What are the drug of choice and alternatives for esophageal varices and portal hypertension?

Drug Therapy for Esophageal Varices and Portal Hypertension

Non-selective beta-blockers (NSBBs) are the first-line drug therapy for prevention of bleeding from esophageal varices and management of portal hypertension, with propranolol and nadolol being the most recommended options. 1

First-Line Pharmacological Therapy

Non-selective Beta-Blockers

• Propranolol: Starting dose 20-40 mg orally twice daily, adjusted every 2-3 days until target heart rate of 55-60 beats per minute is achieved. Maximum daily dose: 320 mg/day in patients without ascites, 160 mg/day in patients with ascites 1
• Nadolol: Starting dose 20-40 mg orally once daily, adjusted every 2-3 days until target heart rate of 55-60 beats per minute is achieved. Maximum daily dose: 160 mg/day in patients without ascites, 80 mg/day in patients with ascites 1
• Carvedilol: Starting dose 6.25 mg once daily, increasing after 3 days to 6.5 mg twice daily. Maximum dose: 12.5 mg/day (except in patients with persistent arterial hypertension) 1

Mechanism of Action of NSBBs

• NSBBs reduce portal pressure through two mechanisms: 1
  • Decreasing cardiac output (β1-receptor blockade)
  • Producing splanchnic vasoconstriction (β2-receptor blockade), thereby reducing portal blood flow 1, 2
• A decrease in hepatic venous pressure gradient (HVPG) ≥20% from baseline or to <12 mmHg significantly reduces the risk of first variceal hemorrhage 1

Alternative Pharmacological Therapies

Vasopressin Analogs

• Terlipressin: A synthetic vasopressin analog with twice the selectivity for vasopressin V1 receptors versus V2 receptors 3
• Mechanism: Reduces portal hypertension by causing splanchnic vasoconstriction and increasing mean arterial pressure 3
• Primarily used in acute variceal bleeding rather than for long-term management 4

Somatostatin and Analogs

• Octreotide: A synthetic analog of somatostatin with longer half-life 1
• Used primarily in acute bleeding episodes rather than for long-term management 1
• Has a good safety profile compared to vasopressin 1

Vasodilators

• Isosorbide mononitrate: Acts by decreasing portal pressure through peripheral vasodilation 1
• Not recommended as monotherapy due to systemic hypotensive effects 1
• Combination with NSBBs has shown conflicting results and increased side effects 1

Treatment Algorithms Based on Clinical Scenario

1. Primary Prevention (No Prior Bleeding)

• For patients with medium/large varices that have not bled: 1

  • First-line: NSBBs (propranolol, nadolol) or carvedilol
  • Alternative: Endoscopic variceal ligation (EVL)
  • Note: Combination therapy (NSBB plus EVL) is not recommended in this setting 1

• For patients with small varices with high-risk features (Child B/C or red wale marks): 1

  • NSBBs are recommended 1

• For patients with small varices without high-risk features: 1

  • NSBBs can be used, although long-term benefit not established 1

2. Secondary Prevention (After Bleeding Episode)

• Combination of NSBBs and EVL is recommended 1
• NSBBs should be continued indefinitely 1

3. Acute Variceal Bleeding

• Vasoactive drugs (terlipressin or octreotide) to reduce splanchnic blood flow and portal pressure 1, 4
• Short course of prophylactic antibiotics 1
• Endoscopic therapy (band ligation preferred over sclerotherapy) 4
• In refractory cases, consider transjugular intrahepatic portosystemic shunt (TIPS) 4

Special Considerations and Monitoring

Contraindications to NSBBs

• Hypotension (systolic blood pressure <90 mmHg) 1, 2
• Bradycardia 1
• Severe reactive airway disease 2

Monitoring Requirements

• Patients on NSBBs for primary prophylaxis do not require monitoring with serial endoscopies 1
• Target heart rate: 55-60 beats per minute 1
• Systolic blood pressure should not decrease below 90 mmHg 1

Common Pitfalls

• Using selective beta-blockers (metoprolol, atenolol) instead of non-selective beta-blockers (propranolol, nadolol) - selective beta-blockers are less effective for portal hypertension 1
• Discontinuing beta-blockers after initial response - therapy should be continued indefinitely 1
• Failure to adjust dosage in patients with ascites - maximum doses should be lower 1
• Overlooking the potential for adverse events with NSBBs, which occurred in 48% of patients in one study 1

Efficacy of Pharmacological Therapy

• NSBBs reduce the risk of first variceal bleeding from 30% to 14% in patients with medium/large varices 1
• One bleeding episode is avoided for every 10 patients treated with NSBBs 1
• NSBBs also reduce mortality, though the effect is modest 1
• NSBBs are the most cost-effective form of prophylactic therapy compared to sclerotherapy and shunt surgery 1

NSBBs remain the cornerstone of pharmacological management for esophageal varices and portal hypertension, with vasopressin analogs and somatostatin analogs reserved primarily for acute bleeding episodes.