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Hydrochlorothiazide, Losartan

Merck Sharp & Dohme
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2019-09-19
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Clinical Pharmacology

Hyzaar - an antihypertensive drug of combined composition.

The active ingredients of the drug Hyzaar have an additive antihypertensive effect, reducing the level of blood pressure to a greater extent than each of the components separately. Due to the diuretic effect, hydrochlorothiazide increases plasma renin activity (ARP), stimulates the secretion of aldosterone, increases the level of angiotensin II and reduces the level of potassium in blood serum. Taking losartan blocks all the physiological effects of angiotensin II and, due to the suppression of the effects of aldosterone, reduces the potassium loss caused by the diuretic.

Losartan has a moderate and transient uricosuric effect. Hydrochlorothiazide causes a slight increase in the level of uric acid in the blood; the combination of losartan and hydrochlorothiazide helps to reduce the severity of diuretic hyperuricemia.

- Losartan Losartan is an antagonist of angiotensin II receptors. Angiotensin II is a powerful vasoconstrictor, the main active hormone of the renin-angiotensin system, as well as the crucial pathophysiological link in the development of arterial hypertension. Angiotensin II binds to the receptor subtype AT 1, found in many tissues (for example, in vascular smooth muscle, adrenal glands, kidneys and heart) and causes a number of important biological effects, including vasoconstriction and release of aldosterone. Angiotensin II also stimulates the proliferation of smooth muscle cells. The role of the second type of angiotensin II receptor - the AT 2 subtype - in the cardiovascular homeostasis is unknown. Losartan and its pharmacologically active metabolite (E-3174) both in vitro and in vivo block all the physiological effects of angiotensin II, regardless of the source or route of synthesis. Unlike some angiotensin II peptide antagonists, losartan does not have agonist effects. Losartan binds selectively to AT 1 receptors and does not bind or block the receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. In addition, losartan does not inhibit ACE, which contributes to the degradation of bradykinin. Consequently, effects not directly related to the blockade of AT 1 receptors, in particular, enhancing the effects associated with the effects of bradykinin or the development of edema (losartan 1.7%, placebo 1.9%) are not related to the action of losartan. Due to the suppression of the effects of aldosterone, losartan helps to reduce the potassium loss caused by the diuretic intake. Losartan has a moderate and transient uricosuric effect. Losartan inhibits the increase in systolic and diastolic blood pressure observed with the introduction of angiotensin II. At the time of maximum effect, losartan potassium at a dose of 100 mg suppresses the above effect by approximately 85%; and 24 hours after a single and multiple dose, by 26-39%. During the administration of losartan, the elimination of negative feedback, consisting in the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity (ARP). An increase in ARP is accompanied by an increase in plasma angiotensin II levels. With 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 plasma angiotensin II levels was observed. Some patients showed an even greater increase, especially with a short duration of treatment (2 weeks). However, antihypertensive activity and a decrease in plasma aldosterone concentration manifested after 2 and 6 weeks of therapy, which indicates an effective blockade of angiotensin II receptors. ARP and the level of angiotensin II decreased to baseline values ​​observed before the start of the drug, 3 days after the withdrawal of losartan. The effects of Hyzaar on ARP and the level of angiotensin II was comparable to that of 50 mg of losartan.Since losartan is a specific antagonist of AT 1 receptor angiotensin II, it does not inhibit ACE (kininase II) - an enzyme that inactivates bradykinin. A study comparing the effects of 20 mg and 100 mg of losartan potassium with the effects of an ACE inhibitor on the reaction 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. These results are consistent with data on the specificity of the mechanism of action of losartan. In contrast, an ACE inhibitor blocked the response to angiotensin I and increased the severity of the response to bradykinin, without affecting the intensity of the response to angiotensin II, which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors. The concentration 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, both of them contribute to the antihypertensive effect. In a clinical study with a single dose of 100 mg of losartan potassium, which included healthy men, administration of the drug in high- and low-salt diets did not affect the glomerular filtration rate (GFR), the effective renal plasma flow and filtration fraction. Losartan has 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 arterial hypertension, proteinuria (? 2g / 24 h), not suffering from diabetes and taking losartan potassium in a dose of 50 mg for 8 weeks with a gradual increase to 100 mg, there was a significant decrease in proteinuria by 42%. Fractional excretion of albumin and IgG also significantly decreased. In these patients, losartan stabilized GFR and reduced the filtration fraction. In postmenopausal women with arterial hypertension, who took potassium losartan at a dose of 50 mg / day for 4 weeks, no effect of therapy on renal and systemic prostaglandins was detected. Losartan does not affect vegetative reflexes and does not have a lasting effect on the level of norepinephrine in the blood plasma. In patients with arterial hypertension, losartan potassium in doses up to 150 mg / day did not cause clinically significant changes in fasting triglycerides, total cholesterol and HDL cholesterol. In the same doses, losartan had no effect on fasting blood glucose levels. In general, losartan caused a decrease in serum uric acid levels (usually less than 0.4 mg / dL), which was maintained during long-term therapy. In controlled clinical trials in which patients with arterial hypertension were included, no cases of drug withdrawal due to increased levels of creatinine or potassium were registered. In a 12-week parallel study that included patients with left ventricular failure (functional class II-IV according to the NYHA classification) and most of them received diuretics and / or digitalis, the effects of potassium losartan were compared in doses of 2.5, 10, 25, and 50 mg / day with placebo. At doses of 25 mg and 50 mg / day, the drug had positive hemodynamic and neurohormonal effects, which were maintained 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 aldosterone and noradrenaline levels in the blood.In patients with arterial hypertension and left ventricular hypertrophy, losartan, often in combination with hydrochlorothiazide, reduces the risk of cardiovascular morbidity and mortality, which was proven by assessing the combined incidence of cardiovascular death, stroke and myocardial infarction in this group of patients LIFE).

- Hydrochlorothiazide The mechanism of the antihypertensive action of thiazides is unknown. Thiazides do not affect normal blood pressure. Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the reabsorption of electrolytes in the distal tubules of the kidneys. Hydrochlorothiazide approximately equally increases the excretion of sodium and chloride. Natriuresis may be accompanied by a small loss of potassium ions and bicarbonate. When ingested, the diuretic effect begins after 2 hours, reaches a maximum on average after 4 hours and lasts from 6 to 12 hours.

Indications

- Treatment of arterial hypertension in patients for whom it is advisable to use combination therapy.
- To reduce the risk of cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy.

Composition

1 tablet contains:

- Losartan potassium 50 mg
- Hydrochlorothiazide 12.5 mg
- Excipients: microcrystalline cellulose, aqueous lactose, pregelatinized starch, magnesium stearate.
- Shell composition: hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, quinoline yellow aluminum varnish, carnauba wax.

Hydrochlorothiazide, Losartan is marketed under different brands and generic names, and comes in different dosage forms:

Brand nameManufacturerCountryDosage form
Hyzaar Merck Sharp & Dohme USA pills
Lozap plus Zentiva KS Czech pills
Vasotens N Actavis AO Switzerland pills
Losartan-N Canonpharma Russia pills
Lorista N Krka dd Novo mesto AO Slovenia pills
Lorista ND Krka dd Novo mesto AO Slovenia pills
Losartan-N Gedeon Richter Hungary pills
Lozarel Sandoz Switzerland pills
Hyzaar Forte Merck Sharp & Dohme USA pills

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Hydrochlorothiazide, Losartan

Dosage and Administration

Hyzaar can be prescribed in combination with other antihypertensive agents. Hyzaar can be taken regardless of the meal.

- With arterial hypertension, the usual initial and maintenance doses of the drug - 1 tab. Hyzaara 1 time / day. In the absence of an adequate therapeutic effect within 2-4 weeks, the dose should be increased to 2 tab. Hyzaara 50 / 12.5 mg 1 time / day. The maximum dose - 2 tab. Hyzaara 50 / 12.5mg 1 time / day. As a rule, the antihypertensive effect is achieved within 3 weeks after the start of therapy. Selection of the initial dose of Gizar for elderly patients is not required.

- To reduce the risk of cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy. The drug is prescribed in a standard initial dose of losartan, 50 mg 1 time / day. Patients who fail to reach the target values ​​of blood pressure while receiving losartan 50 mg / day require therapy by combining losartan with low doses of hydrochlorothiazide (12.5 mg), and, if necessary, increase the dose of losartan to 100 mg in combination with hydrochlorothiazide in a dose of 12.5 mg / day, in the future - to increase the dose to 2 tab. Hyzaara 50 mg / 12.5 mg (only 100 mg of losartan and 25 mg of hydrochlorothiazide once a day).

Adverse reactions

In clinical studies with losartan / hydrochlorothiazide, no adverse events specific to this combination preparation were observed.
Adverse reactions were limited to those already reported with losartan and / or hydrochlorothiazide alone. The cumulative incidence of adverse reactions reported with this combination was comparable to that used with placebo. The frequency of discontinuation of therapy was also comparable to that in patients who received placebo. In most cases, adverse reactions were mild, were transient, and did not require discontinuation of therapy.
In controlled clinical trials, dizziness was the only adverse reaction associated with taking the drug, the frequency of which exceeded that when taking placebo more than 1 percent or more.
Losartan in combination with hydrochlorothiazide is generally well tolerated in patients with arterial hypertension and left ventricular hypertrophy. The most frequent adverse reactions were dizziness, weakness, and fatigue.
During the post-marketing experience using the drug, the following additional adverse reactions have been reported.
Allergic reactions and immunopathological reactions: anaphylactic reactions, angioedema, including laryngeal and glottis edema with the development of airway obstruction and / or swelling of the face, lips, pharynx and / or tongue in patients taking losartan; some of these patients had indications of the development of angioedema in the history of using other drugs, including ACE inhibitors. There are rare reports of vasculitis development (including Schoenlein-Henoch purpura) with losartan.
On the part of the digestive system: rarely - hepatitis, diarrhea (in patients taking losartan).
On the part of the respiratory system: possible cough (in patients taking losartan).
Dermatological reactions: urticaria, increased light and photosensitivity.
From the laboratory indicators: in controlled clinical trials on the background of taking Hyzaar®, clinically significant changes in standard laboratory parameters were rarely observed. Hyperkalemia (serum potassium more than 5.5 mEq / l) was observed in 0.7% of patients, which did not require discontinuation of the drug. Increased ALT activity was rarely observed and usually disappeared after discontinuation of therapy.

Contraindications

- Anuria.
- Severe renal dysfunction (creatinine clearance (CC) less than 30 ml / min).
- Severe abnormal liver function.
- Hypersensitivity to any of the components of the drug.
- Hypersensitivity to other drugs derived from sulfonamides.

With caution should use the drug for:

- Violation of water and electrolyte balance (dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia), which can develop against the background of intercurrent diarrhea or vomiting.
- Bilateral renal artery stenosis or arterial stenosis of a single kidney.
- Diabetes.
- In patients with hypercalcemia, hyperuricemia and / or gout.
- In patients with allergic history and bronchial asthma.
- In systemic diseases of the connective tissue (including SLE).
- Hypovolemia (including on the background of high doses of diuretics.
- Simultaneous administration with NSAIDs (including those with COX-2 inhibitors).

Drug interactions

- Losartan In clinical studies of pharmacokinetics, no clinically significant interaction of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin was detected. Rifampicin and fluconazole are reported to reduce the level of the active metabolite. The clinical significance of this interaction has not been studied. The combination of losartan, as well as other agents blocking angiotensin II or its effects, with potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium supplements or potassium salts can lead to an increase in the level of 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 with simultaneous use with NSAIDs (including COX-2 inhibitors). In some patients with impaired renal function who received NSAID therapy (including COX-2 inhibitors), treatment with angiotensin II receptor antagonists can cause further deterioration of renal function, including acute renal failure, which is usually reversible. The antihypertensive effect of losartan, like other antihypertensive drugs, may be weakened by taking indomethacin.

- Hydrochlorothiazide With simultaneous use of thiazide diuretics with barbiturates, opioid analgesics, ethanol, an increased risk of orthostatic hypotension may be increased. With simultaneous use may require dose adjustment hypoglycemic agents (for oral administration and insulin). When using hydrochlorothiazide with other antihypertensive agents, an additive effect is observed. In the presence of anionic exchange resins, the absorption of hydrochlorothiazide is impaired. Kolestiramine or colestipol in single doses bind hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by 85% and 43%, respectively. The use of corticosteroids, ACTH leads to a marked decrease in the level of electrolytes, in particular, can cause hypokalemia. Perhaps a decrease in the severity of the response to the introduction of pressor amines (eg, epinephrine). Perhaps increased action of muscle relaxants non-depolarizing type of action (for example, tubocurarine). Diuretics reduce the renal clearance of lithium and increase the risk of its toxic action; combined use of diuretics and lithium preparations is not recommended. In some cases, the use of NSAIDs (including selective COX-2 inhibitors) can reduce the diuretic, natriuretic and antihypertensive effects of diuretics. Due to the effect of thiazides on calcium metabolism, their intake may distort the results of a study of the function of the parathyroid glands.

Pregnancy and Lactation

The use of drugs that have a direct effect on the renin-angiotensin system in the second and third trimesters of pregnancy can have a teratogenic effect and cause fetal death.Immediately after the pregnancy is established, Hyzaara should be stopped.

Adequate and strictly controlled clinical studies of the safety of the use of Hyzaar during pregnancy was not conducted.

Experimental studies on animals have shown that the use of losartan can have a teratogenic effect and cause death of the fetus and newborn, which is probably due to the effect of this active substance on the renin-angiotensin system.

In the human fetus, renal perfusion, which depends on the development of the renin-angiotensin system, begins in the second trimester; thus, the risk of impaired development and fetal death increases with the use of Hyzaar in the II or III trimesters of pregnancy.

Thiazides penetrate the placental barrier and are detected in cord blood. Routine use of diuretics in pregnant women without comorbidities is not recommended, because This increases the risk of adverse events in the mother and fetus such as fetal jaundice and jaundice in newborns, thrombocytopenia, and possibly other adverse reactions that occur in adults. Diuretics do not prevent the development of toxicosis of pregnancy, while there is no convincing evidence that they have a positive effect on the course of toxicosis.

There is no evidence that losartan is excreted in breast milk. However, it is known that thiazides are excreted in breast milk. If necessary, the use of the drug during lactation should assess the intended benefit of therapy for the mother and the existing risk of side effects in an infant.

Special instructions

- Application for violations of the liver function The drug is contraindicated for use in marked disorders of liver function.

- Use in cases of impaired renal function The drug is contraindicated for use in marked impaired renal function (CC less than 30 ml / min). There are reports that a number of patients taking the drug, in connection with the suppression of the function of the renin-angiotensin system, showed changes in renal function, including renal failure; these changes were reversible and disappeared after discontinuation of therapy.

- Precautions for losartan There are reports that a number of patients taking the drug, in connection with the suppression of the function of the renin-angiotensin system, were observed changes in renal function, including renal failure; these changes were reversible and disappeared after discontinuation of therapy. Other agents that affect the renin-angiotensin system can lead to an increase in the urea and creatinine levels in the blood of patients with bilateral renal artery stenosis and arterial stenosis of a single kidney. Similar effects were observed while taking losartan; These changes in renal function were reversible and disappeared after discontinuation of therapy.

- Precautions for hydrochlorothiazide. As with all antihypertensive agents, symptomatic hypotension may occur in some patients. Patients should be monitored for the timely detection of clinical signs of impaired water and electrolyte balance, for example, dehydration, hyponatremia, hypochloraemic alkalosis, hypomagnesemia, or hypokalemia that may develop during intercurrent diarrhea or vomiting. In such patients, control of serum electrolytes is necessary. Thiazide therapy can lead to impaired glucose tolerance. In some cases, it may be necessary to adjust the dose of hypoglycemic agents (including insulin). Thiazides can reduce the excretion of calcium in the urine and cause an episodic and insignificant increase in the serum calcium level. Severe hypercalcemia may indicate latent hyperparathyroidism.Thiazide diuretic should be canceled before the study of the functions of the parathyroid glands. Increased blood cholesterol and triglycerides may also be associated with thiazide diuretic therapy. In some patients, the administration of thiazide diuretics can lead to hyperuricemia and / or the development of gout. Since losartan reduces uric acid levels, its combination with hydrochlorothiazide reduces the severity of diuretic hyperuricemia. In patients receiving thiazides, hypersensitivity reactions can be observed even in the absence of indications of allergies or bronchial asthma in history. There are reports of the development of worsening or progression of SLE in patients receiving thiazide diuretics. When analyzing the entire population of patients included in the LIFE study (Losartan Intervention for Endpoint Reduction in Hypertension), the effect of losartan on reducing the frequency of the end points in patients with arterial hypertension, n = 9193 vascular death, stroke, and myocardial infarction) by 13% (p = 0.021) compared with atenolol. However, patients of the Negroid race who received atenolol had a lower risk of developing the events of the primary combined endpoint compared with black patients who received Losartan (p = 0.03).

- Use in pediatrics There are no data on the efficacy and safety of Hyzaar use in children, so the use of this category of patients is not recommended.

Overdosage

Data on the specific treatment of Hyzaara overdose are not available. The drug should be stopped, the patient should be monitored. Symptomatic therapy is shown - induction of vomiting if the drug is taken recently, as well as the elimination of dehydration, electrolyte abnormalities, hepatic coma and a decrease in blood pressure by standard methods.

Data on overdose of losartan in humans is limited. The most likely symptoms of overdose are marked reduction in blood pressure and tachycardia; bradycardia may be due to parasympathetic (vagal) stimulation.

Treatment: in case of symptomatic arterial hypotension, supportive therapy is indicated. Losartan and its active metabolite are not excreted by hemodialysis.

The most common symptoms of hydrochlorothiazide overdose are due to electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. With simultaneous intake of cardiac glycosides, hypokalemia may aggravate the course of arrhythmias. It has not been established to what extent hydrochlorothiazide can be removed from the body through hemodialysis.

  • Brand name: Gizaar
  • Active ingredient: Hydrochlorothiazide, Losartan
  • Dosage form: Coated tablets.
  • Manufacturer: Merck Sharp and Dome
  • Country of Origin: USA

Studies and clinical trials of Hydrochlorothiazide, Losartan (Click to expand)

  1. Stability study of losartan/hydrochlorothiazide tablets
  2. Multi-syringe chromatography (MSC) system for the on-line solid-phase extraction and determination of hydrochlorothiazide and losartan potassium in superficial water, groundwater and wastewater outlet samples
  3. Simultaneous determination of losartan and hydrochlorothiazide in tablets by high-performance liquid chromatography
  4. Analysis of binary mixtures of losartan potassium and hydrochlorothiazide by using high performance liquid chromatography, ratio derivative spectrophotometric and compensation technique
  5. Determination of losartan and hydrochlorothiazide in tablets by CE and CEC
  6. Development and validation of a stability-indicating HPLC method for the simultaneous determination of Losartan potassium, hydrochlorothiazide, and their degradation products
  7. Simultaneous determination of losartan, EXP-3174 and hydrochlorothiazide in plasma via fully automated 96-well-format-based solid-phase extraction and liquid chromatography–negative electrospray tandem mass spectrometry
  8. Simultaneous determination of hydrochlorothiazide and losartan potassium in tablets by high-performance low-pressure chromatography using a multi-syringe burette coupled to a monolithic column
  9. A multivariate approach for the simultaneous determination of losartan potassium and hydrochlorothiazide in a combined pharmaceutical tablet formulation
  10. Fixed-dose manidipine/delapril versus losartan/hydrochlorothiazide in hypertensive patients with type 2 diabetes and microalbuminuria
  11. Ambulatory monitoring of systolic hypertension in the elderly: Eprosartan/hydrochlorothiazide compared with losartan/hydrochlorothiazide (INSIST trial)
  12. Effects of losartan titrated to losartan/hydrochlorothiazide and amlodipine on blood pressure and peripheral capillary microcirculation in patients with mild-to-moderate hypertension
  13. A study of losartan, alone or with hydrochlorothiazide vs nifedipine GITS in elderly patients with diastolic hypertension
  14. Telmisartan vs losartan plus hydrochlorothiazide in the treatment of mild-to-moderate essential hypertension—a randomised ABPM study
  15. Comparison of the antihypertensive effects of the fixed dose combination enalapril 10 mg/nitrendipine 20 mg vs losartan 50 mg/hydrochlorothiazide 12.5 mg, assessed by 24-h ambulatory blood pressure monitoring, in essential hypertensive patients
  16. Simultaneous RP-LC Determination of Losartan Potassium, Ramipril, and Hydrochlorothiazide in Pharmaceutical Preparations
  17. Simultaneous Determination of Losartan Potassium, Atenolol and Hydrochlorothiazide in Pharmaceutical Preparations by Stability-Indicating UPLC
  18. Antihypertensive effect of a fixed-dose combination of losartan /hydrochlorothiazide in patients with uncontrolled hypertension: a multicenter study
  19. Effect of Losartan and Hydrochlorothiazide on Exercise Tolerance in Exertional Hypertension and Left Ventricular Diastolic Dysfunction
  20. Efficacy and safety of losartan/hydrochlorothiazide in patients with severe hypertension
  21. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipne ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension
  22. Chronic administration of losartan plus hydrochlorothiazide improves vascular status in young cardiomyopathic hamsters
  23. Antiproteinuric and Blood Pressure-Lowering Effects of a Fixed-Dose Combination of Losartan and Hydrochlorothiazide in Hypertensive Patients with Stage 3 Chronic Kidney Disease
  24. Simultaneous spectrophotometric determination of losartan potassium, amlodipine besilate and hydrochlorothiazide in pharmaceuticals by chemometric methods

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