NEW APPROACHES IN THE PHARMACOLOGICAL TREATMENT OF PORTAL-HYPERTENSION

To alleviate the risk of variceal bleeding, the portal pressure gradient - usually evaluated as the hepatic venous pressure gradient (HVPG) - must be reduced to less-than-or-equal-to 12 mmHg. Although beta-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to less-than-or-equal-to 12 mmHg in only 12% of patients, while only 24% of patients have a greater-than-or-equal-to 20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorbide-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5-mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolactone, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a beta-blocker, a nitrate and spironolactone may be feasible. Serotonin constricts mesenteric veins in experimental models of portal hypertension and may also play a role in portal hypertension secondary to cirrhosis. Serotonin S2-receptor blockers, such as ritanserin and ketanserin, have been shown to lower portal-collateral resistance in animal models and patients with cirrhosis. These serotonin antagonists should be assessed for their potential in coadministration with non-selective beta-blockers, perhaps with the addition of spironolactone.