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Pharmacology: Pharmacodynamics: Valsartan + Amlodipine combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: Amlodipine belongs to the calcium antagonist class and Valsartan to the angiotensin II (Ang II) antagonist class of medicines. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than
either component alone.
Amlodipine: The Amlodipine component inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of Amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and blood pressure. 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.
Following administration of therapeutic doses to patients with hypertension, Amlodipine produces vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of Amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of
cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with Amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.
In hemodynamic studies, Amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse experiences on electrocardiographic parameters were observed.
Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.
Valsartan: Valsartan is an orally active, potent, and specific angiotensin II receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of angiotensin II following AT1 receptor blockade with Valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2
receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with cough. In clinical trials where Valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P <0.05) lower in patients treated with Valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving Valsartan and 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (P <0.05).
Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Administration of Valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Abrupt withdrawal of Valsartan has not been associated with rebound hypertension or other adverse clinical events.
In patients with chronic heart failure (NYHA class II-IV), Valsartan has been demonstrated to significantly reduce hospitalizations in patients with chronic heart failure (NYHA class II-IV). The benefits were greatest inpatients not receiving either an ACE inhibitor or a beta blocker. In post-MI patients, Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Pharmacokinetics: Linearity: Valsartan and Amlodipine exhibit linear pharmacokinetics.
Amlodipine: Absorption: After oral administration of therapeutic doses of Amlodipine alone, peak plasma concentrations of Amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution: Volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins. Amlodipine crosses the placenta and is excreted into breast milk.
Biotransformation: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Elimination: Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady state plasma levels are reached after continuous administration for 7-8 days. 10% of original Amlodipine and 60% of Amlodipine metabolites are excreted in urine.
Valsartan: Absorption: Following oral administration of Valsartan alone, peak plasma concentrations of Valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%.
Food decreases the exposure (as measured by AUC) to Valsartan by about 40% and peak plasma concentration (C) by about 50%, although from max about 8 h post dosing plasma Valsartan concentrations are similar for the fed and fasted group. This reduction in AUC, however, is not accompanied by a clinically significant reduction in the therapeutic effect, and Valsartan can therefore be given either with or without food.
Distribution: The steady-state volume of distribution of Valsartan after intravenous administration is about 17 liters indicating that Valsartan is not distributed into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the Valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t½ α<1 h and t½ β about 9 h). Valsartan is primarily eliminated unchanged in feces (about 83% of dose) and urine (about 13% of dose) mainly as unchanged drug. 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). The half-life of Valsartan is 6 hours.
Valsartan/Amlodipine: Following oral administration of Amlodipine + Valsartan peak plasma concentrations of Amlodipine + Valsartan are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of Amlodipine + Valsartan are equivalent to the bioavailability of Valsartan and amlodipine when administered as individual tablets.
Special populations: Geriatric patients: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects.
Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients.
Systemic exposure to Valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance
Renal impairment: The pharmacokinetics of Amlodipine is not significantly influenced by renal impairment. There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to Valsartan in patients with different degrees of renal impairment.
Patients with mild to moderate renal impairment may therefore receive the usual initial dose.
Hepatic impairment: Patients with hepatic impairment have decreased clearance of Amlodipine with resulting increase in AUC of approximately 40-60%. On average, in patients with mild to moderate chronic liver disease exposure (measured by AUC values) to Valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Care should be exercised in patients with liver disease.
