Losartan: AT1 Receptor Blocker for Hypertension and Kidney Protection
Losartan was the first angiotensin II receptor blocker (ARB) approved for clinical use, entering the market in 1995. It selectively blocks the AT1 receptor, which mediates the vasoconstrictive and aldosterone-stimulating effects of angiotensin II. Unlike ACE inhibitors, losartan does not inhibit the enzyme responsible for bradykinin breakdown, which is why it does not cause the dry cough that limits ACE inhibitor use in up to 20 percent of patients.
Losartan carries a unique advantage among sartans: it has a mild uricosuric effect, increasing renal uric acid excretion. This makes it a preferred ARB choice for hypertensive patients with concurrent gout or hyperuricaemia. Its nephroprotective properties in diabetic nephropathy are supported by landmark trial evidence.
Mechanism of Action
Angiotensin II is the primary effector of the renin-angiotensin-aldosterone system (RAAS). It binds to AT1 receptors on vascular smooth muscle cells causing vasoconstriction, and to AT1 receptors in the adrenal cortex stimulating aldosterone release and sodium retention. Losartan competitively and selectively blocks AT1 receptors, reducing peripheral vascular resistance, lowering blood pressure, and reducing aldosterone-mediated sodium and water retention. The AT2 receptor remains unblocked and mediates vasodilatory and antiproliferative effects that may contribute to additional cardiovascular protection. Losartan's active metabolite EXP-3174 is 10 to 40 times more potent and has a longer half-life than losartan itself, accounting for the majority of the pharmacological effect.
Indications
Losartan is indicated for hypertension in adults and children over six years. It is approved for nephroprotection in type 2 diabetic patients with microalbuminuria or proteinuria (diabetic nephropathy), where it reduces progression to end-stage renal disease. Losartan is approved for heart failure in patients intolerant to ACE inhibitors. It also reduces the risk of stroke in hypertensive patients with left ventricular hypertrophy, as shown in the LIFE trial. The uricosuric effect is a practical additional benefit in patients with gout-associated hypertension.
Dosage and Administration
Standard starting dose for hypertension is 50 mg once daily; the dose can be increased to 100 mg once daily if blood pressure control is inadequate. For diabetic nephropathy, 50 mg once daily initially, titrated to 100 mg once daily. For heart failure, starting dose is 12.5 mg once daily, gradually uptitrated to the maximum tolerated dose of 150 mg. In patients with hepatic impairment, reduced starting doses are recommended. Losartan can be taken with or without food. Twice-daily dosing is not required due to the long duration of action of the active metabolite.
Side Effects
Losartan is generally well tolerated. Dizziness and hypotension, particularly with the first dose or in volume-depleted patients, are the most common adverse effects. Hyperkalemia can occur, especially in patients with renal impairment, diabetes, or those taking potassium-sparing diuretics or potassium supplements. Renal function can deteriorate, particularly in patients with bilateral renal artery stenosis. Unlike ACE inhibitors, dry cough is not a significant adverse effect of losartan. Angioedema can occur but is rare and occurs at lower rates than with ACE inhibitors. Mild elevation of serum creatinine in the early weeks of therapy is expected and usually not a reason to discontinue.
Interactions
Concurrent use with ACE inhibitors, direct renin inhibitors (aliskiren), or other ARBs (dual RAAS blockade) is contraindicated due to increased risk of hypotension, hyperkalemia, and renal failure. NSAIDs reduce the antihypertensive effect of losartan and increase the risk of renal impairment. Potassium supplements and potassium-sparing diuretics (spironolactone, eplerenone) increase hyperkalemia risk. Losartan is metabolised by CYP2C9 and CYP3A4; inhibitors of these enzymes can increase losartan and EXP-3174 levels. Fluconazole, a CYP2C9 inhibitor, significantly increases losartan exposure.
Special Notes
Losartan and all ARBs are absolutely contraindicated in pregnancy (all trimesters); foetal exposure can cause oligohydramnios, limb defects, and neonatal renal failure. Women of childbearing age must use effective contraception. Losartan should not be combined with aliskiren in patients with diabetes or renal impairment. Regular monitoring of renal function, electrolytes, and blood pressure is essential during treatment. The uricosuric effect of losartan distinguishes it from other ARBs and should be considered when selecting therapy in patients with hyperuricaemia. Generic losartan is available and widely used; several sartan products were subject to nitrosamine contamination recalls between 2018 and 2021.
Related Topics
Frequently Asked Questions
Why does losartan not cause cough unlike ACE inhibitors?
ACE inhibitors block angiotensin-converting enzyme, which also degrades bradykinin. The accumulation of bradykinin in the airways triggers the dry cough seen in up to 20 percent of patients on ACE inhibitors. Losartan blocks the AT1 receptor directly without affecting bradykinin metabolism, so cough does not occur through this mechanism.
What is the uricosuric effect of losartan?
Losartan and its metabolite inhibit the URAT1 transporter in the kidney, which reabsorbs uric acid from the urine back into the blood. By blocking this transporter, losartan increases renal uric acid excretion and lowers serum uric acid levels. This effect is unique among ARBs and is clinically useful in hypertensive patients with gout or elevated uric acid.
Can losartan protect the kidneys in diabetes?
Yes. The RENAAL trial demonstrated that losartan 100 mg daily significantly reduced the risk of progression to end-stage renal disease, doubling of serum creatinine, and combined cardiovascular and renal endpoints in type 2 diabetic patients with nephropathy, independent of its blood pressure-lowering effect.
Sources
- Brenner BM et al: RENAAL Trial. N Engl J Med 2001
- Dahlof B et al: LIFE Trial. Lancet 2002
- ESC Hypertension Guidelines 2023