WDHA Syndrome Medication

Updated: Dec 01, 2016
  • Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Praveen K Roy, MD, AGAF  more...
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Medication

Medication Summary

Medications used to treat WDHA syndrome are divided into 2 categories: (1) antisecretory agents (eg, somatostatin and its synthetic derivatives) to treat secretory diarrhea and (2) chemotherapeutic agents. Conventional antidiarrheals are useful adjuncts to somatostatin analogs.

Preliminary data suggest that octreotide administered postoperatively is associated with a lower rate of complications, such as the development of pancreatic fistula. As a result, many surgical units routinely administer octreotide until the abdominal drains have been removed and the patient is eating normally.

Histamine 2 (H2)–receptor antagonists or proton pump inhibitors should be administered postoperatively to prevent hyperacidity, because rebound hyperchlorhydria is common in the postoperative period.

Surgery, however, is the only curative therapy. Neither somatostatin nor interferon alfa has significant tumoricidal properties, although they may have a tumorostatic effect.

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Somatostatin Analogs

Class Summary

Antisecretory agents are used to treat the profuse secretory diarrhea of WDHA syndrome after patients have been resuscitated adequately. Although conventional antidiarrheals may play an adjunctive role, somatostatin derivatives are the most effective and cost-saving drugs for treating diarrhea in this disease.

Because VIPomas possess somatostatin receptors, somatostatin and its synthetic derivatives are used not only for tumor imaging but also to inhibit hormonal secretion of functional tumors. Radioactively labeled somatostatin derivatives currently are being investigated in the treatment of these tumors.

Octreotide (Sandostatin, Sandostatin LAR)

Octreotide is a synthetic analog of somatostatin with a half-life of approximately 100 minutes.

It is a potent physiologic inhibitor of numerous gastrointestinal (GI) functions, including the following:

These inhibitory effects, either alone or in combination, contribute to the antidiarrheal effect. Antisecretory agents improve diarrhea in as many as 86% of patients with WDHA syndrome and have been reported to decrease tumor size in up to 16% patients.

Octreotide may stabilize tumor growth in some patients but has only minimal tumoricidal activity. Some patients with troublesome diarrhea experience reduced responsiveness to octreotide with time, and, although the VIP levels decline, they do not return to baseline values. Two possible reasons for such tachyphylaxis are accelerated octreotide degradation and down-regulation of somatostatin receptors. Regardless of the mechanism, rebound diarrhea can be difficult to treat.

Sandostatin LAR is a long-acting somatostatin analog that is currently not available in the United States.

Lanreotide (Somatuline LA)

Lanreotide is a somatostatin octapeptide analog with a considerably longer half-life than octreotide. It inhibits multiple endocrine, exocrine, and neuroendocrine mechanisms. Lanreotide reduces insulinlike growth factor-1 and growth hormone secretion.

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Antineoplastics, Other

Class Summary

Chemotherapeutic agents are used to treat metastatic WDHA syndrome when surgical resection is not possible. The combination of streptozotocin and doxorubicin is superior to streptozotocin and 5-FU in the treatment of advanced islet cell carcinoma. Chlorozotocin alone is similar in efficacy to streptozotocin plus 5-FU but has fewer adverse effects than streptozotocin-containing regimens.

Streptozotocin (Zanosar)

Streptozotocin is a naturally occurring nitrosourea that was originally discovered as an antibiotic obtained from Streptomyces achromogenes. It is capable of inhibiting deoxyribonucleic acid (DNA) synthesis during all stages of the mammalian cycle through liberation of alkylating and carbamoylating moieties.

Streptozotocin has a methylnitrosourea (MNU) moiety attached to 2 carbon of glucose and has a special affinity for islet of Langerhans cells. It has a half-life of approximately 15 minutes; only 10-20% of the dose is recovered in urine.

Chlorozotocin (DCNU, Dome, NSC 178248)

Chlorozotocin is not available in the United States. It is an antineoplastic nitrosourea in which the 2 carbon of glucose is substituted with the chloronitrosourea group (CNU).

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline antibiotic derived from the fungus S peucetius var caesius. It intercalates with DNA and disrupts many functions, including DNA and RNA synthesis. Its maximum toxicity occurs during S phase of the cell cycle.

Doxorubicin has a multiphasic disappearance curve, with half-lives ranging up to 30 hours. It does not cross the blood-brain barrier but is taken up rapidly by the heart, lungs, liver, kidneys, and spleen.

Fluorouracil (Adrucil)

Fluorouracil is a pyrimidine analog of uracil, which inhibits RNA function and thymidylate synthesis. Fluorouracil requires enzymatic conversion to a nucleotide to exert cytotoxic activity. Interruption of thymidylate synthesis results in inhibition of DNA synthesis while RNA and protein production continues. This causes an imbalance in growth that is not compatible with cell survival.

Fluorouracil is administered parenterally and is metabolized primarily in the liver. It is inactivated by reduction of the pyrimidine ring by dihydrouracil dehydrogenase. Because this enzyme is widely distributed in body, dose modification of fluorouracil is not required in the presence of liver disease. Fluorouracil readily enters the cerebrospinal fluid (CSF), with values that slowly subside over 9 hours. Urinary excretion of a single intravenous (IV) dose is only 11% in 24 hours.

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Immunomodulators

Class Summary

Interferons are glycoproteins with a variety of biologic actions. They are important cytokines that have immunomodulating, antiviral, and antiproliferative properties. Interferons alfa and beta are produced by most cells in response to viral infections, while interferon gamma is produced only by T lymphocytes.

Interferon alfa-2b (Intron A)

Interferon alfa is a highly purified protein containing 165 amino acid residues. Interferons must be administered subcutaneously or intramuscularly. Interferon alfa is rapidly inactivated in body fluids and various tissues, with an initial half-life of 40 minutes and a terminal half-life of 5 hours. Negligible amounts are excreted renally. Interferon has been used as monotherapy and in combination with octreotide.

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Antidiarrheals

Class Summary

These agents are often used with somatostatin analogs. Although a wide variety of these medications has been tried, the most commonly used antidiarrheal is loperamide (Imodium).

Loperamide (Imodium, Diamode)

Loperamide is a synthetic piperidine derivative that slows intestinal transit by direct effect on nerve endings and intestinal wall ganglia. It interferes with cholinergic and noncholinergic mechanisms involved in peristalsis, resulting in reduced activity of the intestinal wall muscles. Like diphenoxylate and morphine, it may enhance contractions of intestinal circular muscles, thus increasing segmentation and retarding intestinal forward motion.

Loperamide is more specific, longer-acting, and 3 times more potent than diphenoxylate on a weight basis. Neither tolerance to the antidiarrheal effect of loperamide nor physical dependence on the drug has been reported.

The apparent elimination half-life of loperamide in healthy adults is 9-14 hours. Less than 2% of the drug is excreted in urine; 30% is excreted as an intact molecule in feces. Enterohepatic circulation has been described in animals. Whether loperamide crosses the placenta or is distributed in milk is unknown.

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Histamine H2 Antagonists

Class Summary

H2 blockers are reversible competitive blockers of histamine at H2 receptors, particularly those in the gastric parietal cells (where they inhibit acid secretion). The H2 antagonists are highly selective, they do not affect the H1 receptors, and they are not anticholinergic agents.

Histamine 2 (H2)–receptor antagonists or proton pump inhibitors should be administered postoperatively to prevent hyperacidity, because rebound hyperchlorhydria is common in the postoperative period.

Ranitidine (Zantac)

This agent inhibits histamine stimulation of H2 receptors in gastric parietal cells, which reduces gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at the H2 receptors in gastric parietal cells, reducing gastric acid secretion, gastric volume, and hydrogen concentrations.

Nizatidine (Axid, Axid AR)

This agent competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Cimetidine (Tagamet HB 200)

This agent inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

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Proton Pump Inhibitors

Class Summary

PPIs inhibit gastric acid secretion by inhibition of the H+/K+/ATPase enzyme system in the gastric parietal cells. IV therapy may be a useful adjunct via stabilization of the clot by increasing intragastric pH.

H2-receptor antagonists or proton pump inhibitors should be administered postoperatively to prevent hyperacidity, because rebound hyperchlorhydria is common in the postoperative period.

Lansoprazole (Prevacid)

Lansoprazole is a substituted benzimidazole that covalently and irreversibly binds the hydrogen potassium/ATPase, thereby inhibiting acid secretion. This agent is available as an IV formulation, oral (PO) capsule, or SoluTab. Strawberry-flavored SoluTabs can be dissolved in water for easy administration to children. Dissolve the 15-mg SoluTab in 4 mL of water and the 30-mg SoluTab in 10 mL of water.

Omeprazole (Prilosec)

Omeprazole is a substituted benzimidazole that suppresses acid secretion by specific inhibition of hydrogen potassium/ATPase at the secretory surface of the parietal cell.

Pantoprazole (Protonix)

Pantoprazole is a substituted benzimidazole that suppresses acid secretion by specific inhibition of hydrogen potassium/ATPase at the secretory surface of the parietal cell.

Esomeprazole magnesium (Nexium)

This agent suppresses gastric acid secretion by specifically inhibiting the H+/K+/ATPase enzyme system at the secretory surface of gastric parietal cells.

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