Pharmacology: Mechanism of Action:
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin angiotensin system (RAS), with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1
receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1
receptor than for the AT2
receptor. Blockade of the RAS with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.
Angiotensin II is the principal pressor agent of the RAS, with effects that include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium.
Oral doses of olmesartan medoxomil 2.5 to 40 mg inhibited the pressor response to exogenous angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity increased after single or repeated administration of olmesartan medoxomil to healthy subjects or hypertensive patients. Olmesartan medoxomil administration had little effect on plasma levels of aldosterone and no effect on serum potassium.
The antihypertensive effects of olmesartan medoxomil have been demonstrated in seven placebo controlled studies at doses ranging from 2.5 to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2,693 patients (2,145 olmesartan medoxomil; 548 placebo) with essential hypertension were studied. Olmesartan medoxomil once daily (QD) lowered diastolic and systolic blood pressure. The response was dose related, as shown in the following graph. An olmesartan medoxomil dose of 20 mg daily produces a trough sitting BP reduction over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting BP reduction over placebo of about 12/7 mmHg. Olmesartan medoxomil doses greater than 40 mg had little additional effect. The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2 weeks. (See figure.)
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Data as previously mentioned are from seven placebo-controlled studies (2,145 olmesartan medoxomil patients, 548 placebo patients). The blood pressure lowering effect was maintained throughout the 24 hour period with olmesartan medoxomil once daily, with trough-to-peak ratios for systolic and diastolic response between 60% and 80%.
The blood pressure lowering effect of olmesartan medoxomil, with and without hydrochlorothiazide, was maintained in patients treated for up to 1 year. There was no evidence of tachyphylaxis during long term treatment with olmesartan medoxomil or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1 year of treatment.
The antihypertensive effect of olmesartan medoxomil was similar in men and women and in patients older and younger than 65 years. The effect was smaller in black patients (usually a low-renin population), as has been seen with other ACE inhibitors, angiotensin receptor blockers and beta-blockers. Olmesartan medoxomil had an additional blood pressure lowering effect when added to hydrochlorothiazide.
The Randomised Olmesartan And Diabetes Microalbuminuria Prevention (ROADMAP) clinical study included 4,447 patients with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor. Patients were randomized to olmesartan 40 mg daily or placebo. The trial met its primary endpoint, delayed onset of microalbuminuria. For the secondary endpoints, which the study was not designed to formally assess, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients [0.67%] vs. 3 patients [0.14%] [HR=4.94, 95% CI=1.43-17.06]).
Pharmacokinetics: Absorption and Distribution:
Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours.
Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once daily dosing.
The mean absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax
) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan.
Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The mean volume of distribution after intravenous dosing is in the range of 16-29 L.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Metabolism and Excretion:
Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h; with a renal clearance of 0.6 L/h. Approximately 30% to 50% of the systematically absorbed drug is excreted in the urine whilst the remainder is excreted in feces (via the bile).
Depending on ethnic origin, the terminal elimination half-life of olmesartan varied between 6 and 15 hours. Steady-state was reached after the first few doses, and no further accumulation was evident with repeated dosing. Renal clearance was approximately 0.5-0.7 L/h.
Pharmacokinetics in Special Populations:
Pediatric: The pharmacokinetics of olmesartan have not been investigated in patients <18 years of age.
Elderly: In Caucasian patients, the AUC at steady-state was increased by about 33% in elderly patients. These increases in bioavailability corresponded to reductions in renal clearance of about 30% in elderly.
Gender: Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and Cmax
were 10%-15% higher in women than in men.
Renal Impairment: In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min).
The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.
Hepatic Impairment: Mean olmesartan AUC after single oral administration to patients with moderate hepatic impairment was increased by about 48% compared with healthy controls (total group), or by about 60% when compared with matched controls only.
No significant pharmacokinetic interactions were observed in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacid (aluminium magnesium hydroxide). Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce or are metabolized by those enzymes are not expected.
Drug Interaction with Bile Acid Sequestering Agent Colesevelam: Concomitant administration of 40 mg olmesartan medoxomil and 3,750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax
and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax
and AUC, respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride (see INTERACTIONS).
Toxicology: PRECLINICAL SAFETY DATA:
Preclinical carcinogenicity studies revealed no clinically relevant risk for humans. In reproductive studies in rats, olmesartan medoxomil did not affect fertility. In common with other angiotensin II receptor antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil, and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats; however, there was no indication of a fetotoxic effect.