Cozaar, 100 mg 28 pcs.

Pharmgroup:

An angiotensin II receptor blocker.

Pharm Action:

Cosaar is a specific angiotensin II receptor antagonist (type AT1) for oral administration. Angiotensin II binds selectively to AT1 receptors located in many tissues (vascular smooth muscle tissues, adrenal glands, kidneys, and heart) and has several important biological functions including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell overgrowth. 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 synthesis pathway. Unlike some peptide angiotensin II antagonists, losartan has no agonist effects.

Lozartan selectively binds to AT1 receptors and does not bind to or block receptors for other hormones and ion channels that play an important role in the regulation of cardiovascular function. In addition, losartan does not inhibit ACE, which is responsible for bradykinin degradation. Consequently, effects not directly related to blockade of AT1 receptors, such as increased bradykinin-related effects or development of edema (losartan 1.7%, placebo 1.9%), are not relevant to the action of losartan.

In long-term (6-week) treatment of patients with arterial hypertension with losartan at a dose of 100 mg/day, a 2-3-fold increase in angiotensin II levels was observed when the drug reached Cmax in plasma; even greater increases in losartan concentrations were observed in some patients, especially with short duration of treatment (2 weeks). During treatment, antihypertensive activity and decreased plasma aldosterone concentrations were evident after 2 and 6 weeks of therapy, indicating effective angiotensin II receptor blockade. However, after losartan withdrawal, plasma renin activity and angiotensin II levels decreased after 3 days to baseline values observed before initiation of therapy.

As losartan is a specific angiotensin II AT1-receptor antagonist, it does not inhibit ACE kinase II, an enzyme that inactivates bradykinin. A study comparing the effects of 20 mg and 100 mg of losartan with those of an ACE inhibitor with respect to responses to angiotensin I, angiotensin II, and bradykinin showed that losartan blocks the effects of angiotensin I and angiotensin II without affecting the effects of bradykinin, due to the specific mechanism of action of losartan. In contrast, ACE inhibitors block the angiotensin I response and increase the bradykinin response without affecting the angiotensin II response, demonstrating a pharmacodynamic difference between losartan and ACE inhibitors.

The plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing drug dose. Because losartan and its active metabolite are angiotensin II receptor antagonists, they are both responsible for the antihypertensive effect.

In a study with a single dose of 100 mg of losartan in healthy volunteers (men), use of the drug in both patients following a diet low in table salt and patients with a high intake of table salt had no effect on glomerular filtration rate, effective renal plasma flow, or filtration fraction. Losartan has 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 uric acid excretion.

In patients with arterial hypertension, proteinuria (greater than 2 g/24 h), non-diabetic patients taking losartan for 8 weeks at a dose of 50 mg to 100 mg, there was a 42% significant reduction in proteinuria, fractional albumin excretion, and IgG. In these patients, losartan stabilized glomerular filtration rate and decreased filtration fraction.
In postmenopausal women with arterial hypertension who received potassium losartan at a dose of 50 mg/day for 4 weeks, no effect of therapy on renal and systemic prostaglandin levels was detected.

Lozartan has no effect on autonomic reflexes and no lasting effect on plasma norepinephrine levels.

In patients with arterial hypertension, losartan at doses up to 150 mg/day does not cause clinically significant changes in fasting triglyceride, total cholesterol (TC) and HDL-C levels. At the same doses, losartan has no effect on fasting blood glucose levels.

In general, losartan caused a decrease in serum uric acid levels (generally less than 0.4 mg/dL) that persisted during long-term therapy. In controlled clinical trials in which patients with arterial hypertension were included, there were no cases of drug withdrawal due to increased serum creatinine or potassium levels.

Pharmacokinetics

Intake
When ingested, losartan is well absorbed from the GI tract and undergoes a “first pass” effect through the liver, resulting in the formation of the active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan is approximately 33%. Mean Cmax of losartan and its active metabolite is reached after 1 h and 3-4 h, respectively. No clinically significant effect on the plasma concentration profile of losartan has been identified when losartan is taken with a normal meal.

PDistribution
Losartan and its active metabolite bind to plasma proteins (mainly to albumin) by more than 99%. The Vd of losartan is 34 liters. Studies in rats have shown that losartan has almost no penetration through the BBB.

Metabolism
Approximately 14% of the dose of losartan (when given orally and intravenously) is converted to its active metabolite. After oral or IV administration of 14C-labeled losartan, the radioactivity of circulating blood plasma is primarily due to the presence of losartan and its active metabolite. Biologically inactive metabolites are also formed, including two major metabolites formed by hydroxylation of the butyl side chain and one minor metabolite, N-2-tetrazol-glucuronide.

Elimation
Plasma clearance of losartan and its active metabolite is approximately 600 ml/min and 50 ml/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, approximately 4% of the dose is excreted unchanged in the urine and approximately 6% of the dose is excreted as an active metabolite in the urine. After oral administration, plasma concentrations of losartan and its active metabolite are decreased polyexponentially with a final T1/2 of approximately 2 and 6-9 hours, respectively. There is no significant plasma cumulation of either losartan or its active metabolite at a dose of 100 mg once daily.
Excretion of losartan and its metabolites occurs in the bile and urine. After oral administration of 14C-labeled losartan, approximately 35% of the radioactive label is detected in the urine and 58% in the feces. After intravenous administration of 14C-labeled losartan, approximately 43% of the radioactive label is detectable in urine and 50% in feces.

Farmacokinetics in special patient groups

Plasma concentrations of losartan and its active metabolite in elderly patients with arterial hypertension are not significantly different from those in younger patients with arterial hypertension.

In patients with mild to moderate alcoholic cirrhosis taking losartan orally, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times (respectively) higher than in young healthy male volunteers.

Plasma concentrations of losartan in patients with creatinine clearance above 10 ml/min did not differ from those in subjects with normal renal function. When compared, the AUC in patients on hemodialysis was approximately 2-fold higher than in patients with normal renal function. Plasma concentrations of the active metabolite are unchanged in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite cannot be removed by hemodialysis.

Indications

Active ingredient

Composition

Dthe active ingredient:

Potassium losartan 100 mg.

How to take, the dosage

In case of arterial hypertension, the average daily dose is 50 mg.

The frequency of administration is 1 time per day.

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

The daily dose of the drug can be increased up to 100 mg, if necessary.

Interaction

No clinically significant interaction of Cozaar with other medicinal products has been noted.

Hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital and ketoconazole have been used in pharmacokinetic clinical studies.

Special Instructions

Symptomatic hypotension may occur in patients with dehydration (e.g., those treated with high-dose diuretics) at the beginning of treatment with Cozaar. It is necessary to correct dehydration before prescribing Cozaar or to start treatment with a lower dose of the drug.

Pharmacological data indicate that plasma concentrations of losartan are significantly increased in patients with cirrhosis, so patients with a history of liver disease should use the drug in a lower dose.

Some drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine levels in patients with bilateral renal stenosis or arterial stenosis of the sole kidney. Angiotensin II receptor antagonists could potentially have a similar effect, although such data are not currently available.

Clinical studies have not shown any differences regarding the safety and efficacy of Cozaar in elderly patients.

Contraindications

Side effects

Cardiovascular disorders: In controlled clinical trials, dizziness was observed more frequently than with placebo; orthostatic reactions depending on the dose of the drug were also observed.

Laboratory parameters:In controlled clinical trials, significant changes in standard laboratory parameters were rarely associated with the administration of Cozaar. Hyperkalemia (serum potassium over 5.5 mEq/L) in 1.5% of patients, increased ALT levels were noted.

Allergic reactions: angioedema (including swelling of the face, lips, pharynx and/or tongue), urticaria.

Digestive system disorders:diarrhea.

CNS side:migraine.

Dermatological reactions: itching.

Other: disorders of renal function, myalgia.

In most cases Cozaar is well tolerated, side effects are mild and transient and do not require withdrawal of the drug. The cumulative incidence of side effects of Cozaar is comparable with placebo.

Overdose

The information on overdose is limited.

The most likely symptoms of overdose:A marked decrease in BP and tachycardia; bradycardia may occur due to parasympathetic stimulation.

Treatment: symptomatic therapy. Losartan and its active metabolite are not removed from the bloodstream by hemodialysis.

Pregnancy use

There are no data on the use of Cozaar in pregnancy. However, it is known that drugs acting directly on the renin-angiotensin system when used in the second and third trimesters of pregnancy may cause developmental defects or even death of the developing fetus. Therefore, if pregnancy occurs, the use of Cozaar should be stopped immediately.

It has been shown in experimental studies that the drug causes developmental defects and death of the fetus or newborn. It is believed that the mechanism of this effect is a pharmacologically mediated effect on the renin-angiotensin system. Renal perfusion of the human fetus, which depends on the development of the renin-angiotensin system, begins in the second trimester; the risk to the fetus increases if Cozaar is taken in the second or third trimester of pregnancy.

It is not known whether losartan is excreted with breast milk. If Cozaar is used during lactation, a decision should be made either to discontinue breastfeeding or to discontinue treatment with the drug, taking into account its importance to the mother.

Similarities