Pharmacology: Telmisartan is an orally effective and specific angiotensin-II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long lasting.
Telmisartan does not show affinity for other receptors, including AT2 and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by Telmisartan. Plasma aldosterone levels are decreased by Telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore, it is not expected to potentiate bradykinin-mediated adverse effects.
In man, an 80 mg dose of Telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
Treatment of Essential Hypertension: After the first dose of Telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 weeks after the start of treatment and is sustained during long-term therapy.
The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of Telmisartan 40 and 80 mg in placebo-controlled clinical studies.
There is an apparent trend to a dose relationship to a time to recovery of baseline systolic blood pressure (SBP). In this respect, data concerning diastolic blood pressure (DBP) are inconsistent.
In patients with hypertension, Telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of Telmisartan has been compared to antihypertensive drugs such as amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, lisinopril, ramipril and valsartan.
Upon abrupt cessation of treatment with Telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
Telmisartan treatment has been shown in clinical trials to be associated with statistically significant reductions in Left Ventricular Mass and Left Ventricular Mass Index in patients with hypertension and Left Ventricular Hypertrophy.
Telmisartan treatment has been shown in clinical trials (including comparators like losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.
The incidence of dry cough was significantly lower in patients treated with Telmisartan than in those given with angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.
Cardiovascular Risk Reduction: ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) compared the effects of Telmisartan, ramipril and the combination of Telmisartan and ramipril on cardiovascular outcomes in 25,620 patients aged 55 years or older with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a broad cross-section of cardiovascular high risk patients.
Patients were randomized to one of the three following treatment groups: Telmisartan 80 mg (n=8,542), ramipril 10 mg (n=8,576), or the combination of Telmisartan 80 mg plus ramipril 10 mg (n=8,502), and followed for a mean observation time of 4.5 years. The population studied was 73% male, 74% Caucasian, 14% Asian and 43% were 65 years of age or older. Hypertension was present in nearly 83% of randomized patients: 69% of patients had a history of hypertension at randomization and an additional 14% had actual blood pressure readings above 140/90 mmHg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose levels. Baseline therapy included acetylsalicylic acid (76%), statins (62%), beta-blockers (57%), calcium-channel blockers (34%), nitrates (29%) and diuretics (28%).
The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure.
Adherence to treatment was better for Telmisartan than for ramipril or the combination of Telmisartan and ramipril, although the study population had been pre-screened for tolerance to treatment with an ACE-inhibitor. The analysis of adverse events leading to permanent treatment discontinuation and of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with Telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with Telmisartan.
Telmisartan had similar efficacy to ramipril in reducing the primary endpoint. The incidence of the primary endpoint was similar in the Telmisartan (16.7%), ramipril (16.5%) and Telmisartan plus ramipril combination (16.3%) arms. The hazard ratio for Telmisartan vs. ramipril was 1.01 [97.5% CI 0.93-1.10, p (non-inferiority)=0.0019]. The treatment effect was found to persist following corrections for differences in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint based on age, gender, race, baseline therapies or underlying disease.
Telmisartan was also found to be similarly effective to ramipril in several pre-specified secondary endpoints, including a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, the primary endpoint in the reference study HOPE (The Heart Outcomes Prevention Evaluation Study), which had investigated the effect of ramipril vs. placebo. The hazard ratio of Telmisartan vs. ramipril for this endpoint in ONTARGET was 0.99 [97.5% CI 0.90-1.08, p (non-inferiority)=0.0004].
Combining Telmisartan with ramipril did not add further benefit over ramipril or Telmisartan alone. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination arm. Therefore, the use of a combination of Telmisartan and ramipril is not recommended in this population.
Pharmacokinetics: Absorption of Telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for Telmisartan is about 50%.
When Telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC) of Telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). By 3 hours after administration, plasma concentrations are similar whether Telmisartan is taken fasting or with food.
The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.
Gender differences in plasma concentrations were observed, Cmax and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males without relevant influence on efficacy.
Telmisartan is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 acid glycoprotein. The mean steady-state apparent volume of distribution (Vss) is approximately 500 L.
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of Telmisartan.
After oral (and intravenous) administration, Telmisartan is nearly exclusively excreted with the faeces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose. Total plasma clearance (ClTot) is high (approximately 900 mL/min) compared with hepatic blood flow (about 1,500 mL/min).
Elderly Patients: The pharmacokinetics of Telmisartan do not differ between younger and elderly patients.
Patients with Renal Impairment: Lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.
Patients with Hepatic Impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.
In addition to taking Telmisartan, treatment for your high blood pressure may include weight control and a change in the foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.
Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.
Remember that Telmisartan will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You might have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.
Telmisartan comes with patient instructions. Read and follow these instructions carefully. Ask your doctor if you have any questions.
You may take Telmisartan with or without food.
Telmisartan works best when there is a constant amount in the blood. To help keep the amount constant, do not miss any doses. Also, it is best to take the dose at the same time each day.
The dose of Telmisartan will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Telmisartan. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of Telmisartan, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Protect the tablets from moisture. Do not remove them from the blister pack until you are ready to take a dose.
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Your doctor may occasionally change your dose to make sure you get the best results
You may take Telmisartan with or without food.
Your blood pressure will need to be checked often. Visit your doctor regularly.
It may take 2 to 4 weeks of using this medicine before your blood pressure is under control. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 4 weeks of treatment.
If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store at room temperature away from moisture and heat.
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.
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.
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.
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.
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.
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 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.
Total plasma clearance of Telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration.
In patients with hepatic insufficiency, plasma concentrations of Telmisartan are increased, and absolute bioavailability approaches 100%.
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.
The pharmacokinetics of Telmisartan do not differ between the elderly and those younger than 65 years.
Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.
There are no reviews yet. Be the first to write one!
Information checked by Dr. Sachin Kumar, MD Pharmacology