Plendil Mechanism of Action

Pharmacotherapeutic group: Calcium antagonist. ATC Code: C08CA02.
Pharmacology: Pharmacodynamics: Felodipine (Plendil) is a vasoselective calcium antagonist for the treatment of hypertension and stable angina pectoris.
The active substance in Plendil, felodipine, is a dihydropyridine derivate. Felodipine is a racemate. Felodipine exerts its effect by reducing peripheral vascular resistance, particularly in arterial resistance vessels. The electrical and contractile activity of vascular smooth muscle cells is inhibited via an effect on the calcium channels in the cell membranes.
Due to the selective effect on smooth muscle in arterial resistance vessels, felodipine in therapeutic doses has no negative inotropic effects on the heart, nor any clinically significant electrophysiological cardiac effects. Felodipine relaxes smooth muscle in the airways. Clinical experience has shown that felodipine has little effect on gastrointestinal muscle motor function. No clinically significant effect of felodipine on blood lipids has been observed during long-term treatment, nor have any clinically significant effects on metabolic control (HbA1c) been observed in patients with type II diabetes during six months of treatment.
Felodipine can generally also be given to patients with concomitant impairment of left ventricular function who receive conventional therapy, or with asthma, diabetes mellitus, gout or hyperlipidaemia.
Anti-hypertensive effect: Felodipine lowers arterial blood pressure by decreasing peripheral vascular resistance. Treatment of hypertensive patients with Plendil reduces the blood pressure, both in the sitting and standing position and at rest and during exercise. Felodipine does not give rise to orthostatic hypotension, as the substance has no effect on venous smooth muscle or adrenergic control mechanisms.
The lowered blood pressure may initially cause a temporary reflex increase in heart rate and cardiac output. The increased heart rate is counteracted when felodipine is given together with β-blockers. Plasma concentrations of felodipine are positively correlated to the decrease in total peripheral resistance and blood pressure. At steady state the effect remains over the entire dose range and gives a 24-hour reduction in blood pressure.
Treatment with felodipine is associated with regression of left ventricular hypertrophy.
Felodipine has a natriuretic and diuretic effect but no potassiuretic effect. The tubular reabsorption of sodium and water is reduced, which may explain the absence of salt and fluid retention in the patient. Felodipine reduces renal vascular resistance and increases renal perfusion. The glomerular filtration rate is unchanged. Felodipine does not influence urinary albumin excretion.
In the so-called HOT (Hypertension Optimal Treatment) study, including 18,790 patients with mild to moderate hypertension, treatment with Plendil, in combination with an angiotensin-converting enzyme (ACE) inhibitor, a β-blocker and/or a diuretic, if needed, resulted in a diastolic blood pressure (DBP) of ≤ 90 mmHg in 93% of the patients.
In the same study, the incidence of cardiovascular events in patients with type II diabetes (n=1501) was significantly lower (50%) in the group where the target DBP was ≤ 80 mmHg (11.9/1000 patient years), compared with the group where the target DBP was below 90 mmHg (24.4/1000 patient years).
Plendil was included as one of two calcium antagonists in the Swedish STOP-2 study, performed in 6,614 patients aged 70-84 years. The study indicates that hypertensive treatment initiated with dihydropyridine calcium antagonists and with the addition of β-blockers, if needed, has no effect of cardiovascular mortality compared with conventional treatment with β-blockers and/or diuretics.
For the treatment of hypertensive patients, Plendil can be used as monotherapy or in combination with other antihypertensive drugs, such as β-blockers, diuretics or ACE inhibitors.
Anti-anginal effect: Felodipine exerts its effect through dilatation of coronary vessels, which also improves perfusion and the oxygen supply to the heart. Cardiac workload is decreased through a reduction of the peripheral arterial resistance (reduced afterload), which results in reduced oxygen demand in the myocardium. Coronary vasospasm is counteracted by felodipine.
Felodipine improves exercise capacity and reduces anginal attacks in patients with stable effort-induced angina pectoris.
Initially during treatment there is a transient reflex increase in heart rate, which is counteracted if Plendil is given in combination with a β-blocker. The time to onset of effect is two hours and the effect duration is 24 hours.
Felodipine can be used in combination with β-adrenoceptor blockers or as monotherapy for the treatment of patients with angina pectoris.
Pharmacokinetics: The active substance in Plendil extended-release tablets, felodipine, is imbedded in a polymer that forms a gel layer in contact with water, from which felodipine is released continuously, which leads to a slow onset of effect.
The bioavailability of felodipine is approximately 15% and is independent of concomitant food intake. However, the rate of absorption, although not the degree of absorption, is affected by concomitant intake of food, and the maximum plasma concentration is thereby increased by approximately 65%. The maximum plasma concentration is reached after 3-5 hours. The degree of binding to plasma proteins is approximately 99%. The distribution volume at steady state is 10 L/kg. The half-life of felodipine in the elimination phase is approximately 25 hours and steady state is reached after 5 days. There is no risk of 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 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 recovered 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.