What is the mechanism of action of losartan (angiotensin II receptor antagonist)?

From the Guidelines

Losartan works by blocking angiotensin II receptors in the body, specifically the AT1 receptors, which relaxes blood vessels and lowers blood pressure. This medication belongs to a class called angiotensin II receptor blockers (ARBs) [ 1 ]. When losartan blocks these receptors, it prevents angiotensin II from binding to them, which not only lowers blood pressure but also reduces the workload on the heart and helps prevent kidney damage in people with diabetes and high blood pressure.

Key Mechanisms and Effects

• Losartan's primary mechanism is the blockade of AT1 receptors, leading to vasodilation and a decrease in blood pressure.
• It has renoprotective properties, which are beneficial for patients with diabetes and nephropathy [ 1 ].
• The medication has been shown to reduce the risk of cardiovascular end points and all-cause mortality in patients with hypertension and signs of left ventricular hypertrophy [ 1 ].

Clinical Use and Dosage

• The typical starting dose of losartan is 50 mg once daily, which may be increased to 100 mg daily if needed for blood pressure control.
• For patients with reduced kidney function or those taking diuretics, a lower starting dose of 25 mg may be recommended.
• Losartan takes effect within 1-2 hours after taking it, with peak effects occurring in 6-8 hours, and its blood pressure-lowering effect lasts about 24 hours, making it suitable for once-daily dosing.

Side Effects and Considerations

• Common side effects include dizziness, fatigue, and occasional cough, though the cough is less common than with ACE inhibitors, another type of blood pressure medication.
• The choice of losartan over other antihypertensive medications may depend on patient-specific factors, including tolerance of the drug and the presence of conditions like diabetes or nephropathy [ 1 ].

From the FDA Drug Label

1. 1 Mechanism of Action Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)] is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). Neither losartan nor its principal active metabolite exhibits any partial agonist activity at the AT1 receptor, and both have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor.

Losartan works by blocking the binding of angiotensin II to the AT1 receptor, which is found in many tissues, including vascular smooth muscle and the adrenal gland. This blockage prevents the vasoconstrictor and aldosterone-secreting effects of angiotensin II. Losartan is a reversible, competitive inhibitor of the AT1 receptor and has a much greater affinity for the AT1 receptor than for the AT2 receptor 2. The key effects of losartan include:

• Blocking the vasoconstrictor effects of angiotensin II
• Blocking the aldosterone-secreting effects of angiotensin II
• Inhibiting the pressor effect of angiotensin II infusions Losartan does not inhibit ACE (kininase II), nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation 2.

From the Research

Mechanism of Action

• Losartan is a selective, orally administered, nonpeptide blocker of the angiotensin II type 1 receptor 3.
• It works by blocking the interaction of angiotensin II with its receptor, thereby inhibiting the renin-angiotensin system 4.
• Losartan has a sustained duration of action, permitting once-daily dosing in many patients, and lacks partial agonist activity 3.

Effects on the Renin-Angiotensin-Aldosterone System

• Losartan increases plasma renin activity and angiotensin II levels, while decreasing plasma aldosterone concentration 5.
• The increases in plasma renin activity and angiotensin II are greater at 2 weeks than at 6 weeks of treatment with losartan 5.
• Losartan's effects on the renin-angiotensin-aldosterone system are dose-related 5.

Comparison with ACE Inhibitors

• Losartan and ACE inhibitors have similar efficacy in animal models of hypertension and complications of hypertension, such as kidney dysfunction and cardiac hypertrophy 4.
• Losartan blocks only AT1 sites, while ACE inhibitors functionally block angiotensin II interaction with both AT1 and AT2 sites 4.
• The physiological role of AT2 sites is unknown, making the relevance of this difference between ACE inhibitors and losartan questionable 4.

Clinical Effects

• Losartan reduces blood pressure and has a beneficial effect on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy 6.
• Losartan decreases the incidence of a doubling of the serum creatinine concentration and end-stage renal disease, and reduces the level of proteinuria 6.
• Losartan has a similar overall incidence of adverse experiences to placebo 3.