Cardepine Mechanism of Action

Pharmacology: Pharmacodynamics: SR cap: CARDEPINE is a new generation calcium antagonist for the prevention and treatment of angina pectoris, hypertension, peripheral and cerebral insufficiencies. CARDEPINE unlike conventional calcium blockers, exerts a preferential dilating effect on coronary and cerebral arteries by inhibiting the influx of calcium into the vascular smooth muscle cells. This potent coronary and cerebral dilatory properties of CARDEPINE with concomitant improvements in oxygen supply and demand and reductions in systemic vascular resistance, are of major importance in the treatment of hypertension and myocardial ischaemic states.
CARDEPINE dilates the cerebral blood vessels thereby enhancing blood flow and oxygenation into the brain. This makes CARDEPINE effective in the prevention of cerebrovascular accidents among hypertensive patients. As an anti-anginal, CARDEPINE reduces myocardial oxygen consumption by dilating the coronary arteries.
CARDEPINE lowers blood pressure by reducing peripheral vascular resistance. However, in contrast to other antihypertensive drugs that tend to diminish blood supply as the cardiac output is decreased. CARDEPINE increases coronary and cerebral blood flow while it brings down blood pressure. Since it has a higher specificity for blood vessels, CARDEPINE does not affect the conduction system of the heart in dosages sufficient for its hypotensive action, thereby eliminating the risk of atrioventricular conduction disturbance.
CARDEPINE may also increase renal blood flow and glomerular filtration rate. It decreases renovascular resistance although plasma renin may be increased. Although aldosterone concentration do not appear to be significantly affected, administration of CARDEPINE has resulted in modest and short-acting natriuretic effects due to an effect on the renal tubule.
CARDEPINE is the logical choice in the treatment of hypertension and angina pectoris, especially in patients with co-existing disease conditions such as bronchial asthma, cerebral insufficiency, diabetes mellitus, and peripheral vascular disorder. It is also ideal in cases wherein beta-blockers or diuretics prove to be ineffective or poorly tolerated.
Inj: Nicardipine is a dihydropyridine calcium channel antagonist that inhibits the transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle without changing serum calcium ion concentrations. Vascular smooth muscles are more sensitive to this effect than cardiac muscles because depolarization of vascular smooth muscles is dependent on calcium ion influx whereas cardiac muscle depolarization involves both sodium and calcium ion influx.
Nicardipine demonstrates strong coronary and cerebral vasodilatory activity. The selectivity for arterial and especially cardiac arterial vascular smooth muscle is reflected in relatively large and rapid changes in blood pressure (BP), with minimal inotropic cardiac effects and no significant venodilatory action.
Intravenous (IV) nicardipine produces dose-related decreases in mean arterial BP (up to 30% reduction) and increases in heart rate (by up to 13% to 26%). The duration of these effects, which may be as long as 3 hours, have generally been greater in patients at rest than in those at exercise. Nicardipine-induced increases in heart rate are due to reflex adrenergic stimulation following reduction in total peripheral resistance.
The degree of vasodilation and the resultant BP reduction were more prominent in hypertensive patients compared with normotensive volunteers given intra-arterial nicardipine. In normotensive volunteers, the administration of nicardipine 0.25 to 3 mg/hour for eight hours produced changes of <5 mmHg in systolic BP and <3 mmHg in diastolic BP.
Nicardipine exerts a vasorelaxing action on cerebrovascular smooth muscles thereby enhancing blood flow and oxygenation into the brain. Thus, nicardipine may be beneficial in the prevention of cerebrovascular accidents among hypertensive patients.
Hemodynamic studies in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in cardiac output and coronary blood flow, with no significant change or a small decrease in left ventricular end-diastolic pressure (LVEDP). The ejection fraction is significantly increased by nicardipine.
Administration of nicardipine in patients with coronary artery disease results in increased coronary blood flow due to coronary vasodilatation and decreased coronary vascular resistance. The intracoronary administration of nicardipine in patients with coronary artery disease caused no direct myocardial depression. In patients receiving beta-blockers, the co-administration of nicardipine has further increased coronary blood flow and decreased coronary vascular resistance by as much as 21% and 32%, respectively.
Nicardipine's ability to decrease systemic vascular resistance (afterload) may improve blood distribution in ischemic myocardial tissue. Nicardipine-induced coronary dilation may improve perfusion and aerobic metabolism in chronically ischemic areas, leading to decreased lactate production and augmented oxygen consumption. The administration of nicardipine after beta-­blockade in patients with coronary artery disease significantly improved systolic and diastolic ventricular function.
Nicardipine improve cardiac output both at rest and during exercise in patients with congestive heart failure. Decreases in LVEDP were also seen. However, nicardipine may have a negative inotropic effect in some patients with severe left ventricular dysfunction and could lead to worsened failure.
Coronary steal, the detrimental redistribution of coronary blood flow in patients with coronary artery disease from underperfused areas toward better perfused areas, has not been observed during nicardipine treatment. Nicardipine improves systolic shortening in both normal and hypokinetic segments of myocardial muscle. The wall motion remained improved during increased oxygen demand as confirmed by radionuclide angiography.
Pharmacokinetics: Inj: Nicardipine's pharmacokinetics is linear over the dosage range of 0.5 to 40 mg/hour. Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of an infusion. Plasma concentrations increase at a much slower rate after the first few hours and approach steady state at 24 to 48 hours. On termination of the infusion, nicardipine plasma concentrations decrease rapidly, with at least 50% decrease during the first two hours post-infusion. Nicardipine's effects on blood pressure significantly correlate with plasma concentrations.
After IV infusion, nicardipine plasma concentrations decrease tri-exponentially, with a rapid early distribution phase (α-half-life of 3 minutes), an intermediate phase (β-half-life of 45 minutes), and a slow terminal phase (γ-half-life of 14 hours) that can only be detected after long-term infusions.
Nicardipine's total plasma clearance is 0.4 L/hr•kg. The apparent volume of distribution is 8.3 L/kg.
Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range. Nicardipine has been shown to be rapidly and extensively metabolized by the liver and its excretion is mainly renal. It does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes.
After concomitant administration of a radioactive intravenous dose of nicardipine with an oral 30 mg dose given every 8 hours, 49 and 43% of the radioactivity was recovered in urine and feces, respectively, within 96 hours. None of the dose was recovered as unchanged nicardipine.