There have been major advances in drug therapy for portal hypertension since the discovery of nonselective beta-blockers (NSBBs) by Lebrec and colleagues over 30 years ago. This review focuses on drug therapy for patients with cirrhosis and portal hypertension.
US Food and Drug Administration
hepatic venous pressure gradient
Pathophysiology of Portal Hypertension and Targets for Drug Therapy
Ohms law dictates that the change in portal pressure is the product of portal blood flow and resistance to flow. Portal hypertension results from increased intrahepatic resistance principally as a result of fibrosis and regenerative nodules. Intrahepatic resistance can be reduced by 20% to 30% with pharmacological therapy. The elevated intrahepatic resistance leads to the development of the collateral circulation, which allows portal blood to be diverted into the systemic circulation and results in gastroesophageal varices. This process aims to reduce portal pressure. However, the converse occurs, with splanchnic vasodilatation resulting in increased portal blood flow, which maintains a high portal pressure. Therefore, the splanchnic circulation is a key target for pharmacological manipulation.
Drugs Used in Clinical Practice
The main drugs presently used are detailed in Table 1. Hemodynamic goals for drug therapy are reduction in the hepatic venous pressure gradient (HVPG) to <12 mm Hg or 20% reduction from baseline.[3, 4]
|Drug||Class||Dosage||Mechanism of Action of Reducing Portal Pressure||Reduction in HVPG from Baseline||Major Side Effects/Adverse Events||Cautions|
|Propranolol||NSBB||Start at 40 mg/day; dose titrated to maximum tolerated or once heart rate of 50-55 bpm is reached, to a maximum dose of 320 mg||β1 blockade - splanchnic vasoconstriction due to unopposed effect on α1 receptors||10%-29%||Fatigue; shortness of breath; symptomatic hypotension; bradycardia; conduction defects; sleep disturbance; peripheral circulation insufficiency, including claudication and Raynaud's phenomenon; impotence||Asthma and obstructive airway disease; uncontrolled heart failure; severe peripheral vascular disease; reduced dosage may be required in severe hepatic and renal impairment|
|β2 blockade; prevents splanchnic vasodilatation|
|Nadolol||NSBB||Start 40 mg/day; dose titrated to maximum tolerated or once heart rate of 50-55 bpm reached, to a maximum dose of 240 mg||As propranolol||19%-22%|
|Carvedilol||NSBB||Starting dose of 6.25 mg od to increase to maintenance of 12.5 mg if tolerated or once heart rate of <50-55 bpm is reached||As propranolol (2-4 times more potent beta blockade action) with additional α1 antagonism||15%-43%|
|Isosorbide-5- Mononitrate||Long acting organic nitrate||Use in combination with NSBB. Start at 10 mg once daily. Dose increased to 40 mg twice daily if well tolerated and aiming to keep systolic blood pressure >95 mm Hg||Uncertain. Vasodilatation may be the result of enhanced production of intrahepatic nitric oxide or cyclic-GMP. Reduced intrahepatic resistance||7.5%-30%||Headache, hypotension, dizziness||Heart failure due to obstruction. Hypthyroidism. Hypothermia. Glaucoma. Aortic/ mitral stenosis. Severe hepatic and renal impairment|
NSBBs, such as propranolol and nadolol, principally act on β1 receptors, resulting in splanchnic vasoconstriction and a reduction of portal inflow. These drugs are used for primary and secondary prevention of variceal hemorrhage. Carvedilol is an NSBB and α1 blocker. Several studies have shown that carvedilol is significantly more potent than propranolol at reducing HPVG. It is proposed that carvedilol has an additional effect on reducing intrahepatic resistance. A randomized controlled trial has demonstrated carvedilol to be effective in the primary prevention of variceal bleeding. The dosage regimes are detailed in Table 1. Dose reduction or discontinuation of beta-blockers is necessary if the patient's heart rate is <50 to 55 beats per minute or if their systolic blood pressure falls to <85 mm Hg and the patient has heart failure or unstable diabetes. Patients with advanced liver disease and ascites may have particular difficulty tolerating NSBBs, and some authors have reported a potential detrimental effect in such patients. There is no indication to withdraw beta-blockers in patients with portal vein thrombosis or hepatic encephalopathy.
NSBBs have been assigned to pregnancy category C by the US Food and Drug Administration (FDA). Propranolol may cause intrauterine growth retardation in the first and second trimester. It is also associated with neonatal hypoglycemia, hypotension, and bradycardia. Careful counseling of patients with portal hypertension wishing to become pregnant is recommended. Propranolol is the preferred agent. Long-acting agents are best avoided. Only a small amount is expressed in breast milk. Information on nadolol and carvedilol is lacking.
Isosorbide-5-mononitrare (ISMN) is an organic nitrate. The exact mechanism is unclear, but it may act through increased intrahepatic production of nitric oxide. The dosage regimen is detailed in Table 1. The hypotensive effect can be exacerbated by concurrent use of vasodilators or alcohol. ISMN has been assigned to pregnancy category C by the FDA, although it is not known to be harmful.
There is no role for nitrates in primary prophylaxis.[3, 9] They may be used in combination with NSBB as a secondary prophylaxis, particularly in patients who do not exhibit a hemodynamic response.[3, 9] Recurrent bleeding is also associated with a lack of hemodynamic response to NSBB + ISMN. However, measurement of HVPG is not practical in most institutions.
Terlipressin is used extensively for the management of acute variceal hemorrhage in combination with endoscopic therapy and in hepatorenal syndrome. It causes an acute reduction in portal pressure that lasts up to 4 hours (Fig. 1).
Terlipressin is currently not available in the United States. Terlipressin is a prodrug, lysine vasopressin. Cleavage of the glycyl component by endothelial peptidases results in the active form. This helps to localize the drug in the splanchnic circulation and increase its half-life, thereby permitting bolus injection. Terlipressin acts on V1 receptors to cause splanchnic vasoconstriction, which reduces portal inflow and pooling of blood in the splanchnic circulation. This results in reduced portal pressure and improved renal perfusion. V2 receptor blockade results in free water absorption in the renal collecting ducts. A dilutional hyponatremia can result, which usually resolves rapidly on discontinuation of the drug.
There are many adverse events associated with terlipressin (Table 2). Regular clinical examination of the skin, limb peripheries, and cardiovascular system (supplemented by electrocardiography) is essential during therapy. The dose should be reduced once there is control of hemorrhage. Terlipressin is best avoided in pregnancy, where an oxytocic effect can occur.
|Class||Vasopressin analogue||Somatostatin analogue|
|Indications||Acute variceal hemorrhage; hepatorenal syndrome||Acute variceal hemorrhage|
|Dosage||Acute variceal hemorrhageb: 2 mg every 4 hours; dose can be titrated down to 1 mg every 4 hours after control of hemorrhage; consider discontinuation after 3 days; avoid therapy longer than 5 days||Bolus of 50 μg followed by 50 μg/hour for up to 5 days|
|Hepatorenal syndromec: 0.5-1 mg every 4-6 hours increasing to 2 mg every 4 hours; dose titration to aim for 10% increase in mean arterial pressure and/or reduction in creatinine of at least 88 μmol/L (1 mg/dL)|
|Mode of administration||Intravenous bolus||Intravenous infusion|
|Major side effects/adverse events||Vasoconstriction and ischemic complications; abdominal pain; nausea and diarrhea may be experienced; arrhythmia; skin necrosis; hyponatremia||Rare and minor: nausea, vomiting, abdominal pain, diarrhea; hypoglycemia and hepatitis have been reported; rarely pancreatitis, arrhythmias, dyspnea, alopecia, rash|
|Cautions||History of coronary artery disease; cardiac arrhythmias; cardiomyopathy; obliterative arterial disease of the lower limbs; cerebrovascular disease; age >70 years||Possible reduced demand for insulin and oral diabetic medication in diabetes mellitus|
Octreotide is an alternative to terlipressin in acute variceal hemorrhage. The mechanism of action is not clear, but it may occur through inhibition of glucagon-mediated vasodilatation rather than a direct vasoconstrictive effect like with terlipressin. Postprandial gut hyperemia is also reduced. The actions of octreotide on hepatic and systemic hemodynamics are transient, making a continuous infusion necessary (Fig. 1).
Side effects are rare and mild compared with terlipressin (Table 2). Octreotide has been assigned to pregnancy category B by the FDA and should only be used where the benefits outweigh the risk to the individual patient.
Drug therapy with NSBBs is considered by many to be first line for primary and secondary prevention of variceal hemorrhage. Carvedilol is a promising agent and deserves further study. Caution is necessary in patients with advanced liver failure who are at higher risk of side effects. There is only a limited role for ISMN. There is more evidence for terlipressin than octreotide in treating acute variceal hemorrhage and hepatorenal syndrome. Careful monitoring of the potentially severe side effects allows for safe use of this effective agent. The role of HVPG monitoring is presently reserved for clinical trials and larger academic institutions.