Gi - Drugs Used In Gi Disease

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Pharmacological target

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The metabolic or biochemical point at which an agent exerts an effect.

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Histamine

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Released from enterochromaffin-like cells (ECL) in the stomach and stimulates parietal cell acid secretion.

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Acetylcholine

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Secreted from the autonomic enteric nervous system (ENS) and stimulates parietal cell acid secretion; hence the value of vagotomy in ulcer surgery.

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Gastrin

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Secreted from antral G cells and stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility; hence the value of antrectomy in ulcer surgery.

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H2 receptor blockers

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Cimetidine, ranitidine, famotidine, nizatidine

Inhibit acid production by reversibly competing with histamine for binding at H2 receptors on the basolateral parietal cell membrane.

Combining H2 receptor blockers with PPIs reduces efficacy of the later.

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Proton pump inhibitors

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Omeprazole, iansoprazole, rabeprazole, pantoprazole, esomeprazole

Irreversibly inhibits gastric-parietal cell proton pump. They are prodrugs that require activation in an acid environment of the secretory canaliculus of the parietal cell; best administered with or before a meal since food will stimulate acid production by parietal cells.

Given for short term treatment of gastric and duodenal ulcers. Used to treat GERD. Superior to H2s and misoprostol in healing of NSAID induced ulcers. Part of H. pylori treatment. Medical treatment of choice for Zollinger-Ellison syndrome, MEN, and systemic mastocytosis.

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Somatostatin

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The main inhibitor of gastric acid secretion, mediated via somatostatin subtype 2 receptor.

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GERD

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Gastroesophageal reflux disease

PPIs are more effective than H2s. Healing rates after 4 and 8 weeks of therapy with PPIs are 80% and 90% respectively, compared with 50% and 75% with H2s. An empirical trial of PPIs is appropriate (for up to 12 weeks) for patients with non-cardiac chest pain and no "alarm symptoms" including weight loss, dysphagia, advanced age, i nwhich case a direct esophageal inspection with endoscopy is warranted prior to a trial.

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Octreotide

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Targets somatostatin receptors; inhibits secretion of several peptides as well as gastric and pancreatic secretion. Parenteral long acting synthetic somatostatin analog.

This agent is most often used with patients with Zollinger-Ellison syndrome; also used in portal hypertensive bleeding although it may not improve survival.

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NERD

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Subcategory of GERD; defined as reflux related symptoms in the absence of mucosal injury at the time of endoscopy, without recent use of acid suppresive drugs. The cause of discomfort (heartburn) in NERD is unclear. Symptom response to treatment is about 50%.

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Peptic ulcer disease treatment

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Treatment of uncomplicated ulcers is with PPIs. For bleeding peptic ulcers, IV PPIs are importnat adjuncts to endoscopy for the earlier cessation of bleeding and prevention of rebleeding. For NSAID related ulcers, NSAIDs should be discontinued or substituted with a selective COX-2 inhibitor and the patient should be treated with PPIs.

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Dopamine receptor agonists

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Metaclopromide (US), Domperidone (not US)

Dopamine inhibits intestinal motility; results from suppression of ACh release from ENS.

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Serotonin receptor modulators

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Targets 5-HT3 and 5-HT4 receptors in the gut present in ECL cells and ENS.

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5HT3 and 5HT4

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5HT3 - receptor located on post-synaptic enteric neurons and afferent sensory fibers; mediates inhibitory responses when angonized.

5HT4 - receptor mediates excitatory responses when agonized.

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Metaclopromide

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Metaclopromide is widely used in the US as a promotility agent for its antidopaminergic and serotonin receptor modulating effects.

Provides symptomatic relief to patients with gastric motor failure (i.e. diabetic gastroparesis). Decreases heartburn in GERD. Anti-emetic effect in cancer chemotherapy.

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Cisapride

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A parasympathomimetic and gastroprokinetic agent that acts as a serotonin 5-HT4 receptor agonist.

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Motilin agonists

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Erythromycin (macrolide antibiotic)

When motilin receptors found on smooth muscle cells are stimulated, they induce and amplify MMC. Potent contractile agents primarily of the upper GI tract. Useful in diabetic gastroparesis and intestinal pseudo-obstruction.

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Botulinum toxin

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Inhibits ACh release from cholinergic nerves, inhibiting GI motility. Given as a intrapyloric injection.

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Pancreatin

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Pancreatic enzyme replacement product; Alcoholic extract of hog pancreas.

Should be given with cimetidine to enhance effectiveness by increasing gastric pH.

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Pancrelipase

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Pancreatic enzyme replacement product; enriched hog pancreas preparation.

Should be given with cimetidine to enhance effectiveness by increasing gastric pH.

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5-aminosalicylates

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IBD treatment

Targets multiple sites in the arachadonic acid pathway critical in the pathogenesis of inflammation; inhibition of leukotrienes, interleukins most important. Cannot be taken orally in sufficient dosage to produce a useful effect in the colon without excessive toxicity. 5-ASA compounds are first line therapy for mild and moderate IBD.

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Sulfasalazine

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Combines sulfapyridine with 5-ASA linked by an azo bond. Proven value in mild or moderately active UC; that is, in patients who do not need to be hospitalized, without high fever, leukocytes, profuse rectal bleeding, or severe abdominal pain and weight loss.

More effective in maintaining remission in UC that in achieving it.

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Sulfapyridine

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Sulfapyridine is not prescribed for treatment in humans any more. However, it may be used to treat Linear IgA Disease. It is a good antibacterial drug, but its water solubility is very pH dependent. Thus there is a risk of crystallization within the bladder or urethra, which could lead to pain or blockage.

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Mesalamine

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Coated 5-ASA; lacks the sulfa moiety. Oral preparations allow the drug to be released more slowly as it transits down the bowel. Also available topically.

Asacol is a coated form that releases mostly in the terminal ileum and colon. Pentasa has a semipremeable membrane, allowing the drug to be released from the jejunum through the colon.

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Olsalazine

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Not used very much; 2 5-ASA molecules linked by a diazo bond. Bond is broken by bacteria in colon.