Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Pharmacotherapeutic group: Calcium channel blockers; Selective calcium channel blockers with mainly vascular effects
ATC code: C08CA05
The active substance in Nifelat, the dihydropyridine derivative nifedipine, is a calcium antagonist with effect in stable angina pectoris, hypertension and Raynaud disease. The mechanism of action of nifedipine is a selective inhibition of the flow of calcium ions through effect on specific calcium channels (L-type voltage-dependent channels) in the cell membrane.
Nifedipine is relatively vascular-selective with significantly less effect on heart muscle than smooth musculature of the blood vessels. Nifedipine has no direct effect on the contractility of the heart, conductivity or on the conduction system in clinically used doses.
Calcium antagonists are lipid neutral. Calcium ions are essential for insulin release. Treatment with nifedipine may theoretically adversely affect glucose metabolism. In rare cases, this may have clinical relevance.
Antihypertensive effect: Nifedipine reduces the tone of the smooth muscles of the arterioles, which causes a decrease in the peripheral vascular resistance and thus a decrease in the arterial blood pressure. Long-term treatment with nifedipine results in a lasting reduction in the total peripheral resistance without affecting heart rate and minute volume both at rest (lying down and sitting position) and during work. Normal physiological functions in a standing position and during work is not affected. Full therapeutic effect is achieved after about 4-6 weeks of treatment.
The effect duration is at least 12 hours. At the recommended dosage, nifedipine provides an effective reduction of blood pressure throughout the day. Regression of left ventricular hypertrophy is seen with long-term treatment with nifedipine.
Nifedipine has a natriuretic and diuretic, but not caliuretic effect. The tubular reabsorption of sodium and water decreases, which may explain the absence of salt and water retention. Nifedipine is increasing renal perfusion and glomerular filtration rate at both normal and decreased renal function. Information on whether nifedipine affects the morbidity/mortality of cardiovascular disease is lacking. Nifelat may be used as monotherapy or in combination with another blood pressure lowering treatment, such as beta-receptor blockers, diuretics and ACE inhibitors.
Antianginal effect: Nifedipine dilates the coronary arteries resulting in an improved myocardial perfusion and increased oxygen supply. The effort of the heart is relieved by a marked reduction of the peripheral arterial resistance (reduction of afterload). This entails a decreased oxygen demand in the myocardium. Occurring spasms in the coronary vessels and in peripheral vessels are attenuated. Good effect has also been observed in other types of angina, such as Prinzmetal’s variant angina. At the beginning of the treatment one may experience a transient reflexive increase of heart rate; impact decreases during long-term treatment. The time to start of effect is 1 hour and maximum effect is reached after 2-3 hours.
The duration of effect is at least 12 hours.
Nifedipine may, if necessary, be combined with beta-receptor blockers and both short-acting and long-acting nitro-preparations.
Effect in Raynaud disease: Nifedipine prevents and reduces digital vasospasm leading to a reduction in the number of attacks in Raynaud disease (primary and secondary).
There is limited information regarding comparisons between nifedipine and other antihypertensive drugs, for both acute hypertension and chronic hypertension with various dosage forms and different dosages.
Antihypertensive effect of nifedipine has been demonstrated, but dosing recommendations, safety in long-term treatment and the effect on cardiovascular events have not yet been documented.
Formulations for children are lacking.
The bioavailability is 40-60%. Maximum plasma concentration is reached after about 2-4 hours. Concomitant food intake delays absorption without reducing it. In plasma nifedipine is highly protein bound (92-98%), mainly to albumin. The volume of distribution (based on 3-compartment model Vss, intravenous administration) is 0.6-1.2 + 0.5 l/kg body weight. The half-life is 6-11 hours (depending on its slowed absorption). Nifedipine is metabolised by the cytochrome P450 3A4 system.
Nifedipine is almost completely metabolised in the liver to 3 inactive metabolites. The metabolites are mainly excreted by the kidneys. About 5-15% is excreted via bile to faeces. Less than 0.1% nifedipine is excreted unchanged in the urine.
In a study in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment, a 2-fold and a 4.5-fold increase in nifedipine exposure were observed (based on unbound plasma concentrations) compared to patients with normal liver function.
Clearance decreased and the half-life was prolonged. The pharmacokinetics of nifedipine have not been studied in patients with severe hepatic impairment (see sections 4.2 and 4.4).
Limited data suggest that the bioavailability of nifedipine may be increased in the elderly in administration of rapid-release formulation such as Nifelat tablets (see section 4.2).
Preclinical data reveal no special hazard for humans based on conventional studies regarding single and multiple dose toxicity, genotoxicity and carcinogenic potential.
Nifedipine has been shown to cause teratogenic effects in rats, mice and rabbits, including digital anomaly, limb deformity, cleft palate, split sternum, rib deformity. Digital anomaly and limb deformity may be a result of inhibited uterine perfusion, but has also been observed in animals treated with nifedipine only after the organogenesis period.
Nifedipine has been associated with various embryotoxic, placental toxicants and fetotoxic effects, including inhibited fetal growth (rats, mice, rabbits), small placenta and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice, rabbits) and prolonged gestation/decreased neonatal survival (rats; not evaluated in other species). All doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were toxic to the mother and several times higher than the recommended maximum dose.
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