DRUGS USED TO TREAT VARICEAL HEMORRHAGE
Portal hypertension most commonly occurs as a consequence of chronic liver disease. Portal hypertension is caused by increased blood flow within the portal venous system and increased resis-tance to portal flow within the liver. Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors. Intrahepatic vascular resis-tance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins as well as reversible vasoconstric-tion of hepatic sinusoids and venules. Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices. Varices can rupture, leading to massive upper gastrointestinal bleeding.
Several drugs are available that reduce portal pressures. These may be used in the short term for the treatment of active variceal hemorrhage or long term to reduce the risk of hemorrhage.
The pharmacology of octreotide is discussed above under Antidiarrheal Agents. In patients with cirrhosis and portal hyper-tension, intravenous somatostatin (250 mcg/h) or octreotide (50 mcg/h) reduces portal blood flow and variceal pressures; however, the mechanism by which they do so is poorly understood. They donot appear to induce direct contraction of vascular smooth muscle. Their activity may be mediated through inhibition of release of glucagon and other gut peptides that alter mesenteric blood flow. Although data from clinical trials are conflicting, these agents are probably effective in promoting initial hemostasis from bleeding esophageal varices. They are generally administered for 3–5 days.
Vasopressin (antidiuretic hormone) is a polypeptide hormonesecreted by the hypothalamus and stored in the posterior pituitary. Although its primary physiologic role is to maintain serum osmolality, it is also a potent arterial vasoconstrictor. When administered intravenously by continuous infusion, vasopressin causes splanchnic arterial vaso-constriction that leads to reduced splanchnic perfusion and low-ered portal venous pressures. Before the advent of octreotide, vasopressin was commonly used to treat acute variceal hemorrhage. However, because of its high adverse-effect profile, it is no longer used for this purpose. In contrast, for patients with acute gastroin-testinal bleeding from small bowel or large bowel vascular ectasias or diverticulosis, vasopressin may be infused—to promote vasos-pasm—into one of the branches of the superior or inferior mesen-teric artery through an angiographically placed catheter. Adverse effects with systemic vasopressin are common. Systemic and peripheral vasoconstriction can lead to hypertension, myocardial ischemia or infarction, or mesenteric infarction. These effects may be reduced by coadministration of nitroglycerin, which may fur-ther reduce portal venous pressures (by reducing portohepatic
vascular resistance) and may also reduce the coronary and periph-eral vascular vasospasm caused by vasopressin. Other common adverse effects are nausea, abdominal cramps, and diarrhea (due to intestinal hyperactivity). Furthermore, the antidiuretic effects of vasopressin promote retention of free water, which can lead to hyponatremia, fluid retention, and pulmonary edema.
Terlipressin is a vasopressin analog that appears to have similarefficacy to vasopressin with fewer adverse effects. Although this agent is available in other countries, it has never been approved for use in the USA.
Beta-receptor antagonists reduce portal venous pres-sures via a decrease in portal venous inflow. This decrease is due to a decrease in cardiac output (β1 blockade) and to splanchnic vasoconstriction (β2 blockade) caused by the unopposed effect of systemic catecholamines on α receptors. Thus, nonselective β blockers such as propranolol and nadolol are more effective than selective β1 blockers in reducing portal pressures. Among patients with cirrhosis and esophageal varices who have not previously had an episode of variceal hemorrhage, the incidence of bleeding among patients treated with nonselective β blockers is 15% compared with 25% in control groups. Among patients with a history of variceal hemorrhage, the likelihood of recurrent hem-orrhage is 80% within 2 years. Nonselective β blockers signifi-cantly reduce the rate of recurrent bleeding, although a reduction in mortality is unproved.