Besartan Mechanism of Action

Pharmacotherapeutic group: Angiotensin II antagonists, plain. ATC code: C09CA01.
Pharmacology: Pharmacodynamics: Losartan is a synthetic oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin/angiotensin system and an important 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 selectively blocks the AT₁ receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.
Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is no potentiation of undesirable bradykinin-mediated effects.
During administration of losartan, removal of the angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, PRA and angiotensin II values fell within three days to the baseline values.
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.
Hypertension Studies: In controlled clinical studies, once-daily administration of losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurement of blood pressure 24 hours post-dose relative to 5-6 hours post-dose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood pressure reduction at the end of the dosing interval was 70-80% of the effect seen 5-6 hours post-dose.
Discontinuation of losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, losartan had no clinically significant effect on heart rate.
Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.
LIFE-Study: The Losartan Intervention for Endpoint Reduction in Hypertension [LIFE] study was a randomized, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECG-documented left-ventricular hypertrophy. Patients were randomized to once daily losartan 50 mg or once daily atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. Other antihypertensive, with the exception of ACE-inhibitors, angiotensin II antagonists or beta-blockers were added if necessary to reach the goal blood pressure.
The mean length of follow up was 4.8 years.
The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. Blood pressure was significantly lowered to similar levels in the two groups. Treatment with losartan resulted in a 13.0% risk reduction (p=0.021, 95% confidence interval 0.77-0.98) compared with atenolol for patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.
Race: In the LIFE-Study, Black patients treated with losartan had a higher risk of suffering the primary combined endpoint, i.e. a cardiovascular event (e.g. cardiac infarction, cardiovascular death) and especially stroke, than the Black patients treated with atenolol. Therefore, the results observed with losartan in comparison with atenolol in the LIFE study with regard to cardiovascular morbidity/mortality do not apply for Black patients with hypertension and left ventricular hypertrophy.
RENAAL Study: The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan RENAAL study was a controlled clinical study conducted worldwide in 1513 Type 2 diabetic patients with proteinuria, with or without hypertension. 751 patients were treated with losartan.
The objective of the study was to demonstrate a nephroprotective effect of losartan potassium over and above the benefit of lowering blood pressure.
Patients with proteinuria and a serum creatinine of 1.3-3.0 mg/dL were randomized to receive losartan 50 mg once a day, titrated if necessary, to achieve blood pressure response, or to placebo, on a background of conventional antihypertensive therapy excluding ACE-inhibitors and angiotensin II antagonists. Investigators were instructed to titrate the study medication to 100 mg daily as appropriate; 72% of patients were taking the 100 mg daily dose for the majority of the time. Other antihypertensive agents (diuretics, calcium antagonists, alpha- and beta-receptor blockers and also centrally acting antihypertensive) were permitted as supplementary treatment depending on the requirement in both groups. Patients were followed up for up to 4.6 years (3.4 years on average). The primary endpoint of the study was a composite endpoint of doubling of the serum creatinine end-stage renal failure (need for dialysis or transplantation) or death.
The results showed that the treatment with losartan (327 events) as compared with placebo (359 events) resulted in a 16.1% risk reduction (p=0.022) in the number of patients reaching the primary composite endpoint. For the following individual and combined components of the primary endpoint, the results showed a significant risk reduction in the group treated with losartan: 25.3% risk reduction for doubling of the serum creatinine (p=0.006); 28.6% risk reduction for end-stage renal failure (p=0.002); 19.9% risk reduction for end-stage renal failure or death (p=0.009); 21.0% risk reduction for doubling of serum creatinine or end-stage renal failure (p=0.01).
All-cause mortality rate was not significantly different between the two treatment groups. In this study, losartan was generally well tolerated, as shown by a therapy discontinuation rate on account of adverse reactions that was comparable to the placebo group.
ELITE I and ELITE II Studies: In the ELITE Study carried out over 48 weeks in 722 patients with heart failure (NYHA Class II-IV), no difference was observed between the patients treated with losartan and those treated with captopril was observed with regard to the primary endpoint of a long-term change in renal function. The observation of the ELITE I Study, that compared with captopril, losartan reduced the mortality risk, was not confirmed in the subsequent ELITE II Study, which is described in the following.
In the ELITE II Study, losartan 50 mg once daily (starting dose 12.5 mg, increased to 25 mg, then 50 mg once daily) was compared with captopril 50 mg three times daily (starting dose 12.5 mg, increased to 25 mg and then to 50 mg three times daily). The primary endpoint of this prospective study was the all-cause mortality. In this study, 3152 patients with heart failure (NYHA Class II-IV) were followed for almost two years (median: 1.5 years) to determine whether losartan is superior to captopril in reducing all-cause mortality. The primary endpoint did not show any statistically significant difference between losartan and captopril in reducing all-cause mortality.
In both comparator-controlled (not placebo-controlled) clinical studies on patients with heart failure the tolerability of losartan was superior to that of captopril, measured based on a significantly lower rate of discontinuations of therapy on the account of adverse reactions and a significantly lower frequency of cough.
An increased mortality was observed in ELITE II in the small subgroup (22% of all HF patients) taking beta-blockers at baseline.
Pharmacokinetics: Absorption: 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.
Distribution: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres.
Biotransformation: 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.
Elimination: 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 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. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma. Both biliary and urinary excretions contribute to the elimination of losartan and its metabolites. Following an oral dose/intravenous administration of ¹⁴C-labelled losartan in man, about 35%/43% of radioactivity is recovered in the urine and 58%/50% in the faeces.
Characteristics in patients: 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.
Plasma concentrations of losartan are not altered in patients with a creatinine clearance above 10 mL/minute. Compared to patients with normal renal function, the AUC for losartan is about 2-times higher in haemodialysis patients.
The 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.
Pharmacokinetics in paediatric patients: The pharmacokinetics of losartan have been investigated in 50 hypertensive paediatric patients >1 month to <16 years of age following once daily oral administration of approximately 0.54 to 0.77 mg/kg of losartan (mean doses).
The results showed that the active metabolite is formed from losartan in all age groups. The results showed roughly similar pharmacokinetic parameters of losartan following oral administration in infants and toddlers, preschool children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups. When comparing preschool children with adolescents these differences became statistically significant. Exposure in infants/toddlers was comparatively high.