Losartan and Valsartan

Mechanism

Pharmacological Class and Group

Antihypertensives, nephroprotectors and vasodilators belonging to the group of Angiotensin II Type 1 Receptor Antagonists (AT₁).

Mechanism of Action

Angiotensin II exerts its systemic effects through two main G protein-coupled receptors: the AT₁ receptor (responsible for vasoconstriction, sodium retention, cellular hypertrophy and pro-inflammatory signaling) and the AT₂ receptor (associated with protective vasodilator and antiproliferative effects).

Clinical Pearl: The Unique Uricosuric Mechanism of Losartan

Losartan has a unique pharmacological property not shared with other ARBs (such as valsartan, candesartan or telmisartan): at therapeutic doses, it potently inhibits the apical organic anion exchanger URAT1 in the kidney. This blocks the proximal reabsorption of filtered uric acid:

Losartan URAT1 ↓ Uric acid reabsorption ↑ Uricosuria and ↓ Serum uric acid

This property makes it the antihypertensive drug of choice for patients with high blood pressure associated with gout or severe hyperuricemia.

Pharmacokinetics

Comparative Pharmacokinetics

• Losartan: Rapid oral absorption with a bioavailability of 33%. It undergoes massive hepatic first-pass metabolism mediated by the cytochrome isoenzymes CYP2C9 and CYP3A4, transforming into the long-lived active metabolite EXP3174. The plasma elimination half-life of losartan is 2 hours, while that of its active metabolite is 6 to 9 hours. 35% is eliminated through the kidneys and the rest through biliary/fecal excretion.
• Valsartan: Rapid oral absorption with an average bioavailability of 25% (food significantly decreases its absorption). It does not require active hepatic metabolism to exert its therapeutic action. It is eliminated unchanged mainly by biliary/fecal (83%) and urinary (13%) excretion. It has a terminal elimination half-life of 9 to 12 hours, ideal for a single daily administration.

Indicators and dose

Clinical Indications and Uses

• Systemic Arterial Hypertension: Monotherapy or combined therapy, excellent tolerability profile.
• Heart Failure with Reduced Ejection Fraction (HFrEF): As a gold standard alternative in patients intolerant to ACE inhibitors due to the appearance of dry cough or angioedema.
• Diabetic Nephropathy in Type 2 Diabetes: Progressive slowing of chronic renal failure by reducing intraglomerular capillary hyperfiltration.
• Losartan (Single Profile Uricosuria): Selectively inhibits the renal urate transporter URAT1 in the proximal convoluted tubule, thereby decreasing serum uric acid levels in hyperuricemic or gout patients.

Dosage and Clinical Adjustment

Losartan:

• Hypertension / Nephropathy: Usual dose of 50 mg to 100 mg once daily orally. It can be divided into two shots if required for tension control.
• Hepatic Adjustment: Requires a reduced starting dose to 25 mg once daily in patients with a history of cirrhosis or mild to moderate liver failure.

Valsartan:

• Hypertension / Heart Failure: Starting dose of 40 mg to 80 mg once daily. Maximum maintenance dose of 160 mg to 320 mg once daily (or divided every 12 hours in heart failure).
• Renal Adjustment: No initial adjustment is required in patients with eGFR greater than 10 mL/min/1.73 m².

Security

Selective Blocking of AT Receiver₁ and Local Interaction

1. Competitive and highly selective antagonism of the AT₁ receptor: Losartan (along with its active long-chain metabolite EXP3174, which has a 10- to 40-fold higher non-competitive antagonist potency) and valsartan displace angiotensin II from its binding site on the AT₁ receptor, selectively blocking its intracellular signaling pathways mediated by the subunit G_q and phospholipase C:

ARA-II AT₁ Receptor ↓ Release of intracellular Ca²⁺ Arterial vasodilation

2. Redirection of Angiotensin II towards the AT₂ receptor: As AT₁ receptors are blocked, free circulating angiotensin II binds preferentially to AT₂ receptors. This union stimulates the local synthesis of bradycidin and endothelial nitric oxide, promoting synergistic vasodilation and a protective effect against apoptosis and cardiac and renal tissue remodeling.

3. No effect on Kininase II: Unlike ACEIs, ARBs do not inhibit the degradation of tissue bradycidin, which substantially reduces the incidence of dry cough and the probability of clinical angioedema.

Absolute and Relative Contraindications

Absolute Contraindications

• Pregnancy: Like ACEIs, they cause serious fetal damage and mortality due to interference in the development of the fetal kidney mediated by the RAAS.
• Concomitant use with Aliskiren in diabetic patients or patients with renal failure.
• Known hypersensitivity to the active ingredient or excipients.

Relative Contraindications

• Bilateral renal artery stenosis (risk of acute renal failure).
• Active hyperkalemia (K⁺ > 5.5 mEq/L).
• Severe arterial hypotension or cardiogenic shock.

Adverse Effects and Toxicity

• Orthostatic Hypotension: More common at the beginning of therapy or in volume-depleted patients due to concurrent use of diuretics.
• Hyperkalemia: Especially problematic in patients with chronic kidney disease or concomitant use of potassium supplements.
• Transient elevation in creatinine: It usually stabilizes after the first weeks of treatment.
• Cough and angioedema (Very rare): Its incidence is comparable to that of placebo, although a previous history of angioedema due to ACEI requires extreme clinical vigilance when starting an ARB.

Relevant Drug Interactions

• NSAIDs: They reduce the antihypertensive effect of ARBs due to the inhibition of vasodilatory renal prostaglandins, and increase the risk of functional renal toxicity.
• Diuretics and potassium supplements: They substantially increase the risk of hyperkalemia.
• Fluconazole (and CYP2C9 Inhibitors): Losartan is a direct metabolic substrate of CYP2C9; Inhibition of this enzyme may reduce the conversion of losartan to its highly active form EXP3174, attenuating the overall long-term vasodilatory effect.