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Experimental data suggest that Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly or vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanism by which amlodipine relieves angina have not been fully delineated, but are thought to include the following: Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (after-load) against which the heart works and reduces the rate pressure product and thus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore brood flow in corona), arteries and arterioles in response to calcium, potassium epinephrine, serotonin and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro, This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.
Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decrease in plasma aldosterone were observed after administration of Valsartan; very little effect on serum potassium was observed. In multiple dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, Valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
Administration of Valsartan to patients with essential hypertension results in a significant reduction of sitting, supine and standing systolic blood pressure, usually with little or no orthostatic change.
Pharmacology: Pharmacokinetics: Absorption: After oral administration of therapeutic doses of Amlodipine alone, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of Amlodipine when administered alone is not altered by the presence of food.
Following oral administration of Valsartan alone peak plasma concentrations of Valsartan are reached in 2-4 hours. Absolute bioavailability is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to Valsartan by about 40% and peak plasma concentration (Cmax) by about 50%.
Distribution: Ex vivo studies have shown that approximately 93% of the circulating Amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Metabolism: Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.
Valsartan shows bi-exponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. The enzyme(s) responsible for Valsartan metabolism have not been identified but do not seem to be CYP 450 isoenzymes.
Excretion: Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Ten percent of the parent Amlodipine compound and 60% of the metabolites of Amlodipine are excreted in the urine.
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).
