minute standing blood pressure and heart rate measurements were obtained 24 hours after dosing. At the end point of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p < 0.001) in the sitting and standing positions. Nifedipine GITS was more effective than sustained-release propranolol in reducing standing (p < 0.005) and sitting (p < 0.001) systolic blood pressure and sitting diastolic blood pressure (p < 0.02). Sustained-release propranolol caused a greater reduction in standing (p < 0.001) and sitting (p < 0.0006) resting heart rate than nifedipine GITS. Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension already receiving diuretics, and may be more effective than sustained-release propranolol and better tolerated than conventional nifedipine capsule treatment.