Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Unicorn Pharmaceuticals (Pty) Ltd, Corner of Searle & Pontac Streets, Woodstock, Cape Town, 8001, enquiries@unicornpharma.co.za
A 7.1.3 Vascular medicines – other hypotensives.
Pharmacotherapeutic group: Angiotensin II antagonists, plain
ATC code: C09CA01
Losartan is a synthetic, orally active nonpeptide angiotensin II receptor antagonist with high affinity and selectivity for the AT1 receptor. Both losartan and its principal active metabolite have a far greater affinity for the AT1-receptor than for the AT2-receptor. The active metabolite is 10- to 40-times more active than losartan on a weight for weight basis. Angiotensin II is a potent vasoconstrictor, a primary active hormone of the renin-angiotensin 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 and its pharmacologically active carboxylic acid metabolite (E-3174) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by inhibiting the binding of angiotensin II to the AT1 receptor, regardless of the source or route of synthesis.
Losartan is a specific antagonist of the angiotensin II receptor type AT1; it does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit angiotensin converting enzyme (ACE) (kininase II), the enzyme that degrades bradykinin. Consequently, effects not directly related to blocking the AT1 receptor, such as the potentiation of bradykinin-mediated effects or the generation of oedema are not associated with losartan. This provides a pharmacodynamic distinction between losartan and ACE inhibitors. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity, during losartan administration. A 2 to 3-fold increase in angiotensin II in plasma comes as a result of increases in plasma renin activity. However, antihypertensive activity and suppression of plasma aldosterone concentration are apparent, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, plasma renin activity and angiotensin levels decline to untreated levels within 3 days.
Following oral administration, bioavailability is approximately 33%. It undergoes first-pass metabolism to form an active carboxylic acid metabolite (which has greater pharmacological activity than losartan) and some inactive metabolites. About 14% of orally administered dose is converted to its active metabolite. The mean peak concentrations of losartan and its active metabolite are reached in 1 hour and 3–4 hours respectively.
Both losartan and carboxylic acid metabolite are greater than, or equal to 99% bound to plasma proteins. The distribution volume of losartan is 34 litres.
About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labelled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.
In addition to the active metabolite, inactive metabolites are formed.
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. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg.
The terminal half-life of losartan is about 2 hours and that of its active metabolite is 6–9 hours. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Losartan is excreted in the urine, and in the faeces, as unchanged losartan and metabolites.
Following oral dosing of 14C-labeled losartan in man, about 35% of the dose is excreted in the urine and about 60% in the faeces. Neither losartan nor the active metabolite can be removed by haemodialysis.
In elderly hypertensive patients the plasma concentrations of losartan and its active metabolite do not differ essentially from those found in young hypertensive patients.
In female hypertensive patients the plasma levels of losartan were up to twice as high as in male hypertensive patients, while the plasma levels of the active metabolite did not differ between men and women.
In patients with mild to moderate alcohol-induced hepatic cirrhosis, the plasma levels of losartan and its active metabolite after oral administration were respectively 5 and 1,7 times higher than in young male volunteers.
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.
Plasma concentrations of losartan are not altered in patients with impaired renal function and a creatinine clearance above 10 ml/min. Compared to patients with normal renal function, the area under the curve (AUC) for losartan is approximately 2-fold greater in patients on haemodialysis.
Plasma concentrations of the active metabolite are not altered in patients with renal impairment or in haemodialysis patients. Neither losartan nor the active metabolite can be removed by haemodialysis.
Not applicable.
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