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 (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 (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 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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