Fixed-dose combination of telmisartan and hydrochlorothiazide is another contemporary option of effective treatment of hypertension. (1) It is a combination of an angiotensin II receptor blocker, telmisartan and thiazide diuretic, hydrochlorothiazide. The both substances help to control high blood pressure (BP).

Telmisartan belongs to a group of angiotensin II receptor blockers. Angiotensin II is a substance produced in the body, leading to the narrowing of the blood vessels, thereby elevating BP. Telmisartan blocks the effect of angiotensin II so that it relaxes blood vessels and lowers BP. Hydrochlorothiazide belongs to a group of thiazide diuretics, which cause increased urine output, which also leads to lowering BP.

The combination of these ingredients has an additive antihypertensive effect, which lowers BP to a greater extent than what every component does separately. Dosing once a day leads to an efficient and uniform BP reduction in the therapeutic dose range.

Telmisartan is a long-term orally efficient and specific potent antagonist of the angiotensin II receptor (AT1) where it does not show partial agonist activity on the AT receptors. It shows no affinity for other receptors, including AT2 and other less characterized AT receptors. Aldosterone levels in plasma are reduced by taking telmisartan. Telmisartan neither inhibits renin in human plasma nor does it block ion channels. Also it does not inhibit angiotensin converting enzyme (kininase II), so no degradation of bradykinin is caused, and accordingly there is no enhancement of side effects mediated by bradykinin. The incidence of dry cough was significantly lower in patients treated with telmisartan than in those who were administered angiotensin converting enzyme according to the results of clinical trials that directly compare these two antihypertensive treatment methods. (2, 3)

Dose of 80 mg of telmisartan administered to healthy volunteers almost completely inhibit BP elevation caused by angiotensin II. The inhibitory effect is maintained during 24 hours and can be objectified up to 48 hours. After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction of BP is generally achieved in 4-8 weeks after the start of treatment and is maintained during long-term treatment. The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose, as shown by continuous measurements of BP.

Telmisartan reduces systolic and diastolic BP in patients with hypertension without affecting the heart rate. Antihypertensive efficacy of telmisartan is comparable to the efficacy of antihypertensive agents that belong to some other groups for instance with amlodipine (calcium channel blocker), atenolol (beta-receptor blocker), enalapril (ACE inhibitor) or hydrochlorothiazide (thiazide diuretic). (4) Following abrupt cessation of the treatment with telmisartan, BP gradually returns to the pre-treatment values over a period of several days, without the objectification of the so-called rapid return of the phenomenon of high BP. The clinical study ONTARGET demonstrated that telmisartan is as efficient as ramipril in reducing cardiovascular events in different groups of high-risk cardiovascular patients with better tolerability. (5)

Telmisartan reduces cardiovascular risk not only by reducing blood pressure (BP), but also by reducing other metabolic parameters that have a positive effect on cardiovascular diseases, especially selective modulation of PPAR-γ. This implies the ability of activation of this intracellular receptor which is a major regulator of lipid and carbohydrate metabolism, that is, the regulator of differentiation of fat cells which makes it unique within the ARB group. Activators of PPAR-γ have antiinflammatory, antioxidant and antiproliferative effects on vascular cells. This causes the benefit of effect on glucose and lipid metabolism, which is especially useful in patients with arterial hypertension and/or metabolic syndrome or in the process of reducing the risk of atherosclerosis. (6) Telmisartan is the only ARB with an indication of reducing the risk of cardiovascular events.

Hydrochlorothiazide is a thiazide diuretic. Hydrochlorothiazide drugs have an effect on the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equal amounts. Diuretic action of hydrochlorothiazide reduces plasma volume, increases the renin activity in plasma, increases aldosterone secretion with consequential increase in the loss of potassium and bicarbonate in urine and decrease in potassium in serum. The presumption is that by the renin-angiotensinaldosterone blocking, the concomitant use of telmisartan has a tendency to annul the potassium loss associated with the thiazide diuretics. With hydrochlorothiazide, the onset of diuresis occurs in about 2 hours, and the peak effect occurs after approximately 4 hours, while the action persists for approximately 6-12 hours. Epidemiological studies have shown that long-term treatment by hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity (Figure 1).

Different combinations of telmisartan and hydrochlorothiazide (40/12.5; 80/12.5 and 80/25 mg) are used in the treatment of essential hypertension) in adults whose BP is not well controlled by using telmisartan alone or in patients who have been previously stabilized by telmisartan and hydrochlorothiazide administered separately. (7)

After intravenous or oral administration of 14C labeled telmisartan most of the administered dose (>97%) is eliminated by the faeces by biliary excretion. Only minor amounts were found in urine. Total plasma clearance of telmisartan after oral administration is >1,500 ml/min. Elimination halflife is >20 hours. Hydrochlorothiazide is excreted almost entirely in unchanged form in the urine. About 60% of the oral dose is eliminated within 48 hours. Renal clearance is about 250-300 ml/min. Elimination half-life of hydrochlorothiazide is 10-15 hours. The concentrations of telmisartan in plasma are generally 2-3 times higher in women than in men. However, clinical studies have not found significant increases in response to BP or the incidence of orthostatic hypotension in women. (8) No dosage adjustment is necessary. There was a trend toward higher concentrations of hydrochlorothiazide in plasma in women than in men, which is not considered clinically significant.

Double-blind controlled clinical trial (efficacy was evaluated on n = 687 patients) in persons who have not responded to the 80/12.5 mg combination, showed the incremental effect of lowering BP by 80/25 mg combination compared to continuous treatment with 80/12.5 mg combination, evaluated at 2.7/1.6 mmHg (SBP/DBP) (difference in adjusted mean changes compared to the baseline). BP continued to be lowered in follow-up by the 80/25 mg combination (which resulted in a total reduction of 11.5/9.9 mmHg (SBP/DBP). (9)

Telmisartan and the telmisartan/hydrochlorothiazide combination have a low potential for interactions with other drugs. Telmisartran is not metabolized via cytochrome P 450 system, while hydrochlorothiazide is particularly not metabolized and is almost completely excreted by the kidneys in the form of an unchanged substance. (8)

In the end we can say that there is another good news that comes to the Croatian market, namely, the above mentioned telmisartan and hydrochlorothiazide combination, called Tolucombi® in three doses in the range of 40/12.5 mg, via 80/12.5 mg to 80/25 mg which can be expected to efficiently treat hypertension.