Telswift Mechanism of Action

Pharmacotherapeutic group: Angiotensin II receptor (type AT1) antagonist. ATC Code: C09CA07.
Pharmacology: Pharmacodynamics and Mechanism of Action: Telmisartan blocks the vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
Telmisartan has much greater affinity ( > 3,000 fold) 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 widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
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 angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.
Pharmacodynamics: 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 and repeated administration to hypertensive patients. The once-daily administration for up to 80 mg telmisartan did not influence plasma aldosterone concentrations. After multiple dose, 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).
Pharmacokinetics and Drug Metabolism: Absorption: Following oral administration, peak concentration (Cmax) 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 (Cmax and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Through plasma concentrations of telmisartan with once daily dosing are about 10% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.
Distribution: Telmisartan is highly bound to plasma proteins (> 99.5%), mainly albumin and 1-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.
Metabolism and Elimination: 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 acyl glucuronide; 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.
Special Populations: Pediatric: Telmisartan pharmacokinetics have not been investigated in patients < 18 years of age.
Geriatric: The 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, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary.
Renal insufficiency: Renal excretion does not contribute to the clearance of telmisartan. With mild-to-moderate renal impairment (creatinine clearance of 30-80 mL/min, mean clearance approximately 50 mL/min), no dosage adjustment is necessary with decreased renal function. Telmisartan is not removed from blood by haemodialysis.
Hepatic insufficiency: In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100%.