Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: Bayer New Zealand Limited, 3 Argus Place, Hillcrest, North Shore, Auckland 0627 Free Phone 0800 233 988 www.bayer.co.nz
Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effect, dihydropyridine derivatives
ATC code: C08CA05
Nifedipine is a calcium antagonist of the 1, 4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels.
In the heart, nifedipine dilates the coronary arteries, especially the large conductance vessels, even in the free wall segment of partially stenosed areas. Further, nifedipine reduces the vascular smooth muscle tone in the coronary arteries and prevents vasospasm. The end result is an increased poststenotic blood flow and an increased oxygen supply. Parallel to this, nifedipine reduces the oxygen requirement by lowering peripheral resistance (afterload). With long-term use, nifedipine can also prevent the development of new atherosclerotic lesions in the coronary arteries.
Nifedipine reduces the smooth muscle tone of the arterioles, thus lowering the increased peripheral resistance and consequently the blood pressure. At the beginning of the nifedipine treatment there may be a transient reflex increase in heart rate and thus in the cardiac output. However, this increase is not enough to compensate for the vasodilation. In addition, nifedipine increases sodium and water excretion both in the short-term and long-term use. The blood-pressure-lowering effect of nifedipine is particularly pronounced in hypertensive patients.
In Raynaud’s syndrome, nifedipine can prevent or reduce the occurring digital vasospasm.
After oral administration, nifedipine is rapidly and almost completely absorbed. The systemic availability of orally administered nifedipine is 45 to 56% owing to a first pass effect. Maximum plasma and serum concentrations are reached at 1.5 to 4.2 hours with ADALAT 10 and ADALAT 20. Simultaneous food intake leads to delayed, but not reduced absorption.
Two ADALAT 10 tablets were shown to be bioequivalent to one ADALAT 20 tablet.
Table 2 shows the peak plasma concentrations (cmax) of ADALAT 20 and the corresponding times (tmax).
Table 2. Peak plasma concentrations and the time to reach peak plasma concentrations:
| Dose | cmax (mg/L) | tmax (h) |
|---|---|---|
| 20mg | 26-74 | 1.6-4.2 |
Nifedipine is about 95% bound to plasma protein (albumin). The distribution half-life after intravenous administration was determined to be 5 to 6 minutes.
After oral administration, nifedipine is metabolised in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is excreted in the form of its metabolites, predominantly via the kidneys and about 5 to 15% via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1%) in the urine.
The terminal elimination half-life is 6 to 11 hours because of delayed absorption. No accumulation of the substance after the usual dose was reported during long-term treatment.
In cases of impaired kidney function, no substantial changes have been detected in comparison with healthy volunteers.
In a study comparing the pharmacokinetics of nifedipine in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment with those in patients with normal liver function, oral clearance of nifedipine was reduced by on average 48% (Child Pugh A) and 72% (Child Pugh B). As a result, AUC and Cmax of nifedipine increased on average by 93% and 64% (Child Pugh A) and by 253% and 171% (Child Pugh B), respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine have not been investigated in patients with severe hepatic impairment (see Special warnings and precautions for use).
Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.
Acute toxicity has been investigated in various animal species and the individual results are listed in Table 3.
Table 3. Acute toxicity in various animal species:
| LD50 (mg/kg) | ||
|---|---|---|
| Oral | Intravenous | |
| Mouse | 494 (421-572)* | 4.2 (3.8-4.6)* |
| Rat | 1022 (950-1087)* | 15.5 (13.7-17.5)* |
| Rabbit | 250-500 | 2-3 |
| Cat | ~100 | 0.5-8 |
| Dog | >250 | 2-3 |
* 95% confidence level
Daily oral administration to rats (50 mg/kg body weight) and to dogs (100 mg/kg body weight) over periods of 13 and 4 weeks respectively, were tolerated without toxic effects.
After parenteral (intravenous) administration, dogs tolerated up to 0.1 mg/kg body weight/day for 6 days without damage. Daily intravenous administration of 2.5 mg/kg body weight in rats over a period of 3 weeks was also tolerated without signs of damage.
Dogs tolerated up to 100 mg/kg body weight as a daily oral dose over a period of 1 year without toxic damage. In rats, toxic effects occurred at concentrations above 100 ppm in the feed (about 5 to 7 mg/kg body weight).
A long-term study in rats (2 years) yielded no evidence of a carcinogenic effect of nifedipine.
Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum and malformation of the ribs.
Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.
Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans (see Fertility, pregnancy and lactation).
To assess the mutagenic effects the Ames test, the Dominant-lethal-test and the Micronucleus-test were performed in the mouse. No evidence of a mutagenic effect of nifedipine could be found.
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