Colixtan Mechanism of Action

Angiotensin II Receptor Blocker (ARB)/Calcium Channel Blocker (Dihydropyridine Derivative).
Pharmacology: Pharmacodynamics: Fixed-dose combination of Losartan and Amlodipine has been shown to be effective in lowering blood pressure. Both losartan and amlodipine lower blood pressure by reducing peripheral resistance. Calcium influx blockade and reduction of angiotensin II vasoconstriction are complementary mechanisms.
Losartan inhibits systolic and diastolic pressor responses to angiotensin II infusions. At peak, 100 mg of Losartan Potassium inhibits these responses by approximately 85%; 24 hours after single and multiple-dose administration, inhibition is about 26-39%. Since Losartan is a specific antagonist of the angiotensin II receptor type AT1, it does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Plasma concentrations of Losartan and its active metabolite and the antihypertensive effect of Losartan increase with increasing dose. Since Losartan and its active metabolite are both angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.
Generally, Losartan caused a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy.
Amlodipine Hemodynamics: 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. With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with Amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg).
Pharmacokinetics: Absorption: Losartan: Following oral administration, Losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of Losartan tablets is approximately 33%. Mean peak concentrations of Losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively.
Amlodipine: After oral administration of therapeutic doses of Amlodipine, 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 is not altered by the presence of food.
Distribution: Losartan: Both Losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of Losartan is 34 liters.
Amlodipine: Approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients.
Metabolism: Losartan: About 14% of an intravenously or orally administered dose of Losartan is converted to its active metabolite.
Amlodipine: Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination: Losartan: Plasma clearance of Losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of Losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite.
Amlodipine: Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing.