Telmisartan

Telmisartan is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class. Telmisartan is approved for the treatment of Hypertension and Cardiovascular risk reduction.

Telmisartan is highly bound to plasma proteins such as albumin and alpha 1 -acid glycoprotein. The bioavailability of Telmisartan depends on its dosage, and the volume of distribution is found to be 500L. Telmisartan is metabolized to form a pharmacologically inactive acyl glucuronide in human plasma and urine. Almost 90% of the administered dose of Telmisartan is eliminated unchanged in feces via biliary excretion.

The common side effects of Telmisartan include dizziness, back pain, Stomach pain, Low blood pressure, Diarrhoea, Weakness, Muscle pain, Fever, and vision changes.

Telmisartan is available in the form of Tablets.

Telmisartan is available in India, the US, Canada, Japan, Europe, South America, Thailand, Philippines.

Telmisartan, belonging to the angiotensin II receptor blocker, acts as an antihypertensive agent.

Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively restricting the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor that stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance.

The time taken for Telmisartan to show its effect is not clinically established.

Telmisartan may remain in your body for approximately 1-2 days.

The Tmax was found within 0.5-1 hours following the administration of Telmisartan, and the Cmax was about 522.29 ng/mL.

Telmisartan is available in the form of Tablets.

Tablets to be swallowed whole with water. Telmisartan comes as a tablet to be taken by mouth. It is usually taken once a day.

Telmisartan can be used to treat Hypertension or high blood pressure and cardiovascular risk reduction, which helps lower high blood pressure and prevents strokes and heart attacks.

Telmisartan is also found to bring about regression of proteinuria in diabetic and nondiabetic, hypertensive patients which kidney diseases and those with renal failure.

Telmisartan belongs to a drug class called angiotensin receptor blockers which works by relaxing blood vessels, so blood flows more efficiently to treat high blood pressure or Hypertension.

Telmisartan is approved for use in the following clinical indications:

• Hypertension

Telmisartan is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the classes to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Telmisartan.

• Cardiovascular Risk Reduction

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals.

Telmisartan is indicated for the reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. A high risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage. Telmisartan can be used in addition to other needed treatments (such as antihypertensive, antiplatelet, or lipid-lowering therapy)

• Delay Progression of Chronic Kidney Disease

Telmisartan effectively and safely reduced blood pressure and brought about regression of proteinuria in diabetic and nondiabetic, hypertensive, proteinuric patients with chronic kidney disease, even in those with mild-to-moderate chronic renal failure.

Although not approved, there have been certain off-label indications. These include

• ACE inhibitor replacement therapy

For patients who cannot tolerate ACE inhibitors because of the ACE inhibitor-induced chronic, non-productive cough.

Telmisartan is available in the form of tablets.

• Hypertension

The initial dose of Telmisartan tablets is 40 mg once a day. The blood pressure response is dose-related over the range of 20 to 80 mg. Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. When additional blood pressure reduction beyond that achieved with 80 mg Telmisartan is required, a diuretic may be added.

Telmisartan tablets may be administered with other antihypertensive agents. It may be administered with or without food.

• Cardiovascular Risk Reduction

The recommended dose of Telmisartan tablets is 80 mg once a day and can be administered with or without food. It is not known whether doses lower than 80 mg of telmisartan are effective in reducing the risk of cardiovascular morbidity and mortality. When initiating telmisartan therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary.

Telmisartan is available in dosage strengths of 20mg,40mg, and 80mg.

Telmisartan is available in a tablet dosage form.

• Hypertension

Avoid foods rich in potassium like bananas, nuts, and sweet potatoes when taking Telmisartan, as it may cause hyperkalemia or high blood potassium levels.

The dietary restriction should be individualized as per patient requirements.

Telmisartan is contraindicated in patients with

• Hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, hydrochlorothiazide, or sulfonamides
• Do not coadminister with Aliskiren in patients has diabetes
• Pregnancy (2nd and 3rd trimesters): Significant risk of fetal/neonatal morbidity and mortality
• Combination therapy with anuria
• Not for initial treatment

• Fetal Toxicity

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. The resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Telmisartan as soon as possible.

• Hypotension

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with Telmisartan. Either correct this condition prior to administration of Telmisartan or start treatment under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. The transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

• Hyperkalemia

Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.

• Impaired Hepatic Function

As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients

• Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

• Dual Blockade of the Renin-Angiotensin-Aldosterone System

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.

Intake of alcohol with Telmisartan can cause drowsiness, dizziness, lightheadedness, or fainting; therefore, is better to avoid alcohol while taking Telmisartan.

Telmisartan is not recommended during the breastfeeding period due to the risk of serious adverse effects, including hypotension, hyperkalemia, and renal impairment, to the infant.

Pregnancy Categories C (first trimester) and D (second and third trimesters)

Telmisartan is an angiotensin II receptor antagonist that should not be initiated during pregnancy as it can lead to fetal harm when administered to pregnant women. When pregnancy is detected, discontinue Telmisartan as soon as possible because Telmisartan can reduce fetal renal function and result in oligohydramnios related to skeletal deformities. Patients planning pregnancy should be considered alternative antihypertensive treatments with an established safety profile for use in pregnancy.

Telmisartan is used in caution with food rich in potassium, such as bananas, nuts, and sweet potatoes, as it can lead to hypercalcemia.

The adverse reactions related to Telmisartan can be categorized as

• Common: Serious adverse reactions include anaphylactic reaction, which causes swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs and angioedema, which may occur rarely, and acute renal failure. Other adverse effects include hoarseness, difficulty breathing or swallowing, pain and cramping in the lower leg that comes and goes during walking or exercise, blistering of the skin, or rash.

• Infrequent adverse effects: Abdominal or stomach pain, back pain, bloating or gas, changes in appetite, increased sweating, diarrhea.

• Rare adverse effects: Changes in vision, dizziness, lightheadedness, or fainting, fast heartbeat, giant hives, painful urination, or changes in urinary frequency

The clinically relevant drug interactions of Telmisartan are briefly summarized here.

• Digoxin: When Telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range.
• Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including Telmisartan. Therefore, monitor serum lithium levels during concomitant use.
• Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.
• Diuretics: Hyperkalemia may occur with concomitant use of potassium-sparing diuretics and Telmisartan, which requires periodic electrolyte monitoring, particularly in patients with increased risk of hyperkalemia—potassium-sparing diuretics such as Amiloride, Eplerenone, Spironolactone, Triamterene.
• Ramipril and Ramiprilat: 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 decreased 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. Concomitant use of TELMISARTAN and ramipril is not recommended.
• 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.

The common side effects of Telmisartan includes the following

Major side effects

• Sinus pain and congestion
• Dizziness
• Stomach pain
• Low blood pressure
• Diarrhea
• Back pain
• Weakness
• Muscle pain
• Fever

Minor side effects

• Change in vision
• Difficulty or painful urination
• Increased heartbeat

The use of the Telmisartan should be prudent in the following group of special populations:

• Paediatric:

Appropriate studies to evaluate the safety and efficacy of Telmisartan have not been performed on the significance of age to the effects of Telmisartan in the pediatric population.

• Geriatric:

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Telmisartan in the elderly.

• Pregnancy Categories C (first trimester) and D (second and third trimesters):

Telmisartan is an angiotensin II receptor antagonist that should not be initiated during pregnancy as it can lead to fetal harm when administered to pregnant women. When pregnancy is detected, discontinue Telmisartan as soon as possible because Telmisartan can reduce fetal renal function and result in oligohydramnios related to skeletal deformities. Patients planning pregnancy should be considered alternative antihypertensive treatments with an established safety profile for use in pregnancy.

• Nursing Mothers:

It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

• Hepatic Insufficiency:

Monitor carefully and up titrate slowly in patients with biliary obstructive disorders or hepatic insufficiency

Limited data are available about the overdosage of telmisartan in humans. The most likely manifestations of overdosage with telmisartan are hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

Pharmacodynamics:

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. 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 an 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.

Pharmacokinetics:

• Absorption: After oral administration, peak concentrations of Telmisartan are reached in 0.5-1 hour after dosing. The bioavailability of Telmisartan is decreased with food, with a reduction in plasma concentration-time curve of about 6% with the 40 mg tablet. The absolute bioavailability of Telmisartan is dose-dependent. At doses of 40 and 160 mg, the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered Telmisartan is nonlinear over the dose range of 20-160 mg, with more than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Telmisartan shows a half-life of approximately 24 hours. The plasma concentrations of Telmisartan with once-daily dosing show about 10-25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma which is repeated once-daily dosing.
• Distribution: There is high binding to plasma proteins, mainly including albumin and α1 - acid glycoprotein. Telmisartan's distribution volume is approximately 500 liters, indicating additional tissue binding.
• Metabolism: Telmisartan is metabolized by the process of conjugation to form a pharmacologically inactive acyl glucuronide, the glucuronide of the parent compound and the only metabolite with been identified in human plasma and urine. The isoenzymes cytochrome P450 is not involved in the metabolism of Telmisartan. The total plasma clearance of Telmisartan is >800 mL/min, irrespective of the dose

• Elimination: After either intravenous or oral administration of 14C-labeled Telmisartan, the majority of the administered dose is eliminated unchanged in feces through biliary excretion, and only minute amounts were found in the urine.

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