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Somatostatin is a 14-amino-acid peptide that is released in the gastrointestinal tract and pancreas from paracrine cells, D cells, and
enteric nerves as well as from the hypothalamus (see Chapter 37). Somatostatin is a key regulatory peptide that has many physiologic

1. It inhibits the secretion of numerous hormones and transmitters, including gastrin, cholecystokinin, glucagon, growth
hormone, insulin, secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT.
2. It reduces intestinal fluid secretion and pancreatic secretion.
3. It slows gastrointestinal motility and inhibits gallbladder contraction.
4. It induces direct contraction of vascular smooth muscle, leading to a reduction of portal and splanchnic blood flow.
5. It inhibits secretion of some anterior pituitary hormones.

The clinical usefulness of somatostatin is limited by its short half-life in the circulation (3 minutes) when it is administered by
intravenous injection. Octreotide is a synthetic octapeptide with actions similar to somatostatin. When administered intravenously, it
has a serum half-life of 1.5 hours. It also may be administered by subcutaneous injection, resulting in a 6- to 12-hour duration of
action. A longer-acting formulation is available for once-monthly depot intramuscular injection.

Clinical Uses

Inhibition of Endocrine Tumor Effects

Two gastrointestinal neuroendocrine tumors (carcinoid, VIPoma) cause secretory diarrhea and systemic symptoms such as flushing
and wheezing. For patients with advanced symptomatic tumors that cannot be completely removed by surgery, octreotide decreases
secretory diarrhea and systemic symptoms through inhibition of hormonal secretion and may slow tumor progression.

Other Causes of Diarrhea

Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility. In low doses (50 mcg subcutaneously), it
stimulates motility, whereas at higher doses (eg, 100250 mcg subcutaneously), it inhibits motility. Octreotide is effective in higher
doses for the treatment of diarrhea due to vagotomy or dumping syndrome as well as for diarrhea caused by short bowel syndrome or
AIDS. Octreotide has been used in low doses (50 mcg subcutaneously) to stimulate small bowel motility in patients with small bowel
bacterial overgrowth or intestinal pseudo-obstruction secondary to scleroderma.

Other Uses
Because it inhibits pancreatic secretion, octreotide may be of value in patients with pancreatic fistula. The role of octreotide in the
treatment of pituitary tumors (eg, acromegaly) is discussed in Chapter 37. Octreotide is sometimes used in gastrointestinal bleeding
(see below).

Adverse Effects

Impaired pancreatic secretion may cause steatorrhea, which can lead to fat-soluble vitamin deficiency. Alterations in gastrointestinal
motility cause nausea, abdominal pain, flatulence, and diarrhea. Because of inhibition of gallbladder contractility and alterations in fat
absorption, long-term use of octreotide can cause formation of sludge or gallstones in over 50% of patients, which rarely results in the
development of acute cholecystitis. Because octreotide alters the balance among insulin, glucagon, and growth hormone,
hyperglycemia or, less frequently, hypoglycemia (usually mild) can occur. Prolonged treatment with octreotide may result in
hypothyroidism. Octreotide also can cause bradycardia.
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 resistance 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 resistance is increased in cirrhosis due to fixed fibrosis within
the spaces of Disse and hepatic veins as well as reversible vasoconstriction 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.

Somatostatin & Octreotide

The pharmacology of octreotide is discussed above under Antidiarrheal Agents. In patients with cirrhosis and portal hypertension,
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 do not 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 35 days.

Vasopressin & Terlipressin

Vasopressin (antidiuretic hormone) is a polypeptide hormone secreted by the hypothalamus and stored in the posterior pituitary. Its
pharmacology is discussed in Chapters 17 and 37. 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
vasoconstriction that leads to reduced splanchnic perfusion and lowered 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 gastrointestinal bleeding from small bowel or large bowel vascular
ectasias or diverticulosis, vasopressin may be infusedto promote vasospasminto one of the branches of the superior or inferior
mesenteric 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 further reduce portal venous pressures (by reducing portohepatic
vascular resistance) and may also reduce the coronary and peripheral 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 similar efficacy 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-ReceptorBlocking Drugs

The pharmacology of -receptorblocking agents is discussed in Chapter 10. Beta-receptor antagonists reduce portal venous
pressures via a decrease in portal venous inflow. This decrease is due to a decrease in cardiac output ( 1 blockade) and to splanchnic
vasoconstriction ( 2 blockade) caused by the unopposed effect of systemic catecholamines on receptors. Thus, nonselective
blockers such as propranolol and nadolol are more effective than selective 1 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 patient treated with nonselective blockers is 15% compared with 25% in control groups. Among patients with a history of
variceal hemorrhage, the likelihood of recurrent hemorrhage is 80% within 2 years. Nonselective blockers significantly reduce the
rate of recurrent bleeding, although a reduction in mortality is unproved.