Olmetec Plus Mechanism of Action

Pharmacotherapeutic Group: Angiotensin II antagonists and diuretics. ATC Code: C09D A.
Pharmacology: Pharmacodynamics: Olmetec Plus is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone. Once-daily dosing with Olmetec Plus provides an effective and smooth reduction in blood pressure over the 24-hr dose interval.
Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT₁) antagonist. Angiotensin II is the primary vasoactive hormone of the reninangiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT₁) receptors by olmesartan results in increases in plasma renin levels, and angiotensin I and II concentrations and some decrease in plasma aldosterone concentrations.
In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of 1st-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.
Once-daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24-hr dose interval. Once-daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.
With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is observed after 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and morbidity is not yet known. Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin aldosterone link is mediated by angiotensin II and therefore, co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With hydrochlorothiazide, onset of diuresis occurs at about 2 hrs and peak effect occurs at about 4 hrs post-dose, while the action persists for approximately 6-12 hrs.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The combination of olmesartan medoxomil and hydrochlorothiazide produces additive reductions in blood pressure which generally increase with the dose of each component. In pooled placebo-controlled studies, administration of the 20/12.5 mg, 40/12.5 mg and 40/25 mg combinations of olmesartan medoxomil/hydrochlorothiazide resulted in mean placebo-subtracted systolic/diastolic blood pressure reductions at trough ranging from 12/7-16/9 mmHg. Age and gender had no clinically relevant effect on response to treatment with olmesartan medoxomil/hydrochlorothiazide combination therapy.
Administration of hydrochlorothiazide 12.5 mg and 25 mg in patients insufficiently controlled by olmesartan medoxomil 20 mg monotherapy gave additional reductions in 24-hr diastolic/systolic blood pressures measured by ambulatory blood pressure monitoring of 7/5 mmHg and 12/7 mmHg, respectively, compared with olmesartan medoxomil monotherapy baseline. The additional mean systolic/diastolic blood pressure reductions at trough compared with baseline, measured conventionally, were 11/10 mmHg and 16/11 mmHg, respectively. The addition hydrochlorothiazide 12.5 mg in patients not achieving target blood pressure (≤130/85 mmHg) on olmesartan medoxomil 40 mg decreased systolic/diastolic blood pressure by an additional 13/6 mmHg, and titration of the hydrochlorothiazide dose to 25 mg in non-achievers at the lower add-on dose resulted in a further blood pressure decrease of 9/5 mmHg. Conversely, addition of olmesartan medoxomil 10-20 mg in patients with moderate to severe hypertension insufficiently controlled by hydrochlorothiazide 25 mg monotherapy provided mean systolic/diastolic blood pressure reductions at trough of 21/18 mmHg compared with hydrochlorothiazide monotherapy baseline.
The effectiveness of olmesartan medoxomil/hydrochlorothiazide combination therapy was maintained over long-term (1 year) treatment. Withdrawal of olmesartan medoxomil therapy, with or without concomitant hydrochlorothiazide therapy, did not result in rebound hypertension. The effects of fixed dose combination of olmesartan medoxomil/hydrochlorothiazide on mortality and cardiovascular morbidity are currently unknown.
Pharmacokinetics: Concomitant administration of olmesartan medoxomil and hydrochlorothiazide had no clinically-relevant effects on the pharmacokinetics of either component in healthy subjects.
Absorption and Distribution: Olmesartan medoxomil 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 hrs 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 bound 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 a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after IV dosing is low (16-29 L).
Hydrochlorothiazide: Following oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5-2 hrs after dosing. Hydrochlorothiazide is 68% protein bound in the plasma apparent volume of distribution is 0.83-1.14 L/kg.
Metabolism and Elimination: Olmesartan Medoxomil: Total plasma clearance of olmesartan was typically 1.3 L/hr (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/hr). Following a single oral dose of ¹⁴C-labelled olmesartan medoxomil, 10-16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hrs of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepatobiliary 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 (see Contraindications).
The terminal elimination half-life of olmesartan varied between 10 and 15 hrs after multiple oral dosing. Steady state was reached after the 1st few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5-0.7 L/hr and was independent of dose.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized in man and is excreted almost entirely as unchanged drug in urine. About 60% of the oral dose is eliminated as unchanged drug within 48 hrs. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hrs.
Special Populations: Elderly: In hypertensive patients, the olmesartan area under the curve (AUC) at steady state was increased by ca 35% in elderly patients (65-75 years) and by ca 44% in very elderly patients (≥75 years) compared with the younger age group (see Dosage & Administration).
Renal Impairment: In renally impaired patients, the olmesartan AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls (see Dosage & Administration and Interactions).
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 hrs 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. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see Dosage & Administration and Interactions).
Toxicology: Preclinical Safety Data: The toxic potential of Olmetec Plus was evaluated in repeated-dose oral toxicity studies with olmesartan medoxomil/hydrochlorothiazide combinations for up to 6 months in rats and dogs. Most observations were due to the pharmacological activity of the combination and there were no findings that would preclude administration to humans at the therapeutic dosage level.
There was no evidence of relevant genotoxic activity under conditions of clinical use. Olmesartan medoxomil/hydrochlorothiazide in a ratio of 20:12.5 was negative in the bacterial reverse mutation test up to the maximum recommended plate concentration for the standard assays. Olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20: 12.5 and 10:12.5, for clastogenic activity in the in vitro Chinese hamster lung chromosomal aberration assay. As expected, a positive response was seen for each component and combination ratio. However, no synergism in clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio. Olmesartan medoxomil/hydrochlorothiazide in a ratio of 20:12.5, administered orally, tested negative in the in vivo mouse bone marrow erythrocyte micronucleus assay at administered doses of up to 1935/1209 mg/kg.
The carcinogenic potential of a combination of olmesartan medoxomil and hydrochlorothiazide was not investigated as there was no evidence of relevant carcinogenic effects for the 2 individual components under conditions of clinical use.
There was no evidence of teratogenicity in mice or rats treated with olmesartan medoxomil/hydrochlorothiazide combinations. As expected from this class of drug, foetal toxicity was observed in rats, as evidenced by significantly reduced foetal body weights, when treated with olmesartan medoxomil/hydrochlorothiazide combinations during gestation (see Contraindications and Use in pregnancy & lactation under Precautions).