ATC Code: C08C A02.
Pharmacology: Pharmacodynamics: Felodipine is a vascular selective calcium antagonist which lowers arterial blood pressure by decreasing systemic vascular resistance. Due to the high degree of selectivity for smooth muscle in the arterioles, felodipine in therapeutic doses has no direct effect on cardiac contractility or conduction. Because there is no effect on venous smooth muscle or adrenergic vasomotor control, felodipine is not associated with orthostatic hypotension.
Felodipine possesses a mild natriuretic/diuretic effect and fluid retention does not occur.
Felodipine is effective in all grades of hypertension. It can be used as monotherapy or in combination with other antihypertensive drugs, e.g. ß-adrenoceptor blockers, diuretics or ACE-inhibitors, in order to achieve an increased antihypertensive effect. Felodipine reduces both systolic and diastolic blood pressure and can be used in isolated systolic hypertension.
Felodipine maintains its antihypertensive effect during concomitant therapy with non-steroidal anti-inflammatory drugs (NSAID).
Felodipine has anti-anginal and anti-ischaemic effects due to improved myocardial oxygen supply/demand balance. Coronary vascular resistance is decreased and coronary blood flow and myocardial oxygen supply are increased by felodipine due to dilatation of both epicardial arteries and arterioles. Felodipine effectively counteracts coronary vasospasm. The reduction in systemic blood pressure caused by felodipine leads to decreased left ventricular afterload and myocardial oxygen demand.
Felodipine improves exercise tolerance and reduces anginal attacks in patients with stable effort-induced angina pectoris. Both symptomatic and silent myocardial ischaemia are reduced by felodipine in patients with vasospastic angina. Felodipine can be used as monotherapy or in combination with ß-adrenoceptor blockers in patients with stable angina pectoris.
Felodipine is effective and well tolerated in adult patients irrespective of age and race and is also well tolerated in the presence of concomitant diseases such as congestive heart failure, asthma and other obstructive pulmonary disease, impaired renal function, diabetes mellitus, gout, hyperlipidaemia, Raynaud's disease and in renal transplant recipients. Felodipine has no effect on blood glucose levels or lipid profile.
Site and Mechanism of Action: The predominant pharmacodynamic feature of felodipine is its pronounced vascular vs myocardial selectivity. Myogenically active smooth muscles in arterial resistance vessels are particularly sensitive to felodipine. Felodipine inhibits electrical and contractile activity of vascular smooth muscle cells via an effect on the calcium channels in cell membranes.
Haemodynamic Effects: The primary haemodynamic effect of felodipine is a reduction of total peripheral vascular resistance which leads to a decrease in blood pressure. These effects are dose-dependent. Generally, a reduction in blood pressure is evident two hours after the first oral dose and lasts for at least 24 hours and the trough/peak ratio is usually well above 50%.
Plasma concentrations of felodipine are positively correlated to the decrease in total peripheral resistance and blood pressure.
Cardiac Effects: Felodipine in therapeutic doses has no effect on cardiac contractility or atrioventricular conduction or refractoriness. In patients with heart failure, felodipine favourably affects left ventricular function, as assessed by ejection fraction or stroke volume, and does not cause neurohormonal activation. However, felodipine does not seem to affect survival. In patients with hypertension or angina pectoris, felodipine can be used also in case of impaired left ventricular function.
Antihypertensive treatment with felodipine is associated with significant regression of pre-existing left ventricular hypertrophy.
Renal Effects: Felodipine has a natriuretic and diuretic effect due to reduced tubular reabsorption of filtered sodium. This counteracts the salt and water retention observed with other vasodilators. Felodipine does not affect daily potassium excretion. The renal vascular resistance is decreased by felodipine. Normal glomerular filtration rate is unchanged. In patients with impaired renal function, the glomerular filtration rate may increase. Felodipine does not influence urinary albumin excretion.
In cyclosporin-treated renal transplant recipients, felodipine reduces blood pressure and improves both the renal blood flow and the glomerular filtration rate. Felodipine may also improve early renal graft function.
Mortality/Morbidity Data: In the HOT (Hypertension Optimal Treatment) study, the effect on major cardiovascular events (i.e. acute myocardial infarction, stroke and cardiovascular death) was studied in relation to diastolic blood pressure targets ≤90 mmHg, ≤85 mmHg and ≤80 mmHg and achieved blood pressure, with felodipine as baseline therapy.
A total of 18.790 hypertensive patients (DBP 100-115 mmHg), aged 50-80 years were followed for a mean period of 3.8 years (range 3.3-4.9). Felodipine was given as monotherapy or in combination with a betablocker, and/or an ACE-inhibitor and/or a diuretic. The study showed benefits of lowering SBP and DBP down to 139 and 83 mmHg, respectively. When the baseline DBP was lowered from 105 mmHg to 83 mmHg, it suggests that from five to ten major cardiovascular events can be prevented in every 1000 patients treated for 1 year. This implies a 30% risk reduction. Active lowering of blood pressure was particularly beneficial in the subgroup of patients with diabetes mellitus.
According to the Swedish Trial in Old Patients with Hypertension-2 study, performed in 6614 patients, aged 70-84 years, dihydropyridine calcium antagonists (felodipine and isradipine) have shown the same preventive effect on cardiovascular mortality and morbidity as other commonly used classes of antihypertensive drugs–ACE inhibitors, beta-blockers and diuretics.
Paediatric Population: There is limited clinical experience of the use of felodipine in hypertensive paediatric patients. In a randomised, double-blind, parallel group study, the antihypertensive effect of once daily felodipine in children aged 6-16 years with primary hypertension was studied. They were treated for three weeks with 2.5 mg (n=33), 5 mg (n=33), 10 mg (n=31) or placebo (n=35). The study failed to demonstrate any antihypertensive effect in children aged 6-16 years.
The long-term effects of felodipine on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy as therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.
Pharmacokinetics: Absorption and Distribution: Felodipine is administered as extended-release tablets, from which it is completely absorbed in the gastrointestinal tract. The systemic availability of felodipine is approximately 15% and is independent of dose in the therapeutic dose range. The plasma protein binding of felodipine is approximately 99%. It is bound predominantly to the albumin fraction.
The extended-release tablets produce a prolonged absorption phase of felodipine. This results in even felodipine plasma concentrations within the therapeutic range for 24 hours. Plasma concentrations are directly proportional to dose within the therapeutic dose range 2.5-10 mg.
Metabolism and Elimination: There is no significant accumulation during long-term treatment.
Average clearance is 1200 ml/min. Reduced clearance in elderly patients and patients with impaired liver function leads to higher plasma concentrations of felodipine. However, age can only partly explain the interindividual variations in plasma concentrations. Felodipine is metabolised in the liver by cytochrome P450 3A4 and none of the identified metabolites has a vasodilating effect.
About 70% of a given dose is excreted as metabolites in the urine and the rest is excreted in the faeces. Less than 0.5% of a given dose is excreted unchanged in the urine.
Impaired renal function does not affect plasma concentrations of felodipine, although there is accumulation of inactive metabolites. Felodipine is not eliminated by haemodialysis.
Paediatric Population: In a single-dose (felodipine prolonged-release tablet 5 mg) pharmacokinetic study with a limited number of children aged between 6 and 16 years (n=12) there was no apparent relationship between the age and AUC, Cmax or half-life of felodipine.
Toxicology: Preclinical Safety Data: Reproductive Toxicity: In a study on fertility and general reproductive performance in rats treated with felodipine, a prolongation of parturition resulting in difficult labour/increased foetal deaths and early postnatal deaths was observed in the medium and high dose groups. These effects were attributed to the inhibitory effect of felodipine in high doses on uterine contractility. No disturbances of fertility were observed when doses within the therapeutic range were given to rats.
Reproduction studies in rabbits have shown a dose-related reversible enlargement of the mammary glands of the parent animals and dose-related digital anomalies in the foetuses. The anomalies in the foetuses were induced when felodipine was administered during early foetal development (before day 15 of pregnancy).