Losartan

Losartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker.

Losartan is approved for the treatment of Hypertension, Diabetic nephropathy, and left ventricular hypertrophy. It is also used in the treatment of heart failure, Marfan syndrome, acute coronary syndrome, stable coronary artery disease, and intolerant of ACEI.

Losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of the Losartan is approximately 33%. The volume of distribution of Losartan and active metabolite is about 34 liters and 12 liters, respectively. Losartan is an orally active agent that undergoes substantial first-pass metabolism by the cytochrome P450 enzymes. After single doses of Losartan are administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as an active metabolite. Biliary excretion contributes to the elimination of Losartan and its metabolites

The common side effects associated with Losartan include Blurred vision, difficulty in breathing, dizziness, faintness or lightheadedness when getting up suddenly from sitting position, fast or irregular heartbeat, nausea or vomiting, numbness or tingling in hands, feet, or lips, stomach pain, weakness or heaviness of the legs.

Losartan is available in the form of Tablets.

Losartan is available in India, Denmark, the UK, the USA, Spain, and Belgium.

Losartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker.

Losartan reversibly and competitively prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT₁ receptor with 1000 times more affinity than they bind to the AT₂ receptor. The active metabolite of Losartan is 10-40 times more potent by weight than unmetabolized Losartan as an inhibitor of AT₁ and is a non-competitive inhibitor. Losartan helps in the prevention of angiotensin II binding causing vascular smooth muscle relaxation and lowering blood pressure. Angiotensin II would otherwise bind to the AT₁ receptor and induce vasoconstriction, raising blood pressure.

The time taken for Losartan to show its effect is not clinically established.

The Duration of Action for Losartan in the body is approximately 24 hours.

The Tmax was found within 3-4 hours following the administration of Losartan and the Cmax was about 200-250 ng/mL.

Losartan is available in the form of tablets.

Tablets: Tablets to be swallowed whole with water. Losartan comes as a tablet to be taken by mouth. It is usually taken once or twice a day.

Losartan is approved for the treatment of Hypertension, Diabetic nephropathy, and left ventricular hypertrophy. It is also used in the treatment of heart failure, Marfan syndrome, acute coronary syndrome, stable coronary artery disease, and intolerant of ACEI.

Losartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker. Blocks vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues. It has shown benefits in controlling hypertension, reducing proteinuria, slowing the progression of type 2 diabetic nephropathy, and reducing the risk of stroke in certain populations.

Losartan is approved for use in the following clinical indications

• Hypertension:

First-line therapy for stage 1 hypertension along with thiazide diuretics, calcium channel blockers, and ACEI. In patients with atherosclerotic cardiovascular disease (ASCVD) risk greater than or equal to 10%, combination therapy is used to attain blood pressure goals. Angiotensin II receptor blockers (ARBs) are useful as monotherapy in absence of comorbidities like diabetes, ischemic heart disease, cerebrovascular disease, heart failure, and chronic kidney disease.

• Adult Hypertension:

The usual starting dose of Losartan is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure. A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

• Pediatric Hypertension:

The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension. Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients.

Losartan is not recommended in pediatric patients less than 6 years of age or in pediatric patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m².

• Diabetic nephropathy:

Losartan is indicated for the treatment of diabetic nephropathy with elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Losartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation)

• Left Ventricular Hypertrophy:

Losartan is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients.

Although not approved, there have been certain off-label indications. These include:

• Treatment of heart failure:

A study involving elderly heart-failure patients, Evaluation of Losartan in the Elderly Study (ELITE), concluded that compared to captopril, Losartan correlated with lower mortality and was tolerated better than captopril. In the ELITE II study, the conclusion was that Losartan was as competent as captopril in improving the heart failure-related outcomes, NYHA class, and quality of life.

• Marfan’s syndrome with aortic aneurysm:

Marfan's syndrome is an inherited condition that affects the connective tissue, like eyes, blood vessels, etc. Sometimes people with Marfan's syndrome develop a balloon-like outpouching of the aorta (the largest artery), which is potentially life-threatening. Treating with Losartan can help to reduce the likelihood of aneurysm rupture.

It is also used to treat acute coronary syndrome, stable coronary artery disease, and intolerant of ACEI.

Losartan is available in the form of tablets.

Hypertension

• Adult Hypertension:

The usual starting dose of Losartan is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure. A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

• Pediatric Hypertension:

The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension. Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients.

Losartan is not recommended in pediatric patients less than 6 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m².

• Hypertensive Patients with Left Ventricular Hypertrophy:

The usual starting dose is 50 mg of Losartan once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of LOSARTAN should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response.

• Nephropathy In Type 2 Diabetic Patients:

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response.

Losartan can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Losartan is available in various strengths as 25mg, 50mg, and 50mg.

Losartan is available in the form of tablets.

Losartan is approved for the treatment of Hypertension, Diabetic nephropathy, and left ventricular hypertrophy.

• Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

• Diabetic Nephropathy: Limit carbohydrates with added sugars or those with refined grains, such as white bread and white rice. Instead, eat carbohydrates from fruit, vegetables, whole grains, beans, and low-fat or nonfat milk.

• Left Ventricular hypertrophy: No more than 25 to 35 percent of your daily calories should come from total fat (including saturated fat). Less than 7 % of your daily calories should come from saturated fat. Avoid trans fats and consume less than 200 milligrams a day of dietary cholesterol.

The dietary restriction should be individualized as per patient requirements

Losartan may be contraindicated in the following

• Hypersensitivity
• Co-administration with aliskiren in patients with diabetes mellitus

• Fetal Toxicity

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. The resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losartan as soon as possible.

• Hypotension in Volume- or Salt-Depleted Patients

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Losartan. Correct volume or salt depletion prior to administration of Losartan

• Renal Function Deterioration

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Losartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Losartan

• Hyperkalemia

Monitor serum potassium periodically and treat appropriately. Dosage reduction or discontinuation of Losartan may be required

Consuming alcoholic drinks while talking Losartan can cause a sedative effect. This means you may have slowed reflexes, poor judgment, and sleepiness. This effect can be dangerous if you drive or use other machinery. Alcohol can also increase the blood pressure-lowering effect of Losartan.

It is unknown if Losartan is excreted in the milk; therefore the use of Losartan is not recommended when lactating.

There is no sufficient scientific evidence traceable regarding the use and safety of Losartan in breastfeeding.

Pregnancy Category D

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy decreases fetal renal function and increases fetal and neonatal morbidity and death. The resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue the use of Losartan as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Losartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Losartan for hypotension, oliguria, and hyperkalemia.

Potassium-Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium

• Take with or without food. Food delays absorption, but does not affect the extent of absorption.

There is no sufficient scientific evidence traceable regarding the use and safety of Losartan in Food warnings.

The adverse reactions related to Losartan can be categorized as

Common Adverse effects:

• Fatigue
• Hypoglycemia
• Chest pain
• Cough

Less Common Adverse effects:

• Diarrhea
• URI
• Hypotension
• Dizziness
• Nausea

Rare adverse effects:

• Heart failure, tachyarrhythmia, bronchospasm, depression, decreased exercise tolerance, Raynaud's phenomenon, etc.

The clinically relevant drug interactions of Losartan are briefly summarized here

• Agents Increasing Serum Potassium:

Coadministration of Losartan with the other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

• Lithium:

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors):

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including Losartan) may result in the deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in the patient receiving Losartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

• Dual Blockade Of The Renin-Angiotensin System (RAS):

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

The common side effects associated with Losartan include:

Cough, Headache, Edema, Stomach pain, Constipation, Diarrhea, Blurred vision, difficult breathing, Sore throat, dizziness, faintness, or lightheadedness when getting up suddenly sitting position, fast or irregular heartbeat, nausea or vomiting, numbness or tingling in the hands, feet, or lips, stomach pain, weakness or heaviness of the legs.

The use of Losartan should be prudent in the following group of special populations:

Pregnancy

• Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Losartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Losartan for hypotension, oliguria, and hyperkalemia.

Losartan has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioural development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of Losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

• Nursing Mothers:

It is not known whether Losartan is excreted in human milk, but significant levels of Losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use:

Neonates With A History Of In Utero Exposure To Losartan

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing the hypotension and substituting for disordered renal function.

Antihypertensive effects of Losartan have been established in a hypertensive pediatric patients aged 6 to 16 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rates <30 mL/min/1.73 m².

• Geriatric Use:

Of the total number of patients receiving L in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

• Race:

In the LIFE study, Black patients with hypertension and left ventricular hypertrophy treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with Losartan (both cotreated with hydrochlorothiazide in the majority of patients). The primary endpoint was the first occurrence of stroke, myocardial infarction, or cardiovascular death, analyzed using an intention-to-treat (ITT) approach. In the subgroup of Black patients (n=533, 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on Losartan. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study provides no evidence that the benefits of Losartan on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients.

• Renal Impairment:

Patients with renal insufficiency have elevated plasma concentrations of Losartan and its active metabolite compared to subjects with normal renal function. No dose adjustment is necessary for patients with renal impairment unless a patient with renal impairment is also volume depleted.

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on an mg/m² basis.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither Losartan nor its active metabolite can be removed by hemodialysis.

Pharmacodynamics:

Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of Losartan on aldosterone secretion, very little effect on serum potassium was observed.

The effect of Losartan is substantially present within one week but in some studies, the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of Losartan appeared to be maintained for up to a year. There is no apparent rebound effect after the abrupt withdrawal of Losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials.

Pharmacokinetics:

• Absorption:

Following oral administration, Losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of Losartan is approximately 33%. Mean peak concentrations of Losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of Losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of Losartan. A meal slows the absorption of Losartan and decreases its Cmax but has only minor effects on Losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of Losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time.

• Distribution:

The volume of distribution of Losartan and the active metabolite is about 34 liters and 12 liters, respectively. 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. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that Losartan crosses the blood-brain barrier poorly, if at all.

• Metabolism:

Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 14% of an orally-administered dose of Losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of Losartan to its metabolites.

• Elimination:

Total plasma clearance of Losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with a renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of Losartan is about 2 hours and the metabolite is about 6-9 hours. After single doses of Losartan are administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as an active metabolite. Biliary excretion contributes to the elimination of Losartan and its metabolites. Following oral ¹⁴C-labeled Losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of ¹⁴C-labeled Losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.

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