Losartan Monograph

Introduction / Overview

Losartan is a nonpeptide antagonist of the angiotensin II type 1 (AT1) receptor, belonging to the class of angiotensin II receptor blockers (ARBs). Its primary therapeutic role has been established in the management of hypertension and in the prevention of target organ damage associated with chronic kidney disease. In addition, losartan has gained recognition for its benefits in heart failure with reduced ejection fraction, diabetic nephropathy, and as part of combination therapies in various cardiovascular conditions. The drug’s pharmacologic profile, including its high selectivity for the AT1 receptor and its active metabolite, underpins its clinical efficacy and safety considerations.

Learning objectives for this chapter are:

• To outline the classification and chemical nature of losartan.
• To delineate the pharmacodynamic mechanisms that confer therapeutic effects.
• To describe the pharmacokinetic properties and dosing considerations.
• To identify approved therapeutic indications and commonly encountered off‑label uses.
• To review the spectrum of adverse effects, drug interactions, and special population considerations.

Classification

Drug Class

Losartan is categorized as an angiotensin II receptor blocker (ARB). ARBs competitively inhibit angiotensin II at the AT1 receptor, thereby attenuating the downstream vasoconstrictive and aldosterone‑mediated effects of the renin‑angiotensin system.

Chemical Classification

Losartan possesses an imidazole core linked to a biphenyl ether moiety. The imidazole ring confers the ability to coordinate with the AT1 receptor binding pocket, while the biphenyl segment enhances lipophilicity, facilitating membrane penetration. The molecule is not a peptide; it is a small, nonpeptide heterocyclic compound with a molecular formula of C₂₂H₂₀ClN₄O₄.

Mechanism of Action

Pharmacodynamics

Losartan binds with high affinity to the AT1 receptor located on vascular smooth muscle cells, renal tubular cells, and cardiomyocytes. By occupying this receptor, losartan prevents angiotensin II from eliciting its canonical signaling cascade. The blockade of AT1 receptor activation results in reduced intracellular calcium mobilization, diminished activation of phospholipase C, and subsequent inhibition of protein kinase C pathways. Consequently, vasoconstriction is attenuated, systemic vascular resistance decreases, and aldosterone secretion from the adrenal cortex is suppressed. The combination of vasodilation and reduced sodium and water retention contributes to lowered blood pressure and mitigated cardiac preload and afterload.

In addition to its immediate effects on vascular tone, losartan influences renal hemodynamics. Blockade of the AT1 receptor in the juxtaglomerular apparatus leads to afferent arteriolar vasodilation, which decreases intraglomerular hypertension. This effect is particularly valuable in chronic kidney disease, where reduced glomerular capillary pressure slows the progression of nephropathy.

Active Metabolite

Losartan undergoes hepatic oxidation primarily via cytochrome P450 isoenzyme CYP2C9 to form losartan carboxylate, a metabolite with comparable AT1 antagonistic activity. The presence of the active metabolite extends the pharmacologic effect and contributes to the drug’s prolonged half‑life relative to the parent compound.

Pharmacokinetics

Absorption

Following oral administration, losartan is absorbed with a bioavailability of approximately 70%. Peak plasma concentrations (C_max) are typically reached within 2 to 3 hours (t_max). Food intake can modestly delay absorption but does not significantly alter overall bioavailability.

Distribution

The drug demonstrates extensive distribution with a volume of distribution of roughly 1.2 L/kg. Protein binding is high, exceeding 90%, predominantly to albumin and alpha‑1‑acid glycoprotein. The extensive binding limits free plasma concentration but favors tissue penetration, particularly in vascular and renal compartments.

Metabolism

Losartan is metabolized mainly in the liver through oxidation by CYP2C9 to produce the active metabolite losartan carboxylate. Minor contributions arise from CYP3A4, CYP2C19, and CYP2D6 pathways. The metabolic process is subject to inhibition by potent CYP2C9 inhibitors such as ketoconazole and rifampin, which can increase systemic exposure to losartan.

Excretion

Elimination occurs through both renal and fecal routes. Approximately 70% of the administered dose is recovered in feces, predominantly as unchanged drug, while 20% is eliminated via urine as unchanged drug or as metabolites. Renal clearance is modest, and hepatic metabolism predominantly dictates overall elimination.

Half‑Life and Dosing Considerations

The parent compound has a half‑life (t_1/2) of 2 to 3 hours. The active metabolite, losartan carboxylate, possesses a longer half‑life of 6 to 9 hours. Due to the accumulation of the metabolite, the effective pharmacologic half‑life is extended to approximately 12 hours, supporting once‑daily dosing regimens. Standard adult doses range from 25 mg to 100 mg once daily, with titration guided by blood pressure response and tolerability. Steady state is typically achieved within one week of continuous therapy.

Therapeutic Uses / Clinical Applications

Approved Indications

Losartan is approved for the following indications:

• Hypertension, either as monotherapy or in combination with other antihypertensive agents.
• Heart failure with reduced ejection fraction, where it improves morbidity and mortality outcomes.
• Diabetic nephropathy, particularly in patients with albuminuria, to reduce progression to end‑stage renal disease.
• Reduction of left ventricular mass and improvement of diastolic function in patients with mild to moderate hypertension.

Off‑Label and Emerging Uses

In clinical practice, losartan is frequently employed in several off‑label contexts:

• Management of hypertension in patients intolerant to ACE inhibitors due to cough.
• Adjunctive therapy in patients with chronic kidney disease of non‑diabetic etiology, aiming to attenuate intraglomerular hypertension.
• Use as part of a dual ARB or ARB/ACE inhibitor strategy in certain experimental protocols, although evidence suggests increased risk of adverse events, and such combinations are generally discouraged.
• High‑dose losartan (up to 200 mg/day) has been explored in preclinical models for its potential to mitigate radiation‑induced fibrosis, but clinical data remain limited.

Adverse Effects

Common Side Effects

Patients may experience the following frequently reported adverse events:

• Dizziness or light‑headedness, particularly during initiation or dose escalation.
• Hypotension, especially when combined with diuretics or in susceptible individuals.
• Hyperkalemia, due to reduced aldosterone‑mediated potassium excretion.
• Renal function changes, manifested as a rise in serum creatinine, notably in patients with pre‑existing renal impairment or concomitant nephrotoxic agents.
• Headache and fatigue, which are generally mild and transient.

Serious or Rare Adverse Reactions

More severe reactions, though uncommon, include:

• Angioedema, presenting as swelling of the face, lips, tongue, or airway; immediate discontinuation is advised.
• Severe hyperkalemia, particularly in patients on potassium‑sparing diuretics or potassium supplements, which can precipitate cardiac arrhythmias.
• Marked renal impairment, especially when losartan is combined with ACE inhibitors or other agents affecting glomerular filtration.
• Transient cough, though less frequent than with ACE inhibitors, has been reported in a minority of patients.

Boxed Warning

Losartan carries a boxed warning regarding the potential for renal impairment and hyperkalemia. The risk is heightened in patients with chronic kidney disease, those taking potassium‑sparing diuretics, potassium supplements, or ACE inhibitors. Routine monitoring of serum creatinine and potassium levels is recommended when initiating or titrating therapy. The warning underscores the importance of vigilance in these high‑risk groups.

Drug Interactions

Major Drug‑Drug Interactions

Losartan’s pharmacologic profile leads to significant interactions with several classes of medications:

• Potassium‑sparing diuretics (e.g., spironolactone, triamterene): Concurrent use can elevate serum potassium levels, potentially leading to hyperkalemia.
• NSAIDs (e.g., ibuprofen, naproxen): NSAIDs may blunt the antihypertensive effect and exacerbate renal impairment by reducing prostaglandin‑mediated vasodilation.
• ACE inhibitors (e.g., lisinopril, enalapril): Dual blockade of the renin‑angiotensin system increases the risk of hyperkalemia and acute kidney injury; concomitant use is generally avoided.
• Potassium supplements or potassium‑rich diets: These can potentiate hyperkalemia when combined with losartan.
• Cytochrome P450 inhibitors and inducers: Ketoconazole, fluconazole, and itraconazole inhibit CYP2C9, leading to higher plasma concentrations; rifampin, carbamazepine, and phenobarbital induce CYP2C9, potentially decreasing efficacy.

Contraindications

Losartan is contraindicated in:

• Pregnancy, due to teratogenic risk and fetal renal damage.
• Patients with known hypersensitivity to losartan or any component of the formulation.
• Severe hepatic impairment (Child‑Pugh class C), where metabolism may be significantly reduced.
• Patients with advanced renal failure (eGFR <30 mL/min/1.73 m²) without careful dose adjustment and monitoring.

Special Considerations

Use in Pregnancy and Lactation

Losartan is classified as pregnancy category D. Exposure during the second and third trimesters can lead to fetal renal dysgenesis and oligohydramnios. Consequently, it is contraindicated in pregnancy and should be discontinued prior to conception. In lactation, losartan and its metabolites are excreted into breast milk; the potential for adverse effects in nursing infants warrants avoidance of therapy during the lactation period.

Pediatric and Geriatric Populations

Pediatric use is not formally approved for children under 16 years. Limited studies suggest that dosing should be weight‑based and cautiously titrated, with close monitoring for hypotension and electrolyte disturbances. In geriatric patients, physiological changes in renal and hepatic function may affect drug disposition. Dose adjustments are typically required, particularly in the presence of renal insufficiency or concomitant medications that influence CYP2C9 activity.

Renal and Hepatic Impairment

In patients with mild to moderate renal impairment (eGFR 30–60 mL/min/1.73 m²), a reduced dose (e.g., 25 mg daily) may be considered. Severe renal impairment warrants caution; losartan may be avoided or used only with rigorous monitoring of serum creatinine and potassium. Hepatic impairment, especially in the Child‑Pugh B or C categories, necessitates dose reduction or discontinuation due to decreased metabolic clearance. Regular assessment of liver function tests is advisable during therapy.

Summary / Key Points

• Losartan is a selective AT1 receptor antagonist with proven efficacy in hypertension, heart failure, and diabetic nephropathy.
• Its pharmacologic activity is sustained by the active metabolite losartan carboxylate, which extends the effective half‑life.
• Common adverse effects include dizziness, hypotension, hyperkalemia, and renal function changes; serious reactions such as angioedema and severe hyperkalemia require prompt intervention.
• Drug interactions necessitate caution when combined with potassium‑sparing agents, NSAIDs, ACE inhibitors, and CYP2C9 modulators.
• Contraindications encompass pregnancy, lactation, severe hepatic or renal impairment, and hypersensitivity; dose adjustments are advised in geriatric and pediatric populations.

Clinical practice should balance the benefits of losartan in target organ protection against its potential risks, particularly in patients with compromised renal function or those receiving concomitant medications that influence potassium homeostasis or CYP2C9 activity. Ongoing monitoring of blood pressure, serum creatinine, and potassium levels remains integral to safe and effective therapy.

References

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