Medication Summary
The goals of pharmacotherapy are to reduce mortality and morbidity, and prevent complications associated with acute bleeding related to portal hypertension. Two main categories of drugs, vasoconstrictors and vasodilators, are used.
The main advantages to using vasoactive agents include the ability of these drugs to treat variceal bleeding in the emergency department, lower portal pressure, and offer the endoscopist a clearer view of varices because of less active bleeding. Vasoactive agents represent an ideal treatment for sources of portal hypertensive bleeding other than esophageal varices (eg, gastric varices >2 cm below the gastroesophageal junction or portal hypertensive gastropathy). [8, 15]
The vasoconstrictors somatostatin and octreotide are used to treat acute bleeding in patients with portal hypertension before performing endoscopy. [47, 51] Intravenous infusions of octreotide will lower portal blood pressure and can prevent rebleeding during the patient's initial hospitalization. Vasodilators such as isosorbide mononitrate (ISMN) reduce intrahepatic vascular resistance without decreasing the peripheral or portal-collateral resistance.
Beta-blockers, which include propranolol, nadolol, and timolol, are used to provide primary and secondary prophylaxis. Beta-blockers lower the cardiac output (via blockade of beta1 adrenoreceptors) and cause splanchnic vasoconstriction (via blockade of vasodilatory adrenoreceptors of the splanchnic circulation), reducing portal and collateral blood flow.
Somatostatin Analogs
Class Summary
Somatostatin, an orphan drug, is a naturally occurring tetradecapeptide isolated from the hypothalamus and from pancreatic and enteric epithelial cells. Through vasoconstriction, somatostatin diminishes blood flow to the portal system, thus decreasing variceal bleeding. It has effects similar to those of vasopressin but does not cause coronary vasoconstriction. Somatostatin has an initial half-life of 1-3 minutes and is rapidly cleared from the circulation.
Somatostatin analogs inhibit the secretion of hormones involved in vasodilation. Octreotide is a synthetic octapeptide. Compared with somatostatin, octreotide has similar pharmacologic actions with greater potency and longer duration of action. In the US, octreotide is used off-label for the management of variceal hemorrhage. [47]
Octreotide (Sandostatin)
Octreotide, a synthetic octapeptide, acts primarily on somatostatin receptor subtypes II and V. It inhibits growth hormone secretion and has a multitude of other endocrine and nonendocrine effects, including the inhibition of glucagon, vasoactive intestinal peptide, and GI peptides. Octreotide has greater potency and a longer duration of action than somatostatin.
Beta-Blockers, Nonselective
Class Summary
Nonselective beta-blocking agents decrease hepatic arterial and portal venous perfusion. Beta-adrenergic blockers may block the effect of vasodilators, decrease platelet adhesiveness and aggregation, and increase the release of oxygen to tissues.
Nonselective beta-blockers have been shown to prevent bleeding in more than 50% of patients with medium or large varices. [8] These agents exert a moderate effect on the reduction of portal flow, and smaller effects on the increase in portal resistance and decrease in portal pressure.
Propranolol is used off-label for primary prophylaxis — in combination with endoscopic variceal ligation (EVL) — for esophageal varices. This agent is also indicated for secondary prophylaxis for esophageal varices.
Propranolol (Inderal, InnoPran XL)
Propranolol is a noncardioselective beta-blocker that reduces portal pressure through the reduction of portal and collateral blood flow. It competes with adrenergic neurotransmitters (eg, catecholamines) at sympathetic receptor sites. Similar to atenolol and metoprolol, propranolol blocks sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscles.
Nadolol (Corgard)
Nadolol is a noncardioselective beta-blocker that reduces portal pressure through the reduction of portal and collateral blood flow.
Timolol
Timolol is a noncardioselective beta-blocker that reduces portal pressure through the reduction of portal and collateral blood flow.
Carvedilol
Carvedilol is a nonselective beta blocker and also a selective alpha 1 blocker.
Vasopressin-Related
Class Summary
Vasoconstrictors reduce portal blood flow and/or increase resistance to variceal blood flow inside the varices. Therefore, these drugs reduce blood flow in the gastroesophageal collaterals because of their vasoactive effects on the splanchnic vascular system. When used in combination with nitrates, the efficacy and safety of vasoconstrictors have been shown to improve. However, their use may be limited as the risk of adverse events is higher with combination therapy.
In the US, vasopressin is used off-label for the management of acute variceal bleeding.
Terlipressin is widely used in Europe but has not received FDA approval for use in the United States. This is a synthetic analogue of vasopressin. It is the only pharmacologic agent shown to reduce mortality from variceal bleeding. Terlipressin has longer biologic activity than vasopressin. It significantly reduces portal and variceal pressure and azygos flow. The drug is beneficial when combined with sclerotherapy. Terlipressin also has the advantage of preserving renal function, which is a particularly important feature in patients with cirrhosis.
Vasopressin (Pitressin)
Vasopressin has vasopressor and antidiuretic hormone (ADH) activity. It increases water resorption at the distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). However, vasoconstriction is also increased in the splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels. Vasopressin decreases the portal pressure in portal hypertension.
A notable adverse effect of this agent is coronary artery constriction, which may provoke patients with coronary artery disease to cardiac ischemia. This can be prevented with the concurrent use of nitrates. Vasopressin is rarely used.
Vasodilators
Class Summary
Vasodilators have been shown to exert a small effect on the reduction of portal flow, an increase in portal resistance, and decrease on portal pressure. These agents reduce intrahepatic vascular resistance without decreasing peripheral or portal-collateral resistance.
Nitrates, however, technically work by decreasing resistance. They reduce portal flow by decreasing mean arterial pressure. Oral nitroglycerin is used off-label for the management of variceal bleeding.
Nitroglycerin PO (Nitro-Bid, Nitrostat, Nitro-Time)
Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is a decrease in blood pressure.
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Large esophageal varices with red wale signs seen on endoscopy. Courtesy of Wikimedia Commons.
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Uphill esophageal varices. Barium swallow demonstrates multiple serpiginous filling defects primarily involving the lower one third of the esophagus with striking prominence around the gastroesophageal junction. The patient had cirrhosis secondary to alcohol abuse.
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Barium swallow demonstrating esophageal varices involving the entire length of the esophagus. This appearance may be seen in advanced uphill varices or downhill varices secondary to superior vena cava obstruction at or below the level of the azygous vein.
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Computed tomography scan showing esophageal varices. Note the extensive collateralization within the abdomen adjacent to the spleen as a result of severe portal hypertension.
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Normal venous flow through the portal and systemic circulation. IMC = inferior mesenteric vein; IVC = inferior vena cava; SVC = superior vena cava.
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Redirection of flow through the left gastric vein secondary to portal hypertension or portal venous occlusion. Uphill varices develop in the distal one third of the esophagus. IMC = inferior mesenteric vein; IVC = inferior vena cava; SVC = superior vena cava.
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Portal vein and associated anatomy.
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Power Doppler sonogram through the spleen shows varices at the hilum of an enlarged spleen. The final diagnosis was hepatitis C cirrhosis, hepatocellular carcinoma of the left hepatic lobe (which had ruptured into the peritoneum), and portoarterial fistula (which had developed inside the ruptured tumor, giving rise to severe portal hypertension).
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Duplex spectral Doppler sonogram of the portal vein (same patient as in the previous image) shows a bidirectional flow within the vein. The final diagnosis was hepatitis C cirrhosis, hepatocellular carcinoma of the left hepatic lobe (which had ruptured into the peritoneum), and portoarterial fistula (which had developed inside the ruptured tumor, giving rise to severe portal hypertension).
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Digital subtraction selective common hepatic artery angiogram shows immediate filling of the portal venous radicles in the left lobe of the liver (straight arrow) and early filling of portal vein (curved arrow), suggestive of hepatic arterial-portal vein fistula. The final diagnosis was hepatitis C cirrhosis, hepatocellular carcinoma of the left hepatic lobe (which had ruptured into the peritoneum), and portoarterial fistula (which had developed inside the ruptured tumor, giving rise to severe portal hypertension).
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Delayed venous phase of a selective common hepatic angiogram (same patient as in the previous image) shows the portal vein (P), with filling of the left gastric vein caused by retrograde flow feeding gastric and lower esophageal varices (arrows). Retrograde flow in enlarged umbilical veins also is seen. The final diagnosis was hepatitis C cirrhosis, hepatocellular carcinoma of the left hepatic lobe (which had ruptured into the peritoneum), and portoarterial fistula (which had developed inside the ruptured tumor, giving rise to severe portal hypertension).
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Digital subtraction venous phase of a superior mesenteric artery angiogram (same patient as in the previous 2 images) shows retrograde flow into the left gastric vein (curved arrow) and the inferior mesenteric vein (straight arrow). Note the flow defect of the distal portal vein caused by retrograde flow (open arrowhead). The final diagnosis was hepatitis C cirrhosis, hepatocellular carcinoma of the left hepatic lobe (which had ruptured into the peritoneum), and portoarterial fistula (which had developed inside the ruptured tumor, giving rise to severe portal hypertension).
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This video, captured via esophagoscopy, shows band ligation of esophageal varices. Video courtesy of Dan C Cohen, MD, and Dawn Sears, MD, Division of Gastroenterology, Scott & White Healthcare.
Tables
Etiology of Portal Hypertension |
WHVP |
FHVP |
HVPG |
|
Prehepatic |
Normal |
Normal |
Normal |
|
Intrahepatic |
Presinusoidal |
Normal |
Normal |
Normal |
Sinusoidal |
Increased |
Increased |
Increased |
|
Postsinusoidal |
Increased |
Normal |
Increased |
|
Posthepatic |
Budd-Chiari syndrome |
N/A |
Hepatic vein cannot be cannulated |
N/A |
Other posthepatic causes |
Increased |
Increased |
Normal |
|
FHVP = free hepatic venous pressure; HVPG = hepatic venous pressure gradient; N/A = not applicable; WHVP = wedged hepatic venous pressure. |
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