Mechanism of Action of Olmesartan
Olmesartan works by selectively blocking angiotensin II from binding to the AT1 receptor in vascular smooth muscle, thereby preventing vasoconstriction and the downstream effects of the renin-angiotensin-aldosterone system; it blocks the hormone angiotensin II. 1
How Olmesartan Functions
Blocking Angiotensin II at the Receptor Level
Olmesartan selectively blocks the binding of angiotensin II to the AT1 receptor, which is the principal receptor mediating the cardiovascular effects of angiotensin II, including vasoconstriction, aldosterone release, cardiac stimulation, and sodium reabsorption in the kidneys. 1
The drug has more than 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor, making it highly selective for blocking the pathological effects of angiotensin II. 1
Olmesartan demonstrates insurmountable antagonism against the AT1 receptor in vascular tissues, meaning it binds tightly to the receptor and produces potent, persistent blockade that cannot be easily overcome by increased angiotensin II levels. 2, 3
Key Structural Features
Olmesartan medoxomil is a prodrug that is rapidly and completely converted to the active metabolite olmesartan through ester hydrolysis during absorption from the gastrointestinal tract. 1
After conversion to olmesartan, there is virtually no further metabolism of the drug, and it does not interact with cytochrome P450 enzymes, minimizing drug-interaction potential. 1, 3
The unique structural elements include a hydroxyalkyl substituent at the imidazole 4-position and a hydrolyzable ester group at the imidazole 5-position, which contribute to inter- and intramolecular hydrogen bonding that may potentiate antagonist activity. 4
The Hormone Blocked: Angiotensin II
Formation and Effects of Angiotensin II
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, also known as kininase II). 1
Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include:
Distinction from ACE Inhibitors
Olmesartan's action is independent of the pathways for angiotensin II synthesis, unlike ACE inhibitors which block the conversion of angiotensin I to angiotensin II. 1
Because olmesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin, which is degraded by ACE. This is a key difference from ACE inhibitors, which inhibit bradykinin degradation and may cause side effects like cough. 1
The clinical relevance of this difference is that side effects, notably cough, are significantly less with angiotensin II receptor antagonists than with ACE inhibitors. 5
Pharmacodynamic Effects
Compensatory Responses
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, resulting in increased plasma renin activity and circulating angiotensin I and II levels. 1
However, the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure, as the AT1 receptors remain blocked. 1
Duration and Potency
Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion, with the duration of inhibitory effect related to dose. 1
Doses greater than 40 mg give more than 90% inhibition at 24 hours, supporting once-daily dosing. 1
The drug achieves peak plasma concentration within 1 to 2 hours after oral administration, with a terminal elimination half-life of approximately 13 hours. 1, 2
Clinical Implications
Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium in healthy subjects and hypertensive patients. 1
The safety profile is similar to other ARBs and no different than placebo in well-designed clinical trials. 2
Olmesartan has demonstrated superior blood pressure lowering compared to other ARBs (losartan, valsartan, irbesartan, candesartan) at their recommended maintenance doses in head-to-head trials. 3, 6