Tozam Mechanism of Action

Pharmacology: Pharmacodynamics: Losartan Potassium: it is an angiotensin II receptor (type AT1) antagonist. Angiotensin II is a potent vasoconstrictor and an important component in the pathophysiology of hypertension. Losartan potassium blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g. Vascular smooth muscle, adrenal gland).
Amlodipine Besilate: Amlodipine besilate is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile process of cardiac muscle and vascular smooth muscle are dependent upon movement of extra cellular calcium ions into these cells through specific ion channels. By inhibiting calcium ion influx, it directly dilates vascular smooth muscle, resisting hypertension. The mechanism of relieve angina pectoris with amlodipine is not yet determined completely, but it is clear that this product can bate myocardial ischemia through the following functions: Dilate the peripheral small artery, decreasing peripheral resistance, causing the reduction of energy consumption and oxygen requirement of cardiac muscle.
Dilate the coronary artery and the small coronary artery at normal and ischaemic areas, increasing the oxygen supply of cardiac muscle in patients with coronary spasm.
Pharmacokinetics: Losartan Potassium: The pharmacokinetics of Losartan potassium and its active metabolite (E-3174) are linear with oral doses up to 200 mg and do not change overtime. Neither Losartan potassium, nor its metabolite accumulates in plasma upon repeated once-a-day dosing. Following oral administration, Losartan potassium has a systemic bioavailability of around 33%. Losartan potassium undergoes substantial first pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows Losartan potassium treatment. About 14% of an orally administered dose is converted to the active metabolite. After oral administration Losartan potassium is rapidly absorbed, reaching peak plasma concentrations within an hour. Losartan potassium and E-3174 have been reported to reach peak plasma concentration of 296 ng/mL and 249 ng/mL in 1.0 and 4.1 hours respectively after single oral dose of 50 mg in healthy volunteers. The area under the plasma concentration time curve (AUC) for E-3174 is approximately 4 fold greater than for Losartan potassium (1915 vs 476 ng*h/mL). Absorption is slowed and Cmax reduced by food. Losartan potassium and E-3174 are highly protein bound (98.7% and 99.8%) with volumes of distribution of 34L and 12L respectively. Approximately 35% of the drug is eliminated in the urine and approximately 60% is excreted in the feces. Losartan potassium and E-3174 have elimination half-lives of 2 and 6-9 hours respectively. The rate of renal clearance of Losartan potassium and E-3174 is 4.3 and 1.6L/h.
AMLODIPINE BESILATE: After oral administration of therapeutic doses of amlodipine besilate, absorption occurs gradually with peak plasma concentration occurring between 6 to 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food. Amlodipine has a large volume of distribution (Vd) of 21L/kg and highly plasma protein bound (95%).
Amlodipine undergoes extensive, but slow hepatic metabolism. The dihydropyridine moiety is oxidized to the pyridine analogue during initial biotransformation, with minimal first-pass or presystemic metabolism. Metabolites have no significant activity. Less than 10% of an oral dose is excreted unchanged. Following oral administration 60% of oral dose is recovered in the urine mainly as metabolites and 20 to 25% in the feces. The elimination half-life of Amlodipine is in the range of 30 to 50 hours in healthy subjects.