indication

Used alone or in combination with other classes of antihypertensives for the treatment of hypertension. Also used in the treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus, as well as the treatment of congestive heart failure (only in patients who cannot tolerate ACE inhibitors).

pharmacology

Telmisartan is an orally active nonpeptide angiotensin II antagonist that acts on the AT₁ receptor subtype. It has the highest affinity for the AT₁ receptor among commercially available ARBS and has minimal affinity for the AT₂ receptor. New studies suggest that telmisartan may also have PPARγ agonistic properties that could potentially confer beneficial metabolic effects, as PPARγ is a nuclear receptor that regulates specific gene transcription, and whose target genes are involved in the regulation of glucose and lipid metabolism, as well as anti-inflammatory responses. This observation is currently being explored in clinical trials. 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 works by blocking the vasoconstrictor and aldosterone secretory effects of angiotensin II.

mechanism of action

Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT₁-receptor by binding reversibly and selectively to the receptors in vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor, which also stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance. Telmisartan does not inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels. Studies also suggest that telmisartan is a partial agonist of PPARγ, which is an established target for antidiabetic drugs. This suggests that telmisartan can improve carbohydrate and lipid metabolism, as well as control insulin resistance without causing the side effects that are associated with full PPARγ activators.

toxicity

Intravenous LD₅₀ in rats is 150-200 mg/kg in males and 200 to 250 mg/kg in females. Acute oral toxicity is low: no deaths and no changes occurred in rats or dogs at 2000 mg/kg, the highest dose tested. Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.

biotransformation

Minimally 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. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

absorption

Absolute bioavailability depends on dosage. Food slightly decreases the bioavailability (a decrease of about 6% is seen when the 40-mg dose is administered with food).

half life

Bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours.

route of 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).

drug interactions

Acetylsalicylic acid: Concomitant use of Telmisartan and Acetylsalicylic acid may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Amifostine: Telmisartan may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Telmisartan should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.

Amiloride: Telmisartan may increase the hyperkalemic effect of Amiloride. Monitor for increased serum potassium concentrations during concomitant therapy.

Celecoxib: Concomitant use of Telmisartan and Celecoxib may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Diclofenac: Concomitant use of Telmisartan and Diclofenac may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Diflunisal: Concomitant use of Telmisartan and Diflunisal may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Digoxin: Telmisartan may increase plasma Digoxin concentrations. Monitor Digoxin levels and adjust dose as required if Telmisartan is initiated, discontinued or dose changed.

Drospirenone: Telmisartan may increase the hyperkalemic effect of Drospirenone. Monitor for increased serum potassium concentrations during concomitant therapy.

Fenoprofen: Concomitant use of Telmisartan and Fenoprofen may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Flurbiprofen: Concomitant use of Telmisartan and Flurbiprofen may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Indomethacin: Concomitant use of Telmisartan and Indomethacin may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Ketoprofen: Concomitant use of Telmisartan and Ketoprofen may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Ketorolac: Concomitant use of Telmisartan and Ketorolac may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Lithium: Telmisartan may increase serum Lithium concentrations. Monitor serum Lithium levels during concomitant therapy to avoid Lithium toxicity.

Lumiracoxib: Concomitant use of Telmisartan and Lumiracoxib may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Meclofenamic acid: Concomitant use of Telmisartan and Meclofenamic acid may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Meloxicam: Concomitant use of Telmisartan and Meloxicam may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Nabumetone: Concomitant use of Telmisartan and Nabumetone may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Naproxen: Concomitant use of Telmisartan and Naproxen may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Oxaprozin: Concomitant use of Telmisartan and Oxaprozin may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Piroxicam: Concomitant use of Telmisartan and Piroxicam may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Potassium: Potassium may increase the hyperkalemic effect of Telmisartan. Monitor serum potassium levels during concomitant use.

Potassium Chloride: Potassium Chloride may increase the hyperkalemic effect of Telmisartan. Monitor serum potassium levels during concomitant use.

Rituximab: Telmisartan may increase the hypotensive effect of Rituximab. Telmisartan should be withheld prior to and throughout Rituximab administration.

Spironolactone: Telmisartan may increase the hyperkalemic effect of Spironolactone. Monitor for increased serum potassium concentrations during concomitant therapy.

Sulindac: Concomitant use of Telmisartan and Sulindac may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Tiaprofenic acid: Concomitant use of Telmisartan and Tiaprofenic acid may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Tobramycin: Increased risk of nephrotoxicity

Tolmetin: Concomitant use of Telmisartan and Tolmetin may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Trandolapril: The angiotensin II receptor blocker, Telmisartan, may increase the adverse effects of Trandolapril.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Triamterene: Telmisartan may increase the hyperkalemic effect of Triamterene. Monitor for increased serum potassium concentrations during concomitant therapy.