LOZAP AM PILLS 5MG + 50MG

Lozap am pills

Composition

Description of the dosage form

Tablets 5 mg + 50 mg: white or almost white, oblong, biconvex, film-coated, with the engraving “AT1” on one side.

Tablets 5 mg + 100 mg: pink or light pink, oblong, biconvex, film-coated, engraved with “AT2” on one side.

Mechanism of action

Pharmacological action - antihypertensive.

Pharmacodynamics

Drug Lozap ® AM

The results of two bioequivalence studies involving healthy volunteers showed that Lozap® AM in doses of 5 + 50 mg and 5 + 100 mg of bioequivalent to the combined use of the corresponding doses of amlodipine camsylate and losartan potassium in the form of separate tablets.

Amlodipine

The bioequivalence of amlodipine besylate and amlodipine camsilate was evaluated in a randomized blind crossover comparative study involving healthy volunteers.

The results obtained in the study showed that 5 mg amlodipine camsilate pills are 5 mg bioequivalent to 5 mg amlodipine besilate tablets.

Mechanism of action

Drug lozap® AM The composition of the drug Lozap® AM includes 2 active ingredients with a complementary mechanism of action to improve blood pressure control in patients with arterial hypertension (AH): losartan potassium, an angiotensin II receptor antagonist (ARA II), and amlodipine (BPC). Losartan blocks the vasoconstrictor effect of angiotensin II and the stimulation by the latter of the release of aldosterone by selectively inhibiting the binding of angiotensin II to the AT receptors1 in many tissues. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure.

Losartan. Angiotensin II is a powerful vasoconstrictor, the main active hormone RAAS, as well as the crucial pathophysiological link in the development of hypertension. Angiotensin II binds to AT1-receptors located in many tissues (vascular smooth muscle tissue, adrenal glands, kidneys and heart), and performs several important biological functions, including vasoconstriction and the release of aldosterone. In addition, angiotensin II stimulates the growth of smooth muscle cells. AT2-receptors - the second type of receptor, which binds to angiotensin II, but its role in regulating the function of the CAS is unknown. Losartan is a selective antagonist of APA II (AT1-receptors), highly effective by ingestion. Losartan and its pharmacologically active carboxylated metabolite (E-3174) as in vitroso and in vivo block all the physiological effects of angiotensin II, regardless of its source or route of synthesis. Unlike some peptide APA II, losartan does not possess agonist properties. Losartan binds selectively to AT1-receptors and does not bind and does not block the receptors of other hormones and ion channels, which play an important role in regulating the function of the CAS. In addition, losartan does not inhibit ACE (kininase II), which is responsible for the destruction of bradykinin.

Consequently, effects not directly related to the blockade of AT1-receptors, such as enhancing bradykinin-mediated effects or the development of edema (losartan 1.7%, placebo 1.9%), are not related to the effect of losartan.

Amlodipine. Amlodipine is a dihydropyridine Calcium antagonist (calcium ion antagonist or BPC) that inhibits the transmembrane entry of calcium ions into vascular smooth muscle cells and cardiomyocytes. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites on receptors of slow calcium channels.The process of contraction of the myocardium and vascular smooth muscle depends on the transmembrane entry of extracellular calcium ions into the cell through specific ion channels. Amlodipine selectively inhibits the transmembrane entry of calcium, affecting the cells of vascular smooth muscle more than cardiomyocytes.

In vitro a negative inotropic effect can be detected, however, in studies on intact animals with the use of amlodipine in therapeutic doses, this effect has not been identified.

Amlodipine does not affect the serum calcium level. Within the physiological pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by gradual association and dissociation with the receptor binding site, which leads to the gradual development of the effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on the vascular smooth muscle, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure.

Other pharmacological properties

Drug lozap® AM It is shown that the drug Lozap® AM effectively lowers blood pressure. Both losartan and amlodipine reduce blood pressure by reducing peripheral resistance. Blocking the entry of calcium into the cell and reducing the vasoconstrictor effect caused by exposure to angiotensin II are complementary mechanisms.

Losartan. Losartan suppresses the increase in blood pressure and dad with the infusion of angiotensin II. At the time of reaching Cmax losartan in the blood plasma after taking losartan at a dose of 100 mg, the above effect of angiotensin II is suppressed by approximately 85%, and 24 hours after single and multiple doses, by 26-39%.

In the period of receiving losartan, the elimination of negative feedback, which consists in the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity (ARP). An increase in ARP leads to an increase in plasma angiotensin II concentration. With long-term (6-week) treatment of patients with hypertension with losartan at a dose of 100 mg / day, there was a 2-3-fold increase in plasma angiotensin II concentration at the time of reaching Cmax losartan. Some patients showed an even greater increase in the concentration of angiotensin II, especially with a short duration of treatment (2 weeks).Despite this, in the course of treatment, the antihypertensive effect and the decrease in plasma aldosterone concentration were manifested after 2 and 6 weeks of therapy, which indicates an effective blockade of angiotensin II receptors. After the abolition of losartan, ARP and the concentration of angiotensin II decreased within 3 days to the values ​​observed before the start of losartan.

Since losartan is a specific AT antagonist1- angiotensin II receptors, it does not inhibit ACE (kininase II) - an enzyme that inactivates bradykinin. A study comparing the effects of losartan at doses of 20 and 100 mg with the effects of an ACE inhibitor on the effects on angiotensin I, angiotensin II and bradykinin, showed that losartan blocks the effects of angiotensin I and angiotensin II without affecting the effects of bradykinin. This is due to the specific mechanism of action of losartan. The ACE inhibitor blocked responses to angiotensin I and increased the severity of the effects caused by bradykinin, without affecting the intensity of the response to angiotensin II, which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors.

The concentrations of losartan and its active metabolite in the blood plasma, as well as the antihypertensive effect of losartan increase with increasing dose of the drug. Since losartan and its active metabolite are antagonists of angiotensin II receptors, they both contribute to the antihypertensive effect.

In a study with a single dose of losartan at a dose of 100 mg, which included healthy volunteers (men), taking the drug orally under conditions of high and low salt diet did not affect the GFR, the effective renal plasma flow and the filtration fraction. Losartan had a natriuretic effect, which was more pronounced on a low-salt diet and was apparently not associated with the suppression of early sodium reabsorption in proximal renal tubules. Losartan also caused a transient increase in uric acid excretion by the kidneys.

In patients with hypertension, proteinuria (at least 2 g / 24 h), without diabetes mellitus and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, a significant decrease in proteinuria (by 42%) and fractional excretion of albumin were observed and IgG. In these patients, losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women with hypertension who took losartan at a dose of 50 mg for 4 weeks, no effect of therapy on the renal and systemic GH levels was detected.

Losartan does not affect vegetative reflexes and does not have a lasting effect on the concentration of norepinephrine in the blood plasma.

In patients with hypertension, losartan in doses up to 150 mg / day did not cause clinically significant changes in the concentration of triglycerides on an empty stomach, total HD and HDL. In the same doses, losartan did not affect the fasting blood glucose concentration.

In general, losartan caused a decrease in serum uric acid concentration (usually less than 0.4 mg / dL), which was maintained during long-term treatment. In controlled clinical trials involving patients with hypertension, there have been no cases of drug withdrawal due to an increase in creatinine concentration or serum potassium content.

In a 12-week parallel study that included patients with left ventricular failure (functional class II-IV NYHA), most of which took diuretics and / or cardiac glycosides, compared the effects of losartan in doses of 2.5; ten; 25 and 50 mg / day with placebo. At doses of 25 and 50 mg / day, the drug showed positive hemodynamic and neurohormonal effects that persisted throughout the study. Hemodynamic effects included an increase in cardiac index and a decrease in wedging pressure in the pulmonary capillaries, as well as a decrease in OPS, mean systemic blood pressure and heart rate. The frequency of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included a decrease in the concentration of aldosterone and noradrenaline in the blood.

Amlodipine

Hemodynamics. In patients with hypertension after administration in therapeutic doses, amlodipine causes vasodilation, which leads to a decrease in blood pressure in prone and standing positions. This decrease in blood pressure is not accompanied by significant changes in heart rate or plasma concentration of catecholamines with prolonged use. Despite the fact that hemodynamic indices for the evaluation of patients with stable angina with single on / in the administration of amlodipine showed a decrease in blood pressure and an increase in heart rate, in clinical studies, repeated administration of amlodipine did not lead to clinically significant changes in heart rate or blood pressure in normotensive patients with exertional angina.

With prolonged ingestion 1 time per day, the antihypertensive effect persists for at least 24 hours.The concentration of amlodipine in the blood plasma correlates with the antihypertensive effect in both young and elderly patients. The magnitude of the decrease in blood pressure when taking amlodipine also correlates with the severity of the increase in blood pressure before the start of treatment. Thus, patients with hypertension of moderate severity (105–144 mm Hg) exhibited an approximately 50% greater antihypertensive effect than patients with mild hypertension (DAD 90–104 mm Hg). In patients with normal blood pressure, there was no clinically significant change in blood pressure (+ 1 / -2 mm Hg).

In patients with hypertension and normal renal function, taking therapeutic doses of amlodipine led to a decrease in renal vascular resistance, increased GFR and effective renal plasma flow without changing the filtration fraction or proteinuria.

As with other BPCs, hemodynamic parameters of heart function at rest and under load (or cardiac pacing) in patients with normal ventricular function who took amlodipine generally showed a slight increase in cardiac index without a significant change in the rate of increase in pressure in the left ventricular cavity at the beginning of the period expulsion (dP / dt) of either the final dad or volume of the left ventricle. In hemodynamic assessment studies, amlodipine did not have a negative inotropic effect when used in therapeutic doses in healthy volunteers, even when used simultaneously with beta-blockers. However, similar results were observed in healthy volunteers or patients with heart failure in the compensation stage with the use of drugs that have a pronounced negative inotropic effect.

Electrophysiological effects. Amlodipine did not affect the sinoatrial node function or AV conductivity in healthy volunteers. In patients with chronic stable angina pectoris, injecting 10 mg of amlodipine did not significantly affect the A – H and H – V conductivity and the recovery time of the sinus node after cardiostimulation. Similar results were obtained in patients simultaneously taking amlodipine and beta-blockers. In clinical studies in which patients with hypertension or angina pectoris took amlodipine at the same time as beta-blockers, no adverse effect on ECG parameters was observed.In clinical trials involving patients with only angina pectoris, amlodipine therapy did not affect ECG intervals and did not cause AV blockade to a greater degree.

Pharmacokinetics

Suction

Amlodipine. After ingestion in therapeutic doses Cmax amlodipine in plasma is reached after 6–12 h. The absolute bioavailability of amlodipine ranges from 64 to 90% of the dose taken. Eating does not affect the bioavailability of amlodipine.

Losartan. When ingested, losartan is well absorbed and metabolized during the initial passage through the liver to form an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan in tablet form is about 33%. Medium Cmax losartan and its active metabolite are reached after 1 and 3-4 h, respectively.

When taking losartan in the process of normal eating a clinically significant effect on the profile of the concentration of losartan in the blood plasma was found.

Distribution

Amlodipine. Studies have shown that in patients with hypertension, approximately 93% of the circulating drug binds to plasma proteins .

Losartan. Losartan and its active metabolite are not less than 99% bound to plasma proteins (mainly albumin). Vd Losartan is 34 liters. Studies in rats have shown that losartan hardly penetrates the BBB.

Metabolism

Amlodipine. Amlodipine is extensively (about 90%) metabolized to inactive metabolites in the liver. The kidneys excrete 10% of the accepted dose in the form of unchanged amlodipine and 60% in the form of metabolites.

Losartan. Approximately 14% of the dose of losartan with the on / in the introduction or ingestion turns into its active metabolite. After ingestion or in / in the introduction of labeled with radioactive carbon losartan (14C losartan) the radioactivity of circulating blood plasma is primarily due to the presence of losartan and its active metabolite. The low conversion efficiency of losartan into its active metabolite was observed in approximately 1% of the patients participating in the study.

In addition to the active metabolite, biologically inactive metabolites are formed, including 2 main, resulting from the hydroxylation of the side butyl chain, and one minor - N-2-tetrazole-glucuronide.

Removal

Amlodipine. Amlodipine elimination from blood plasma occurs in 2 phases, the final phase T1/2 is about 30-50 h. Css amlodipine in plasma is reached after 7-8 days with daily intake.

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

After ingestion, plasma concentrations of losartan and its active metabolite are reduced polyexponentially with the final phase T1/2 about 2 and 6-9 hours, respectively. When the dosage regimen of the drug is 100 mg 1 time per day, neither losartan nor its active metabolite accumulates in the blood plasma.

Elimination of losartan and its metabolites is carried out by the kidneys and through the intestines with bile. After ingestion 14With losartan, about 35% of radioactivity in men is found in urine and 58% in feces. After the / in the introduction 14With losartan in men, approximately 43% of the radioactivity is found in the urine and 50% in the feces.

Drug lozap® AM

Drug lozap® AM has not been studied in any special groups of patients due to a good knowledge of the active ingredients of the drug, losartan and amlodipine. Losartan should be used with caution in violation of the kidneys and liver. It is contraindicated during pregnancy and during breastfeeding. No separate studies have been conducted with pediatric and elderly patients. Amlodipine should be used with caution when liver dysfunction.

It is contraindicated for unstable cardiovascular disease, as well as during pregnancy and during breastfeeding.

Amlodipine

Impaired renal function. Impaired renal function does not significantly affect the pharmacokinetic parameters of amlodipine, so patients with renal insufficiency can be prescribed the usual initial dose of amlodipine.

Older age and impaired liver function. In elderly patients and patients with liver failure, the clearance of amlodipine is reduced, which leads to an increase in AUC of about 40-60%. Such patients may require a lower initial dose of amlodipine. A similar increase in AUC was observed in patients with moderate or severe heart failure.

Children and teenagers. Pharmacokinetic studies involving patients with hypertension aged 6 to 17 years who took amlodipine in a dose of 1.25 to 20 mg showed that body weight and V clearance were adjustedd amlodipine were comparable to those in adult patients.

Losartan

Elderly age. The concentrations of losartan and its active metabolite in the blood plasma of elderly male patients with hypertension do not significantly differ from these indicators in young male patients with hypertension.

Floor. Plasma concentrations of losartan in women with hypertension were 2 times higher than the corresponding values ​​in men with hypertension. The concentrations of the active metabolite in men and women did not differ. This clear pharmacokinetic difference, however, has no clinical significance.

Liver dysfunction. When losartan was taken orally by patients with mild and moderate alcoholic cirrhosis of the liver, 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.

Impaired renal function. Plasma losartan concentrations in patients with creatinine Cl above 10 ml / min did not differ from those in patients with unchanged renal function. The AUC value of losartan for patients on hemodialysis was about 2 times greater than the AUC value of losartan for patients with normal renal function. Plasma concentrations of the active metabolite did not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite are not excreted through hemodialysis.