What is the role of terlipressin in managing complications of chronic liver disease?

Role of Terlipressin in Managing Complications of Chronic Liver Disease

Terlipressin is primarily indicated for treating hepatorenal syndrome-acute kidney injury (HRS-AKI) in patients with cirrhosis, and as a vasoactive drug for acute variceal hemorrhage (AVH), with proven efficacy in improving outcomes in these life-threatening complications of chronic liver disease. 1

Mechanism of Action

Terlipressin is a synthetic vasopressin analogue with:

• Greater selectivity for vasopressin V1 receptors than V2 receptors
• Acts as both a prodrug for lysine-vasopressin and has direct pharmacologic activity
• Increases mean arterial pressure through splanchnic vasoconstriction
• Reduces portal pressure and improves renal perfusion in cirrhotic patients 2

Role in Hepatorenal Syndrome

Indications

• First-line treatment for HRS-AKI (formerly known as HRS type 1) in combination with albumin 1
• Reverses HRS-AKI in 40-50% of patients 3, 1

Dosage and Administration

• Continuous infusion is preferred over bolus dosing:
  • Starting dose: 2 mg/day IV continuous infusion
  • May be increased every 24-48 hours up to 12 mg/day if no response
  • Continue until serum creatinine decreases to within 0.3 mg/dL of baseline or for maximum 14 days 1
• Must be combined with albumin:
  • 1 g/kg IV (maximum 100 g) on day 1
  • 20-40 g/day on subsequent days 3, 1

Response Predictors

• Better liver function (bilirubin ≤10 mg/dL)
• Better baseline kidney function (serum creatinine ≤5 mg/dL)
• Increase in mean arterial pressure ≥5 mmHg with treatment
• Lower grades of acute-on-chronic liver failure 1

Role in Acute Variceal Hemorrhage

Indications

• First-line vasoactive therapy for suspected or confirmed variceal hemorrhage 3
• Should be initiated as soon as variceal bleeding is suspected, preferably before endoscopy 3

Dosage and Administration

• Traditionally given as bolus injections (2 mg every 4 hours)
• Emerging data supports continuous infusion (4 mg/24 hours) for AVH, similar to HRS-AKI treatment 3
• Should be continued for 2-5 days after initial endoscopic hemostasis to prevent early rebleeding 3

Efficacy

• Reduces 7-day mortality (relative risk 0.74)
• Improves hemostasis (relative risk 1.21)
• Lowers transfusion requirements
• Shortens hospitalization 3

Safety Considerations

Contraindications

• Patients experiencing hypoxia or worsening respiratory symptoms
• Ongoing coronary, peripheral, or mesenteric ischemia
• Serum creatinine ≥5 mg/dL
• Oxygen saturation <90% 1, 2

Adverse Events

• Cardiovascular complications (12% of patients): angina, arrhythmias, digital ischemia
• Respiratory complications (8-30%): pulmonary edema, respiratory failure
• Gastrointestinal symptoms: abdominal pain, nausea, diarrhea
• Other: dyspnea, cyanosis, stroke 3, 1, 2

Monitoring Requirements

• Regular monitoring of vital signs, especially blood pressure and heart rate
• Continuous pulse oximetry for respiratory status
• Renal function tests
• Careful clinical screening including ECG before starting treatment 1

Comparison with Other Vasoactive Drugs

For variceal hemorrhage:

• Octreotide is preferred in the US due to better safety profile
• Terlipressin and vasopressin have 2.39-fold higher adverse event rates compared to octreotide/somatostatin
• Terlipressin may have greater portal pressure reduction effects than somatostatin 3

For HRS-AKI:

• Terlipressin plus albumin is the first-line treatment with highest efficacy
• Noradrenaline can be an alternative but requires central venous line and ICU admission
• Midodrine plus octreotide is less effective but can be used when terlipressin/noradrenaline unavailable 3

Emerging Applications

While the primary indications remain HRS-AKI and AVH, there is some evidence (though insufficient for formal recommendations) for terlipressin use in:

• Refractory ascites
• Hepatic hydrothorax
• Paracentesis-induced circulatory dysfunction
• Perioperatively during liver transplantation 4, 5

Practical Considerations

• Terlipressin has only recently received FDA approval in the US, though it has been widely used internationally 3
• For HRS-AKI, treatment should be repeated if recurrence occurs after treatment cessation 3
• Long-term terlipressin administration for HRS-NAKI (formerly HRS type 2) is not recommended due to high recurrence rates after withdrawal 3
• In patients with variceal bleeding, terlipressin should be discontinued if endoscopy reveals non-variceal bleeding 3