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Pharmacology: Pharmacodynamics: Losartan potassium: Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex.
Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the angiotensin II subtype I (AT1) receptor found in many tissues such as vascular smooth muscles, adrenal gland, kidneys, and the heart. A second angiotensin II receptor has been identified as the AT2 receptor subtype found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than that for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
Losartan does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin). Angiotensin II receptor antagonism results in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
Amlodipine besilate: Amlodipine, a dihydropyridine calcium antagonist (slow channel blocker or calcium ion antagonist), inhibits the transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. Its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle resulting in decreased peripheral vascular resistance and blood pressure.
Amlodipine's exact mechanism in relieving angina has not been fully established; however, amlodipine decreases total ischemic burden by dilating peripheral arterioles thereby reducing total peripheral resistance (afterload) against which the heart works. The unloading of the heart decreases myocardial energy consumption and oxygen requirements as the heart rate remains stable; and dilating the main coronary arteries and arterioles, both in normal and ischemic areas. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
Pharmacokinetics: Losartan potassium: Losartan is well absorbed after oral administration. It undergoes presystemic metabolism, forming an active metabolite (E-3174) and other inactive metabolites. Systemic bioavailability of losartan tablets is about 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and 3 to 4 hours, respectively. There is no clinically significant effect on the plasma concentration profile of losartan when the drug is administered with a meal.
Both losartan and its metabolite are highly bound (≥99%) to plasma proteins, primarily albumin. Losartan's volume of distribution is 34 L.
Plasma concentrations of the active metabolite are higher than those of losartan at all doses; Cmax and AUC for E-3174 are about 2 and 5 to 8 times greater than the corresponding values for losartan itself.
After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with terminal half-lives of about 2 hours (1.5 to 2.5 hours) and 6 to 9 hours, respectively. As anticipated from their short half-lives, neither losartan nor its active metabolite accumulates significantly in plasma during once-daily dosing with losartan 100 mg.
The plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. Losartan is extensively metabolized in the liver. Approximately 35% of an oral losartan dose is excreted in urine as unchanged compound and metabolites; only 4% of the dose is eliminated unchanged via the kidneys. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. Losartan and its metabolites are also eliminated by biliary excretion, with 58% of an oral dose recovered in the feces.
Amlodipine besilate: After oral administration of therapeutic doses of amlodipine, peak plasma concentrations are reached between 6 and 12 hours. Amlodipine's absolute bioavailability is between 64 and 90%; its bioavailability is unaffected by food. Amlodipine's volume of distribution is about 20 L/kg.
About 90% of amlodipine is converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Studies have shown that about 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Plasma elimination is biphasic with a terminal elimination half-life of 30 to 50 hours. Steady state plasma amlodipine concentrations are reached after 7 to 8 days of consecutive dosing.
The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Thus, the usual initial dose may be given to patients with renal failure.
Amlodipine's clearance is decreased and the AUC increased (by 40 to 60%) in elderly patients and patients with hepatic impairment. Plasma amlodipine elimination half-life (t1/2) is prolonged (56 hours) in patients with hepatic impairment. Thus, a lower initial dose may be given in these patients. A comparable increase in AUC was seen in patients with moderate to severe heart failure.
