Drugs used in therapy of portal hypertension

Abstract

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.1 This review focuses on drug therapy for patients with cirrhosis and portal hypertension. 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.2 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 NSBBs. NSBBs, such as propranolol and nadolol, principally act on b1 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 a1 blocker. Several studies have shown that carvedilol is significantly more potent than propranolol at reducing HPVG.5 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.6 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.7 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).8 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. Nitrates. Isosorbide-5-mononitrare (ISMN) is an organic nitrate. The exact mechanism is unclear, but it may act through increased intrahepatic production of nitric oxide.4 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.8 There is no role for nitrates in primary prophylaxis.3,9 They may be used in combination with NSBB as a secondary