What is Losartan (angiotensin II receptor antagonist)?

What is Losartan?

Losartan is an orally active angiotensin II receptor blocker (ARB) that selectively blocks the AT1 receptor subtype, representing the first nonpeptide drug in this class used to treat hypertension and provide cardiovascular and renal protection. 1

Mechanism of Action

Losartan and its active metabolite E-3174 selectively block angiotensin II from binding to the AT1 receptor, thereby preventing vasoconstriction and aldosterone secretion without affecting the AT2 receptor. 1

• Losartan has approximately 1000-fold greater affinity for the AT1 receptor compared to the AT2 receptor 1
• The drug acts as a reversible, competitive inhibitor at the AT1 receptor, while its active metabolite E-3174 functions as a reversible, non-competitive inhibitor 1
• E-3174 is 10 to 40 times more potent than losartan itself and is responsible for most of the therapeutic effects 1, 2
• Unlike ACE inhibitors, losartan does not inhibit the enzyme that degrades bradykinin, which explains its lower incidence of cough 1

Chemical Structure and Formulation

Losartan potassium is a white to off-white powder with the molecular formula C22H22ClKN6O and molecular weight of 461.01. 1

• The drug is a biphenyltetrazole molecule, representing a unique chemical class distinct from all other antihypertensive agents 3, 4
• Available in oral tablets containing 25 mg, 50 mg, or 100 mg of losartan potassium 1
• Each tablet contains potassium: 2.12 mg (25 mg tablet), 4.24 mg (50 mg tablet), or 8.48 mg (100 mg tablet) 1

Pharmacokinetics

Losartan is rapidly absorbed after oral administration with peak concentrations reached in 1 hour, while its active metabolite E-3174 peaks in 3-4 hours. 1, 2

• Systemic bioavailability is approximately 33% due to substantial first-pass metabolism 1
• About 14% of an oral dose is converted to the active E-3174 metabolite 1, 2
• The terminal half-life of E-3174 ranges from 6 to 9 hours, allowing for once-daily dosing 2
• Pharmacokinetics are linear and dose-proportional up to 200 mg, with no accumulation over time 1, 2
• Food slows absorption and decreases peak concentration but has minimal effect on overall drug exposure 1
• Both losartan and E-3174 are highly protein-bound (primarily to albumin) with plasma free fractions of 1.3% and 0.2%, respectively 1

Metabolism and Elimination

Losartan undergoes substantial first-pass metabolism primarily via cytochrome P450 enzymes CYP3A4, 2C9, and 2C10. 1, 2

• The major metabolic pathway produces the active carboxylic acid metabolite E-3174, along with several inactive metabolites 1
• Neither losartan nor E-3174 is removed during hemodialysis 2

Clinical Indications

Losartan is recommended as a first-line antihypertensive agent by major cardiovascular societies, with particular benefits in specific patient populations. 5

Hypertension

• European Society of Cardiology recommends ARBs including losartan as first-line treatment alongside ACE inhibitors, calcium channel blockers, and thiazide diuretics 5
• Effective in mild to moderate hypertension at doses of 50-100 mg once daily 6
• Maximum recommended daily dose is 100 mg 2

Special Populations with Enhanced Benefits

Patients with left ventricular hypertrophy: Losartan demonstrated superiority over atenolol in reducing cardiovascular events, particularly stroke, in the LIFE trial 5

Diabetic patients: A blocker of the renin-angiotensin system should be a regular component of combination treatment in diabetic hypertensive patients, with losartan showing pronounced benefits including statistically significant differences in all-cause mortality 7, 5

Diabetic nephropathy: The RENAAL study showed losartan reduced hospitalization for heart failure in diabetics with nephropathy, though composite cardiovascular outcomes were not significantly different from placebo 7

Tolerability and Safety Profile

Losartan has an exceptionally favorable tolerability profile, with dizziness being the only drug-related adverse effect reported more frequently than placebo. 6, 8

• Patient withdrawal rate due to adverse effects is lower with losartan (2.3%) than placebo (3.7%) 8
• Significantly lower incidence of cough compared to ACE inhibitors, making it an excellent alternative for ACE inhibitor-intolerant patients 5, 6
• First-dose hypotension is uncommon due to slower onset of action 6, 8
• No clinically relevant adverse metabolic effects or laboratory abnormalities documented 6
• Angioedema can occur but is rare 8

Important Monitoring Requirements

Renal function must be monitored before initiation and periodically during treatment, especially in patients with renal impairment. 5

• Blood pressure should be measured in both sitting and standing positions, particularly in elderly patients, due to increased risk of postural hypotension 5
• Careful monitoring of potassium levels is essential, especially in patients with chronic kidney disease, due to risk of hyperkalemia 5

Contraindications and Precautions

Losartan is absolutely contraindicated in pregnancy and should be avoided during all trimesters. 5, 2

• When given in the second and third trimester, losartan is often associated with serious fetal toxicity 2
• Dual RAAS blockade (combining losartan with ACE inhibitors or aliskiren) is not recommended due to increased adverse events without additional benefit 7, 5
• The ONTARGET trial showed no improvement in cardiovascular events with combined telmisartan and ramipril, but increased risk of serum creatinine doubling and hyperkalemia 7
• The NEPHRON-D study demonstrated that combining losartan with lisinopril increased acute kidney injury and hyperkalemia risk with no mortality or cardiovascular benefit 7

Dosage Considerations

No dosage adjustment is necessary based on age, sex, race, mild hepatic impairment, or various degrees of renal insufficiency. 2

• Can be administered without regard to food 2
• The 100 mg daily dose can be given once daily or split into two doses 2

Drug Interactions

Losartan has a favorable drug-drug interaction profile with no clinically relevant interactions with most commonly used medications. 2

• No significant interactions with hydrochlorothiazide, warfarin, or digoxin 2
• Despite metabolism via CYP450 enzymes, there is a lack of clinically relevant interactions with most CYP450 inhibitors and stimulators 2

Unique Metabolic Effects

Losartan increases uric acid secretion and lowers plasma uric acid levels. 8

• This may be beneficial when combined with thiazide diuretics (which increase uric acid) 8
• However, increased uric acid secretion could potentially lead to uric acid stone formation or nephropathy in susceptible individuals 8