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® AM
Pharmacological properties
Drug Lozap® AM
The results of two bioequivalence studies involving healthy volunteers showed that Lozap® AM in doses of 5 mg + 50 mg and 5 mg + 100 mg is bioequivalent to the combined use of corresponding doses of amlodipine camsylate and losartan potassium in the form of separate tablets.
Amlodipine
The bioequivalence of amlodipine besylate and amlodipine camsylate was assessed in a randomized, blinded, crossover study in healthy volunteers. The results obtained in the study showed that amlodipine camsylate 5 mg tablets are bioequivalent to amlodipine besylate 5 mg tablets.
Mechanism of action
Drug Lozap® AM
The drug Lozap® AM contains two active substances with a complementary mechanism of action to improve blood pressure (BP) control in patients with arterial hypertension (AH): losartan potassium, an angiotensin II receptor antagonist (ARA II), and amlodipine, a blocker " slow" calcium channels (SCMC).
Losartan blocks the vasoconstrictor effect of angiotensin II and the latter's stimulation of aldosterone release by selectively inhibiting the binding of angiotensin II to AT1 receptors in many tissues.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, resulting in a decrease in peripheral vascular resistance and a decrease in blood pressure.
Losartan
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 hypertension.
Angiotensin II 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.
AT2 receptors are the second type of receptor to which angiotensin II binds, but its role in the regulation of cardiovascular function is unknown.
Losartan is a selective antagonist of AT1 - angiotensin II receptors, highly effective when taken orally. Losartan and its pharmacologically active carboxylated metabolite (E-3174) both in vitro and in vivo block all physiological effects of angiotensin II, regardless of its source or route of synthesis.
Unlike some peptide angiotensin II antagonists, losartan does not have agonist properties.
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. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), which is responsible for the destruction of bradykinin. Therefore, effects not directly related to AT1 receptor blockade, such as increased bradykinin-mediated effects or the development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.
Amlodipine
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) 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 slow calcium channel receptors. The process of contraction of the myocardium and vascular smooth muscle depends on the transmembrane entry into the cell of extracellular calcium ions through specific ion channels. Amlodipine selectively inhibits transmembrane calcium entry, affecting vascular smooth muscle cells more than cardiomyocytes.
In vitro
a negative inotropic effect can be detected, however, in studies on intact animals using amlodipine in therapeutic doses, this effect was not detected. Amlodipine does not affect serum calcium levels. 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 a gradual development of the effect.
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.
Pharmacodynamics
Drug Lozap® AM
The drug Lozap®AM has been shown to effectively reduce blood pressure. Both losartan and amlodipine reduce blood pressure by reducing peripheral resistance. Blocking the entry of calcium into the cell and reducing the vasoconstrictive effect caused by the action of angiotensin II are complementary mechanisms.
Losartan
Losartan suppresses the increase in systolic and diastolic blood pressure during angiotensin II infusion. At the moment of reaching the maximum concentration (Cmax) of 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%.
During the period of taking losartan, elimination of the negative feedback, which consists in the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity (PRA). An increase in ARP leads to an increase in the concentration of angiotensin II in the blood plasma. With long-term (6-week) treatment of patients with hypertension with losartan at a dose of 100 mg/day, a 2-3-fold increase in the concentration of angiotensin II in the blood plasma was observed at the time the losartan Cmax was reached.
In some patients, an even greater increase in angiotensin II concentrations was observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, an antihypertensive effect and a decrease in plasma aldosterone concentrations appeared after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, ARP and angiotensin II concentrations decreased within 3 days to the values observed before the start of losartan administration.
Since losartan is a specific antagonist of angiotensin II AT1 receptors, it does not inhibit ACE (kininase II), an enzyme that inactivates bradykinin. A study comparing the effects of losartan at doses of 20 mg and 100 mg with the effects of an ACE inhibitor on angiotensin I, angiotensin II and bradykinin showed that losartan blocked 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 effects due to bradykinin without affecting the response to angiotensin II, demonstrating a pharmacodynamic difference between losartan and ACE inhibitors.
Plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing dose of the drug. Since losartan and its active metabolite are angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.
In a study with a single dose of 100 mg of losartan, which included healthy volunteers (men), oral administration of the drug under high- and low-salt diets did not affect the glomerular filtration rate (GFR), effective renal plasma flow and filtration fraction. Losartan had a natriuretic effect that was more pronounced with a low-salt diet and did not appear to be associated with suppression of early sodium reabsorption in the proximal renal tubules.
Losartan also caused a transient increase in renal excretion of uric acid.
In patients with hypertension, proteinuria (at least 2 g/24 hours), 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%), fractional excretion of albumin was observed and immunoglobulins (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, there was no effect of therapy on the renal and systemic levels of prostaglandins.
Losartan does not affect autonomic reflexes and does not have a long-term 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 fasting triglycerides, total cholesterol and high-density lipoprotein cholesterol. At the same doses, losartan had no effect on fasting blood glucose concentrations.
In general, losartan caused a decrease in serum uric acid concentrations (usually less than 0.4 mg/dL) that persisted during long-term treatment. In controlled clinical studies involving patients with hypertension, no cases of drug withdrawal due to an increase in creatinine concentration or serum potassium levels were recorded.
A 12-week parallel study, which included patients with left ventricular failure (NYHA functional class II-IV), most of whom were taking diuretics and/or cardiac glycosides, compared the effects of losartan at doses of 2.5, 10, 25 and 50 mg/day with placebo. At doses of 25 and 50 mg/day, the drug exhibited positive hemodynamic and neurohormonal effects, which persisted throughout the study.
Hemodynamic effects included an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, as well as a decrease in total peripheral vascular resistance, mean systemic blood pressure, and heart rate (HR). The incidence of arterial hypotension in these patients depended on the dose of the drug.
Neurohormonal effects included decreased concentrations of aldosterone and norepinephrine in the blood.
Amlodipine
Hemodynamics
In patients with hypertension, after taking therapeutic doses, amlodipine causes vasodilation, which leads to a decrease in blood pressure in the supine and standing positions. This decrease in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine concentrations with long-term use. Although in studies evaluating hemodynamic parameters in patients with stable angina pectoris, a decrease in blood pressure and an increase in heart rate was observed with a single intravenous administration of amlodipine, in clinical studies, repeated oral administration of amlodipine did not lead to clinically significant changes in heart rate or blood pressure in normotensive patients with angina pectoris.
With long-term oral administration once a 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 treatment. Thus, patients with moderate hypertension (diastolic pressure 105-114 mm Hg) had an approximately 50% greater antihypertensive effect than patients with mild hypertension (diastolic pressure 90-104 mm Hg. ).
In patients with normal blood pressure, no clinically significant changes in blood pressure were observed (+1/-2 mmHg).
In patients with hypertension and normal renal function, taking amlodipine in therapeutic doses led to a decrease in renal vascular resistance, an increase in GFR and effective renal plasma flow without changing the filtration fraction or proteinuria.
As with other CBCMs, hemodynamic parameters of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine generally showed a slight increase in cardiac index without a significant change in the rate of increase in left ventricular cavity pressure at the beginning of the period. ejection (dP/dt) or left ventricular end-diastolic pressure or volume. In studies assessing hemodynamic parameters, amlodipine did not have a negative inotropic effect when used at therapeutic doses in healthy volunteers, even when used simultaneously with beta-blockers. However, similar results were observed in healthy volunteers or in patients with heart failure in the compensation stage when using drugs that have a pronounced negative inotropic effect.
Electrophysiological effects
Amlodipine did not affect sinoatrial node function or atrioventricular conduction in healthy volunteers. In patients with chronic stable angina, intravenous administration of 10 mg amlodipine did not have a significant effect on A-H and HV conduction and sinus node recovery time after cardiac stimulation.
Similar results were obtained in patients taking amlodipine and beta-blockers concomitantly.
In clinical studies in which patients with hypertension or angina pectoris took amlodipine concomitantly with beta-blockers, no adverse effects on electrocardiographic parameters were observed.
In clinical studies in patients with angina only, amlodipine therapy did not affect electrocardiographic intervals or cause greater atrioventricular block.
LOZAP PLUS (tablets)
Hypertension, if expressed in popular language, is high blood pressure.
Now all diseases are getting younger, including hypertension. If grandparents used to talk about high blood pressure, today a child in the first grade brings a certificate to the physical education teacher stating that he has hypertension. This is a terrible state when you feel bad because you respond to the weather, because you’ve bent over and you’re dizzy and it’s a problem to climb to the 4th floor and you can’t run half a meter. Having worked at schools for a long time, I can say that more and more often I meet students of different ages who already have such problems.
As for me, all my life I have not been distinguished by either hypertension or hypotension. Everything is okay. Doctors are always surprised that age goes by, but the pressure is like that of an astronaut. br> But my husband sometimes complains of feeling unwell precisely based on these indicators. Although I won’t say that he has it like his grandmothers, the condition is permanent, but sometimes you have to undergo either a course of prevention or a course of treatment. The weather takes its toll and reacts instantly.
Like many hypertensive patients, we turn to both folk and traditional medicine. It should also be said that people who have problems with both high and low blood pressure should never self-medicate and select treatment based on the recommendations of friends and reviews on the Internet. 100% consultation with a doctor and nothing else. Because an incorrectly selected drug brings many consequences in the worst case, and in the best case, it will not bring any effect at all.
Tablets for the treatment of hypertension Zentiva Lozap Plus - this is the case when we learned from friends and decided to try it.
I can immediately say that this drug did not suit us. No, no side effects, nothing criminal, but no effect either. After consumption, we realized that it had no effect on my husband. Previously, we took a more expensive version of anti-hypertensive drugs, the result was obtained in 20-30 minutes, but these tablets did not bring results either after 30 minutes or after an hour.
When we asked a doctor for advice, he said that this is not a strong drug, which, if it doesn’t help, then you need to take it with something else in tandem. But why pay more when you can buy one that helps?
I can also say that this drug helped my friend, who recommended it to us. Therefore, it is impossible to say unequivocally what helped whom. The drug works in one case, but not in another. This once again proves that you need to consult a doctor. High blood pressure is no joke.
Lozap, 50 mg, film-coated tablets, 30 pcs.
Hypersensitivity.
Patients with a history of angioedema (swelling of the face, lips, pharynx and/or tongue) should be closely monitored.
Arterial hypotension and water-electrolyte imbalance.
Symptomatic hypotension, especially after the first dose or after dose increases, may occur in patients with hypovolemia and/or hyponatremia as a result of high-dose diuretics, a low-salt diet, diarrhea, or vomiting.
It is necessary to either correct these conditions before prescribing Lozap®, or use initial doses of the drug.
Water and electrolyte disturbances.
Water and electrolyte disturbances are typical for patients with impaired renal function in combination with or without diabetes mellitus and require correction. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalemia in the losartan group was higher than in the placebo group. This indicates the need for constant monitoring of potassium levels in the blood plasma and creatinine Cl levels - patients with heart failure and creatinine Cl levels from 30 to 50 ml/min require especially strict monitoring.
Prescribing potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes simultaneously with Lozap® is not recommended.
Liver dysfunction.
Taking into account pharmacokinetic data indicating a significant increase in plasma concentrations of losartan in patients with cirrhosis, patients with a history of impaired liver function (more than 9 points on the Child-Pugh scale) are recommended to prescribe the drug in lower doses. There is no experience with the use of the drug in patients with severe liver failure. Taking this into account, Lozap® is contraindicated in patients with severe liver failure.
Double blockade of the RAAS.
There is evidence that the simultaneous use of ACE inhibitors, ARB II or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure).
The use of Lozap® in combination with aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal failure (GFR <60 ml/min/1.73 m2) and is not recommended in other patients (see “Contraindications”).
The use of Lozap® in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy and is not recommended for other patients (see “Contraindications”).
IHD and cerebrovascular diseases.
As with the use of any antihypertensive drugs, too sharp a decrease in blood pressure in patients with coronary artery disease and cerebrovascular diseases can lead to myocardial infarction or ischemic stroke.
Heart failure.
In patients with heart failure with or without renal impairment, as with other drugs acting on the RAAS, there is a risk of developing severe hypotension and acute renal failure.
experience with the use of losartan in the treatment of patients with heart failure and concomitant severe renal failure in patients with severe CHF (functional class IV according to the NYHA
), as well as in patients with heart failure and life-threatening arrhythmias. With this in mind, caution should be exercised when prescribing losartan to these categories of patients.
Combined use with ACE inhibitors for CHF.
When using Lozap® in combination with ACE inhibitors, the risk of side effects may increase, especially renal dysfunction and hyperkalemia (see “Side Effects”). In these cases, careful observation and monitoring of laboratory parameters is necessary.
Hemodialysis.
During hemodialysis, the sensitivity of blood pressure to the action of AT1 receptor antagonists increases as a result of a decrease in blood volume and activation of the RAAS. It is necessary to adjust the dose of Lozap® under careful monitoring of blood pressure in patients on hemodialysis.
Kidney transplantation.
There are no data on the use of Lozap® in patients who have recently undergone a kidney transplant.
General anesthesia.
Patients receiving ARA II during general anesthesia and surgical procedures may develop arterial hypotension as a result of blockade of the RAAS. Very rarely, cases of severe arterial hypotension may occur, requiring IV fluids and/or vasopressors.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy.
When using the drug Lozap®, as well as other vasodilators, caution should be exercised in patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism are usually resistant to treatment with antihypertensive drugs that affect the RAAS. In this regard, Lozap® is not recommended for use in such patients.
Elderly patients.
As a rule, patients over 75 years of age are recommended to start treatment with Lozap® with a dose of 25 mg/day.
Other special instructions and precautions.
As clinical experience with the use of ACE inhibitors, losartan and other AT1 receptor antagonists shows, these drugs are less effective in reducing blood pressure in patients of the Negroid race than in representatives of other races, possibly due to low renin activity in patients of this race.
Impact on the ability to drive vehicles and machinery.
Not studied. When driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, it should be taken into account that when using the drug, dizziness, drowsiness and fainting may occur.
