Sign Out
Pharmacology: Pharmacodynamics: Mechanism of action: Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting. Telmisartan does not show affinity for other receptors, including AT2 and other less characterized AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by Telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore, it is not expected to potentiate bradykinin-mediated adverse effects.
An 80 mg dose of Telmisartan administered to healthy volunteers almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides have an effect on 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, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of telmisartan tends to reverse the potassium loss associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
80 mg/12.5 mg: Telmisartan/Hydrochlorothiazide is a combination of an angiotensin II receptor antagonist, telmisartan, 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. Telmisartan/Hydrochlorothiazide once daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.
Pharmacokinetics: Absorption: Telmisartan: Following oral administration peak concentrations of Telmisartan are reached in 0.5-1.5 h after dosing. The absolute bioavailability of Telmisartan at 40 mg and 160 mg was 42% and 58%, respectively. Food slightly reduces the bioavailability of Telmisartan with a reduction in the area under the plasma concentration time curve (AUC) of about 6% with the 40 mg tablet and about 19% after a 160 mg dose. By 3 hours after administration plasma concentrations are similar whether Telmisartan is taken fasting or with food. The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. Telmisartan does not accumulate significantly in plasma on repeated administration.
Hydrochlorothiazide: Following oral administration of Telmisartan and Hydrochlorothiazide peak concentrations of Hydrochlorothiazide are reached in approximately 1.0-3.0 hours after dosing. Based on cumulative renal excretion of Hydrochlorothiazide the absolute bioavailability was about 60%.
Distribution: Telmisartan is highly bound to plasma proteins (>99.5%) mainly albumin and alpha 1-acid glycoprotein. The apparent volume of distribution for Telmisartan is approximately 500 liters indicating additional tissue binding.
Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 L/kg.
Biotransformation: Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide. The glucuronide of the parent compound is the only metabolite that has been identified in humans. After a single dose of 14C-labelled Telmisartan the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of Telmisartan.
Hydrochlorothiazide is not metabolized in man.
Elimination: Telmisartan: Following either intravenous or oral administration of 14C-labelled Telmisartan most of the administered dose (>97%) was eliminated in feces via biliary excretion. Only minute amounts were found in the urine. Total plasma clearance of Telmisartan after oral administration is >1500 mL/min. Terminal elimination half-life was >20 hours.
Hydrochlorothiazide is excreted almost entirely as unchanged substance in urine. About 60% of the oral dose is eliminated within 48 hours. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hours.
Linearity/non-linearity: Telmisartan: The pharmacokinetics of orally administered telmisartan are non-linear over doses from 20-160 mg with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses.
Hydrochlorothiazide exhibits linear pharmacokinetics.
Elderly: Pharmacokinetics of Telmisartan do not differ between the elderly and those younger than 65 years.
Gender: Plasma concentrations of Telmisartan are generally 2-3 times higher in females than in males. In clinical trials however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. There was a trend towards higher plasma concentrations of Hydrochlorothiazide in female than in male subjects. This is not considered to be of clinical relevance.
Renal impairment: Renal excretion does not contribute to the clearance of Telmisartan. Based on modest experience in patients with mild to moderate renal impairment (creatinine clearance of 30-60 mL/min, mean about 50 mL/min) no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemodialysis. In patients with impaired renal function the rate of Hydrochlorothiazide elimination is reduced. In a typical study in patients with a mean creatinine clearance of 90 mL/min the elimination half-life of Hydrochlorothiazide was increased. In functionally anephric patients the elimination half-life is about 34 hours.
Hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.
80 mg/12.5 mg: Concomitant administration of hydrochlorothiazide and telmisartan does not appear to affect the pharmacokinetics of either substance in healthy subjects.
