Esatec 20/Esatec 40 Mechanism of Action

Pharmacology: Mechanism of Action: Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT₁) antagonist. It is expected to block all actions of angiotensin II mediated by the AT₁ receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT₁) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT₁) receptor.
Pharmacokinetics: Absorption and distribution: Olmesartan is a prodrug. It is rapidly converted to the pharmacologically active metabolite, Olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract.
No intact Olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of Olmesartan from a tablet formulation was 25.6%.
The mean peak plasma concentration (C_max) of Olmesartan is reached within about 2 hours after oral dosing with Olmesartan medoxomil, and Olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.
Food had minimal effect on the bioavailability of Olmesartan and therefore Olmesartan medoxomil may be administered with or without food.
No clinically relevant gender-related differences in the pharmacokinetics of Olmesartan have been observed.
Olmesartan is highly tound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between Olmesartan and other highly bound co-administered drugs is low (as confirmed by the lack of clinically significant interaction between Olmesartan medoxomil and Warfarin). The binding of Olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16-29 L).
Biotransformation and elimination: Total plasma clearance was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of ¹⁴C-labelled Olmesartan medoxomil, 10-16% o the administered radioactivity was exerted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the feces. Based on the systemic availability of 25.6%, it can be calculated that absorbed Olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as Olmesartan. No other significant metabolite was detected. Enterohepatic recycling of Olmesartan is minimal. Since a large proportion of Olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.
The terminal elimination half-life of Olmesartan varied between 10 and 15 hours after multiple dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5-0.7 L/h and was independent of dose.
Pharmacokinetics in special populations: Pediatric population: The pharmacokinetics of Olmesartan was studied in pediatric hypertensive patients aged 1 to 16 years. The clearance of Olmesartan in pediatric patients was similar to that in adult patients adjusted by the body weight.
There is no pharmacokinetic information available in renally impaired pediatric subjects.
Elderly (age 65 years or over): In hypertensive patients, the AUC at steady state was increased by ca 35% in elderly people (65-75 years old) and by ca 44% in very elderly people (≥75 years old) compared with the younger age group. This may be at least in part related to a mean decrease in renal function in this group of patients.
Renal impairment: In renally impaired patients, the AUC at steady state increased by 62%, 82% and 179% patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls.
Hepatic impairment: After single oral administration, Olmesartan AUC values were 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of Olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, Olmesartan mean AUC was again about 65% higher than in matched healthy controls. Olmesartan mean C_max values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.