Pharmacology: Pharmacodynamics: This fixed dose combination combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: Valsartan belongs to the angiotensin II antagonist class and amlodipine to the calcium antagonist class of medicines.
Valsartan: Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on the receptor subtype AT1, 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 receptor subtype AT2, 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 coughing.
Administration of valsartan to patients with hypertension results in a drop in 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 drop in 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.
Amlodipine: The amlodipine component of this fixed dose combination 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 in blood pressure. Amlodipine binds to both dihydropyridine and non-dihydropyridine 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 vasodilation, 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, haemodynamic 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 haemodynamic 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 effects on electrocardiographic parameters were observed.
Amlodipine/Valsartan: The combination of amlodipine and valsartan produces dose-related additive reduction in blood pressure across its therapeutic dose range. The antihypertensive effect of a single dose of the combination persisted for 24 hours.
Pharmacokinetics: Valsartan: Valsartan is rapidly absorbed following oral administration, with a bioavailability of about 23%. Peak plasma concentrations of valsartan occur 2 to 4 hours after an oral dose. It is between 94 and 97% bound to plasma proteins. Valsartan is not significantly metabolized and is excreted mainly via the bile as unchanged drug. The terminal elimination half-life is about 5 to 9 hours. Following an oral dose about 83% is excreted in the feces and 13% in urine.
Amlodipine: Amlodipine is well absorbed following oral administration with peak blood concentrations occurring after 6 to 12 hours. The bioavailability varies but is usually about 60 to 65%. Amlodipine is reported to be about 97.5% bound to plasma proteins. It has a prolonged terminal elimination half-life of 35 to 50 hours and steady-state plasma concentrations are not achieved until after 7 to 8 days of administration. Amlodipine is extensively metabolized in the liver; metabolites are mostly excreted in urine together with less than 10% of a dose as unchanged drug. Amlodipine is not removed by dialysis.