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| __NOTOC__
| | #REDIRECT [[Telmisartan#Pharmacology]] |
| {{Telmisartan}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Clinical Pharmacology==
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| ===12.1 Mechanism of Action===
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| 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. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the 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.
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| There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.
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| 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]]. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
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| 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.
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| ===12.2 Pharmacodynamics===
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| 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.
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| 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).
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| 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.
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| ===12.3 Pharmacokinetics===
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| Following oral administration, peak concentrations (Cmax) of telmisartan are reached in 0.5 to 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 to 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. Trough 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.
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| ====Distribution ====
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| 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.
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| ====Metabolism and Elimination====
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| 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).
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| 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.
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| Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
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| ====Specific Populations====
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| =====Renal Insufficiency=====
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| No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see Warnings and Precautions (5.5) and Dosage and Administration (2.1)].
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| =====Hepatic Insufficiency =====
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| In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
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| =====Gender =====
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| Plasma concentrations of telmisartan are generally 2 to 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.
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| =====Geriatric Patients =====
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| The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see Dosage and Administration (2.1)].
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| =====Pediatric Patients =====
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| Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = MICARDIS (TELMISARTAN) TABLET [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cfb9309f-e0df-4a55-9542-0e869fce05fb | publisher = | date = | accessdate = 24 February 2014 }}</ref></div></div>
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| ==References==
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| {{reflist|2}}
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| {{Angiotensin II receptor antagonists}}
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| [[Category:Angiotensin II receptor antagonists]]
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| [[Category:Benzimidazoles]]
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| [[Category:Benzoic acids]]
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| [[Category:Biphenyls]]
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| [[Category:PPAR agonists]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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