Nifedipine. Precautions. Interactions
Precautions
Nifedipine should be used with caution in patients with hypotension, in patients whose cardiac reserve is poor, and in those with heart failure since deterioration of heart failure has been noted. Nifedipine should not be used in cardiogenic shock, in patients who have suffered a myocardial infarction in the previous 2 to 4 weeks, or in acute unstable angina. Nifedipine should not be used to treat an anginal attack in chronic stable angina. In patients with severe aortic stenosis nifedipine may increase the risk of developing heart failure. Sudden withdrawal of nifedipine might be associated with an exacerbation of angina. The dose may need to be reduced in patients with hepatic impairment. Nifedipine should be stopped in patients who experience ischaemic pain after use.
Nifedipine is reported to be teratogenic in animals and may inhibit labour, but it has been used in hypertension in pregnancy (see Hypertension, under Uses and Administration, below).
Breastfeeding. Nifedipine is distributed into breast milk but the amount present is probably too small to be harmful. There have been no reports of any clinical effects in breast-fed infants whose mothers were receiving nifedipine and the American Academy of Pediatrics therefore considers that it is usually compatible with breast feeding.
Diabetes mellitus. Nifedipine may modify insulin and glucose responses (see Effects on Carbohydrate Metabolism under Adverse Effects, above) calling for adjustments in antidiabetic therapy. Also some studies have suggested that nifedipine may worsen proteinuria and renal dysfunction in diabetic patients with some degree of renal insufficiency, but other studies, (see Kidney Disorders under Uses and Administration, below), have suggested that nifedipine may have a beneficial effect on proteinuria.
Some studies have suggested that patients with diabetes mellitus or impaired glucose metabolism may be more susceptible to adverse cardiovascular effects of calcium-channel blockers. The calcium-channel blockers used in these studies were nisoldipine, amlodipine, and isradipine (long-acting or intermediate-acting calcium-channel blockers). However, two of the studies compared the calcium-channel blocker with an ACE inhibitor and it has been suggested that ACE inhibitors may have a protective effect in patients with diabetes that is additional to their antihypertensive action. Thus, ACE inhibitors may be particularly beneficial in these patients rather than calcium-channel blockers being particularly harmful.
Interference with laboratory estimations. Nifedipine may give falsely elevated spectrophotometric values of urinary vanillylmandelic acid; HPTC estimations are unaffected.
Porphyria. Nifedipine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.
Withdrawal. Sudden withdrawal of nifedipine might be associated with an exacerbation of angina.
For a report of life-threatening coronary vasospasm occurring after withdrawal of nifedipine before a revascularisation procedure, see under Effects on the Heart, in Diltiazem.
Interactions
Nifedipine may enhance the antihypertensive effects of other antihypertensive drugs such as beta blockers although the combination is generally well tolerated. Enhanced antihypertensive effects may also be seen if used with drugs such as aldesleukin and antipsychotics that cause hypotension. Nifedipine may modify insulin and glucose responses (see Effects on Carbohydrate Metabolism, above) and therefore diabetic patients may need to adjust their antidiabetic treatment when receiving nifedipine. Nifedipine is extensively metabolised in the liver by the cytochrome P450 isoenzyme CYP3 A4, and interactions may occur with other drugs, such as quinidine, sharing the same metabolic pathway, and with enzyme inducers, such as car-bamazepine, phenytoin, and rifampicin, and enzyme inhibitors, such as cimetidine, erythromycin, and HIV-protease inhibitors.
Alcohol. A study involving 10 healthy subjects showed that the area under the concentration-time profile for nifedipine 20 mg was increased by 54% when taken orally with alcohol, and maximum pulse rate was achieved more rapidly, which was in line with animal and in-vitro studies suggesting that the metabolism of nifedipine is inhibited by alcohol.
Antiarrhythmics. Nifedipine and quinidine probably have a common metabolic pathway in the liver and might be expected to interact if given concurrently. In one study, quinidine appeared to inhibit nifedipine metabolism resulting in increased serum concentrations of nifedipine; quinidine concentrations were unchanged. However, conflicting effects on serum-quinidine concentrations have been reported.
Antibacterials. The macrolide antibacterials are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may inhibit the metabolism of calcium-channel blockers. Two days after clarithromycin was started, vasodilatory shock and heart block occurred in a 77-year-old man whose antihypertensive medication included nifedipine. Clarithromycin was continued and when his condition improved nifedipine was reintroduced at half the previous dose; his blood pressure was stable on discharge.
Antidiabetics. See Diabetes Mellitus under Precautions and Effects on Carbohydrate Metabolism under Adverse Effects, above.
Antiepileptics. The effects of dihydropyridine calcium-channel blockers may be reduced by enzyme-inducing antiepileptics such as carbamazepine, phenobarbital, and phenytoin. In contrast, sodium valproate has been reported to increase plasma-nimodipine concentrations.
For reports of an interaction between dihydropyridines and phenytoin resulting in raised serum-phenytoin concentration.
Antifungals. Azole antifungals inhibitthe cytochrome P450 enzyme system and may therefore interfere with metabolism of calcium-channel blockers. Two women who had been taking felodipine for about a year developed peripheral oedema a few days after starting treatment with itraconazole Plasma-felodipine concentrations were measured in one of the women before and during a subsequent course of itraconazole and increased considerably when the two drugs were used together. A similar interaction occurred when itraconazole therapy was started in a patient already taking nifedipine. Potentiation of the effects of nifedipine by fluconazole has also been reported.
Antihistamines. Severe angina developed in a patient stabilised on nifedipine who took terfenadine 60 mg for seasonal allergy. The pain resolved within an hour or two.
Anti neoplasties. For reports of increased vincristine toxicity in children also receiving itraconazole and nifedipine concomitantly, see Antifungals under Interactions of Vincristine.
Antivirals. The HIV-protease inhibitors are known to inhibit the cytochrome P450 isoenzyme CYP3A4 and may therefore interfere with the metabolism of calcium-channel blockers. A woman stable on felodipine developed oedema in both legs when she was given nelfinavir after a needle-stick injury. The oedema resolved on withdrawal of felodipine, and was attributed to inhibition of felodipine metabolism. A study in healthy subjects found that indinavir plus ritonavir increased exposure to both am-lodipine and diltiazem.
Beta blockers. Although nifedipine is often used with beta blockers without untoward effects, heart failure has been reported in a few patients with angina who were given nifedipine and abetablocker. Severe hypotension has been reported in 1 of 15 angina patients given nifedipine and atenolol; withdrawal of the beta blocker precipitated severe unstable angina in this patient. Severe hypotension in a patient was attributed to the use of nifedipine with propranolol, and was thought to have contributed to fatal myocardial infarction.
Calcium-channel blockers. Plasma concentrations of nifedipine were increased in a study in 6 healthy subjects when pre-treated with diltiazem; the elimination half-life of nifedipine was prolonged from 2.54 hours to 3.40 hours after pretreatment with diltiazem 30 mg daily and to 3.47 hours after 90 mg daily. The effect was probably due to reduced hepatic metabolism of nifedipine. Nifedipine and diltiazem are reported to be metabolised by the same hepatic enzyme and, conversely, pretreatment with nifedipine has resulted in increased concentrations of diltiazem.
Digoxin. For the effect of nifedipine and other dihydropyridine calcium-channel blockers on digoxin.
Grapefruit juice. Grapefruit juice inhibits the cytochrome P450 isoenzyme C YP3A4, particularly in the intestinal wall, and has been shown to increase markedly the bioavailability of oral calcium-channel blockers; calcium-channel blockers given intravenously appear to be unaffected. The interaction may be less significant with calcium-channel blockers such as amlodipine that have a higher bioavailability, but most calcium-channel blockers should not be taken orally at the same time as grapefruit juice. A stereoselective effect has also been reported.
Histamine H2-antagonists. Pharmacokinetic studies have indicated that use of nifedipine with cimetidine can increase the bioavailability of nifedipine. An increase in the area under the plasma concentration-time curve of between 77 and 92% has been reported. Potentiation of the hypotensive effect of nifedipine by cimetidine was also shown in 7 hypertensive patients. The mechanism of the interaction was thought to be due to inhibition of the cytochrome P450 system by cimetidine and thus inhibition of the metabolism of nifedipine.
Ranitidine was found to have little effect on the pharmacokinetics of nifedipine, although there was an increase in the bioavailability of nifedipine during use of ranitidine. Famotidine has been reported not to interact with nifedipine.
Immunosuppressants. Flushing, paraesthesias, and rashes were reported in 2 patients given nifedipine 40 mg daily while taking ciclosporin for psoriasis. A study in 8 psoriatic patients indicated that giving nifedipine with ciclosporin resulted in reduced recovery of the principal metabolite of nifedipine, presumably because ciclosporin reduced nifedipine metabolism through competition for the cytochrome P450 metabolising enzymes. For reference to the effects of calcium-channel blockers on ciclosporin concentrations in blood. For the possible protective effect of nifedipine against ciclosporin-induced nephrotoxicity, see Transplantation under Uses and Administration, below.
Magnesium salts. Profound hypotension has been reported in 2 women in whom a single oral dose of nifedipine 10 mg was added to treatment with magnesium sulfate infusion for pre-eclampsia; both women were also receiving methyldopa. Neuromuscular blockade has been reported in 2 women after use of nifedipine with intravenous magnesium sulfate. In one woman receiving nifedipine as a tocolytic, symptoms of neuromuscular blockade occurred immediately on injection of magnesium sulfate and resolved within 25 minutes of stopping the injection. In another woman who was receiving a magnesium sulfate infusion for pre-eclampsia, symptoms developed 30 minutes after the second of 2 doses of nifedipine had been given and improved after receiving calcium gluconate injection.
Melatonin. Melatonin may cause a reduction in blood pressure and might be expected to have additive effects if given with antihypertensives. However, in a study in hypertensive patients taking nifedipine, giving melatonin led to an increase in both blood pressure and heart rate.
Tobacco. In a study of the effects of cigarette smoking and the treatment of angina with nifedipine, propranolol, or atenolol, smoking was shown to have direct and adverse effects on the heart and to interfere with the efficacy of all 3 anti-anginal drugs, with nifedipine being the most affected.
Xanthines. For the effect of nifedipine on theophylline.
Pharmacokinetics
Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract, but undergoes extensive hepatic first-pass metabolism. Bioavailability of oral liquid-filled capsules is between 45 and 75%, but is lower for longer-acting formulations. Peak blood concentrations are reported to occur 30 minutes after oral doses of liquid-filled capsules. Nifedipine is about 92 to 98% bound to plasma proteins. It is distributed into breast milk. It is extensively metabolised in the liver and 70 to 80% of a dose is excreted in the urine almost entirely as inactive metabolites. The half-life is about 2 hours after intravenous doses or oral liquid-filled capsules.
The pharmacokinetics of nifedipine have been reviewed. Studies have been complicated by the difficulty in preparing a stable intravenous formulation and the problems in developing a sufficiently sensitive and specific method of analysis. Nearly 100% of an oral dose of nifedipine is absorbed in the small intestine although the bioavailability from capsules is 45 to 68%. The rate of absorption from both oral and sublingual capsules varies widely among individuals: there has been a report that high plasma-nifedipine concentrations are achieved more rapidly if the capsule is bitten and swallowed than from standard oral and sub-lingual administration (but this is no longer recommended — see Hypertension, below). The absorption of nifedipine from tablets is slower than from capsules, with maximum plasma concentrations occurring at 1.6 to 4.2 hours compared with 0.5 to 2.17 hours, and absorption may still be occurring at 24 to 32 hours after a dose.
Nifedipine undergoes almost complete hepatic oxidation to 3 pharmacologically inactive metabolites which are excreted in the urine. It has been reported that after oral doses 30 to 40% of the amount absorbed is metabolised during the first pass through the liver. The elimination half-life of nifedipine is apparently dependent upon the dosage form in which it is given, with half-lives of 6 to 11 hours, 2 to 3.4 hours, and 1.3 to 1.8 hours measured after oral tablet, oral capsule, and intravenous doses respectively. The total systemic clearance of nifedipine from plasma ranges from 27 to about 66 litres/hour. Renal impairment does not substantially alter nifedipine pharmacokinetics.
Absorption. Although studies have indicated that the absorption of nifedipine may be affected by food the results appear to vary depending upon the preparation used. A reduction in peak plasma-nifedipine concentrations, and a delay in achieving them, was reported when nifedipine capsules were given after a meal compared with 30 minutes before. In contrast, the bioavailabihty and maximum serum concentrations of nifedipine were markedly increased when a modified-release tablet (Adalat L) was given after a meal rather than fasting, although another modified-release tablet (Slofedipine) showed delayed absorption when given after food. A further tablet formulation (Adalat OROS) was unaffected by food, while a modified-release capsule containing uncoated and enteric-coated granules (Sepamit R) was reported to have essentially the same bioavailabihty when taken before or after a meal.
Hepatic impairment. The pharmacokinetics of nifedipine were found to be considerably altered in 7 patients with liver cirrhosis. Systemic plasma clearance was substantially reduced and the elimination half-life was considerably longer than in healthy subjects. In addition, systemic availability of oral nifedipine was much higher in patients with cirrhosis and was complete in 3 patients with surgical portacaval shunt. Patients with liver cirrhosis seemed to be more sensitive to the effects of nifedipine on diastolic blood pressure and heart rate, and this could be explained by the higher free drug concentrations observed. It was concluded that lower doses of nifedipine may be required in patients with liver cirrhosis, and the patient’s response should be closely monitored.
Interindividual variation. A study in 53 Dutch subjects found a bimodal distribution of plasma concentrations of nifedipine after a single oral dose; it was proposed that the higher plasma concentrations in 17% of subjects represented a slow metaboliser phenotype, with the majority of the population being fast metabolisers. Although further studies in European populations have not confirmed these results, a study in 12 Mexican subjects supported the concept of polymorphic metabolism, with 5 fast and 7 slow metabolisers, a much higher proportion of slow metabolisers than in the European studies Studies have also reported a markedly increased area under the concentration-time curve in South Asian, Mexican, and Nigerian subjects compared with Caucasians. The difference did not appear to be due to diet. The initial dose of nifedipine might need to be lower in these ethnic groups. Another population study found that clearance was slower in blacks compared with whites, and in men compared with women; alcohol ingestion and smoking both also reduced nifedipine clearance.
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