"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
Mechanism of Action
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 aldosteronesecreting 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.
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.
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.
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.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
Following oral administration, peak concentrations (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. 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.
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
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 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.
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.
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 (see DOSAGE AND ADMINISTRATION).
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.
Renal Insufficiency : 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 30-80 mL/min, mean clearance approximately 50 mL/min), no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency : In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
See PRECAUTIONS: DRUG INTERACTIONS.
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.
After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
The antihypertensive effects of telmisartan have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20-160 mg; one of these examined the antihypertensive effects of telmisartan and hydrochlorothiazide in combination. The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95-114 mmHg), 1031 of whom were treated with telmisartan. Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.
Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with telmisartan tablets, blood pressure gradually returned to baseline values over a period of several days to one week. During long-term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors. The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40-80 mg doses of telmisartan was 70-100% for both systolic and diastolic blood pressure. The incidence of symptoma tic orthostasis after the first dose in all controlled trials was low (0.04%).
There were no changes in the heart rate of patients treated with telmisartan in controlled trials.
Telmisartan and Hydrochlorothiazide
In controlled clinical trials with over 2500 patients, 1017 patients were exposed to telmisartan (20 to 160 mg) and concomitant hydrochlorothiazide (6.25 to 25 mg). These trials included one factorial trial with combinations of telmisartan (20, 40, 80, 160 mg, or placebo) and hydrochlorothiazide (6.25, 12.5, 25 mg and placebo). Four other studies of at least six months duration allowed add-on of hydrochlorothiazide for patients who either were not adequately controlled on the randomized monotherapy dose or had not achieved adequate response after completing the up-titration of telmisartan.
The combination of telmisartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 16-21/9-11 mmHg for doses between 40/12.5 mg and 80/25 mg, compared to 9-13/7-8 mmHg for telmisartan 40 mg to 80 mg and 4/4 mmHg for hydrochlorothiazide 12.5 mg alone.
In active controlled studies, the addition of 12.5 mg hydrochlorothiazide to titrated doses of telmisartan in patients who did not achieve or maintain adequate response with telmisartan monotherapy further reduced systolic and diastolic blood pressure.
The antihypertensive effect was independent of age or gender.
There was essentially no change in heart rate in patients treated with the combination of telmisartan and hydrochlorothiazide in the placebo controlled trial.
Last reviewed on RxList: 1/30/2012
This monograph has been modified to include the generic and brand name in many instances.
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