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Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Gastrointestinal Disorders

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Drugs That Increase GI Motility

Decreased GI motility can affect one or more parts of the GI tract and can be the result of a systemic disease, intrinsic GI disorder, or medication. Gastroparesis is the term for delayed gastric emptying.

DRUGS THAT INCREASE GI MOTILITY

 

Decreased GI motility can affect one or more parts of the GI tract and can be the result of a systemic disease, intrinsic GI disorder, or medication. Gastroparesis is the term for delayed gastric emptying. Symptoms may range from postprandial bloating and fullness to nausea and vomiting. Half of ingested liquid should be emptied within 30 minutes, and half of a digestible solid should be emptied within 2 hours. Emptying time can be pro-longed as a result of autonomic neuropathy seen with long-standing diabetes mellitus. Pseudoobstruction due to an idiopathic intestinal muscle disease or intestinal neuropathy may also cause delays in gastric emptying and intestinal transit. Rarer causes of delayed GI motil-ity include Chagas’ disease, muscular dystrophy, sclero-derma, and infiltrative diseases, such as amyloidosis. Decreased GI transit can occur acutely following elec-trolyte disorders and gastroenteritis. In addition, many medications, including anticholinergic medications, tri-cyclic antidepressants, levodopa, and β-adrenergic ago-nists, inhibit GI motility.

Drugs that enhance GI motility are often called pro-kinetics. Their goal is to increase contractile force and accelerate intraluminal transit. Most of these drugs act either by enhancing the effect of acetylcholine or by blocking the effect of an inhibitory neurotransmitter such as dopamine.

Metoclopramide Hydrochloride

Metoclopramide (Reglan) stimulates upper GI tract motility and has both central and peripheral actions. Centrally, it is a dopamine antagonist, an action that is important both for its often desirable antiemetic effect and other less desirable effects. Peripherally, it stimu-lates the release of intrinsic postganglionic stores of acetylcholine and sensitizes the gastric smooth muscle to muscarinic stimulation. The ability of metoclo-pramide to antagonize the inhibitory neurotransmitter effect of dopamine on the GI tract results in increased gastric contraction and enhanced gastric emptying and small bowel transit.

Metoclopramide is rapidly absorbed following an oral dose in a patient with intact gastric emptying. Peak plasma concentration is achieved within 40 to 120 min-utes. With normal renal function, plasma half-life is about 4 hours. About 20% of an oral dose is eliminated unchanged in the urine, while 60% is eliminated as sul-fate or glucuronide conjugates.

Improved gastric emptying will frequently alleviate symptoms in patients with diabetic, postoperative, or id-iopathic gastroparesis. Since metoclopramide also can decrease the acid reflux into the esophagus that results from slowed gastric emptying or lower esophageal sphincter pressure, the drug can be used as an adjunct in the treatment of reflux esophagitis.

Side effects include fatigue, insomnia, and altered mo-tor coordination. Parkinsonian side effects and acute dys-tonic reactions also have been reported. Metoclopramide stimulates prolactin secretion, which can cause galactor-rhea and menstrual disorders. Extrapyramidal side effects seen following administration of the phenothiazines, thioxanthenes, and butyrophenones may be accentuated by metoclopramide.

Cisapride and Tegaserod

Cisapride (Propulsid) and tegaserod (Zelnorm) are both serotonin-4 (5-HT4) receptor agonists that stimu-late GI motility. Cisapride appears to act by facilitating the release of acetylcholine from the myenteric plexus. It has no antiadrenergic, antidopaminergic, or choliner-gic side effects. Following oral administration, peak plasma levels occur in 1.5 to 2 hours; the drug’s half-life is 10 hours. Cisapride has been successfully used to treat gastroparesis and mild gastroesophageal reflux disease. The most frequent side effect has been diarrhea. A few patients had seizure activity that was reversible after medication was discontinued. Cisapride was pulled from the U. S. market after deaths from drug-associated cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT pro-longation.

Tegaserod is being developed as a treatment for con-stipation-predominant irritable bowel syndrome (IBS). Within the first week, patients treated with tegaserod had significant improvements in abdominal pain and dis-comfort, constipation, and overall well-being. Efficacy was maintained throughout the treatment period. Tegaserod also demonstrated significant improvements in the three bowel-related assessments (stool frequency, stool consistency, and straining) within the first week, and these improvements were sustained throughout the treatment period. The most common adverse events re-ported thus far are headache and diarrhea.

Erythromycin

Erythromycin is an antibiotic in the macrolide family  that also has promotility effects be-cause it is a motilin agonist. Erythromycin is used (off-label indication) to accelerate gastric emptying in dia-betic gastroparesis and postoperative gastroparesis. Tachyphylaxis will occur, so it cannot be used uninter-ruptedly for long periods.

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