Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: MSD (Pty) Ltd, 117 16th Road, Halfway House, South Africa, 1685
Pharmacological classification: A 7.1.3. Other hypotensives
Losartan potassium is an angiotensin II receptor (type AT1) antagonist, and hydrochlorothiazide is a diuretic.
Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the reninangiotensin system, and a major determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys, and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation.
Losartan is a synthetic, orally active compound which binds selectively to the AT1 receptor. Both losartan and its pharmacologically active carboxylic acid metabolite (E-3174) block the actions of angiotensin II, regardless of the source of synthesis.
The mechanism of the antihypertensive effect of thiazides is unknown.
Hydrochlorothiazide, when used as a diuretic affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by loss of potassium, magnesium and bicarbonate.
Losartan and hydrochlorothiazide are additive in their antihypertensive efficacy.
Following oral administration, losartan 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. There was no clinically significant effect on the plasma concentration profile of losartan when losartan was administered with a standardised meal.
Both losartan and its active metabolite are 99% and more bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite.
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 potassium 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. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively.
Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the faeces.
Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-fold and 1,7-fold greater than those seen in young male volunteers.
Neither losartan nor the metabolite can be removed by haemodialysis.
When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5,6 and 14,8 hours. Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
In a pharmacokinetic interaction study, hydrochlorothiazide 12,5 mg did not alter the pharmacokinetics of losartan 50 mg and vice versa.
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