Versant-XR Mechanism of Action

Pharmacology: Pharmacodynamics: Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel blockers). Felodipine's predominant pharmacodynamic feature is its pronounced vascular versus myocardial selectivity. Smooth muscles in arterial resistance vessels are particularly sensitive to felodipine. It inhibits electrical and contractile activity of vascular smooth muscle cells via an effect on the calcium channels in cell membranes.
Felodipine's effect on blood pressure is a result of a dose-related decrease of peripheral vascular resistance, with a modest reflex increase in heart rate. With the exception of a mild diuretic effect seen in animals and man, felodipine's effects are due to its effects on peripheral 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. It is not associated with orthostatic hypotension since there is no effect on venous smooth muscle or adrenergic vasomotor control.
Felodipine has a mild natriuretic/diuretic effect due to decreased tubular reabsorption of filtered sodium. This counteracts the salt and water retention observed with other vasodilators. It does not affect daily potassium excretion. It decreases renal vascular resistance while glomerular filtration rate is unchanged. The glomerular filtration rate may increase in patients with impaired renal function. Felodipine decreases blood pressure and improves renal blood flow and glomerular filtration rate in renal transplant patients. It may also improve early renal graft function.
Felodipine is effective in all grades of hypertension. It decreases both systolic and diastolic blood pressure and may be used in isolated systolic hypertension. It may be used as monotherapy or in combination with other antihypertensive agents to achieve increased antihypertensive effect. Felodipine maintains its antihypertensive effect during concomitant therapy with nonsteroidal anti- inflammatory drugs (NSAIDs).
Felodipine has anti-anginal and anti-ischemic effects due to improved myocardial oxygen supply-demand balance. Due to dilatation of epicardial arteries and arterioles, felodipine decreases coronary vascular resistance and increases coronary blood flow and myocardial oxygen supply. Felodipine effectively counteracts coronary vasospasm. It decreases systemic blood pressure resulting in decreased left ventricular afterload and myocardial oxygen demand.
Felodipine favorably affects left ventricular function, as assessed by ejection fraction and stroke volume, and does not cause neurohormonal activation. However, felodipine does not seem to affect survival. Thus, it may be used in patients with hypertension or angina pectoris who also have impaired left ventricular function. Felodipine treatment is associated with significant regression of pre-existing left ventricular hypertrophy.
Felodipine improves exercise tolerance and decreases anginal attacks in patients with stable effort-induced angina pectoris. It decreases symptomatic and silent myocardial ischemia in patients with vasospastic angina. Felodipine may be used as monotherapy or in combination with beta-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, hyperlipidemia, Raynaud's disease, and in renal transplant recipients. Felodipine has no effect on blood glucose levels or lipid profile.
Pharmacokinetics: Felodipine, administered as extended-release tablets, is completely absorbed in the gastrointestinal tract. The systemic bioavailability of felodipine is about 15% and is independent of dose in the therapeutic range. Mean peak concentrations (C_max) are reached in 2.5 to 5 hours after oral administration of the extended-release tablet. Felodipine is about 99% bound to plasma proteins, mainly to albumin.
After multiple oral administration of a 10 mg extended-release tablet once daily for six days to healthy volunteers, mean peak felodipine plasma concentration (C_max) at steady state was 2.712 ± 1.363 ng/mL achieved in 3.563 ± 1.378 hours (T_max). The area under the plasma concentration-time curve (AUC) at steady state was 37.18 ± 14.188 ng·hr/mL.
After oral administration of felodipine to hypertensive patients, mean peak plasma concentrations at steady state are about 20% higher than after a single dose. Blood pressure response is correlated with plasma felodipine concentration.
Felodipine's bioavailability is influenced by the presence of food. When administered either with a high fat or high carbohydrate diet, C_max is increased by about 60%; AUC is unchanged. When felodipine was administered after a light meal (orange juice, toast, and cereal), however, there was no effect on felodipine's pharmacokinetics. Felodipine's bioavailability was increased approximately two-fold when taken with grapefruit juice. Orange juice does not appear to modify felodipine's kinetics. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with felodipine.
Felodipine's systemic plasma clearance in young healthy subjects is about 0.8 L/min and the apparent volume of distribution is about 10 L/kg.
Felodipine is extensively metabolized in the liver by cytochrome P450 3A4 (CYP3A4) and all identified metabolites are inactive. Concurrent administration with CYP3A4 inhibitors may result in increased plasma felodipine levels, either due to increased bioavailability or decreased metabolism. Increases in concentration may lead to lower blood pressure and increased heart rate.
Felodipine is a high clearance agent with an average blood clearance of 1200 mL/min. Felodipine's average half-life in the terminal phase is 24 hours. There is no significant accumulation during long-term treatment.
About 70% of a given dose is excreted as metabolites in the urine; the remaining fraction is excreted in the feces. Less than 0.5% of a dose is recovered unchanged in urine.
Elderly patients and patients with reduced liver function have on average higher plasma felodipine concentrations than younger patients. The pharmacokinetics of felodipine are not changed in patients with renal impairment, including those treated with hemodialysis.