Therapeutic Indication
● High Blood Pressure (Hypertension)
● Severe Hypertension
● Moderate Hypertension
● Coronary Artery Disease
Pharmacology
Mechanism of Action:
Losartan reversibly and competitively prevents angiotensin II binding to the AT1 receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT1 receptor with 1000 times more affinity than they bind to the AT2 receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT1 and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure.
Amlodipine is a popular calcium channel blockers categorized as dihydropyridine and is intensively used as antihypertensive. It shows selectivity for the peripheral blood vessels, dihydropyridine calcium channel blockers are associated with a lower incidence of myocardial depression and cardiac conduction abnormalities than other calcium channel blockers. Amlodipine is commonly indicated for high blood pressure and angina. Amlodipine exhibits antioxidant properties and an ability to enhance the production of nitric oxide (NO), an important endogenous vasodilator that decreases blood pressure. It has maximum half-life among DHP and usually requires once daily administration. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks influx of calcium ion across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells.
Pharmacokinetics:
Losartan Potassium:
Absorption: Losartan is approximately 33% orally bioavailable. Losartan has a Tmax of 1 hour and the active metabolite has a Tmax of 3-4 hours. Taking losartan with food decreases the Cmax but does only results in a 10% decrease in the AUC of losartan and its active metabolite.
Volume of distribution: The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite.
Protein Binding: Losartan is 98.6-98.8% protein bound and the active metabolite (E-3174) is 99.7% protein bound in serum.
Metabolism: Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9.1 Losartan can also be hydroxylated to an inactive metabolite
Route of elimination: A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces.
The terminal elimination half-life of losartan is 1.5-2.5 hours while the active metabolite has a half-life of 6-9 hours.
Amlodipine:
Absorption: Absorbed slowly and almost completely from the gastrointestinal tract
Peak plasma concentrations are achieved 6-12 hours after oral administration
The estimated bioavailability of amlodipine is 64-90%
Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing
Absorption is not affected by food
Volume of distribution: 21 L/kg
Protein binding: About 98%
Metabolism: Metabolised in liver and converted into inactive metabolites with 10% of the parent compound and 60% of the metabolites found excreted in the urine.
The terminal elimination half-life of about 30–50 hours.
Side Effects
Common side effects include:
● Swelling of your legs or ankles.
● Tiredness or extreme sleepiness.
● Stomach pain.
● Nausea.
● Dizziness.
● Hot or warm feeling in your face (flushing)
● Irregular heart rate (arrhythmia)
● Very fast heart rate (palpitations)
● Sinus pain and congestion
● Back pain
● Diarrhea
● Sore throat
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