Losartan-N Canon tablets 12.5 mg+50 mg 30 pcs.
Losartan. Can be used simultaneously with other antihypertensive drugs. There were no clinically significant drug interactions between losartan and hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin. Rifampicin and fluconazole have been reported to reduce plasma concentrations of the active metabolite. The clinical significance of these interactions is currently unknown. As with the use of other drugs that block the formation of angiotensin II and its effects, the concomitant administration of potassium-sparing diuretics (spironolactone and eplerenone, triamterene, amiloride), potassium supplements and salts containing potassium may lead to an increase in the content of potassium ions in the blood serum. Antihypertensive drugs may increase the antihypertensive effect of losartan. Tricyclic antidepressants, antipsychotics, baclofen, amifostine, which reduce blood pressure as a main or side effect and may increase the risk of arterial hypotension, can also enhance the antihypertensive effect of losartan. With simultaneous use of angiotensin II receptor antagonists and nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 inhibitors, acetylsalicylic acid as an anti-inflammatory agent), the antihypertensive effect of losartan may be reduced. In patients with impaired renal function, concomitant use of angiotensin II receptor antagonists or diuretics and NSAIDs may cause a further deterioration of renal function, including acute renal failure and an increase in serum potassium. This combination should be used with caution, especially in elderly patients. With simultaneous use of lithium with ACE inhibitors, a reversible increase in the concentration of lithium in the blood serum and the development of toxicity were recorded; in very rare cases this has been observed with the use of angiotensin II receptor antagonists. Caution should be used when lithium is used concomitantly with losartan. If this combination is necessary, it is recommended to monitor the concentration of lithium in the blood serum. Mutually enhances the effect of beta-blockers and sympatholytics; combined use of losartan with diuretics causes an additive effect. Dual blockade of the RAAS (eg, by combining an angiotensin II receptor antagonist with an ACE inhibitor or aliskiren) in patients with established atherosclerosis, heart failure, or diabetes mellitus with end-organ damage is associated with a higher incidence of hypotension, syncope, hyperkalemia, and dysfunction. kidneys (including the development of acute renal failure) compared with the use of a single-component blockade of the RAAS. The issue of using double blockade of the RAAS should be decided in each case individually and with careful monitoring of blood pressure, water-electrolyte balance of the blood and renal function. Hydrochlorothiazide. With thiazide diuretics, drugs such as ethanol, barbiturates and narcotics may potentiate the risk of orthostatic hypotension. Hypoglycemic agents (oral and insulin) - dosage adjustment of hypoglycemic agents may be required. Metformin should be used with caution due to the risk of lactic acidosis due to possible renal failure associated with hydrochlorothiazide. Other antihypertensive drugs – additive effects are possible. Corticosteroids, ACTH (adrenocorticotropic hormone) - a marked decrease in electrolyte levels, in particular hypokalemia. Pressor amines (for example, epinephrine, norepinephrine) - decreased response to pressor amines. Muscle relaxants of a non-depolarizing type of action (for example, tubocurarine) - enhance the effect of muscle relaxants. Lithium - diuretics reduce the renal clearance of lithium and increase the risk of lithium toxicity; simultaneous use is not recommended. NSAIDs (including cyclooxygenase-2 inhibitors) - may reduce the diuretic, natriuretic and antihypertensive effects of diuretics. Probenecid, sulfinpyrazone, allopurinol - co-administration with drugs for the treatment of gout may require dose adjustment of these drugs, since hydrochlorothiazide can increase the concentration of uric acid in the blood serum: increase the dose of probenecid or sulfinpyrazone. Concomitant use of thiazide diuretics may increase the incidence of hypersensitivity to allopurinol. Anticholinergics (atropine, biperiden) - increase the bioavailability of thiazide diuretics due to a decrease in gastrointestinal motility and the rate of gastric emptying. Cytotoxic drugs (cyclophosphamide, methotrexate) - Thiazides can reduce the renal excretion of cytotoxic drugs and stimulate their myelotoxic effect. Salicylates - when taking high doses of salicylates, hydrochlorothiazide can enhance their toxic effect on the central nervous system. Methyldopa: Cases of hemolytic anemia have been reported separately with the concomitant use of hydrochlorothiazide and methyldopa. Cyclosporine - co-administration with cyclosporine may increase the risk of hyperuricemia and gout-like complications. Cardiac glycosides - Thiazide-stimulated hypokalemia or hypomagnesemia may contribute to the development of cardiac arrhythmias when co-administered with cardiac glycosides. Medicines that can cause aritis. Due to the risk of hypokalemia, caution is required when using Losartan-N Canon simultaneously with the following drugs that can cause torsade de pointes: antiarrhythmic drugs (for example, quinidine, hydroquinidine, disopyramide, amiodarone, sotalol) some antipsychotic drugs (for example, thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopiride, amisulpiride, tiapride, pimozide, haloperidol, droperidol); others (eg, bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, terfenadine, vincamycin IV, saprofloxacin, moxifloxacin, astemizole). Calcium salts - thiazide diuretics can increase the calcium level in the blood serum due to a decrease in its excretion. If it is necessary to use calcium supplements, the dose is selected under the control of calcium levels in the blood serum. Vitamin D - increases the risk of hypercalcemia. Impact on laboratory results - Due to their effect on calcium excretion, thiazides may interfere with the results of tests of parathyroid function. Carbamazepine – increases the risk of symptomatic hyponatremia. Serum sodium levels must be monitored. Iodine contrast agents – with dehydration caused by taking diuretics, the risk of developing acute renal failure increases, especially when high doses of iodine-containing drugs are administered. Before administering such drugs, the patient must be rehydrated. Amphotericin B, corticosteroids, adrenocorticotropic hormone and laxatives - when used together, hydrochlorothiazide can aggravate electrolyte imbalances, especially causing the development of hypokalemia.
Losartan Canon (50mg, 100mg)
Pharmacodynamics
Angiotensin II is a powerful vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), as well as a decisive pathophysiological link in the development of arterial hypertension. Losartan is a highly effective orally selective angiotensin II receptor antagonist (type AT1). Angiotensin II selectively binds to AT1 receptors found in many tissues (vascular smooth muscle, adrenal glands, kidneys and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II 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 angiotensin II, regardless of the source or route of synthesis. Unlike some peptide angiotensin II antagonists, losartan does not have agonist effects.
Losartan selectively binds to AT1 receptors and does not bind to or block receptors of other hormones and ion channels that play an important role in regulating the function of the cardiovascular system (CVS). In addition, losartan does not inhibit angiotensin-converting enzyme (ACE), which is responsible for the destruction of bradykinin. Therefore, effects not directly related to AT1 receptor blockade, including bradykinin-mediated effects and the development of peripheral edema (losartan - 1.7%, placebo - 1.9%), are not related to the action of losartan.
Reduces total peripheral vascular resistance (TPVR), blood concentrations of norepinephrine and aldosterone, blood pressure (BP), pressure in the “lesser” circulation; reduces afterload and has a diuretic effect. Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF). When losartan is taken orally, plasma renin activity (PAR) increases, which leads to an increase in the content of angiotensin II in the blood plasma. After a single dose, the antihypertensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases over 24 hours. During treatment, antihypertensive activity and a decrease in plasma aldosterone concentrations appeared after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. However, after replacing losartan, plasma renin activity and angiotensin II levels through
3 days decreased to the initial values observed before starting the drug.
Both losartan and its active metabolite have a higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10-40 times more active than losartan.
The HEAAL clinical trial to evaluate the effect of high and low doses of ARB II (losartan) on the outcome of treatment in patients with chronic heart failure (CHF) included patients (n=3834) with CHF (II–IV functional class according to the NYHA classification), who were tolerant to therapy with ACE inhibitors. Patients were followed for 4 years (median follow-up 4.7 years) to compare the effects of losartan 50 mg/day with losartan 150 mg/day on reducing all causes of death or hospitalization for heart failure. This study showed that losartan 150 mg/day significantly reduced the risk of all-cause mortality or hospitalization for heart failure compared with losartan 50 mg/day (hazard ratio (HR) 0.899; p=0.027).
Pharmacokinetics
Suction
When taken orally, losartan is well absorbed from the gastrointestinal tract (GIT) and is metabolized during the “primary passage” through the liver by carboxylation with the participation of the CYP2C9 isoenzyme to form an active metabolite.
The systemic bioavailability of losartan is approximately 25-35%. The maximum concentration of losartan and its active metabolite (Cmax) 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
Losartan and its active metabolite bind to plasma proteins (mainly albumin) - 92% losartan and 99% metabolite. The volume of distribution of losartan is 34 liters. Losartan practically does not penetrate the blood-brain barrier (BBB). Losartan and its active metabolite demonstrate linear pharmacokinetics when administered orally in doses up to 200 mg.
Metabolism
It has the effect of “primary passage” through the liver, is metabolized by carboxylation with the participation of the CYP2C9 isoenzyme of cytochrome P450 with the formation of an active (10-40 times) metabolite. Approximately 14% of a dose of losartan administered intravenously or orally is converted into its active metabolite. In addition to the active metabolite, biologically inactive metabolites are formed, including two major ones, formed as a result of hydroxylation of the butyl side chain, and one minor one, N-2-tetrazole glucuronide.
Removal
Plasma clearance of losartan and its active metabolite is about 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 about 6% of the dose is excreted by the kidneys in the form of an active metabolite.
After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal half-life (T½) of approximately 2 and 6-9 hours, respectively. With a dosage regimen of 100 mg once a day, there is no significant accumulation of either losartan or its active metabolite in the blood plasma.
Excretion of losartan and its metabolites occurs through the intestines with bile and kidneys. After oral administration of losartan labeled with radioactive carbon 14C, about 35% of the radioactivity is found in the urine and 58% in the feces. After intravenous administration of 14C radioactively labeled losartan, approximately 43% of the radioactivity is detected in the urine and 50% in the feces.
Pharmacokinetics in special groups of patients
Elderly patients
Plasma concentrations of losartan and its active metabolite in elderly male patients with arterial hypertension do not differ significantly from the values of these parameters in younger male patients with arterial hypertension.
Floor
The values of plasma concentrations of losartan in women with arterial hypertension were 2 times higher than the corresponding values in men with arterial hypertension. Concentrations of the active metabolite did not differ between men and women. This apparent pharmacokinetic difference is, however, not clinically significant.
Patients with liver dysfunction
When losartan was taken orally by patients with mild to moderate alcoholic cirrhosis, the concentrations of losartan and its active metabolite in the blood plasma were 5 and 1.7 times higher, respectively, than in young healthy male volunteers.
Patients with impaired renal function
Plasma concentrations of losartan in patients with creatinine clearance (CC) above 10 ml/min did not differ from those in individuals with unchanged renal function. When comparing the area under the concentration-time curve (AUC) in patients with normal renal function, the AUC of losartan in patients on hemodialysis was approximately 2 times greater. Plasma concentrations of the active metabolite did not change in patients with impaired renal function or on hemodialysis. Losartan and its active metabolite are not eliminated by hemodialysis.
