"What are angiotensin receptor blockers (ARBs) and how do they work?
The class of drugs called angiotensin receptor blockers (ARBs), as the class name suggests, are drugs that block the action of angiotensin. Specifically, ARBs preve"...
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.
Telmisartan does not inhibit ACE (kininase II) nor does it 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 ARB tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood.
In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by approximately 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.
Plasma concentration of angiotensin II and plasma renin activity 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).
The antihypertensive effects of telmisartan have been studied in six placebo-controlled clinical trials including a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 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.
The onset of antihypertensive activity occurs within 3 hours, with a maximal reduction by approximately 4 weeks. At doses of 20, 40, and 80 mg, the antihypertensive effect of once-daily administration of telmisartan was maintained for the full 24-hour dose interval.
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 approximately 6 to 12 hours.
Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.
Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.
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 approximately 6% with 40 mg and approximately 20% after a 160 mg dose MICARDIS HCT can be administered with or without food. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of telmisartan with orally administered MICARDIS 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 approximately 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.
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.
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.
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).
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. 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. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Hepatic Insufficiency: In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Use in Specific Populations].
Gender: 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.
Geriatric Patients: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years of age.
Drug Interaction Studies
Ramipril: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan.
Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.
Telmisartan and Hydrochlorothiazide
In controlled clinical trials with more than 2500 hypertensive patients, 1017 patients were exposed to telmisartan (20 mg to 160 mg) and concomitant hydrochlorothiazide (6.25 mg to 25 mg). These trials included one factorial trial (Study 1) with combinations of telmisartan (20 mg, 40 mg, 80 mg, 160 mg, or placebo) and hydrochlorothiazide (6.25 mg, 12.5 mg, 25 mg, and placebo). The factorial trial randomized 818 patients, including 493 (60%) males; 596 (73%) Non-Black and 222 (27%) Blacks; and 143 (18%) ≥ 65 years of age (median age was 53 years old). The mean supine blood pressure at baseline for the total population was 154/101 mmHg.
The combination of telmisartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressures at trough of 16-21/9-11 mmHg for doses between 40 mg/12.5 mg and 80 mg/25 mg, compared with 9-13/7-8 mmHg for telmisartan 40 mg to 80 mg monotherapy and 4/4 mmHg for hydrochlorothiazide 12.5 mg monotherapy. 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.
Four other studies of hypertensive patients of at least six months' duration allowed add-on of hydrochlorothiazide for patients who either were not adequately controlled on the randomized telmisartan monotherapy dose or had not achieved adequate blood pressure response after completing the up-titration of telmisartan. 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 pressures.
Last reviewed on RxList: 2/6/2017
This monograph has been modified to include the generic and brand name in many instances.
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