Overview

Losartan Potassium and Hydrochlorothiazide Tablets combine two anti hypertansive agents, an angiotensin II receptor (type AT1) antagonist namely Losartan Potassium and a benzothiadiazine diuretic-hydrocholothiazide.

Indications?

Losartan potassium and Hydrochlorothiazide tablet is indicated for the treatment of essential hypertension when monotherapy is ineffective. The fixed dose combination formulation is not intended to be used as an initial therapy.

Warnings

When used in pregnancy during the second and third trimester drugs that act directly on the renin angiotensin system can cause injury and even death to the developing fetus. Also, thiazides cross the placental barrier and appear in cord blood. Hence, if administrated to pregnant woman, there is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse effects that have occurred in adults. Therefore, when pregnancy is detected, losartan potassium and Hydrochlorothiazide tablet should be discontinued as soon as possible. Female patients of childbearing age should be told about consequences of second and third trimester exposure to drugs that act on the renin-angiotensin system and they should be told that consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physician as soon as possible.

Contraindications

It is contraindicated in patients who are hypersensitive to losartan potassium or Hydrochlorothiazide. Because of the Hydrochlorothiazide component , it is contraindicated in patients with anuria or hypersensitivity to other sulfonamidederived drugs.

It is not recommended for patients with impaired liver function. As a consequence of inhibiting the reninangiotensin aldosterone system, changes in renal function have been reported in susceptible individual treated with losartan potassium.In some patients these changes in renal function were reversible upon discontinuation of therapy.

In patient whose renal function may depend on the activity of the renin-angiotension aldosterone system (e.g. patients with severe congstive heart failure), treatment with losartan potassium has been assocaited with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. In patients with unilateral or bilateral renal artery stenosis, increase in serum creatinine or blood urea nitrogen(BUN) have been reported with oral administraiton of losartan potassium. In some patients these effects were reversible upon discontinuation of therapy.

It is not known whether losartan potassium is excreted in human milk but significant levels of losartan and its active metabolite were shown to be present in rat milk. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug,taking into account the importance of the drug to the mother.
Safety and effectiveness in paediatric patients have not been established.
No overall difference in effectiveness or safety were observed between elder and younger patients but greater sensitivity of some older individual cannot be ruled out. In Patients who are intravascularly volume depleted (e.g. those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with losartan potassium and hydrochlorothiazide tablet. Hence such condition should be corrected prior to administration of losartan potassium and Hydrochlorothiazide tablet.

The use of the product should be avoided in patients with systemic lupus Erythematosus because thiazide diuretics have been reported to cause exacerbation or activation of system lupus erythematosus. Concomitant administration of lithium should be avoided.

Side Effects

Fixed dose combination of losartan and Hydrochlorothiazide is well tolerated. Adverse effects have been limited to those that were reported previously with losartan potassium and/or Hydrochlorothiazide, Adverse effects are generally mild and transient in nature and do not require discontinuation of therapy. The most commonly reported adverse effects are abdominal pain, edema/swelling, palpitation, back pain dizziness, cough, sinusitis, rash, predisposition to upper respiratory infection.

Dosage

Oral:
Disclaimer:To be taken only after consulting with the doctor.

Storage

Store protected from light and moisture.

Pharmacology

Pharmacodynamics

Losartan Potassium the first of a new class of antihypertensives is an angiotensin II receptor (type AT1) antagonist - chemically it is described as 2-butyl-4-chloro-1- [p-(0-1H-tetrabol-5-ylphenyl) benyl] imidazole-5-in-methanol Losartan and its principal active metabolite block the vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland) In vitro binding studies indicate that losartan and is a reversible, competitive inhibitor of the AT1 receptor the active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibtor of the AT1 receptor Hydrochlorothiazide is a benzothiadiazine diuretic. Thiazides affect renal tubular mechanism of electrolyte reabsorption and increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.

Neither Losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Pharmacokinetics

Following oral administration,losartan is well absorbed and undergoes substantial first-pass metabolism the systemic bioavailbility of losartan is approximately 33% About 14% of an orally administered does of losartan is converted to the active metabolite. Mean peak plasma concentrations of losartan and its active metabolite are reached in 1 hour and 3-4 hours respectively. While maximum plasma concentration of losartan its active metabolite are approximately equal., The AUC of the metabolite is about 4 times as great as that of losartan . A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decrease). Both losartan and its active metabolite are highly bound to plasma proteins,primarily albumin, with plasma free fractions of 1.3% and 0.2% respectively. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all about 4% of the does is excretion unchanged in urine as active metabolite, Biliary excreted contributes to the elimination of losartan and its metabolites.

Losartan pharmacokinetics have not been investigated in patients <18 years of age Losartan pharmacokinetics have been investigated in elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensive. Plasma concentration of losartan are about twice as high in female hypertensives as in male hypertensive, but concentration of the active metabolite are similar in males and females. No dosage adjustment is necessary.

Hydrochlorothiazide is well absorbed. The plasma half life of Hydrochlorothiazide varies between 5.6 and 14.8 hours. Hydrochlorothiazide crosses the placental but not the blood brain barrier. It is excreted in breast milk.
Hydrochlorothiazide is eliminated primarily by renal pathways and 95% of the absorbed dose is excreted is urine as unchanged drug.

Interactions

Losartan potassium does not affect the pharmacokinetics or pharmacodynamics of a single dose of warfarin and also of intravenous or oral digoxin. Coadministraion of losartan potassium and cimetidine leads to an increase of about 18% in AUC of losartan potassium but does not affect the pharmacokinetics of its active metabolite. There is no pharmacokinetic interaction between losartan potassium and hydrochlorothiazide.

When administered concomitantly with thiazide diuretic, the drugs which may interact are : Alcohol, barbiturates or narcotics, antidiabetic drugs, other antihypertensive drugs,cholestyramine and colestipol resins, corticosteroids, pressor amines (e.g. norepinephrine), skeletal muscle relaxants,lithium, Non Steroidal Anti inflammatory Drugs (NSAIDS).