Pharmacology of Losartan

1. Introduction/Overview

Losartan potassium represents a cornerstone in the modern pharmacotherapy of cardiovascular and renal diseases. As the first orally active, non-peptide angiotensin II receptor blocker (ARB) introduced into clinical practice, it marked a significant advancement in the modulation of the renin-angiotensin-aldosterone system (RAAS). Its development provided a targeted alternative to angiotensin-converting enzyme (ACE) inhibitors, offering a distinct mechanism for interrupting the pathological effects of angiotensin II. The clinical relevance of losartan is substantial, given its primary indications for the management of hypertension, diabetic nephropathy, and heart failure. Understanding its pharmacology is fundamental for clinicians aiming to optimize therapeutic outcomes while minimizing adverse effects in a diverse patient population.

The importance of losartan extends beyond its direct antihypertensive effects. Its role in organ protection, particularly in slowing the progression of renal disease in patients with type 2 diabetes and hypertension, underscores its value in preventive cardiology and nephrology. The drug’s pharmacology provides a model for understanding the entire ARB class, despite subsequent agents offering varied pharmacokinetic profiles.

Learning Objectives

• Describe the molecular mechanism of action of losartan as a selective angiotensin II type 1 (AT₁) receptor antagonist and differentiate it from ACE inhibitors.
• Outline the pharmacokinetic profile of losartan, including its absorption, metabolism to an active metabolite, distribution, and elimination pathways.
• Identify the approved clinical indications for losartan and the evidence supporting its use in hypertension, diabetic nephropathy, and heart failure.
• Analyze the common and serious adverse effect profile of losartan, including its effects on renal function, electrolyte balance, and fetal development.
• Evaluate major drug-drug interactions, contraindications, and necessary dosage adjustments in special populations such as those with renal or hepatic impairment.

2. Classification

Losartan belongs to a well-defined therapeutic and chemical class, which informs its pharmacological behavior and clinical application.

Therapeutic Classification

Losartan is classified therapeutically as an antihypertensive agent. More specifically, it is a member of the angiotensin II receptor blocker (ARB) class, also known as angiotensin II receptor antagonists or sartans. This class is distinct from other RAAS inhibitors, such as ACE inhibitors, direct renin inhibitors, and mineralocorticoid receptor antagonists. Within the ARB class, losartan is considered a biphenyl tetrazole derivative and serves as the prototypical agent.

Chemical Classification

Chemically, losartan potassium is described as 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol monopotassium salt. Its molecular structure includes an imidazole ring and a biphenyl tetrazole moiety, which are critical for its high-affinity, competitive binding to the AT₁ receptor. The tetrazole ring acts as a bioisostere for the carboxylate group found in the natural peptide ligand, angiotensin II, facilitating effective receptor blockade. The potassium salt formulation enhances its aqueous solubility for oral administration.

3. Mechanism of Action

The pharmacological effects of losartan are mediated through a highly specific and competitive antagonism of the renin-angiotensin-aldosterone system at the receptor level.

Detailed Pharmacodynamics

Losartan exerts its effects by selectively and competitively blocking the angiotensin II type 1 (AT₁) receptor. Angiotensin II, the primary effector peptide of the RAAS, binds to AT₁ receptors located on vascular smooth muscle cells, adrenal cortex, heart, kidney, and brain. This binding triggers a cascade of events including vasoconstriction, aldosterone secretion (leading to sodium and water retention), sympathetic nervous system activation, and cellular growth promotion. By occupying the AT₁ receptor without activating it, losartan prevents angiotensin II from binding, thereby inhibiting all these downstream effects.

An important pharmacodynamic distinction is its selectivity for the AT₁ receptor over the AT₂ receptor. The AT₂ receptor is thought to mediate effects that are often opposing to those of the AT₁ receptor, such as vasodilation, apoptosis, and anti-fibrotic actions. Losartan’s high selectivity for AT₁ (approximately 10,000-fold greater than for AT₂) allows unopposed stimulation of AT₂ receptors by elevated angiotensin II levels, which may contribute additional beneficial effects.

The active metabolite of losartan, EXP3174, is a non-competitive antagonist with a longer half-life and greater potency at the AT₁ receptor. This metabolite is responsible for a significant portion of the drug’s long-term therapeutic effect.

Molecular and Cellular Mechanisms

At the molecular level, losartan binds reversibly to the AT₁ receptor, a G-protein coupled receptor (GPCR). This binding inhibits the receptor’s conformational change normally induced by angiotensin II, preventing the activation of associated G-proteins, primarily G_q/11. Consequently, several key signaling pathways are disrupted:

• Vasoconstriction Inhibition: Blockade of G_q-mediated activation of phospholipase C-β (PLC-β) reduces the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂). This decreases the formation of inositol trisphosphate (IP₃) and diacylglycerol (DAG), leading to reduced intracellular calcium mobilization and smooth muscle contraction.
• Aldosterone Suppression: Inhibition of angiotensin II signaling in the zona glomerulosa of the adrenal cortex decreases the synthesis and secretion of aldosterone. This promotes renal excretion of sodium and water (natriuresis and diuresis) while conserving potassium.
• Growth and Fibrosis Modulation: Blockade of AT₁ receptor-mediated activation of mitogen-activated protein kinase (MAPK) pathways, including ERK1/2, JNK, and p38, attenuates cellular proliferation, hypertrophy, and extracellular matrix production. This anti-remodeling effect is crucial in cardiac and renal protection.
• Sympathetic Outflow Reduction: Central and peripheral antagonism of angiotensin II’s facilitatory effect on norepinephrine release from sympathetic nerve terminals contributes to a reduction in sympathetic tone.

The overall hemodynamic result is a reduction in systemic vascular resistance and blood pressure, with no significant reflex tachycardia due to the baroreceptor resetting and lack of direct sympathetic activation.

4. Pharmacokinetics

The pharmacokinetic profile of losartan is characterized by its biotransformation to a more potent active metabolite, which influences its dosing regimen and duration of action.

Absorption

Losartan is rapidly absorbed following oral administration, with peak plasma concentrations (C_max) of the parent drug achieved within 1 hour. The absolute oral bioavailability is approximately 33% due to first-pass metabolism. Food intake may slightly decrease the C_max but does not significantly alter the area under the concentration-time curve (AUC), allowing administration without regard to meals. The time to reach C_max for the active metabolite EXP3174 is later, typically between 3 to 4 hours post-dose.

Distribution

Losartan and EXP3174 are highly bound to plasma proteins, primarily albumin, with binding exceeding 98%. The steady-state volume of distribution for losartan is approximately 34 liters, indicating distribution beyond the plasma compartment. Both compounds cross the blood-brain barrier to a limited extent, which may account for some central effects on sympathetic outflow and thirst regulation. Placental transfer occurs, which is a critical consideration in pregnancy.

Metabolism

Losartan undergoes significant hepatic metabolism, primarily via the cytochrome P450 system. The major pathways involve:

• Formation of EXP3174: Approximately 14% of an oral dose is metabolized by CYP2C9 and, to a lesser extent, CYP3A4, to form the active carboxylic acid metabolite EXP3174. This metabolite is 10 to 40 times more potent than losartan in antagonizing the AT₁ receptor.
• Other Metabolic Pathways: Additional metabolism occurs via CYP3A4 to inactive metabolites, including a secondary alcohol formed by reduction of the hydroxymethyl group.

The formation of the active metabolite is a key determinant of losartan’s efficacy. Genetic polymorphisms in CYP2C9 can influence the rate of this conversion, potentially leading to inter-individual variability in drug response.

Excretion

Elimination occurs through both renal and biliary routes. Following an oral dose, about 35% of the radioactivity is recovered in urine and approximately 60% in feces. In urine, only a small fraction (≈4%) is excreted as unchanged losartan, with the remainder being metabolites. The active metabolite EXP3174 is eliminated primarily by tubular secretion, with a small component of glomerular filtration. The terminal elimination half-life (t_1/2) of losartan is relatively short, about 2 hours, while the half-life of EXP3174 is considerably longer, ranging from 6 to 9 hours. This longer half-life of the active metabolite supports once-daily dosing for hypertension.

Pharmacokinetic Parameters and Dosing Considerations

The pharmacokinetics are linear over the therapeutic dose range. Clearance of losartan is primarily hepatic, while clearance of EXP3174 is renal. The effective half-life for antihypertensive action is more closely aligned with that of EXP3174. For hypertension, the usual starting dose is 50 mg once daily, which can be increased to 100 mg once daily. In patients with intravascular volume depletion, hepatic impairment, or a history of heart failure, a lower starting dose of 25 mg is often recommended. The full antihypertensive effect is typically attained within 3 to 6 weeks of initiation.

5. Therapeutic Uses/Clinical Applications

Losartan is employed in several evidence-based clinical scenarios, primarily centered on cardiovascular and renal risk reduction.

Approved Indications

Hypertension: Losartan is indicated for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents such as thiazide diuretics. It lowers blood pressure effectively in all stages of hypertension and across diverse demographic groups. Its effect is generally comparable to that of ACE inhibitors, beta-blockers, and calcium channel blockers.

Diabetic Nephropathy with Proteinuria: For patients with type 2 diabetes and hypertension, losartan is indicated to slow the progression of diabetic renal disease, as evidenced by reducing proteinuria and the rate of decline in glomerular filtration rate (GFR). This renoprotective effect is independent of its blood pressure-lowering action and is attributed to reduced intraglomerular pressure and anti-fibrotic effects.

Heart Failure: Losartan is approved for the treatment of heart failure (NYHA Class II-IV) in patients who are intolerant of ACE inhibitors. While ACE inhibitors remain first-line, losartan provides an alternative for patients who develop limiting cough or angioedema on ACE inhibitor therapy. It reduces mortality and hospitalization rates by attenuating ventricular remodeling and neurohormonal activation.

Reduction of Stroke Risk in Hypertension with Left Ventricular Hypertrophy: Based on the LIFE trial, losartan is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy documented by ECG. This benefit was observed beyond blood pressure control alone, suggesting specific advantages related to AT₁ receptor blockade.

Off-Label Uses

Several off-label applications are supported by clinical evidence, though they are not formally approved by regulatory agencies.

• Marfan Syndrome: Losartan may be used to slow the rate of aortic root dilation in patients with Marfan syndrome, based on its ability to inhibit TGF-β signaling, which is upregulated in this condition.
• Migraine Prophylaxis: Some evidence suggests ARBs, including losartan, may be effective in preventing migraines, possibly through effects on vascular tone and neurogenic inflammation.
• Atrial Fibrillation Prevention: In the context of hypertension or heart failure, losartan may contribute to a reduced incidence of new-onset atrial fibrillation, likely due to its anti-remodeling effects on the atria.
• Post-Myocardial Infarction: While not a first-line agent, losartan may be considered for secondary prevention post-MI, particularly in ACE-intolerant patients, to prevent ventricular remodeling and heart failure.

6. Adverse Effects

The adverse effect profile of losartan is generally favorable, especially when compared to ACE inhibitors, though significant risks exist.

Common Side Effects

Most adverse reactions are mild, transient, and rarely lead to discontinuation.

• Dizziness: Often related to initial blood pressure reduction, particularly in volume-depleted patients or with the first dose.
• Upper Respiratory Infection and Nasopharyngitis: Reported at rates similar to placebo in clinical trials.
• Fatigue and Asthenia.
• Hyperkalemia: A predictable consequence of aldosterone suppression. Risk is increased in patients with renal impairment, diabetes, or those concurrently using potassium-sparing diuretics, potassium supplements, or other RAAS inhibitors.
• Hypotension: Symptomatic orthostatic hypotension can occur, especially with initial dosing or in volume-contracted states.

Notably, the incidence of dry cough is significantly lower with losartan than with ACE inhibitors (≈3% vs. up to 20%), as it does not affect bradykinin metabolism.

Serious/Rare Adverse Reactions

• Renal Impairment: In susceptible individuals, such as those with bilateral renal artery stenosis, severe heart failure, or volume depletion, losartan can cause an acute decline in renal function due to reduced glomerular filtration pressure. This is typically reversible upon discontinuation.
• Angioedema: Although far less frequent than with ACE inhibitors, angioedema involving the face, lips, tongue, glottis, or larynx has been reported with ARBs, including losartan. This reaction requires immediate discontinuation and may be life-threatening.
• Hepatotoxicity: Rare cases of hepatocellular or mixed liver injury have been documented, usually manifesting as elevated transaminases.
• Hematological Effects: Very rare instances of neutropenia, agranulocytosis, or thrombocytopenia have been reported.
• Rash: Various dermatological reactions, including urticaria and pruritus, can occur.

Black Box Warnings

Losartan carries a black box warning regarding its use during pregnancy. Drugs that act directly on the RAAS, including ARBs, can cause injury and death to the developing fetus when used during the second and third trimesters. Exposure is associated with oligohydramnios, fetal renal dysplasia, pulmonary hypoplasia, skull ossification defects, and fetal death. Losartan is contraindicated in pregnancy and should be discontinued as soon as pregnancy is detected.

7. Drug Interactions

Several clinically significant drug interactions necessitate careful consideration during losartan therapy.

Major Drug-Drug Interactions

• Other RAAS Inhibitors (ACE Inhibitors, Aliskiren): Concurrent use increases the risk of hyperkalemia, hypotension, and renal dysfunction, particularly in patients with diabetic nephropathy or pre-existing renal impairment. Such combinations are generally avoided or require very close monitoring.
• Potassium-Sparing Diuretics (Spironolactone, Eplerenone, Amiloride, Triamterene) and Potassium Supplements: These agents potentiate the risk of hyperkalemia.
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs, including COX-2 selective inhibitors, can attenuate the antihypertensive effect of losartan by inhibiting prostaglandin-mediated vasodilation. Furthermore, they can increase the risk of renal impairment, especially in elderly or volume-depleted patients.
• Lithium: Losartan may reduce renal clearance of lithium, potentially leading to lithium toxicity. Serum lithium levels require close monitoring if co-administration is necessary.
• Inducers and Inhibitors of CYP Enzymes:
  • Enzyme Inducers (e.g., Rifampin, Phenytoin): May increase the metabolism of losartan to inactive pathways, potentially reducing the formation of the active metabolite EXP3174 and diminishing therapeutic efficacy.
  • Enzyme Inhibitors (e.g., Fluconazole, which inhibits CYP2C9): May decrease the conversion of losartan to EXP3174, potentially altering the pharmacokinetic and pharmacodynamic profile. The clinical significance of this interaction is variable.

Contraindications

• Pregnancy (Second and Third Trimesters): Absolute contraindication due to risk of fetal toxicity.
• Hypersensitivity: To losartan, any component of the formulation, or other ARBs. Cross-reactivity with ACE inhibitors is not a given, but caution is warranted in patients with a history of angioedema on any RAAS inhibitor.
• Concomitant Use with Aliskiren in Patients with Diabetes or Renal Impairment: This combination is contraindicated due to an increased risk of renal impairment, hyperkalemia, and hypotension.

8. Special Considerations

Therapeutic decisions involving losartan must account for specific patient characteristics to ensure safety and efficacy.

Use in Pregnancy and Lactation

As noted, losartan is contraindicated in pregnancy. For women of childbearing potential, effective contraception should be advised during treatment. If pregnancy is detected, losartan must be stopped immediately, and alternative antihypertensive therapy considered. Regarding lactation, limited data suggest that losartan and its active metabolite are excreted in human milk in small amounts. Because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Considerations

Losartan is approved for the treatment of hypertension in pediatric patients 6 years of age and older. Dosage is based on body weight. For children weighing 20 to 50 kg, the recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total). For those over 50 kg, the adult starting dose of 50 mg is used. Doses may be titrated based on blood pressure response. Safety and effectiveness in pediatric patients under 6 years of age or with glomerular filtration rate less than 30 mL/min/1.73 m² have not been established.

Geriatric Considerations

No overall differences in efficacy or safety have been observed between elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. Age-related decreases in renal function and potential for volume depletion due to diuretic use or poor intake may increase the risk of hypotension and renal impairment. Initiation with a lower dose (25 mg) may be prudent, with careful monitoring of blood pressure, renal function, and electrolytes.

Renal Impairment

In patients with renal impairment, including those on dialysis, the plasma concentrations of losartan and its active metabolite are not significantly altered. However, the pharmacodynamic effects are potentiated. There is an increased risk of hyperkalemia and acute renal failure, particularly in patients with severe congestive heart failure or renal artery stenosis. Dose titration should be cautious, and renal function and serum potassium should be monitored closely. For patients with a history of renal transplantation, no specific dosage recommendation exists, but similar cautions apply.

Hepatic Impairment

Patients with hepatic impairment, including those with cirrhosis, have increased plasma concentrations of losartan due to reduced first-pass metabolism and possibly decreased clearance. The AUC of losartan may be increased approximately 5-fold in patients with cirrhosis. Consequently, a lower starting dose of 25 mg is recommended for patients with a history of hepatic impairment. Close monitoring of blood pressure and clinical response is advised.

9. Summary/Key Points

Losartan is a foundational agent in cardiovascular and renal pharmacotherapy with a well-characterized pharmacological profile.

Bullet Point Summary

• Losartan is a selective, competitive antagonist of the angiotensin II type 1 (AT₁) receptor, inhibiting the vasoconstrictor, aldosterone-secreting, and pro-fibrotic effects of angiotensin II.
• It is a prodrug metabolized primarily by CYP2C9 to an active metabolite, EXP3174, which is more potent and has a longer half-life, supporting once-daily dosing.
• Approved indications include hypertension, diabetic nephropathy with proteinuria, heart failure (in ACE-intolerant patients), and stroke reduction in hypertensive patients with left ventricular hypertrophy.
• The adverse effect profile is favorable compared to ACE inhibitors, with a significantly lower incidence of cough. Key risks include hyperkalemia, renal impairment in susceptible states, angioedema (rare), and fetal toxicity.
• Major drug interactions involve other RAAS inhibitors (hyperkalemia, renal risk), NSAIDs (blunted antihypertensive effect, renal risk), potassium-sparing diuretics, and lithium.
• Dosage must be adjusted in hepatic impairment, and initiation should be cautious in volume-depleted patients, the elderly, and those with renal impairment. It is contraindicated in pregnancy.

Clinical Pearls

• The full antihypertensive effect of losartan may take 3 to 6 weeks to manifest; avoid rapid dose escalation within the first few weeks of therapy.
• In patients transitioning from an ACE inhibitor due to cough, losartan can be started immediately after discontinuation, as the risk of cross-reactivity for angioedema is low but not zero.
• Monitoring should include baseline and periodic assessments of serum potassium, creatinine, and blood urea nitrogen (BUN), especially after initiation or dose increases, and in high-risk patients.
• For patients with diabetic nephropathy, the renoprotective benefit of losartan is maximized when treatment is initiated upon detection of microalbuminuria, even if blood pressure is within the normal range.
• Patient education should emphasize the importance of avoiding NSAIDs and high-potassium diets or salt substitutes without medical consultation, and the imperative of discontinuing the medication if pregnancy is suspected.

References

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