Nifedipine Capsules Research Articles

“Inappropriate” physician habits in prescribing oral nifedipine capsules in hospitalized patients

Despite the absence of an approved Food and Drug Administration (FDA) indication, the use of oral or "sublingual" nifedipine for hypertension in the hospitalized patient has become an increasingly common practice. The purpose of the study was to assess the clinical circumstances for which the drug was being prescribed and the practices of attending and resident physicians. Dosing of oral nifedipine capsules in medical and surgical inpatients was studied prospectively in three central Connecticut hospitals (University, community-teaching, and private nonteaching) during a 60-day period from January to March, 1994. Through evaluation of computerized pharmacy and medical records, data were collected on diagnostic reasons for ordering nifedipine, pre- and posttreatment blood pressures, dosing frequency, clinical documentation associated with drug prescription, and adverse events. Physicians and nurses at the respective hospitals were unaware of the conduct of the study. The incidence of nifedipine capsule administration at all three hospitals was 3.4% (152 dosings in 83 patients/4489 hospitalized patients/ 60 days). Practice habits and blood pressure changes differed minimally among hospitals and physicians. Sixty-three percent of nifedipine orders were given over the telephone for arbitrary and asymptomatic blood pressure elevations and 98% of the orders lacked bedside patient evaluation. Follow-up of the blood pressure was performed within 1 h in 51% of patients and within 2 h in 24%, while in 25% there was no documentation of follow-up until 2 to 6 h after nifedipine dosing. Mean pretreatment blood pressure was 186/94 +/- 20/16 mm Hg (range: 150 to 260 mm Hg systolic and 50 to 125 mm Hg diastolic). Blood pressure fell 32/16 +/- 22/16 mm Hg (range: -92 to +8 mm Hg systolic and -90 to +28 mm Hg diastolic) and was related to the level of pretreatment blood pressure (r = 0.53 for systolic blood pressure, and r = 0.49 for diastolic blood pressure, P < .001 for both). Large, asymptomatic blood pressure reductions were common. One hypertensive patient experienced severe hypotension accompanied by an anterior wall myocardial infarction. These data demonstrate inappropriate physician prescribing of oral nifedipine in hospitalized patients characterized by a lack of proper assessment prior to drug dosing, highly arbitrary treatment parameters that were written without regard for symptoms or underlying illnesses, and slow follow-up for evaluation of the clinical response to therapy.

Controversies concerning calcium antagonists

The paper discusses the controversial attitude regarding the safety of calcium channel blockers (CCBs), especially of the dihydropyridine nifedipine, induced through several meta-analyses of studies with CCBs by Dr. Furberg et al.; as a result, a detrimental effect of CCBs, especially during acute myocardial infarction, has been claimed. Several independent re-analyses of the 16 studies, all performed in the 1980s and mainly using the short-acting nifedipine capsule, did not confirm Furberg's results and showed an insignificant mortality difference between patients on CCBs versus those on control. Nevertheless, new safety studies applying long-acting CCBs (half-lives of 1 or more days) combined with efficacy assessments are necessary, both in hypertension as well as coronary artery disease, to finally clear up this important question.

Nifedipine in Ischemic Heart Disease

Until the 1980s, Prinzmetal’s variant angina was difficult to treat—nitrates and β-blockers usually did not control symptoms or signs of ischemia. In 1980, Antman et al1 reported the first clinical experience in the United States of the use of nifedipine in patients with Prinzmetal’s angina. They used nifedipine capsules to treat 127 patients with Prinzmetal’s angina, which reduced the weekly occurrences of angina from 16 to 2, reduced nitroglycerin requirements, completely controlled angina in 63% of patients, and reduced the frequency of angina by at least 50% in 87% of cases. Since that time, a number of trials with different calcium channel blockers, including nifedipine, diltiazem, verapamil, amlodipine, and others, have consistently shown that these agents are efficacious in reducing the morbidity of Prinzmetal’s variant angina.2 Additional studies showed that calcium channel blockers, including nifedipine, were effective in patients with chronic stable angina pectoris3 ; they not only reduced symptoms but also reduced objective evidence of ischemia on exercise treadmill tests,4 5 reduced ST-segment changes on ambulatory ECG monitoring,6 increased coronary artery blood flow,7 8 9 and improved ventricular dysfunction associated with ischemia.10 Numerous studies showed that the calcium channel blockers were effective as antihypertensive agents and lacked many of the side effects of diuretics and β-blockers.11 Of course, all drugs have limits, and not all cardiovascular drugs are appropriate for all cardiovascular situations. Calcium channel blockers are no exception. In 1984, Muller et al11 showed for the first time that nifedipine capsules did not reduce the size of myocardial infarction (MI) and did not prevent patients with threatened MIs from infarcting. Patients who received nifedipine capsules in the setting of myocardial infarction had a higher 2-week mortality (7.5%) versus placebo (2.3%) but 6-month mortality was similar between nifedipine-treated (10.8%) and …

Nifedipine and Mortality

When an approved treatment is considered for an unapproved indication, the physician must evaluate the safety of the medication, its value in related conditions, and the individual patient. What is asked is that he make a prudent decision based upon full knowledge of the available evidence.”1 Furberg and his colleagues2 entitle their article “Nifedipine: Dose-Related Increase in Mortality in Patients With Coronary Heart Disease.” They provide a valuable service by making us think more carefully about the benefit/risk ratio of the calcium antagonists as a group. However, by touting calcium antagonists as being unsafe and possibly lethal, they also create a great deal of uncertainty and anxiety among physicians and patients. We feel that they overstate their case. The following is an attempt to show that (1) the allegations focus on short-acting nifedipine, so that even if correct, they cannot be applied to other calcium antagonists; (2) the accusation of a dose-related increase in mortality rests on a biased selection of data chosen for the meta-analysis; and (3) several of the mechanisms suggested for the proposed adverse effects are unlikely. Finally, we shall argue that pharmaceutical companies have been remiss in not obtaining outcome studies for short-acting nifedipine and for other calcium antagonists, especially in the case of ischemic heart disease. Several aspects of the Furberg paper suggest that calcium antagonists in general are accused; for example, the statement that “the literature reviews strongly suggest that the problem may go beyond short-acting nifedipine. Troubling and major adverse cardiovascular events have been linked to other calcium antagonists, primarily dihydropyridines.” It should be clearly and unequivocally stated that Furberg et al2 provide no evidence whatsoever for any adverse effect on mortality or morbidity for any other agent, with one important exception. That exception is nimodipine, approved for use in …

In vitro dissolution studies on nifedipine capsules

The in vitro dissolution rates of 5 and 10 mg nifedipine capsules from eight suppliers were measured in simulated gastric fluid using the rotating paddle apparatus. A total of fourteen products were tested and the performance was found to be satisfactory for all products (> 80% dissolution in 20 min).

A comparison between the haemodynamic effects of oral nifedipine and intravenous dihydralazine in patients with severe pre-eclampsia

To compare the effects of a single oral dose of nifedipine with those of intravenous dihydralazine on central haemodynamics in pregnant women with severe pre-eclampsia. A prospective comparative study. The High Risk Obstetric Unit, University Hospital Rotterdam Dijkzigt, Rotterdam. Twenty patients with severe pre-eclampsia between 27 and 35 weeks gestation with normal cardiac filling pressures and without fetal distress. A pulmonary artery thermodilution catheter and a radial artery line were placed. Ten patients chewed a 10-mg capsule of nifedipine and 10 patients received dihydralazine by intravenous infusion at a rate of 1-3 mg/h. Arterial pressures, heart rate, cardiac output and pulmonary capillary wedge pressure were determined before and after drug administration. Fetal condition was continuously monitored by cardiotocography. The reduction in arterial blood pressure obtained with both drugs was similar, and was associated with a similar rise in heart rate and cardiac output and a similar reduction in systemic vascular resistance. Pulmonary capillary wedge pressures decreased significantly less with nifedipine than with dihydralazine. Signs of fetal distress occurred in none of the nifedipine-treated patients, but in five of the patients treated with dihydralazine. From the haemodynamic viewpoint nifedipine seems to be a useful agent in the treatment of hypertensive emergencies in pregnancy.

G16 - Inappropriate physician prescribing habits of oral nifedipine capsules in hospitalized patients

G16 - Inappropriate physician prescribing habits of oral nifedipine capsules in hospitalized patients

The influence of dose and ethnic origins on the pharmacokinetics of nifedipine.

The pharmacokinetics of nifedipine capsules was investigated in healthy young Caucasian and South Asian subjects. Both the area under the plasma concentration-time curve (AUC) and terminal half-life of nifedipine were significantly higher in South Asians compared with Caucasian subjects after single oral doses of 10 and 20 mg. The AUC and half-life values of the nitropyridine metabolite were also higher in South Asians than in Caucasian subjects. The serum protein binding of nifedipine was similar in the two groups. The pharmacokinetics were essentially linear in both Caucasian subjects (0 to 30 mg; n = 27) and South Asians (0 to 20 mg; n = 16). There was no indication of a separate subgroup of Caucasian subjects with high AUC values equivalent to the poor metabolizers reported previously. Pharmacodynamic modeling for South Asians gave estimates comparable to those previously reported in Caucasian subjects. Patients of South Asian origin may require lower doses of nifedipine.

Evaluation of calcium-antagonist (Nifedipine) in the treatment of pre-eclampsia

The therapeutic effect of the calcium antagonist; Nifedipine was assessed in 30 patients with pre-eclampsia. Cases were randomly allocated into two groups; a study group (n = 20) who received Nifedipine capsules (20 mg every 8 h for 7 days) and a control group (n = 10) who received placebo capsules with the same regimen. After Nifedipine administration, there was a significant decrease in blood pressure, serum urea and creatinine and 24 h urinary proteins. No significant difference was found in FHR and S/D ratio of the umbilical artery between study and control groups or between initial values and after Nifedipine administration. Preliminary results indicated that Nifedipine decreased blood pressure and improved kidney functions without affecting the umbilical artery blood flow in cases of pre-eclampsia.

カルシウムきっ抗薬の血中濃度および降圧効果に及ぼす食事の影響

Food ingestion does not affect the bioavailability of the nifedipine capsule, a calcium channel antagonist, but delays its absorption rate in healthy subjects. On the other hand, in two different sustained-release preparations of nifedipine, both the bioavailability and anti-hypertensive efficacy in one of them increases, whereas the other is not so much affected by meals. Furthermore, the food induces a reduction in the bioavailability of nicardipine sustained-release preparation, while those of nisordipine, benidipine and manidipine increase conversely.Such a change in the bioavailability based on food intake may influence the anti-hypertensive efficacy after the initial dosing of the medicine but not so after multiple dosing.In each medicine or dosage form, there are some differences in the change in the blood level and anti-hypertensive efficacy brought on by food ingestion among the drugs. In general, however, in order to improve patient compliance, we recommend that calcium channel antagonists should be taken after meals following the directions given for this medication.

A comparison of the acute hypotensive effects of two different doses of nifedipine

To determine whether a dose of 5 mg of nifedipine would be useful in the treatment of hypertensive emergencies, we compared the acute hypotensive effects of two different doses of nifedipine, 5 mg and 10 mg, in patients with severe hypertension. In this prospective, randomized, double-blind study, 30 consecutive black patients with diastolic blood pressure that was equal to or greater than 115 mm Hg received either a 5 mg or 10 mg nifedipine capsule and a placebo capsule, which matched that of the alternative strength. Patients were asked to bite the capsules and swallow the contents. Blood pressure response over 4 hours and adverse effects were monitored. Mean systolic blood pressure was reduced from 191.7 mm Hg (95% confidence interval 170.8 to 212.7 mm Hg) to 157.9 mm Hg (137.0 to 178.9 mm Hg) and 206.1 mm Hg (185.1 to 227.0 mm Hg) to 153.7 mm Hg (132.8 to 174.7 mm Hg) in patients who were given 5 mg and 10 mg doses of nifedipine, respectively. Mean diastolic blood pressure in the group of patients that reveived 5 mg doses of nifedipine decreased from 128.2 mm Hg (115.6 to 140.7 mm Hg) to 105.2 mm Hg (92.7 to 117.7 mm Hg); the corresponding values in the group that received 10 mg doses of nifedipine were 129.9 mm Hg (117.4 to 142.5 mm Hg) and 97.5 mm Hg (85.0 to 110.1 mm Hg), respectively. The minimum mean systolic blood pressures occurred 20 and 25 minutes after administration of the 5 mg and 10 mg capsules, respectively; the minimum diastolic blood pressures were reached after 20 and 30 minutes, respectively. The mean basal and maximal post-treatment heart rates in patients who were given the 5 mg and 10 mg capsules were 65.5 beats/min (95% confidence intervals; 56.6 to 74.3 beats/min) and 71.6 beats/min (62.7 to 80.5 beats/min), and 66.5 beats/min (57.7 to 75.4 beats/min) and 72 beats/min (63 to 80 beats/min), respectively. One patient who had fallen asleep between blood pressure measurements woke up restless and mildly agitated 25 minutes after he had been given 10 mg of nifedipine; he settled down after reassurance was provided. There were no other adverse effects. These data indicate that both the 5 mg and the 10 mg doses of nifedipine, which were given in capsule form by the bite and swallow method, would be useful in the treatment of hypertensive emergencies. To avoid profound hypotension, it is advisable to use the lower dose (i.e., 5 mg of nifedipine). If a satisfactory response is not obtained, the dose may be repeated when the blood pressure has reached its nadir (usually within an hour). Thereafter, maintenance antihypertensive therapy will be needed and should be started 2 hours after patients have received 5 mg of nifedipine and 4 hours after they have received 10 mg of nifedipine.

Sublingual Captopril and Nifedipine in Immediate Treatment of Hypertensive Emergencies-Reply

In Reply.— We thank Hasdai for his comments on our article1in theArCHIVES. He raised some criticisms about the sublingual administration of the drugs used in our study on the basis of both pharmacokinetic and pharmacodynamic observations on the chosen drugs and about the guidelines of treatment of hypertensive emergencies. As far as sublingual nifedipine dosage is concerned, we agree that sublingual or buccal absorption of nifedipine is uncertain and that it is small. But, it is really difficult to squeeze a perforated capsule of nifedipine under the tongue without swallowing saliva. We think that the dissolution of the nifedipine capsule in the mouth and swallowing of the content is the critical factor in providing a more rapid rise in plasma nifedipine concentration compared with standard oral administration. Thus, we find it to be more correct to say drug dissolved sublingually than absorbed sublingually, in accordance with other

Captopril, Nifedipine and Their Combination for Therapy of Hypertensive Urgencies

Abstract Twenty patients with acute severe hypertension were randomised to therapy with either nifedipine capsules (10 mg) or captopril tablets (25 mg) given sublingually and the blood pressure recorded for 240 minutes. Oral monotherapy with either agent followed for 3 weeks, then the agents were combined for a further 2 weeks and in the final 6 weeks of the trial a beta-blocker and diuretic were added, if needed. Thirteen patients completed the trial. The major results were: (i) nifedipine decreased blood pressure more rapidly than captopril 60 minutes after first ingestion but at 240 minutes equal degrees of fall in blood pressure had been obtained; (ii) neither agent given as sustained monotherapy was able to reduce blood pressure adequately, although nifedipine was better than captopril; and (iii) combination therapy with both agents was conspicuously successful in achieving reduction in blood pressure. It is suggested that combination nifedipine-captopril therapy be subject to a formal trial for early therapy in acute severe hypertension.

Central effects of the calcium antagonist, nifedipine.

1. Central effects of the calcium antagonist, nifedipine retard (10, 20 and 40 mg) and nifedipine capsules (10 mg) were studied in 14 healthy male subjects. Two placebos and an active control drug, oxazepam (15 mg), were included. Medication was administered double-blind at 10.00 h. The effects of drugs on performance and subjective feelings were assessed before and from 1.5-2.5 h and 3.5-4.5 h after ingestion, and recordings of the electrical activity of the brain (EEG) and body sway carried out. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, together with critical flicker fusion and two flash fusion. The EEG was recorded with eyes open while the subjects carried out a mental arithmetic task, and with eyes closed, when they were required to relax. Body sway was recorded with eyes open and with eyes closed. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. 3. Nifedipine did not alter performance levels on any of the skills tested, while oxazepam (15 mg) increased the number of errors (P less than 0.01) and reduced accuracy at continuous attention (P less than 0.01). 4. Nifedipine (10 mg) reduced total power of the EEG in the frequency range (0.5-30 Hz), and nifedipine (20 mg) increased total alpha power (7.5-13 Hz) (P less than 0.05). Oxazepam reduced alpha and increased beta 1 power (13.5-21 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the antianginal effect of nifedipine: influence of formulation dependent pharmacokinetics

Nifedipine capsules t.d.s. and an extended release formulation of nifedipine, nifedipine-ER tablets, given once daily in corresponding daily doses, have been compared with placebo in a double-blind, three-way cross-over study in 24 patients with stable angina pectoris. The objective was to study the influence on the antianginal effect of the different pharmacokinetics of several preparations of nifedipine. All patients received concomitant treatment with beta-adrenoceptor blockers. Antianginal efficacy was assessed by a dynamic exercise test at the end of the dosage intervals, i.e. 8 and 24 h after nifedipine capsules and nifedipine-ER, respectively, as well as 6 h after dosing. Six h after dosing the time of onset of chest pain and total exercise time were longer and total work was significantly higher during both nifedipine-ER (plasma concentration 260 nmol/l) and placebo treatment than after nifedipine capsules (plasma concentration 78 nmol/l). Time to 1 mm ST depression was longer during nifedipine-ER than during nifedipine capsule treatment. No significant difference was seen between nifedipine-ER and placebo. At the end of the dosage interval (24 and 8 h after nifedipine-ER and nifedipine capsules, respectively), no significant difference was found between nifedipine-ER (plasma concentration 75 nmol/l) and the other two treatments. However, placebo was superior to nifedipine capsules (plasma concentration 58 nmol/l) both in the time to onset of chest pain and total exercise time. The lack of effect at the end of the dosage interval was probably due to the subtherapeutic plasma nifedipine level.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of short- and long-term administration of nifedipine on serum lipoprotein metabolism in patients with mild hypertension

The effects of short- and long-term administration of nifedipine on serum lipids, lipoproteins, and apolipoproteins (apo) were studied. Administration of nifedipine capsule for 4 months significantly decreased triglycerides and increased the HDL2 cholesterol and the HDL2/HDL3 cholesterol ratio. No significant changes in serum lipids and lipoproteins were observed during short-term therapy with slow-release nifedipine tablets. Following administration of tablets for 24 months, the LDL/HDL cholesterol ratio, apo B, and apo B/apo A-I ratio increased at 12 months, but reverted to baseline values at 24 months. Apo E levels were decreased significantly at 24 months. No significant changes were noted in total cholesterol, triglyceride, HDL cholesterol, HDL2,3 cholesterol, apo A-I, apo A-II, apo C-II, or apo C-III levels during long-term therapy with slow-release nifedipine tablets. These results indicate that nifedipine has a neutral or even favorable effect on lipoprotein metabolism. However, a prospective well-controlled study would be required to finally establish this effect. This finding strengthens the indications for using nifedipine as a first-line drug in the long-term treatment of hypertension.

Oral Nifedipine in the Treatment of Hypertensive Urgency: Cerebrovascular Accident Following a Single Dose

To the Editor .—Jaker and coworkers 1 have confirmed earlier studies showing that a single 10-mg dose of oral nifedipine is effective and safe for the treatment of hypertensive urgency. However, there are recent reports of complications related to this treatment: cerebral ischemia 2 or retinal ischemia 3 occurring in the absence of hypotension, severe hypotension following repeated doses given over a short time interval, 4 and hypotension following a single oral dose of nifedipine. 5 While these complications represent the exception to the currently safe use of nifedipine, caution is recommended in the treatment of hypertensive urgency, particularly in the elderly and those with coronary or cerebrovascular disease. 1 We present the case of a young hypertensive man with no history of cerebrovascular disease, who had, on two occasions, ischemic strokes coincident with the use of a single 10-mg capsule of nifedipine. Report of a Case .—A 44-year-old white

Nisoldipine tablets once daily versus nifedipine capsules three times daily in patients with stable effort angina pectoris pretreated with atenolol

Treatment with nisoldipine (2 x 10 mg tablets once daily) and nifedipine (2 x 10 mg capsules three times daily) in patients with severe, but stable effort angina pretreated with atenolol (100 mg once daily in 19 patients and 50 mg once daily in one patient) were compared for their effects on bicycle exercise tolerance and their adverse effects in a randomized 2 x 4 week, double-blind, double-dummy crossover study. All patients had multivessel disease, 16 patients had occlusion of at least one vessel, and eight patients had a history of myocardial infarction. Two patients left the study during the initial nisoldipine period, one because of aggravation of the angina and the other because of suspected allergic reaction. Addition of nifedipine to atenolol treatment significantly improved the variables measured for severity of angina, such as time of exercise until 1 mm and 2 mm ST-segment depression, total exercise time and total workload. In contrast, no such improvement was noted after the addition of nisoldipine to atenolol. However, nisoldipine resulted in a significant prolongation of the time to the initiation of chest discomfort, the maximum heart rate, and the double product. In atenolol-treated patients with severe effort angina pectoris, nifedipine 20 mg tid improved exercise capacity, while nisoldipine 20 mg once daily did not have a similar effect.

Evaluation of five procedures for measuring nonstandard doses of nifedipine liquid

Five methods for removing the maximum volume of liquid from a nifedipine capsule were evaluated for efficiency and reproducibility, and the concentration of nifedipine in Procardia and Adalat 10- and 20-mg capsules was determined The methods evaluated were the needle puncture and squeeze method; the scissors method; the needle and syringe, one-hole method; the needle and syringe, two-hole method; and the capsule in syringe barrel method. The liquid content of 10 Adalat 10-mg capsules was removed by each method, the volume was determined by the weight and specific gravity of the nifedipine liquid, and the mean volumes of nifedipine liquid were compared. A stepwise procedure for using the needle and syringe, one-hole method was developed. The mean nifedipine concentration in Procardia 10- and 20-mg capsules was determined by ultraviolet spectrophotometry by using 30 capsules of each brand and strength. The needle and syringe methods were the most reproducible and efficient procedures for obtaining a desired milligram dosage of nifedipine from the capsules. The two-hole method would be less practical in the clinical setting, however, because it is time consuming and cumbersome. The mean assayed nifedipine concentration in the Procardia and Adalat 10- and 20-mg capsules was within 10% of the concentration reported by the manufacturer for each specific product lot number. Based on reproducibility and efficiency, the needle and syringe methods are the best methods for quantitation of liquid nifedipine doses for patient administration.

The nifedipine gastrointestinal therapeutic system in the treatment of 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.