Studies in vitro and in vivo have shown that losartan and its pharmacologically active metabolite inhibit anavar cycle all important effects of angiotensin physiologically II, regardless of the source or by way of its synthesis. It suppresses the kinase II – the enzyme that destroys bradykinin.
Reduces the total peripheral vascular resistance (SVR) blood levels of aldosterone, blood pressure (BP) pressure in the “small” circle of blood circulation; reduces afterload, has a diuretic effect.
It prevents the development of cardiac hypertrophy, improves exercise tolerance in patients with chronic heart failure (CHF).
After a single oral hypotensive effect (reduced systolic and diastolic blood pressure) reaches a maximum after 6 hours, then for 24 h is gradually reduced. The maximum hypotensive effect develops within 3-6 weeks after regular ingestion.
Not inhibits angiotensin-converting enzyme (ACE) and, accordingly, does not prevent the destruction of bradykinin, losartan therefore not inherent side effects associated with the bradykinin-mediated (e.g., angioneurotic edema).
in patients with hypertension of diabetes without concomitant with proteinuria (greater than 2 g / day), application of the drug significantly reduces proteinuria, urinary albumin and immunoglobulin G.
It stabilizes the urea level in blood plasma. No effect on autonomic reflexes and has no long-term exposure to levels of norepinephrine in the blood plasma.
At a dose of 150 mg once a day did not affect the level of triglycerides, total cholesterol and lipoproteins in the blood serum high density lipoproteins (HDL) in patients with arterial hypertension . In the same dose of losartan does not affect the blood glucose level on an empty stomach. Absorption When administered losartan is well absorbed, systemic bioavailability of losartan is approximately 33%. The maximum concentration of losartan and its active metabolite are achieved in plasma after about 1 h and 3.4 h after applying inwards respectively. Food does not affect the bioavailability of losartan. Distribution Over 99% of losartan and its active metabolite is bound to plasma proteins, mainly albumin. The volume of distribution is 34 liters. Losartan practically does not penetrate the blood-brain barrier. Metabolism Losartan is metabolized in the “original” through the liver by carboxylation involving predominantly isozymes of cytochrome P450 CYP2C9 and CYP3A4 with a pharmacologically active carboxylated metabolite and inactive metabolites. About 14% of losartan when applied intravenously or into the transformed into its active metabolite. In addition to the active metabolite form biologically inactive metabolites, including the two major metabolite resulting from hydroxylation of the butyl side chain, and one minor -. N-2-tetrazolglyukuronid Excretion Plasma clearance of losartan is 600 ml / min, its active metabolite – 50 ml / min. Renal clearance of losartan and its active metabolite is 74 ml / min and 26 ml / min, respectively. Approximately 4% of the dose of the drug excreted by the kidneys in an unmodified form, about 6% of the active metabolite. Losartan and its active metabolite are linear pharmacokinetics when applied orally at doses up to 200 mg. After oral administration, plasma concentrations of losartan and its active metabolite polieksponentsialno End reduced half-life of about 2 hours, losartan, the active metabolite and – about 6-9 hours In application. drug in a dose of 100 mg per day either losartan or an active metabolite substantially not cumulate in the blood plasma. losartan and its metabolites are excreted in bile via the intestine (58%) and kidneys (35%).Pharmacokinetics in special patient groups elderly concentrations losartan and its active metabolite in the blood plasma in elderly male patients with hypertension do not differ significantly from the values of these parameters in young men with hypertension. Gender values of plasma concentrations of losartan in women with hypertension in 2 times higher than the corresponding values for men with arterial hypertension. The concentrations of the active metabolite in both men and women do not differ. This pharmacokinetic difference has clinical significance. Abnormal liver function in patients with alcoholic liver cirrhosis and mild-moderate concentration of losartan 5 times, and the active metabolite – 1.7 times higher than in healthy male volunteers. In patients with hepatic impairment the plasma clearance of losartan were up to 50% lower, and when taking into bioavailability – 2 times higher compared with healthy volunteers. Renal impairment In patients with mild (creatinine clearance (CC) 50-74 mL / min) moderate (30-49 QC ml / min), the degree of renal dysfunction plasma concentration and area under the curve “concentration-time” losartan and its active metabolite is increased by 50-90%. Neither losartan or an active metabolite thereof are not removed from the body by hemodialysis. In renal failure dose adjustment is required (except in cases of dehydrated patients).
• Chronic heart failure (with the ineffectiveness of treatment with ACE inhibitors);
• nephropathy in type 2 diabetes (reducing the risk of hypercreatininemia and proteinuria);
• Reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and hypertrophy of the left ventricle.
• hypersensitivity to the drug, as well as to other drugs that are derivatives of the sulfonamide;
• hereditary lactose intolerance, lactase deficiency, a syndrome of glucose-galactose malabsorption;
• severe hepatic insufficiency (more than 9 points on a scale Child-Pugh);
• simultaneous application aliskiren in patients with type 2 diabetes and renal insufficiency (glomerular filtration rate (GFR) less than 60 mL / min / 1.73 m²) (see section “Interaction with other medicinal products».);
• pregnancy, breast-feeding;
• age of 18 years (effectiveness and safety have been established).
Patients with moderate hepatic and / or renal failure; after kidney transplantation (lack of experience in the application); state, accompanied by a decrease in circulating blood volume (CBV, including diarrhea, vomiting, the use in patients undergoing hemodialysis); violations of water-electrolyte balance; diet with restriction of salt intake; bilateral renal artery stenosis or stenosis of the renal artery to a solitary kidney; cerebrovascular diseases; Chronic heart failure (IV functional class NYHA classification); combination of heart failure associated with severe renal failure, life-threatening arrhythmias; cardiac ischemia; stenosis of the aortic and mitral valves, hypertrophic obstructive cardiomyopathy; angioedema in history; Primary aldosteronism, diabetes (increased risk of hyperkalemia); the combined use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, potassium preparations.
Application of pregnancy and during breastfeeding
Use of the drug during pregnancy is contraindicated.
Application Lozarel during pregnancy can result in oligohydramnios, intrauterine growth retardation, premature birth, fetal death and increased risk of newborn, hypotension, anuria, reversible or irreversible renal failure, hypoplasia skull bones, limb contractures, deformation of the skull bones, hypoplastic lungs.
If during pregnancy the drug is required for health reasons it is necessary to conduct a thorough ultrasonic examination of fetal development. If any abnormalities (especially water scarcity) you must stop using the product.
It is not known whether losartan passes into breast milk, so breast-feeding should be discontinued during treatment with the drug.
Dosing and Administration
Inside, 1 time a day, regardless of meals. Hypertension Standard starting and maintenance dose is 50 mg 1 time a day. If necessary, the dose can be increased to a maximum daily dose of 100 mg. In patients with reduced BCC (for example, against the background of the use of high doses of diuretics) is recommended to start therapy with 25 mg (1/2 tablets of 50 mg), 1 per day. Chronic heart failure The standard initial dose is 12.5 mg / day, followed by a weekly increase of 2 times ( i.e., 12.5 mg / day, 25 mg / day, 50 mg / day, 100 mg / d to 150 mg / day), depending on individual tolerability. The maximum daily dose of 150 mg (for this indication) . to begin therapy with recommended dosage forms with less active ingredient (tablets 25 mg with Valium). in a reduced dosage (12.5 mg) of nephropathy in type 2 diabetes (reducing the risk of hypercreatininemia and proteinuria) Standard starting dose is 50 mg once a day one. During treatment, depending on the blood pressure indicators may increase the daily dose to about 100 mg 1 time per day. The maximum daily dose is 100 mg. The drug anavar cycle may be used in combination with other antihypertensive agents (diuretics blockers “slow” calcium channels, alpha- and beta-blockers, antihypertensive medications central action), insulin and other hypoglycemic agents (sulfonylureas, glitazones and glucosidase inhibitors). Reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy The standard initial 1 time per day; if necessary, may increase the daily dose Lozarel. to 100 mg, according to the degree of blood pressure lowering or adding to the hydrochlorothiazide therapy at low doses, maximum daily dose is 100 mg. Patients with impaired renal function (severe or moderate – creatinine clearance (CC) less than 20 ml / min), with a history of liver disease, dehydration, during the dialysis treatment, and patients over 75 years it recommended lower initial dose – 25 mg (2.1 50 mg tablets) once a day one.
Overall, losartan is well tolerated in patients with hypertension, adverse events are mild and transient in nature and do not require discontinuation of therapy. The overall incidence of side effects of losartan is comparable with the indicator with placebo.
In clinical trials, the most common adverse event in the application of losartan was dizziness.
According to the World Health Organization (WHO), undesirable effects are classified according to their rate of development as follows: very common (> 1/10), common (> 1/100, <1/10), uncommon (> 1/1000, <1/100), rarely (> 1/10000, <1/1000) and very rare (<1 / 10,000), including isolated reports, the frequency is not known (it is impossible to calculate the available data). From the blood system and the lymphatic system often: anemia rare: thrombocytopenia; the frequency is unknown: eosinophilia, Henoch – Schönlein. metabolism and nutrition frequency unknown : decreased appetite, weight gain. On the part of the cardiovascular system is often: a pronounced reduction in blood pressure, orthostatic hypotension (in patients with heart failure); rare: palpitations, arrhythmia (including cinusovaya tachy and bradycardia, ventricular tachycardia , atrial fibrillation), angina frequency is unknown: epistaxis, myocardial infarction, cerebrovascular accident, atrioventricular block II degree. From the digestive systemrare: nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain, rarely dysfunction liver, hepatitis, pancreatitis; frequency not known: anorexia, dryness of the oral mucosa, dental pain, flatulence, gastritis. For the skin uncommon: skin rash, itching skin, hives, the frequency is unknown: dryness of the skin, subcutaneous hemorrhage, photosensitivity, alopecia, cellulitis. On the part of the musculoskeletal system frequency is unknown: cramps, myalgia, arthralgia “swelling” of the joints, rhabdomyolysis, pain in the gluteal muscles, back pain, chest. From the nervous system common:dizziness, asthenia; uncommon: somnolence, headache, sleep disturbances (including insomnia), depression, anxiety, memory disorders, peripheral neuropathy, hypoesthesia, tremor, ataxia, impaired coordination of movement, confusion, rarely: paresthesia; the frequency is unknown: headache. From the senses rare: taste disturbance (dysgeusia); the frequency is unknown: “ringing” in the ears, conjunctivitis, pain / burning sensation in the eye, blurred vision. The respiratory system is often: a dry non-productive cough, swelling of the nasal mucosa; rare: dyspnea, frequency is not known: nasal congestion, infections of the upper respiratory tract, pharyngitis, sinusitis, bronchitis. With the genitourinary system frequently: acute renal failure, renal failure, the frequency is unknown: urgent need to urinate, urinary tract infections, decreased libido, erectile dysfunction / impotence. Allergic reactions are rare: angioedema (including laryngeal edema and language, causing airway obstruction and / or swelling of the face, lips, throat), vasculitis. The laboratory indicators often: hyperkalemia (potassium content in the blood plasma of more than 5.5 mmol / l), hypoglycemia, rarely increasing concentrations of urea and nitrogen residual or creatinine in blood plasma; a moderate increase in activity of “liver” transaminases. hyperbilirubinemia, the frequency is unknown: hyponatremia. General disorders and injection site common: fatigue, fatigue.
Symptoms: marked reduction of blood pressure and tachycardia; as a result of parasympathetic (vagal) stimulation may develop bradycardia.
The treatment: forced diuresis, symptomatic therapy. Hemodialysis is not effective, because losartan and its active metabolite are not removed from the body by hemodialysis.
Interaction with other drugs
There was no pharmacokinetic interactions losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, erythromycin, ketoconazole and lovastatin. It has been reported that fluconazole and rifampicin (isoenzyme inhibitors of cytochrome P450 2C9) reduce the amount of active metabolite of losartan, and increase the concentration in plasma. The clinical significance of these interactions is unknown.
It has been shown that anavar cycle patients who do not metabolize losartan to the active metabolite, has a very rare and specific defect isoenzyme of cytochrome P450 2C9.
Concomitant use of losartan, as well as other drugs that inhibit the enzyme angiotensin II or its effects, with potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride, eplerenone (a derivative of spironolactone)) and potassium preparations (kalisodergaszczye additives) increases the risk of hyperkalemia. Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2),acetylsalicylic acid at a dose higher than 3 grams per day may reduce the effectiveness of angiotensin II receptor antagonists (ARA II), ACE inhibitors, diuretics. Simultaneous use of ARA II with NSAIDs, including selective COX-2 inhibitors, especially in the presence of decreased renal function, may lead to a breach renal function, including acute renal failure and increase in the potassium content in the blood plasma (hyperkalaemia). These effects are usually reversible. In a joint application ARA II and drugs lithium may increase the concentration of lithium in blood plasma. If necessary, they simultaneous application should regularly monitor the plasma concentration of lithium. The combined use of losartan with a diuretic has an additive effect. (Mutually) the effect of other antihypertensive agents (diuretics, beta-blockers, simpatolitikov). With the simultaneous use of ACE inhibitors and ARA II must be checked regularly renal function, as is possible to increase the frequency of side effects, such as pronounced decrease in blood pressure, hyperkalemia, renal dysfunction. Concomitant use of ACE inhibitors with other drugs that affect the renin-angiotensin-aldosterone system (RAAS), including antagonists, ARA II and aliskiren, leads to an increase in the incidence of cases of significant decrease in blood pressure, fainting, hyperkalemia, renal impairment (including acute renal failure), especially in patients with proven atherosclerosis, heart failure or diabetes with end-organ damage. The question of the application of double RAAS blockade must be resolved in each case individually. It is necessary to control blood pressure, renal function, as well as the content of blood plasma electrolytes in the application of losartan with other drugs that affect the RAAS. The simultaneous use of the ARA II (including losartan) with aliskiren is contraindicated in patients with type 2 diabetes and renal impairment (GFR less than 60 mL / min / 1,73m²).
Safety and effectiveness of Lozarel drug ® in children have not been established.
Drugs that affect the RAAS may increase the concentration of urea and creatinine in the blood plasma in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
In patients with dehydration (for example, receiving treatment high doses of diuretics or background vomiting, diarrhea, which are on a salt-free diet), at the beginning of treatment Lozarel ® may be symptomatic hypotension (necessary to carry out the correction of violations of water-electrolyte balance before applying Lozarel drug ® or begin treatment with a lower dose) .
Water and electrolyte disturbances are characteristic of patients with impaired renal function, combined with diabetes or not, and require correction.
in a clinical study involving patients with type 2 diabetes with nephropathy, the incidence of hyperkalemia in the group treated with losartan was higher than in the placebo group. It is necessary to regularly monitor the content of potassium in the blood plasma, and QC, especially in patients with heart failure and CK within 30-50 ml / min.
Patients with liver failure losartan increased plasma concentrations, so a correction of the dose of the drug Lozarel ® .
patients with primary hyperaldosteronism generally do not respond to therapy with inhibitors of the RAAS, so use Lozarel drug ® is not recommended.
in patients with ischemic lesions of vessels of the heart or brain marked decrease in blood pressure can lead to myocardial infarction or ischemic stroke.
As with other drugs, affecting the RAAS, when applying Lozarel drug ® in patients with heart failure (with / without impaired renal function), there is a risk of severe arterial hypotension, and acute renal failure.
there is no experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (IV functional class NYHA classification), as well as in patients with heart failure and symptomatic life-threatening arrhythmias. Thus, to use the drug Lozarel ® in these patients with caution.
In applying Lozarel drug ® in patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve should be careful.
The drug Lozarel ® and other receptor antagonists, angiotensin II less effective in patients blacks, due to the prevalence of hypertensive patients with low renin activity.
There is no need for special precautions during the destruction of the unused product. jintani labs