Lozap

Antihypertensive drug. Specific angiotensin II receptor antagonist (AT1 subtype). Does not inhibit kininase II, an enzyme that catalyzes the conversion of angiotensin I to angiotensin II. Reduces peripheral vascular resistance, blood concentrations of adrenaline and aldosterone, blood pressure, pressure in the pulmonary circulation; reduces afterload and has a diuretic effect. Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure. Losartan does not inhibit ACE kininase II and, accordingly, does not prevent the destruction of bradykinin, so side effects indirectly associated with bradykinin (for example, angioedema) occur quite rarely.

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

Stabilizes the level of urea in blood plasma. Does not affect autonomic reflexes and does not have a long-term effect on the concentration of norepinephrine in the blood plasma. Losartan at a dose of up to 150 mg/day does not affect the levels of triglycerides, total cholesterol and HDL cholesterol in the blood serum in patients with arterial hypertension. At the same dose, losartan does not affect fasting blood glucose levels.

After a single oral dose, the hypotensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases over 24 hours.

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

Pharmacokinetics

Suction

When taken orally, losartan is well absorbed and undergoes first-pass metabolism through the liver by carboxylation with the participation of the cytochrome CYP2C9 isoenzyme to form an active metabolite. Systemic bioavailability of losartan is about 33%. Cmax of losartan and its active metabolite is achieved in the blood serum approximately 1 hour and 3-4 hours after oral administration, respectively. Food intake does not affect the bioavailability of losartan.

Distribution

More than 99% of losartan and its active metabolite are bound to plasma proteins, mainly albumin. Vd of losartan - 34 l. Losartan practically does not penetrate the BBB.

Metabolism

Approximately 14% of losartan administered to a patient intravenously or taken orally is converted into an active metabolite.

Removal

Plasma clearance of losartan is 600 ml/min, and the active metabolite is 50 ml/min. The renal clearance of losartan and its active metabolite is 74 ml/min and 26 ml/min, respectively. When taken orally, approximately 4% of the dose taken is excreted unchanged by the kidneys and about 6% is excreted by the kidneys in the form of an active metabolite. Losartan and its active metabolite exhibit linear pharmacokinetics when administered orally in doses up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a final T1/2 of losartan of about 2 hours, and of the active metabolite - about 6-9 hours. When taking the drug at a dose of 100 mg/day, neither losartan nor the active metabolite accumulate significantly in blood plasma. Losartan and its metabolites are excreted from the body through the intestines and kidneys. In healthy volunteers, after oral administration of 14C-labeled losartan, about 35% of the radioactive label is found in the urine and 58% in the feces.

Pharmacokinetics in special clinical situations

In patients with mild to moderate alcoholic cirrhosis, the concentration of losartan was 5 times higher, and the active metabolite was 1.7 times higher than in healthy male volunteers.

When CC >10 ml/min, the concentration of losartan in the blood plasma does not differ from that with normal renal function. In patients who require hemodialysis, the AUC is approximately 2 times higher than in patients with normal renal function.

Neither losartan nor its active metabolite is removed from the body by hemodialysis.

Plasma concentrations of losartan and its active metabolite in elderly men with arterial hypertension do not differ significantly from the values of these parameters in young men with arterial hypertension.

Plasma concentrations of losartan in women with arterial hypertension are 2 times higher than the corresponding values in men with arterial hypertension. Concentrations of the active metabolite do not differ between men and women. This pharmacokinetic difference is not clinically significant.

Lozap plus tablets 50 mg+12.5 mg 30 pcs.

The combined drug has a hypotensive effect. Contains losartan potassium - an angiotensin II receptor blocker (antagonist) (AT1 subtype) (ARB) and hydrochlorothiazide - a thiazide diuretic. Losartan/hydrochlorothiazide. Losartan and hydrochlorothiazide demonstrate a synergistic hypotensive effect, reducing blood pressure (BP) to a greater extent than either component alone. It is assumed that this effect is the result of the additive action of both components. In addition, as a result of the diuretic effect, hydrochlorothiazide increases plasma renin activity, aldosterone secretion, reduces the concentration of potassium in the blood plasma and increases the content of angiotensin-II. The use of losartan blocks all physiologically significant actions of angiotensin-II and reduces potassium losses associated with diuretic use through inhibition of aldosterone. Losartan has a mild and short-term uricosuric effect. Hydrochlorothiazide leads to a moderate increase in plasma uric acid; the combination of losartan and hydrochlorothiazide helps to attenuate diuretic-induced hyperuricemia. The hypotensive effect of losartan/hydrochlorothiazide persists for 24 hours. Despite a significant decrease in blood pressure, taking losartan/hydrochlorothiazide does not have a significant clinical effect on heart rate (HR). In clinical studies, it was shown that after 12 weeks of therapy with losartan 50 mg/hydrochlorothiazide 12.5 mg, minimum diastolic blood pressure (measured in the sitting position) decreased by an average of 13.2 mmHg. Art. Losartan/hydrochlorothiazide effectively reduces blood pressure in men and women, patients of black and other races, in young (< 65 years) and elderly (≥ 65 years) patients, and in all degrees of arterial hypertension. Losartan. Losartan is a synthetic angiotensin II receptor blocker (AT1 type). Angiotensin II, a powerful vasoconstrictor, is the main active hormone of the renin-angiotensin-aldosterone system (RAAS) and a major factor in the pathophysiology of arterial hypertension. Angiotensin II binds to AT1 receptors found in many tissues (vascular smooth muscle, adrenal glands, kidneys and heart) and causes a number of biologically important effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells. Losartan selectively blocks AT1 receptors. Losartan and its pharmacologically active carboxyl metabolite E-3174 block all physiologically significant effects of angiotensin-II in vitro and in vivo, regardless of the source and route of synthesis of the latter. Losartan does not have an agonistic effect and does not block other hormone receptors or ion channels that play an important role in regulating the function of the cardiovascular system. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE) (kininase II), an enzyme that breaks down bradykinin. Therefore, there is no potentiation of undesirable effects mediated by bradykinin. When using losartan, elimination of the negative feedback reaction of angiotensin-II on renin secretion leads to an increase in the activity of the latter in the blood plasma. An increase in renin activity leads to an increase in the concentration of angiotensin-II in the blood plasma. Despite this increase, hypotensive activity and a decrease in plasma aldosterone concentrations persist, indicating effective blockade of angiotensin-II receptors. After stopping the use of losartan, plasma renin activity and angiotensin-II levels return to baseline values within 3 days. Both losartan and its main active metabolite have a greater affinity for AT1 receptors than for AT2 receptors. This metabolite is 10-40 times more active than losartan. The incidence of cough is comparable in patients taking losartan or hydrochlorothiazide and significantly lower than when using an ACE inhibitor. In patients with arterial hypertension, proteinuria without diabetes mellitus and taking losartan, there was a significant decrease in proteinuria, fractional release of proteins and immunoglobulin G. Losartan stabilizes the glomerular filtration rate and reduces the filtration fraction. In general, losartan causes a decrease in serum uric acid levels that persists during long-term therapy. Losartan does not affect autonomic reflexes and does not have a long-term effect on the level of norepinephrine in the blood plasma. In patients with left ventricular failure, 25 mg and 50 mg of losartan have positive hemodynamic and neurohumoral effects, characterized by an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate, as well as plasma aldosterone and norepinephrine concentrations blood, respectively. The development of hypotension in these patients with heart failure was dose-dependent. Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of this group of drugs is not fully known. Thiazide diuretics affect the renal tubular reabsorption mechanisms of electrolytes, directly increasing the excretion of sodium and chloride in approximately equivalent amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion with a subsequent increase in urinary potassium concentrations and bicarbonate loss and a decrease in plasma potassium concentrations. The coupling of renin to aldosterone is mediated by angiotensin II, and therefore concomitant use of an ARB generally reverses the potassium loss caused by thiazide diuretics. When taken orally, the diuretic effect of hydrochlorothiazide begins after 2 hours, reaches a maximum, on average, after 4 hours and lasts from 6 to 12 hours, the hypotensive effect persists for 24 hours.

Losap Plus

Release form, composition and packaging

Light yellow, oblong, film-coated tablets with a score line on both sides.

1 tab.
losartan potassium 50 mg.
hydrochlorothiazide 12.5 mg.

Excipients: mannitol, microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, hypromellose 2910/5, macrogol 6000, talc, simethicone emulsion, dye Opaspray yellow M-1-22801 (purified water, titanium dioxide, denatured ethanol (methylated alcohol: ethanol 99% and methanol 1%), hypromellose, Quinolin Yellow (E104), Pounceau 4R (E124)).

Clinical and pharmacological group: Antihypertensive drug

pharmachologic effect

Combination antihypertensive drug.

Losartan is a specific angiotensin II receptor antagonist (AT1 subtype). It does not inhibit kinase II, an enzyme that destroys bradykinin. Reduces peripheral vascular resistance, blood concentrations of adrenaline and aldosterone, blood pressure, pressure in the pulmonary circulation; reduces afterload and has a diuretic effect. Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure.

Hydrochlorothiazide is a thiazide diuretic. Reduces the reabsorption of sodium ions, increases the excretion of potassium, bicarbonate and phosphate ions in the urine. Lowers blood pressure by reducing blood volume, changing the reactivity of the vascular wall, reducing the pressor effect of vasoconstrictors and increasing the depressor effect on the ganglia.

The maximum antihypertensive effect is achieved within 3 weeks after the start of treatment.

Pharmacokinetics

Suction

After oral administration, losartan and hydrochlorothiazide are rapidly absorbed from the gastrointestinal tract. The bioavailability of losartan is about 33%. The time to reach Cmax of losartan is 1 hour, its active metabolite is 3-4 hours.

Distribution

The binding of losartan to plasma proteins is 99%.

Metabolism

Losartan undergoes a first-pass effect through the liver and is metabolized by carboxylation to form an active metabolite.

Hydrochlorothiazide is not metabolized in the liver.

Removal

T1/2 of losartan is 1.5-2 hours, and its main metabolite is 3-4 hours. About 35% of the dose is excreted in the urine, about 60% in feces.

T1/2 of hydrochlorothiazide is 5.8-14.8 hours. About 61% is excreted unchanged in the urine.

Pharmacokinetics in special clinical situations

The concentration of losartan in the blood plasma in patients with liver cirrhosis increases significantly.

Indications

arterial hypertension (in patients for whom combination therapy is optimal);
in order to reduce the risk of developing cardiovascular diseases (including stroke) and mortality in patients with arterial hypertension and left ventricular hypertrophy.

Dosage regimen

The drug is taken orally, regardless of food intake.

In the treatment of arterial hypertension, the average initial and maintenance dose is 1 tablet/day. If, when taking the drug at this dose, it is not possible to achieve adequate blood pressure control, the dose of Lozap plus can be increased to 2 tablets. 1 time/day The maximum dose is 2 tablets. 1 time/day

There is no need for special selection of the initial dose in elderly patients.

In order to reduce the risk of developing cardiovascular diseases (including stroke) and mortality in patients with arterial hypertension and left ventricular hypertrophy, losartan (Lozap) is prescribed at a standard initial dose of 50 mg/day. Patients who failed to achieve the target blood pressure level while taking losartan at a dose of 50 mg/day require selection of therapy by combining losartan with hydrochlorothiazide at a low dose (12.5 mg), which is ensured by prescribing Lozap plus. If necessary, the dose of Lozap plus can be increased to 2 tablets. (100 mg losartan and 25 mg hydrochlorothiazide) 1 time/day.

Side effect

All adverse reactions are limited to those previously observed with the use of losartan or hydrochlorothiazide.

From the side of the central nervous system: often - dizziness.

Allergic reactions: urticaria, angioedema, including swelling of the larynx and/or tongue (leading to airway obstruction), and/or swelling of the face, lips, pharynx and/or tongue (rarely reported with losartan); Some of these patients had previously experienced angioedema while using other drugs, incl. and ACE inhibitors. In some cases (when taking losartan) - vasculitis, including Henoch-Schönlein disease.

From the cardiovascular system: arterial hypotension.

From the digestive system: rarely (<1%) when taking losartan - diarrhea, hepatitis, increased activity of liver transaminases.

From the respiratory system: when taking losartan - cough.

From the side of water and electrolyte balance: rarely (<1%) - hyperkalemia (serum potassium more than 5.5 mmol/l).

Contraindications

anuria;
severe arterial hypotension;
severe dysfunction of the liver and kidneys (creatinine clearance≤30 ml/min);
hypovolemia (including against the background of high doses of diuretics);
pregnancy;
lactation period;
children and adolescents under 18 years of age (efficacy and safety have not been established);
hypersensitivity to the components of the drug.

Prescribe with caution to patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, patients with diabetes mellitus, hypercalcemia, hyperuricemia and/or gout, systemic connective tissue diseases (including SLE), as well as patients with a burdened allergic history and bronchial asthma.

Pregnancy and lactation

The use of Lozap plus during pregnancy and lactation is contraindicated. If pregnancy occurs while taking Lozap plus, it should be discontinued.

Taking drugs that directly act on the renin-angiotensin system during the second and third trimesters of pregnancy can lead to fetal death.

The use of diuretics in healthy pregnant women is not recommended due to the risk of jaundice in the fetus and newborn and thrombocytopenia in the mother. Diuretic therapy does not prevent the development of pregnancy toxicosis.

Use for liver dysfunction

Contraindicated in cases of severe liver dysfunction.

Use for renal impairment

Contraindicated in cases of severe renal impairment (creatinine clearance≤30 ml/min).

special instructions

Lozap plus can be prescribed together with other antihypertensive drugs.

During the use of Lozap plus, the concentration of urea and creatinine in the blood plasma may increase in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Hydrochlorothiazide may increase hypotension and water-electrolyte imbalance (decreased blood volume, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia), impair glucose tolerance, reduce urinary calcium excretion and cause a transient slight increase in plasma calcium concentration, increase the concentration of cholesterol and triglycerides, provoke the occurrence of hyperuricemia and/or gout.

Hydrochlorothiazide, due to its effect on calcium metabolism, may interfere with the results of parathyroid function tests.

Use in pediatrics

The safety and effectiveness of Lozap plus in children and adolescents under 18 years of age have not been established.

Impact on the ability to drive vehicles and operate machinery

There is no data on the effect of the drug on the ability to drive vehicles and operate machinery.

Overdose

Symptoms: losartan - marked decrease in blood pressure, tachycardia, bradycardia (as a result of vagal stimulation); hydrochlorothiazide - loss of electrolytes (hypokalemia, hyperchloremia, hyponatremia), as well as dehydration resulting from excess diuresis.

Treatment: if the drug has been taken recently, the stomach should be rinsed; carry out symptomatic and supportive therapy; if necessary, correction of water and electrolyte disturbances. Losartan and its active metabolites are not removed by hemodialysis.