Telday H 40/12.5/Telday H 80/12.5 Mechanism of Action

Pharmacotherapeutic group: Angiotensin II antagonist and diuretics.
Pharmacology: Pharmacodynamics: Telday H 40/12.5: 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.
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 characterised 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.
Telday H 80/12.5: Telmisartan: In normal volunteers, a dose of Telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.
Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose dependent manner after single administration of Telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg Telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).
In 30 hypertensive patients with normal renal function treated for 8 weeks with Telmisartan 80 mg or Telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance.
Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics: Telday H 40/12.5: Concomitant administration of Telmisartan and hydrochlorothiazide does not appear to affect the pharmacokinetics of either substance in healthy subjects.
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 the fixed dose combination, peak concentrations of hydrochlorothiazide are reached in approximately 1-3.0 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 litres indicating additional tissue binding.
Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-14 L/kg.
Biotransformation: Telmisartan is metabolised by conjugation to form a pharmacologically inactive acylglucuronide. 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 metabolised in man.
Elimination: Telmisartan: Following either intravenous or oral administration of ¹⁴C-labelled Telmisartan, most of the administered dose (>97%) was eliminated in faeces via biliary excretion. Only minute amounts were found in 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 (C_max 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 haemodialysis. 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.
Telday H 80/12.5: General: Telmisartan: Following oral administration, peak concentrations (C_max) of Telmisartan are reached in 0.5-1 hour after dosing. 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 20% after a 160 mg dose. The absolute bioavailability of Telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered Telmisartan are nonlinear over the dose range 20-160 mg, with greater than proportional increases of plasma concentrations (C_max and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Trough plasma concentrations of Telmisartan with once daily dosing are about 10-25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.
Hydrochlorothiazide: When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
Metabolism and Elimination: Telmisartan: Following either intravenous or oral administration of ¹⁴C-labeled Telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of Telmisartan. Total plasma clearance of Telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours.
Distribution: Telmisartan: Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for Telmisartan is approximately 500 liters, indicating additional tissue binding.
Hydrochlorothiazide: Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.