What is the effect of Losartan (Angiotensin II receptor antagonist) on patients with cirrhosis?

From the Guidelines

Losartan is generally not recommended for routine use in patients with cirrhosis due to the risk of disrupting the already tenuous hemodynamic balance and potentially precipitating hepatorenal syndrome. In cirrhosis, the renin-angiotensin-aldosterone system (RAAS) is often activated to maintain blood pressure despite splanchnic vasodilation, and blocking this system with losartan can lead to dangerous hypotension 1. The primary focus in managing cirrhosis with ascites is on treating the underlying disease, supplementing protein, and restricting salt intake, along with the use of diuretics such as spironolactone and furosemide as needed 1.

The use of losartan, an angiotensin II receptor blocker (ARB), should be approached with caution in cirrhotic patients, particularly those with ascites or a history of hepatorenal syndrome. If losartan must be used in a cirrhotic patient, it should be started at a low dose of 25 mg daily, with close monitoring of blood pressure, renal function, and electrolytes 1. The dosage should not be increased until stability is confirmed, and the medication should be immediately discontinued if there is worsening renal function or hypotension.

Key considerations in the management of cirrhosis include:

• Treatment of the underlying disease
• Supplementation of protein (1.2-1.5 g/kg/day)
• Restricting salt intake to 5 g/day or less
• Use of diuretics such as spironolactone and furosemide as needed, with careful monitoring for hypokalemia and hyperkalemia
• Avoidance of fluid restriction unless severe hyponatremia is present
• Consideration of alternative agents to losartan for managing hypertension or other conditions requiring RAAS blockade.

Beta-blockers like propranolol or nadolol are generally preferred for portal hypertension management in cirrhosis, and careful risk-benefit assessment is needed for patients requiring RAAS blockade for other conditions, with consideration of alternative agents when possible 1.

From the FDA Drug Label

Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1. 7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic impairment Losartan has not been studied in patients with severe hepatic impairment

Key Points:

• In patients with mild to moderate cirrhosis, losartan plasma concentrations are 5-times higher and its active metabolite is 1.7-times higher compared to normal subjects.
• The total plasma clearance of losartan is 50% lower in patients with hepatic insufficiency.
• The oral bioavailability of losartan is doubled in patients with hepatic insufficiency.
• A starting dose of 25 mg is recommended for patients with mild to moderate hepatic impairment.
• Losartan has not been studied in patients with severe hepatic impairment 2.

From the Research

Losartan in Cirrhosis

• Losartan, an angiotensin II type 1 receptor antagonist, has been reported to have a significant portal hypotensive effect in cirrhotic patients 3.
• A study found that one-week losartan administration increases sodium excretion in cirrhotic patients with and without ascites, with the natriuretic effect being more profound in cirrhotic patients with ascites than in those without ascites 3.
• The use of losartan in cirrhosis is not directly related to the use of midodrine and octreotide, which have shown conflicting results for systemic and renal hemodynamics and renal function in patients with cirrhosis-related complications 4.
• Octreotide has been found to have significant effects on the systemic circulation in patients with cirrhosis, including reductions in pulse rate and cardiac output, and increases in mean arterial pressure and pulmonary capillary wedge pressure 5.
• In patients with type 1 hepatorenal syndrome, a combination of midodrine, octreotide, and albumin, followed by transjugular intrahepatic portosystemic stent shunt (TIPS), has been found to improve renal function and sodium excretion 6.
• Losartan has been associated with rare cases of drug-induced liver injury, with only seven cases described in the literature, highlighting the need for a high index of suspicion for drug-induced liver injury (DILI) and careful exclusion of other diagnoses 7.