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Pharmacology: Pharmacodynamics: Olmesartan is the first-line drug in a new class of antihypertensive agents that are selective angiotensin II receptors (AT1) antagonists. Angiotensin II is a potent vasoconstrictor and primary active hormone of the renin-angiotensin-aldosterone system, which plays a major role in the pathophysiology of hypertension. The cardiovascular homeostatic effects of angiotensin II are expressed through the AT1 receptor. Olmesartan has an affinity for the AT receptor 12,500 times that of the AT receptor, so it can be said that the Angiotensin receptor blocking effect of Olmesartan is highly selective.
Olmesartan is a potent, oral, synthetic active ingredient that selectively binds to AT1 receptors. In vitro and in vivo, both Olmesartan and its pharmacologically active metabolite (E-3174) block all physiologically relevant effects of angiotensin II, including vasoconstrictor effects, salt-water retention, and sympathetic stimulation. This leads to a drop in blood pressure. Olmesartan has no antagonistic activity and does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation.
The effects of angiotensin II on AT1 receptors can be summarized as follows: Vasoconstrictor effect.
Make the heart contract stronger and faster.
At low doses that do not cause vasoconstriction, angiotensin II and III stimulate the synthesis and secretion of aldosterone for sodium retention and potassium excretion.
Angiotensin II also has a spasmolytic effect on certain smooth muscles such as the ileum, uterus, and bronchi.
On the central nervous system, angiotensin II stimulates the sympathetic system and releases noradrenalin, causing the patient to thirst and drink water.
Blocking the AT1 receptor would have the opposite effect of the previously mentioned effects.
Pharmacokinetics: Absorption: Olmesartan medoxomil is rapidly absorbed from the gastrointestinal tract and esterified to the active form. Absorption of the drug is not affected by food.
The drug is not metabolized by cytochrome P450. Olmesartan medoxomil is rapidly absorbed orally.
The mean peak plasma concentration: is reached within about 60-120 minutes after oral administration. Olmesartan is highly bound to plasma protein (99%). Therefore, the drug is released gradually and is stable for 24 hours.
Biotransformation and elimination: Bioavailability: 26%.
Half-life: 13 hours.
Elimination: 35-50% in the urine, the rest in the feces.
The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. A 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: Paediatric 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 when adjusted by the body weight.
There is no pharmacokinetic information available in really impaired pediatric subjects.
Older people (age 65 years or older): In hypertensive patients, the AUC at steady state was increased by 35% in older people (65-75 years old) and by 44% in very old people (≥75 years old) compared with the younger group. This may be at least in part related to a mean decrease in renal function in this group of patients.
Renal impairment: In renal impaired patients, the AUC at steady state increased by 62%, 82%, and 179% in 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 mild and moderate hepatic 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 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 Cmax values are similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.
