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Head of the Department of Internal Medicine No. 1 of the Tashkent Medical Academy. Doctor of Medical Sciences, Associate Professor, N. M. Nurillaeva.

Increased activity of the reninangiotensin system (RAS) is one of the main targets for pharmacological intervention in patients with high blood pressure (BP). Angiotensin type 1 receptor blockers or sartans act directly on angiotensin II type 1 receptors (AT1), suppressing its main physiological effects: vasoconstrictor, increased aldosterone synthesis and catecholamine release from the adrenal glands and presynaptic membranes, stimulation of myocardial hypertrophy and vascular smooth muscle cells , as well as collagen synthesis. By being highly specific and preventing the action of angiotensin II at the tissue level, these drugs provide more complete RAS blockade than angiotensin-converting enzyme inhibitors (ACEIs). Alternative pathways for the formation of angiotensin II have been established, especially at the level of the tissue component of the RAS, where its formation occurs without the participation of ACE, but with the participation of other enzymes (tonin, chymases, cathepsin). Compared to other classes of antihypertensive drugs, sartans cause fewer adverse reactions and are better tolerated. When treated with AT1 receptor blockers, the content of kinins does not increase, which avoids side effects due to the accumulation of bradykinin, such as cough and angioedema, observed when taking ACE inhibitors.

Sartans are the drugs of choice for the treatment of arterial hypertension (AH), with concomitant metabolic syndrome, left ventricular hypertrophy and microalbuminuria/proteinuria of any origin, as well as chronic heart failure (CHF). Currently, the ARB group is represented by four subgroups that differ in chemical structure: biphenyl tetrazole derivatives - losartan, irbesartan, candesartan; non-biphenyl tetrazole derivatives – telmisartan; non-biphenyl non-tetrazoles – eprosartan; non-heterocyclic compounds – valsartan. One of the most famous and widely studied representatives of the class of AT1 receptor blockers with proven organoprotective properties is telmisartan.

The pharmacokinetic properties of telmisartan have a number of advantages that significantly expand the therapeutic possibilities of using antihypertensive drugs: the longest half-life, unlike other AT1 blockers, with the simultaneous absence of metabolic oxidation in the liver through the cytochrome P450 isoenzyme system and the effect of food intake on bioavailability. Moreover, in a comparative in vitro study, it was found that telmisartan has the highest AT1 receptor binding ability among various sartans: telmisartan > olmesartan > candesartan ≥ valsartan ≥ losartan. In this case, the corresponding decay rate constants in the same order were: 0.0032, 0.0042, 0.0052, 0.0099, 0.010 per minute with half-lives of 213, 166, 133, 70, 67 minutes. The high lipophilic properties of telmisartan contribute to its maximum absorption and penetration into tissues with simultaneous blockade of systemic and tissue RAS. The volume of distribution of telmisartan is the largest among AT1 receptor blockers - 500 liters, which contributes to its wide penetration into tissues. Telmisartan is excreted in the bile and no dose adjustment is required in patients with mild to moderate renal insufficiency; however, in patients with severe renal insufficiency, including those on hemodialysis, an initial dose of 20 mg once daily is recommended. Telmisartan is not removed from the blood during hemodialysis. After its withdrawal, the blood pressure level gradually returns to its original level without the manifestation of “rebound” syndrome.

Telmisartan, in addition to blocking AT1 receptors, is a partial agonist of peroxisome proliferator-activated receptor subtype g (PPARg). They are directly involved in the development of insulin resistance and metabolic syndrome, as they provide regulation of glucose formation in the liver. Unlike other AT1 blockers, telmisartan has maximum effectiveness in stimulating PPARg receptors. In a comparative study by S. Benson et al. (2004) in vitro demonstrated the ability of telmisartan to increase the activity of PPARg receptors by 27 times, while the other 6 sartans increased their activity only by 2–3 times. These advantages of telmisartan are associated with the structure of its molecule, which is similar to thiazolidinediones, and the activation of PPARg receptors by telmisartan accounts for 25–30% of the maximum effect of pioglitazone or rosiglitazone, used in the treatment of diabetes mellitus and metabolic syndrome.

The antihypertensive efficacy of telmisartan in real clinical practice was assessed in the MICARDIS Community Access Trial (MICCAT-2), which included 1615 patients with arterial hypertension (AH). To objectify the results obtained, the method of daily monitoring (ABPM) was used. Initially, telmisartan was prescribed at a dose of 40 mg, after 2 weeks the dose was increased to 80 mg for office blood pressure ≥140/85 mm Hg. Art., after 4 weeks, if necessary, hydrochlorothiazide was added at a dose of 12.5 mg, and after 4 subsequent weeks, the achieved antihypertensive effect was analyzed in patients. The decrease in office blood pressure in 675 previously untreated patients and in 940 previously treated patients was -23/-12 and -17/-10 mmHg. Art. respectively. According to ABPM results, the average daily blood pressure decreased by 16.8/11.4 mmHg. Art. in persons with an initial blood pressure level during the day ≥130/85 mm Hg. Art.. In general, at the end of the MICCAT-2 study, 79% of patients achieved control when measuring office blood pressure and 70% achieved control when carrying out ABPM. Control of blood pressure during the day while taking telmisartan was also accompanied by a significant decrease in blood pressure in the early morning hours, the most vulnerable time for patients with cardiovascular diseases (CVD), which amounted to 11.5/-7.0 mm Hg. Art., and in 95 patients with an initially high level of blood pressure during these hours (>30 mm Hg. Art.), it decreased by -17.2/-10.1 mm Hg. Art..

The multicenter randomized trials PRISMA I and II using ABPM compared the hypotensive effects of telmisartan at a dose of 40–80 mg per day and ramipril at a dose of 2.5–10 mg per day in patients with stage I–II hypertension. Patients in two groups were prescribed to take these drugs in the morning. After 14 weeks of treatment, average daily blood pressure decreased by 14.8/9.9 mmHg. Art. in the telmisartan group, which was significantly different from the achieved blood pressure per day in the group of patients taking ramipril, in whom the decrease in blood pressure averaged 7.9/5.4 mm Hg. Art. [23, 50]. Researchers paid special attention to the dynamics of blood pressure in the last 6 hours of the drug dosing time interval to assess their effect on blood pressure in the early morning hours, which are associated with an increased risk of developing acute coronary and cerebrovascular accidents. In patients treated with telmisartan, in the last 6 hours of action of the drug, a decrease in blood pressure was observed to a greater extent, in contrast to those in the ramipril group (-12.7/-8.8 and -7.9/-5.4 mm Hg. Art. respectively; p<0.05).

Other comparative clinical studies have also demonstrated the antihypertensive benefits of telmisartan among representatives of the class of AT1 receptor blockers in terms of duration and strength of action, especially in the early morning hours, and even in the case of skipping a drug dose, in contrast to losartan, candesartan, and valsartan.

Clinical observations were conducted on the effectiveness and safety of the use of telmisartan in patients with hypertension in combination with diabetes mellitus or obesity in the multicenter randomized trial SMOOTH. With the combined use of telmisartan at a dose of 80 mg and hydrochlorothiazide at a dose of 12.5 mg for 6 weeks, a positive effect of treatment on blood pressure control during the day and in the early morning hours was demonstrated with good tolerability and no changes in metabolic parameters (blood glucose, glycated hemoglobin, total cholesterol, triglycerides, potassium...

The prospective ATHOS study in 1000 elderly patients over 60 years of age and with a predominant increase in systolic blood pressure (SBP) analyzed the daily BP profile after 6 weeks of use of telmisartan at a dose of 40–80 mg with hydrochlorothiazide 12.5 mg compared with amlodipine at a daily dose of 5–80 mg. 10 mg with hydrochlorothiazide 12.5 mg [33]. The decrease in SBP in the last 6 hours from the time of taking these drugs was comparable in both groups of elderly patients - 18.3 and -17.4 mmHg. Art. respectively. However, SBP control during the day in the telmisartan group was higher - 65.9% - compared to amlodipine - 58.3% (p = 0.012). Premature discontinuation of treatment was observed more often in patients in the amlodipine group (11.3%) in contrast to the telmisartan group (5%), mainly due to the appearance of peripheral edema.

Despite the fact that in the ProFESS study, additional administration of telmisartan did not significantly reduce the number of recurrent ischemic strokes in patients, experimental studies have shown that telmisartan is able to penetrate the blood-brain barrier and block the vasoconstrictor effect of angiotensin II on cerebral arteries [18, 45, 52 ]. These results may indirectly explain the proven improvement in cognitive function within 24 weeks in elderly patients 61–75 years old with hypertension in the clinical observation of R. Fogari et al. (2006). After 12 weeks of treatment, with the combined use of telmisartan at a dose of 80 mg with hydrochlorothiazide at a dose of 12.5 mg, there was a significant improvement in the assessment of episodic memory on the corresponding scale by 17.1% compared to the baseline, as well as in indicators of visuospatial orientation.

The use of drugs that block the RAAS helps reduce the progression of kidney damage in patients with hypertension and diabetes mellitus by reducing pressure in the renal glomeruli, the activity of inflammation and oxidative stress. Evidence of the renoprotective effect of telmisartan, independent of antihypertensive action, has been demonstrated at all stages of the renal continuum, from improving endothelial function to reducing proteinuria in patients in the TRENDY, DETAIL, INNOVATION studies.

The comparative AMADEO study demonstrated the superiority of the renoprotective effect of telmisartan compared to losartan in patients with hypertension and type 2 diabetes mellitus complicated by nephropathy [4]. After 52 weeks of treatment, in the group of people taking telmisartan, there was a more significant decrease in the ratio of protein to creatinine in the urine, in contrast to those taking losartan (29% versus 20%; p = 0.03) with comparable values of reduction in blood pressure. Another study, VIVALDI, with a similar population to the AMADEO study, found no differences in reductions in urinary protein excretion, creatinine clearance, and GFR between patients taking telmisartan 80 mg daily and valsartan 160 mg daily.

To date, according to the results of clinical studies, there is evidence in addition to the antihypertensive properties of the pleiotropic effects of telmisartan, the main of which are increased sensitivity to insulin, improved endothelial function, renoprotective effect in both hypertensive and normotensive patients, reduction of left ventricular hypertrophy (LVH) and episodes of atrial fibrillation (Table 2).

The most significant multicenter studies that examined the effect of telmisartan on cardiovascular morbidity and mortality are ONTARGET and TRANSCEND.

The aim of the ONTARGET study was to compare monotherapy with telmisartan at a dose of 80 mg per day with monotherapy with the ACE inhibitor ramipril at a dose of 10 mg and their combined use on the effect on the development of cardiovascular complications (CVD) and mortality in patients with vascular diseases or diabetes mellitus with organ damage . The primary composite endpoint included cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and heart failure hospitalizations. At a median follow-up of 56 months, primary endpoint events occurred in 1423 patients (16.7%) in the telmisartan group, 1412 (16.5%) in the ramipril group, and 1386 (16.3%) in the telmisartan group. with simultaneous administration of telmisartan and ramipril. Despite the fact that the ONTARGET study initially did not include patients with intolerance to ACE inhibitors, during the treatment of patients in the ramipril group, 360 people (4.2%) developed a cough, which was observed significantly less often in the group of patients taking telmisartan (1.1%; p<0.001). Angioedema appeared in 25 patients (0.3%) in the ramipril group, in contrast to those in the telmisartan group, where this side effect was observed in 10 people (0.1%; p = 0.01). In the group of combined use of telmisartan and ramipril, in comparison with other groups, the largest number of side effects was recorded: hypotensive episodes occurred in 4.8% of cases, cough - 4.6%, syncope - 0.3%, renal dysfunction - 13, 5%. Based on the increased incidence of severe renal failure in this group of patients, the latest European guidelines on arterial hypertension (2013) prohibit the simultaneous use of ACE inhibitors and sartans in the combined treatment of patients with hypertension [28]. Treatment with RAS blockers had a significant protective effect on LVH. It was concluded that telmisartan was non-inferior to ramipril in reducing cardiovascular mortality and complications and was associated with fewer side effects, particularly cough and angioedema, than ramipril.

The placebo-controlled TRANSCEND trial assessed the effect of telmisartan on the prevention of CV events in high-risk patients with CVD or diabetes mellitus with organ damage (without proteinuria) who were intolerant to ACE inhibitors. The primary endpoint was similar to the ONTARGET study, and composite endpoints similar to the HOPE and ADVANCE studies were also studied. There were no significant differences over 5 years in the number of complications in patients between the telmisartan and placebo groups included in the primary endpoint. However, in the number of adverse outcomes, a composite endpoint of micro- and macrovascular disease, similar to the ADVANCE study, telmisartan treatment compared with placebo achieved a significant 11% reduction in the cumulative incidence of cardiovascular death, non-fatal myocardial infarction or stroke. , hemodialysis, 2-fold increase in serum creatinine, new cases of proteinuria, or use of laser therapy for diabetic retinopathy (RR = 0.89). Also in the TRANSCEND study, significant differences were revealed in secondary endpoints - in the telmisartan group compared with placebo, there was a decrease in new cases of both LVH by 38% and microalbuminuria/proteinuria by 23%, a decrease in the progression of microalbuminuria to proteinuria by 42%, a reduction in cases hospitalizations for CVD by 8%. The renoprotective effect of telmisartan was also demonstrated by the effect on the composite endpoint of hemodialysis, 2-fold increase in serum creatinine, or new cases of microalbuminuria and/or proteinuria - with a 19% reduction in the number of cases compared with patients taking placebo.

A comparative retrospective analysis by JW Lin et al. (2014) with 690,463 Korean patients at high cardiovascular risk demonstrated potential differences between the most common AT1 receptor blockers in their effects on overall and cardiovascular mortality [25]. Patients treated with telmisartan and olmesartan had a 7% lower relative risk of all-cause mortality compared with patients treated with losartan (HR=0.93; 95% CI 0.90–0.96 and HR=0.93; 95 % CI 0.88–0.97, respectively). A study of the causes of deaths showed that treatment of patients with olmesartan reduced the relative risk of cardiovascular mortality by 16%, and telmisartan reduced the relative risk of mortality from cerebrovascular diseases by 11% compared with treatment with losartan.

Thus, the pharmacological properties and proven clinical effects of the AT1 receptor blocker telmisartan provide wide opportunities for its use in daily clinical practice in the treatment of patients with high and very high risk hypertension, especially in combination with obesity, diabetes mellitus, and kidney damage for the purpose of effective control blood pressure and reduce the risk of developing cardiovascular events.

To summarize the still short, but already rich in interesting results, history of the study and use of ARBs in evidence-based cardiology, it should be concluded that telmisartan is a modern and effective antihypertensive drug that has a number of advantages over other ARB drugs in terms of the ability to prevent the development and progression of cardiovascular accidents, nephropathy in patients with diabetes mellitus and having a cardiovascular and nephroprotective effect similar to ACE inhibitors is characterized by better tolerability. In addition, further study of new mechanisms of the positive effect of telmisartan on carbohydrate, fat metabolism and the cardiovascular system through PPARγ modulation can significantly expand the indications for its use in clinical practice.

Currently, the government is actively promoting a course to stimulate import substitution of medicines. One of them is the drug Mirel (telmisartan).

Mirel at a dose of 80 mg completely blocks the hypertensive effect of angiotensin II. Its effect lasts more than 24 hours (including the last 4 hours before taking the next dose) and persists after 48 hours. The onset of the hypotensive effect is noted within 3 hours after the first dose. The maximum reduction in blood pressure is observed 4 weeks after the start of treatment. In patients with arterial hypertension, Mirel (telmisartan) reduces systolic and diastolic blood pressure without affecting heart rate. In case of abrupt discontinuation of the drug, blood pressure gradually returns to its original level without the development of withdrawal syndrome. The effect of Mirel (telmisartan) on cardiovascular disease and mortality has not been established. Clinical studies have shown that the use of Mirel (telmisartan) is associated with a statistically significant decrease in left ventricular mass in patients with arterial hypertension and left ventricular hypertrophy.

Pharmacokinetics. After oral administration, it is quickly absorbed from the gastrointestinal tract. Bioavailability is about 50%. When Mirel (telmisartan) is taken simultaneously with food, the reduction in AUC values ranges from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg). 3 hours after taking the drug, the concentrations of telmisartan in the blood plasma level out, regardless of taking the drug on an empty stomach or with food.

Distribution. Binding to blood plasma proteins is more than 99.5%, mainly with albumin and α1-glycoprotein. The average apparent Vd at equilibrium is approximately 500 L.

Metabolism. Mirel (telmisartan) is metabolized by conjugation with glucuronic acid. The metabolite does not exhibit pharmacological activity.

Excretion. T1/2 - more than 20 hours. Mirel (telmisartan) is mainly excreted in feces, mainly unchanged, through the kidneys - less than 2%. Total plasma clearance is quite high (approximately 900 ml/min) compared to hepatic blood flow (approximately 1,500 ml/min).

Unlike other sartans (Valsartan, Losartan, candesartan, olmesartan, eprosartan, irbesartan), Mirel has a pronounced effect on the receptors that activate peroxisome proliferator (Peroxisome Proliferator Activated Receptor, PPAR), and provides a synergistic effect on key risk factors for the development of cardiovascular complications . Prescribed for adults orally at a dose of 40 mg 1 time / day. In some patients, a hypotensive effect can be achieved by prescribing the drug at a dose of 20 mg/day. If necessary, the dose of the drug can be increased to 80 mg/day. It should be borne in mind that the maximum hypotensive effect develops after 4-8 weeks. In patients with severe arterial hypertension, telmisartan is used in a daily dose of 160 mg (as monotherapy) or in combination with hydrochlorothiazide 12.5-25 mg/day. Patients with renal failure (including those on hemodialysis), elderly patients do not require dose adjustment of the drug. In patients with mild to moderate liver dysfunction, the daily dose of the drug should not exceed 40 mg.

Side effect. From the central nervous system: headache, dizziness, fatigue, insomnia, anxiety, depression, convulsions, visual disturbances. From the cardiovascular system: marked decrease in blood pressure (including orthostatic hypotension), bradycardia, tachycardia, chest pain; rarely - fainting. From the respiratory system: infections of the upper respiratory tract (including pharyngitis, bronchitis, sinusitis), cough; rarely - dyspnea. From the digestive system: nausea, vomiting, dyspepsia, diarrhea, abdominal pain, impaired liver function. From the urinary system: impaired renal function (including acute renal failure), peripheral edema, urinary tract infections (including cystitis), hypercreatininemia. From the musculoskeletal system: myalgia, arthralgia, low back pain, tendinitis-like symptoms, leg cramps. From the hematopoietic system: rarely - anemia, eosinophilia, thrombocytopenia. Laboratory indicators: rarely - hyperkalemia, hyperuricemia; in isolated cases - an increase in the level of CPK in the blood. Allergic reactions: skin rash; rarely - erythema, itching, eczema, sweating, urticaria, angioedema. Other: influenza-like syndrome.

Contraindications: obstruction of the biliary tract; severe liver dysfunction; hereditary fructose intolerance; pregnancy; lactation period (breastfeeding); hypersensitivity to telmisartan and other components of the drug. The drug is not indicated for use in children and adolescents, because There are no data on efficacy and safety in this category of patients. Mirel (telmisartan) is contraindicated for use during pregnancy and during pregnancy. There is no experience with the use of telmisartan in patients after kidney transplantation. When using Mirela (telmisartan) in patients with impaired renal function, it is recommended to regularly determine serum potassium and creatinine levels. In patients with reduced blood volume and hyponatremia resulting from diuretic therapy, restriction of salt intake, diarrhea or vomiting, when using telmisartan, a pronounced decrease in blood pressure may develop, especially when prescribing the drug for the first time. Reduced blood volume and hyponatremia should be restored before using telmisartan. In cases where vascular tone and renal function are largely dependent on the activity of the renin-angiotensin-aldosterone system (for example, in patients with severe chronic heart failure or concomitant kidney diseases, including renal artery stenosis), the use of drugs which affect the state of this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria and, in rare cases, acute renal failure. Therefore, caution should be exercised in prescribing telmisartan to this category of patients. In patients with primary aldosteronism, antihypertensive drugs whose mechanism of action is to inhibit the activity of the renin-angiotensin-aldosterone system are usually ineffective. In such cases, the use of telmisartan is not recommended. In patients with aortic or mitral stenosis, idiopathic hypertrophic subaortic stenosis, the use of telmisartan (as well as other vasodilators) requires special caution. It should be taken into account that when using antihypertensive drugs in patients with ischemic cardiopathy or coronary artery disease, in the event of an excessive decrease in blood pressure, myocardial infarction or cerebrovascular accident may develop. It should be taken into account that when using telmisartan, especially in the presence of kidney disease and/or heart failure, as well as simultaneously with potassium-sparing diuretics, salt substitutes containing potassium, and other drugs that increase the concentration of potassium in the blood (heparin), the risk of developing hyperkalemia increases. Therefore, in these cases it is recommended to monitor the level of potassium in the blood. Telmisartan should be prescribed with caution to patients with impaired liver function. Since telmisartan is excreted mainly in the bile, the elimination of the drug may be delayed in patients with impaired liver function. If pregnancy is planned, telmisartan should be replaced with another antihypertensive drug. If pregnancy is established, the use of telmisartan should be discontinued as soon as possible. Preclinical studies did not reveal a teratogenic effect of the drug, but a fetotoxic effect was noted.

.Drug interaction. The simultaneous use of telmisartan with thiazide diuretics (hydrochlorothiazide) is possible, since this increases the hypotensive effect. Temilsartan may enhance the hypotensive effect of other antihypertensive drugs. No other clinically significant interactions were identified. Digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine were studied in pharmacokinetic studies. There was an increase in the average digoxin concentration by 20% (in one case the increase in concentration reached 39%). When using telmisartan and digoxin simultaneously, it is advisable to periodically determine the concentration of digoxin in the blood. With the simultaneous use of ACE inhibitors and lithium preparations, a reversible increase in the concentration of lithium in the blood was observed, accompanied by a toxic effect. In rare cases, such changes have been reported with the use of angiotensin II receptor antagonist drugs. When using lithium preparations and angiotensin II receptor antagonists simultaneously, it is recommended to determine the concentration of lithium in the blood. With simultaneous use of telmisartan with NSAIDs (including acetylsalicylic acid at a dose of ≥0.3 g/day and COX-2 inhibitors), acute renal failure may develop in patients with dehydration. Patients taking telmisartan in combination with NSAIDs should be adequately hydrated and renal function should be monitored at the start of therapy. Compounds acting on the renin-angiotensin system, such as telmisartan, may exhibit synergism. When used concomitantly with NSAIDs, a decrease in the effect of antihypertensive drugs such as telmisartan was observed due to inhibition of vasodilation by prostaglandins.

Thus, the results of large-scale clinical studies completed in recent years have shown that angiotensin II receptor blockers (ARBs) meet modern requirements for antihypertensive drugs and are effective and safe for the treatment of patients with arterial hypertension (AH) in various clinical situations (metabolic syndrome, diabetes diabetes, renal dysfunction, etc.). They were included in the first-line drugs for the treatment of hypertension according to the 2010 RMOAG/VNOK recommendations.