Pharmacological action Cozaar 100 mg
A specific receptor antagonist of angiotensin II (type AT1) for oral administration. Angiotensin II binds selectively to the AT1-receptors located in many tissues (smooth muscle, blood vessels, the adrenal glands, kidneys and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells. Losartan and its pharmacologically active metabolite (E 3174) as in vitro, and in vivo blocking all the physiological effects of angiotensin II, regardless of the source or route of synthesis. In contrast to some peptide antagonists of angiotensin II losartan has no agonist effects.
Losartan binds selectively to the AT1-receptors and does not bind and does not block other hormone receptors and ion channels that play an important role in the regulation of the cardiovascular system. Furthermore, losartan does not inhibit ACE, which promotes the degradation of bradykinin. Hence the effects are not directly related to the blockade of AT1-receptor, in particular, strengthening effects associated with exposure to bradykinin or the development of edema (losartan – 1.7%, placebo – 1.9%) have no relation to the action of losartan.
With long-term (6-week) treatment of patients with hypertension, losartan 100 mg / day was observed 2-3-fold increase in the level of angiotensin II at the time to Cmax of the drug in plasma was observed in some patients even greater concentrations of losartan, especially when short duration of treatment (2 weeks). However, antihypertensive activity and reduced plasma aldosterone concentration were manifested after 2 and 6 weeks of treatment, indicating effective blockade of receptors of angiotensin II. After the abolition of losartan plasma renin activity and angiotensin II levels after 3 days decreased to baseline values observed before the start of treatment.
The study, which compared the effects of 20 mg and 100 mg of losartan with an ACE inhibitor effects on 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, which is due to specific mechanism of action of losartan. On the contrary, ACE inhibitors block the response to angiotensin I and increased severity of response to bradykinin, without affecting the intensity of response to angiotensin II, demonstrated that the pharmacodynamic difference between losartan and ACE inhibitors.
The concentrations of losartan and its active metabolite in plasma, as well as the antihypertensive effect of losartan increase with dose. Since losartan and its active metabolite are antagonists of angiotensin II, they both cause the antihypertensive effect. In a study with a single dose of 100 mg of losartan in healthy volunteers (men) to use the drug as a patient on a diet with a limited content of salt, and patients who use a lot of salt, had no effect on glomerular filtration rate, effective renal plasma flow and filtration fraction. Losartan has a natriuretic effect, which was more pronounced in malosolevoy diet and, apparently, was not associated with the suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in allocation of uric acid by the kidneys.
In patients with hypertension, proteinuria (more than 2 g/24 h), diabetes mellitus and receiving losartan for 8 weeks at a dose of 50 mg to 100 mg had significantly reduced proteinuria by 42%, fractional excretion of albumin and IgG. In these patients losartan stabilize the glomerular filtration rate and reduced the filtration fraction.
Women in postmenopauznom period with hypertension treated with losartan potassium 50 mg / day for 4 weeks showed no effect of treatment on renal and systemic level of prostaglandins.
Losartan has no effect on autonomic reflexes and has no lasting effect on the level of noradrenaline in blood plasma.
In patients with hypertension, losartan at doses of 150 mg / day did not cause clinically significant changes in fasting triglycerides, total cholesterol (XC) and HDL-C. At the same doses of losartan has no effect on the level of fasting blood glucose.
Overall, losartan caused a decrease in serum uric acid levels (typically less than 0.4 mg / dL) are stored in the long course of therapy. In controlled clinical trials, which included patients with hypertension, cases of drug discontinuation due to increased levels of creatinine or serum potassium have been reported.
Pharmacokinetics Cozaar 100 mg
Absorption
When administered losartan is well absorbed from the gastrointestinal tract and is subjected to the effect of “first pass” through the liver, resulting in formation of the active metabolite of carboxylated and inactive metabolites. Systemic bioavailability of losartan is approximately 33%. Mean Cmax of losartan and its active metabolite are reached in 1 h and 3-4 h respectively. When losartan during normal meal clinically significant effect on the concentration profile of losartan in plasma were detected.
Distribution
Losartan and its active metabolite are bound to plasma proteins (mainly albumin) for more than 99%. Vd losartan is 34 liters. Studies in rats showed that losartan practically does not penetrate the BBB.
Metabolism
Approximately 14% of the dose of losartan (at intake and / in the introduction) is converted to its active metabolite. After oral administration, or on / in a losartan-labeled 14C radioactivity of circulating blood plasma primarily due to the presence in it of losartan and its active metabolite. Are formed as biologically inactive metabolites, including Two main, resulting from hydroxylation butyl side chain, and one secondary – N-2-tetrazol-glucuronide.
Breeding
Plasma clearance of losartan and its active metabolite is about 600 ml / min and 50 ml / min, respectively. Renal clearance of losartan and its active metabolite is about 74 ml / min and 26 ml / min, respectively. When losartan into about 4% of the dose is excreted unchanged in the urine and about 6% of the dose is excreted in the urine as active metabolite. Losartan and its active metabolite are linear pharmacokinetics after oral losartan potassium doses up to 200 mg.
After oral administration, plasma concentrations of losartan and its active metabolite decline with a finite polieksponentsialno T1 / 2 approximately 2 h and 6-9, respectively. In the single dose of the drug at a dose of 100 mg or losartan nor its active metabolite do not accumulate significantly in plasma.
Withdrawal of losartan and its metabolites occurs in the bile and urine. After oral administration, losartan, labeled with 14C, about 35% of the radiolabel found in the urine and 58% – in the feces. After i / v administration of losartan, labeled with 14C, approximately 43% of radiolabel detected in the urine and 50% in feces.
Pharmacokinetics in special patient groups
The concentrations of losartan and its active metabolite in the blood plasma of elderly patients with hypertension were not significantly differ from these indices in younger patients with hypertension.
The concentrations of losartan in plasma were 2 times higher in women with hypertension compared with men who suffer from hypertension. The concentrations of the active metabolite of men and women did not differ. This apparent pharmacokinetic difference has no clinical significance.
When losartan into patients with liver cirrhosis of alcoholic origin of mild to moderate severity concentrations of losartan and its active metabolite in plasma were 5 and 1.7 times (respectively) than in young healthy male volunteers.
The concentrations of losartan in plasma in patients with creatinine clearance above 10 ml / min did not differ from those in patients with normal renal function. When comparing the AUC values in patients on dialysis, was approximately 2 times greater than patients with normal renal function. Plasma concentrations of active metabolite do not change in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite can not be removed by hemodialysis.
Statement Cozaar 100 mg
- Hypertension;
- Reducing the risk of cardiovascular disease and mortality in patients with hypertension and left ventricular hypertrophy;
- Protection of renal function in patients with type 2 diabetes mellitus with proteinuria to reduce the likelihood of increased serum creatinine, renal disease stabilization (to prevent the need for dialysis or kidney transplantation), reduction of proteinuria;
- Chronic heart failure after failure of treatment with ACE inhibitors.
Dosage regimen Cozaar 100 mg
Cozaar ingested, regardless of the meal, can be applied as a monotherapy or in combined with other antihypertensive drugs.
When hypertension standard initial and maintenance dose for most patients is 50 mg 1 time / day. Maximum antihypertensive effect is achieved within 3-6 weeks after starting therapy. In some patients, to achieve greater effect, the dose may be increased to 100 mg 1 time / day.
In patients with reduced BCC (for example, when taking diuretics in high doses) the initial dose should be reduced to 25 mg 1 time / day.
No need for the selection of the initial dose in the elderly and in patients with renal insufficiency, including patients on dialysis.
Patients with liver disease in anamnesis recommended to be prescribed the drug at lower doses.
To reduce the risk of cardiovascular disease and mortality in patients with hypertension and left ventricular hypertrophy standard initial dose is 50 mg 1 time / day. In the future we recommend adding low-dose hydrochlorothiazide or increase the dose to 100 mg Cozaar 1 time / day according to the degree of BP reduction.
In order to protect renal function in patients with type 2 diabetes and proteinuria standard initial dose is 50 mg 1 time / day. In the future it is recommended to increase the dose to 100 mg Cozaar 1 time / day according to the degree of BP reduction. Cozaar can be assigned in conjunction with other antihypertensive drugs (diuretics, calcium channel blockers, alpha-and beta-blockers, centrally acting agents), insulin and other hypoglycemic agents (sulfonylureas, glitazones and glucosidase inhibitors).
In chronic heart failure the initial dose of 12.5 mg Cozaar 1 time / day. Typically, the dose is titrated at weekly intervals (ie 12.5 mg / day, 25 mg / day, 50 mg / day) to usual maintenance dose of 50 mg 1 time / day, depending on individual tolerance.
Side effect Cozaar 100 mg
In controlled clinical trials of the drug in patients with essential hypertension the only side effect associated with taking the drug was dizziness, which occurred more frequently than placebo and occurred in> 1% of patients treated Cozaar. In addition, less than 1% patients had orthostatic reactions, depending on the dose. Rarely reported occurrence of the rash, but the frequency of its occurrence was less than with placebo.
Controlled clinical studies have shown that Cozaar was generally well tolerated by patients with left ventricular hypertrophy, patients with type 2 diabetes and proteinuria. The most common side effects associated with drug intake, were systematic and non-systemic dizziness, asthenia / fatigue, decreased blood pressure and hyperkalemia.
In these studies, the following side effects while taking Cozaar (n = 2085) and placebo (n = 535) occurred in more than 1% of patients:
Part of the body as a whole: pain in the stomach of 1.7% (placebo 1.7%); weakness, and fatigue 3.8% (placebo 3.9%), chest pain 1.1% (placebo 2.6%), edema of 1.7% (placebo 1.9%)
Cardio-vascular system: palpitations 1% (placebo 0.4%), tachycardia 1% (placebo 1.7%).
Part of the digestive system: diarrhea 1.9% (placebo 1.9%) dyspepsia 1.1% (placebo 1.5%), nausea 1.8% (placebo 2.8%).
On the part of the musculoskeletal system: back pain 1.6% (placebo 1.1%) muscle cramps 1% (placebo 1.1%).
CNS: dizziness 4.1% (placebo 2.4%), headache 14.1% (17.2% placebo), insomnia 1.1% (placebo 0.7%).
The respiratory system: cough 3.1 (placebo 2.6%), swelling of the mucous membranes of the nose 1.3% (placebo 1.1%), pharyngitis 1.5% (placebo 2.6%), sinusitis, 1% (placebo 1.3%), infections of upper respiratory tract 6.5% (placebo 5.6%).
The following adverse reactions have been observed in clinical practice.
Allergic reactions: patients treated with losartan, there was rarely angioedema, including laryngeal edema, glottis, causing airway obstruction and / or swelling of face, lips, pharynx, and / or language. Some of these patients had a history of instructions for the transfer of angioedema while taking ACE inhibitors. Rarely reported occurrence of vasculitis, including Henoch-Schonlein purpura.
From the digestive system: hepatitis (rare), abnormal liver function.
From the hemopoietic system: anemia, thrombocytopenia.
With the Musculoskeletal System: myalgia, arthralgia.
CNS: headache.
The respiratory system: cough.
Dermatological reactions: rash, itching.
From the laboratory parameters: the controlled clinical trials in patients with essential hypertension clinically significant changes in standard laboratory parameters were rarely associated with taking Cozaar. At 1.5% of patients had hyperkalemia (serum potassium> 5.5 mEq / L). In a study in patients with type 2 diabetes mellitus with proteinuria hyperkalemia occurred in 9.9% patsentov Kozaarom treated and 3.4% of patients treated with placebo. Elevated ALT levels was observed in rare cases and usually return to normal after discontinuation of therapy.
Overall Cozaar well tolerated, side effects are mild and transient in nature and do not require discontinuation. The total incidence of side effects comparable to Cozaar this indicator in patients receiving placebo.
Contraindications Cozaar 100 mg
- Pregnancy
- Hypersensitivity to the drug.
Pregnancy and breastfeeding Cozaar 100 mg
Application Cozaar during pregnancy is contraindicated.
When used in phase II and III trimester of pregnancy, drugs acting on the renin-angiotenzivnuyu system can cause injury or even death of the developing fetus, so pregnant in establishing reception Cozaar should be immediately discontinued. In fetal renal perfusion, which depends on the development of the renin-angiotensin system, appears in the II trimester, the risk to the fetus increases when administered in Cozaar II or III trimester of pregnancy.
Do not take Cozaar during lactation. Experience with losartan during breast-feeding is not, and it is unclear whether losartan is allocated in breast milk. Since many drugs are excreted in breast milk and may have adverse effects on infants, the need of the drug to the mother should decide to discontinue breast-feeding or withdrawing the drug.
Use in renal impairment Cozaar 100 mg
As a consequence of inhibiting the renin-angiotensin system in some susceptible patients had changes in renal function, including renal failure, these changes may disappear after cessation of therapy.
Cautions
Possible manifestation of the symptoms of hypersensitivity as angioedema.
In patients with reduced BCC (for example, treated with high doses of diuretics) can occur symptomatic hypotension. Correction of such conditions should be conducted prior to the appointment Cozaar or begin treatment with lower doses.
Disruption of water and electrolyte balance is characteristic of patients with renal failure with diabetes or without diabetes, so when a drug of this category of patients should be particularly careful. In clinical trials involving patients with type 2 diabetes with proteinuria, the incidence of hyperkalemia was higher in the group receiving Kozaar than in the placebo group. Several patients had to discontinue therapy due to hyperkalemia occurred.
These pharmacokinetic studies indicate that the concentration of losartan in plasma of patients with cirrhosis of the liver is greatly increased, so patients with liver disease in history to be prescribed the drug at a lower dose.
As a consequence of inhibiting the renin-angiotensin system in some susceptible patients had changes in renal function, including renal failure, these changes may disappear after cessation of therapy.
Some drugs that affect the renin-angiotensin system may increase the level of blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery of a sole kidney. Reports on the occurrence of such effects when taking Cozaar, changes in renal function can disappear at the termination of therapy.
Use in Pediatrics Cozaar 100 mg
Safety and efficacy in children have not been established.
Overdose Cozaar 100 mg
For information about the overdose is limited. The most likely symptoms of overdose: marked reduction of blood pressure and tachycardia, bradycardia may occur due to parasympathetic stimulation.
Treatment: symptomatic therapy. Losartan and its active metabolite are not removed from the circulation by hemodialysis.
Drug Interactions Cozaar 100 mg
There were no clinically significant drug interactions with drugs like hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin.
Rifampin and fluconazole reduced the level of active metabolite. The clinical significance of these interactions is not known.
As with other means of blocking the formation of angiotensin II and its effects, concomitant appointment of potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium supplements and salt containing potassium may lead to an increase in serum potassium.
NSAIDs, including selective COX-2 inhibitors, can reduce the effect of diuretics and other antihypertensive drugs. Therefore, the hypotensive effect of angiotensin II receptor antagonists may be attenuated by coadministration with NSAIDs, including selective COX-2 inhibitors.
In some patients with impaired renal function who were treated with NSAIDs, including selective COX-2 inhibitors, concomitant use of angiotensin II receptor antagonists may cause a further deterioration of renal function. Typically, this effect is reversible.
