Felodipine

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Abstract
Felodipine is a dihydropyridine calcium antagonist which selectively relaxes vascular smooth muscle. By acting at peripheral arterioles, it lowers systemic vascular resistance and thereby produces substantial decreases in blood pressure and increases in cardiac output. Felodipine is indicated for the management of hypertension, and in patients with mild to moderate disease felodipine monotherapy markedly lowers blood pressure. It proved as effective as atenolol, and equivalent to hydrochlorothiazide, either with or without amibride in terms of antihypertensive activity. Comparative studies also demonstrated that once daily administration with an extended-release formulation provides equivalent anti-hypertensive efficacy to the same amount of drug administered twice daily as the standard tablets. As a second- or third-line treatment for patients with moderate to severe hypertension refractory to standard drug combinations, felodipine produced considerable reductions in blood pressure when added to β-blockers and diuretics, either alone or in combination, in studies lasting up to 48 weeks. In comparative studies of multiple-drug treatments felodipine was found to have superior efficacy to hydralazine and prazosin, and was at least as effective as nifedipine, minoxidil and propranolol, when used with diuretics and/or β-blockers. As an alternative to hydrochlorothiazide, in combination with β-blockers, felodipine consistently controlled blood pressure in a greater percentage of patients and usually provided greater decreases in blood pressure. The main side effects with felodipine are ankle oedema, headache and flushing. Although the overall incidence of effects is quite high, they are usually mild in nature. Nevertheless, withdrawal due to side effects has been necessary in about 7% of patients overall. Thus, the efficacy offelodipine has been demonstrated in mild, moderate and severe hypertension. At the present time it seems particularly suitable as a second- or third-line treatment in refractory hypertension, but it also can be used as monotherapy for mild to moderate disease. Felodipine is a calcium channel antagonist of the dihydropyridine class, chemically related to nifedipine, nitrendipine, nimodipine, nisoldipine and nicardipine. The primary effect of felodipine is dilation of peripheral arterioles, and in vitro studies showed it to have a much greater selectivity for vascular smooth muscle than myocardial muscle when compared with either nifedipine or verapamil. Single oral doses offelodipine reduced resting systolic blood pressure by up to 40mm Hg and diastolic blood pressure by up to 27mm Hg in untreated hypertensive patients, and similar reductions were seen in patients also taking β-blockers. Sub-acute and long term studies have demonstrated that these effects are sustained. Reductions in blood pressure are the result of a considerable decrease in systemic vascular resistance (up to 40%); in hypertensive patients there are secondary increases in cardiac output and stroke volume. Acute administration of felodipine produced reflex tachycardia, but this is not sustained during long term treatment. Similar haemodynamic effects occur when felodipine is given to patients with angina pectoris or congestive heart failure. In the latter patients, single oral doses of felodipine increased stroke volume index by up to 58%. In patients with angina pectoris, single oral or intravenous doses of felodipine reduced coronary vascular resistance by 35 to 56% with subsequent increases in coronary sinus blood flow and oxygen saturation of up to 43 and 64%, respectively. Similarly, felodipine reduced coronary vascular resistance and improved coronary blood flow in patients with heart failure. Felodipine is devoid of any negative inotropic actions at therapeutic dosages and there is evidence that it may in fact slightly increase myocardial contractility. In some studies, treatment with felodipine increased exercise tolerance in patients with angina pectoris or heart failure. Administration offelodipine did not significantly affect renal blood flow or glomerular filtration rate in normotensive volunteers. Short term treatment did increase renal plasma flow in hypertensive patients, although in a longer study renal plasma flow and glomerular filtration rate were unchanged by felodipine. However, in hypertensive patients with established renal insufficiency treatment with felodipine for 6 months produced a significant improvement in glomerular filtration rate, except where the initial renal impairment was severe. In both normotensive volunteers and hypertensive patients administration of felodipine produces transient increases in urine production and sodium excretion for up to 8 hours postdose, although 24-hour excretion rates are not altered. With longer term treatment natriuresis and diuresis were only observed during the first 4 days of active treatment, although the negative sodium balance seems to be sustained. In most studies felodipine administration has been associated with increases in plasma renin activity, and in some instances increases in plasma angiotensin II concentrations. Felodipine is well absorbed from the gastrointestinal tract but undergoes extensive first-pass metabolism, resulting in an absolute bioavailability of 13 to 16% in fasted individuals. Oral administration offelodipine 10mg or 0.1 mg/kg as a solution produced peak plasma concentrations of 30 to 47 nmol/L within 30 to 90 minutes postdose, and 10mg doses in tablet form produced mean maximum plasma concentrations of 22 to 25 nmol/L with a slower rate of absorption (time to maximum concentration ranged from 45 to 120 minutes). With each of these formulations a linear relationship was found between dose offelodipine and both maximum plasma concentration and area under the plasma concentration-time curve (AUC). In a comparison between 10mg doses in standard and...