Actions of Ortan in details
Pharmacodynamics: 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, 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.
An AT2 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 renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. Angiotensin-converting enzyme inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Ortan 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.
Pharmacodynamics Properties: Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium.
Oral doses of Ortan 2.5-40 mg inhibited the pressor response to exogenous angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Ortan >40 mg giving >90% inhibition at 24 hrs. Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity increased after single or repeated administration of Ortan to healthy subjects or hypertensive patients. Ortan administration had little effect on plasma levels of aldosterone and no effect on serum potassium.
Clinical Trials: The antihypertensive effects of Ortan have been demonstrated in 7 placebo-controlled studies at doses ranging from 2.5-80 mg for 6-12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2,693 patients (Ortan 2,145; placebo 548) with essential hypertension were studied. Ortan once daily lowered diastolic and systolic blood pressure. The response was dose-related as shown in the following figure. An Ortan dose of 20 mg daily produces a trough sitting blood pressure reduction over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting blood pressure reduction over placebo of about 12/7 mmHg. Ortan doses >40 mg had little additional effect. The onset of the antihypertensive effect occurred within 1 week and was largely manifested after 2 weeks.
Data above are from seven placebo-controlled studies (2,145 Ortan patients, 548 placebo patients). The blood pressure lowering effect was maintained throughout the 24-hour period of Ortan once daily, with trough-to-peak ratios for systolic and diastolic response between 60% and 80%.
The blood pressure-lowering effect of Ortan, 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 Ortan or rebound effect following abrupt withdrawal of Ortan after 1 year of treatment.
The antihypertensive effect of Ortan 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 β-blockers. Ortan 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: Ortan 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 (t½) of approximately 13 hrs.
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 3-5 days and no accumulation in plasma occurs with once-daily dosing.
The absolute mean bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1-2 hrs. 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 IV dosing is in the range of 16-29 L.
In rats, olmesartan crossed the blood-brain barrier, 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 Ortan to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/hr, with a renal clearance of 0.6 L/hr. Approximately 30-50% of the systematically absorbed drug is excreted in the urine while the remainder is excreted in faeces (via the bile).
Depending on ethnic origin, the terminal elimination t½ of olmesartan varied between 6-15 hrs. Steady state was reached after the 1st few doses and no further accumulation was evident with repeated dosing. Renal clearance was approximately 0.5-0.7 L/hr.
Special Populations: Pediatric: The pharmacokinetics of olmesartan have not been investigated in patients <18 years.
Elderly: In Caucasian patients, the area under the concentration-time curve (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. Area under the concentration-time curve 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.
Drug Interactions: No significant pharmacokinetic interactions were observed in studies in which Ortan was co-administered with digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacids (aluminium magnesium hydroxide).
Ortan 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 Colesevalam: Concomitant administration of Ortan 40 mg and colesevalam hydrochloride 3750 mg 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 Ortan was administered 4 hrs prior to colesevelam hydrochloride.
Toxicology: Preclinical Safety Data: Preclinical carcinogenicity studies revealed no clinically relevant risk for humans. In reproductive studies in rats, Ortan did not affect fertility. In common with other angiotensin II receptor antagonists, survival of offspring was reduced following exposure to Ortan and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, Ortan was shown to be more toxic to pregnant rabbits than to pregnant rats; however, there was no indication of a fetotoxic effect.
Ortan 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, 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.
An AT2 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 renin-angiotensin system 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 Ortan 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.
Pharmacodynamics
Ortan doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Ortan >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of Ortan to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg Ortan had minimal influence on aldosterone levels and no effect on serum potassium.
Pharmacokinetics
Absorption
Ortan is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract.
Ortan tablets and the suspension formulation prepared from Ortan tablets are bioequivalent.
The 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.
Distribution
The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.
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 Ortan 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 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
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.
Geriatric
The pharmacokinetics of olmesartan were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Pediatric
The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight.
Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.
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.
Hepatic Insufficiency
Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Renal Insufficiency
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.
Drug Interaction
Bile acid sequestering agent colesevelam
Concomitant administration of 40 mg Ortan and 3750 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 Ortan was administered 4 hours prior to colesevelam hydrochloride.
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Information checked by Dr. Sachin Kumar, MD Pharmacology
