Losartan

Active substance:

 Losartan potassium

Excipients:

MCC;

mannitol;

croscarmellose sodium;

povidone 30;

magnesium stearate;

hypromellose;

titanium dioxide;

talc;

propylene glycol

Losartan is a specific antagonist of angiotensin II receptors (Tina AT1) for oral administration. Angiotensin II binds selectively to AT1 receptors found in many tissues (vascular smooth muscle, adrenal glands, nocturnal glands, and heart) and has several important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells.

Losartan and its pharmacologically active metabolite (E 3174), both in vitro and in vivo, block all physiological effects of angiotension II, regardless of the source or route of synthesis. Losartan binds selectively to AT1 receptors: it does not bind or block receptors of other hormones and ion channels, which play an important role in the regulation of the function of the cardiovascular system. In addition, losartan does not inhibit the angiotensin-converting enzyme (ACE), which contributes to the degradation of bradykinin, so side effects indirectly associated with bradykinin (for example, angioedema) are rare.

When losartan is used, the absence of negative feedback on renin secretion leads to an increase in plasma renin activity. An increase in renin activity leads to an increase in the concentration of angiotensin II in the blood plasma. However, antihypertensive activity and a decrease in plasma aldosterone concentration persist, which indicates an effective blockade of angiotensin II receptors. After discontinuation of losartan, plasma renin activity and the concentration of angiotensin II decreased within 3 days to the initial values ​​observed before the start of drug administration.

Losartan and its active metabolite have a high affinity for angiotensin II receptors (AT1 type).

Plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing dose of the drug.

The maximum antihypertensive effect develops 3-6 weeks after starting the drug.

In patients with arterial hypertension, proteinuria (more than 2 g per day), without diabetes mellitus, the use of the drug reliably reduces proteinuria, the excretion of albumin and immunoglobulin G (IgG).

In women in the postmeionusal period with arterial hypertension, who took losartan at a dose of 50 mg / day for 4 weeks, no effect of therapy on the renal and systemic level of prostaglandins was revealed.

Losartan has no effect on autonomic reflexes and has no long-term effect on the level of norepinephrine in blood plasma.

In patients with arterial hypertension, losartan in doses up to 150 mg per day does not cause clinically significant changes in the concentration of triglycerides, total cholesterol and high-density lipoprotein cholesterol. In the same doses, losartan has no effect on fasting blood glucose concentration. Losartan caused a decrease in serum uric acid concentration (usually less than 0.4 mg / dL), which persisted during long-term therapy. In controlled clinical trials involving patients with arterial hypertension, there were no cases of drug withdrawal due to an increase in serum creatinine or potassium.

Pharmacokinetics

Suction

When taken orally, losartan is well absorbed from the gastrointestinal tract. The systemic bioavailability of losartan is approximately 33%; food intake does not affect the bioavailability of losartan. Average maximum concentrations of losartan and its active metabolite are reached after 1 hour and after 3-4 hours, respectively.

Distribution

Losartan and its active metabolite bind to blood plasma proteins (mainly albumin) by more than 99%. The volume of distribution of losartan is 34 liters. Losartan practically does not penetrate the blood-brain barrier.

Metabolism

Losartan undergoes the effect of "primary passage" through the liver, is metabolized with the participation of the isoenzyme CYP2C9 of cytochrome P450. Approximately 14% of a dose of losartan administered intravenously or orally is converted to its active metabolite (EXP3174) with a carboxyl group. Biologically inactive metabolites are also formed: two main ones (as a result of hydroxylation of the butyl side chain) and a less significant one - N-2-tetrazole-glucuronide.

Withdrawal

Plasma clearance of losartan and its active metabolite is 600 ml / min and 50 ml / min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml / min and 26 ml / min, respectively. When losartan is taken orally, about 4% of the dose is excreted unchanged by the kidneys and within 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered orally with losartan in doses up to 200 mg. After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal T1 / 2 of about 2 and 6-9 hours, respectively.

The excretion of losartan and its metabolites occurs in the bile and kidneys. After oral administration of losartan labeled with 14C, about 35% of the radioactive label is found in urine and 58% in feces.

Pharmacokinetics in special patient groups

Plasma concentrations of losartan and its active metabolite in elderly male patients with arterial hypertension do not significantly differ from these indicators in younger male patients with arterial hypertension.

Plasma concentrations of losartan were 2 times higher in women with arterial hypertension compared with men with arterial hypertension. The concentrations of the active metabolite did not differ in men and women. This clear pharmacokinetic difference has no clinical significance.

When losartan was taken orally in Nazis with mild to moderate alcoholic liver cirrhosis, the plasma concentrations of losartan and its active metabolite were 5 and 1.7 times (respectively) higher than in young healthy male volunteers.

Plasma concentrations of losartan in patients with creatinine clearance above 10 ml / min did not differ from those in patients with normal renal function. In patients requiring hemodialysis, the area under the concentration-time curve (AUC) is approximately 2 times greater than in patients with normal renal function. Plasma concentrations of the active metabolite do not change in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite are not removed from the bloodstream by hemodialysis.

• Arterial hypertension; 
• chronic heart failure (as part of combination therapy, with intolerance or ineffectiveness of therapy with ACE inhibitors); 
• reducing the risk of stroke in patients with arterial hypertension and left ventricular hypertrophy; 
• protection of renal function in patients with type 2 diabetes mellitus with proteinuria in order to reduce proteinuria, reduce the progression of kidney damage, reduce the risk of end-stage development (prevent the need for dialysis, the likelihood of an increase in serum creatinine levels).

Hypersensitivity, pregnancy, breastfeeding.

From the nervous system and sensory organs:  ≥1% - dizziness, asthenia / fatigue, headache, insomnia; <1% - anxiety, sleep disturbance, drowsiness, memory disorders, peripheral neuropathy, paresthesia, hypesthesia, migraine, tremor, ataxia, depression, syncope, ringing in the ears, taste disturbance, vision changes, conjunctivitis.

From the respiratory system:  ≥1% - nasal congestion, cough, upper respiratory tract infections (fever, sore throat, etc.), sinusopathy, sinusitis, pharyngitis; <1% - dyspnea, bronchitis, rhinitis.

From the digestive tract:  ≥1% - nausea, diarrhea, dyspeptic symptoms, abdominal pain; <1% - anorexia, dry mouth, toothache, vomiting, flatulence, gastritis, constipation.

From the musculoskeletal system : ≥1% - convulsions, myalgia, pain in the back, chest, legs; <1% - arthralgia, shoulder pain, knee pain, arthritis, fibromyalgia.

From the side of the cardiovascular system and blood (hematopoiesis, hemostasis):  <1% - orthostatic reactions (dose-dependent), hypotension, palpitations, tachy- or bradycardia, arrhythmias, angina pectoris, anemia.

On the part of the genitourinary system:  <1% - urgency to urinate, urinary tract infections, impaired renal function, weakened libido, impotence.

On the part of the skin:  <1% - dry skin, erythema, flushing, photosensitivity, increased sweating, alopecia.

Allergic reactions:  <1% - urticaria, rash, itching, angioedema, incl. face, lips, pharynx and / or tongue.

Others:  ≥1% - hyperkalemia; <1% - fever, gout, increased levels of hepatic transaminases and bilirubin in the blood.

Losartan is taken orally, for adults, regardless of food intake, 1 time per day.

With arterial hypertension - 50 mg, if necessary, a gradual increase in the dose is possible (in some cases, up to a maximum daily dose of 100 mg).

In chronic heart failure - 12.5 mg with a gradual increase in 2 stages (after 1 week - up to 25 mg and after 1 week - 50 mg) to the usual maintenance dose of 50 mg.

pills