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

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Pharmacological Modulation of Vomiting

Vomiting is a complex series of integrated events culmi-nating in the forceful expulsion of gastric contents through the mouth.

PHARMACOLOGICAL MODULATION OF VOMITING

Vomiting is a complex series of integrated events culmi-nating in the forceful expulsion of gastric contents through the mouth. The sequence of events frequently begins with nausea, which may be accompanied by in-creased salivation, pupillary dilation, sweating, and pal-lor. Duodenal and jejunal tone is increased, while gastric tone and peristalsis are diminished, tending to cause a re-flux of duodenal contents into the stomach. Retching fol-lows nausea, during which the abdominal muscles con-tract with simultaneous attempts at inspiration against a closed glottis. The gastric antrum contents and gastric contents begin to move into the esophagus. During vom-iting, which is the third and final stage, there is sustained contraction of the diaphragm and abdominal muscula-ture. The resultant high intragastric pressure moves more gastric contents into the esophagus, and with continued force, contents are expelled through the mouth.

 

These events are coordinated by the emetic center, which lies within the lateral reticular formation of the medulla oblongata close to the respiratory and salivary centers. Stimulation of the emetic center may occur from peripheral sites, the cortex, or the chemoreceptor trigger zone (CTZ). Peripheral stimulation, which is me-diated by vagal and sympathetic nerves, may originate from the vestibular system (motion sickness), from the coronary arteries (cardiac ischemia), or from distention and inflammation of sites in the GI tract.

 

The CTZ, which is responsive to chemical (particu-larly dopamine) stimulation, is connected to the emetic center through the fasciculus solitarius. Most drug-in-duced emesis, including emesis induced by apomor-phine, levodopa, cardiac glycosides, most cancer chemotherapeutic agents, and nicotine, appears to be mediated by this route. Cytotoxic chemotherapy also stimulates the release of serotonin from enterochro-maffin cells of the upper GI tract. Vomiting may then be induced through serotonergic stimulation of enteric va-gal afferents or possibly through direct central nervous system stimulation.

 

Emetics

 

The most commonly used emetics are ipecac and apo-morphine. Induced emesis is the preferred means of emptying the stomach in awake patients who have in-gested a toxic substance or have recently taken a drug overdose. Emesis should not be induced if the patient has central nervous system depression or has ingested certain volatile hydrocarbons and caustic substances.

 

Ipecac syrup is prepared from the dried rhizome and roots of Cephaelis ipecacuanha or Cephaelis acuminata, plants from Brazil and Central America that have the alkaloid emetine as their active principal ingredient. It acts directly on the CTZ and also indirectly by irritating the gastric mucosa. Ipecac is cardiotoxic if absorbed and can cause cardiac conduction disturbances, atrial fibril-lation, or fatal myocarditis. If emesis does not occur, gastric lavage using a nasogastric tube must be per-formed.

 

Apomorphine, a derivative of morphine, acts di-rectly on the CTZ. It also is more effective if water is first administered before oral or subcutaneous dosing. Excessive dosage may cause respiratory depression and circulatory collapse. Opioid antagonists such as nalox-one usually reverse the depressant actions of apomor-phine. Because of the possibility of respiratory depres-sion, apomorphine is infrequently used as an emetic.

 

Antiemetics

 

Antiemetics may prevent emesis by blocking the CTZ or by preventing peripheral or cortical stimulation of the emetic center.

 

Antihistamines

 

The antihistamines appear to block peripheral stimula-tion of the emetic center. They are therefore most ef- fective in motion sickness and inner ear dysfunction, as is seen in Ménière’s syndrome, labyrinthitis, and streptomycin ototoxicity. Dimenhydrinate, diphenhy-dramine, and meclizine hydrochloride are the three an-tihistamines primarily used in the prevention of nausea from inner ear stimulation.

 

Anticholinergics

 

The transdermal adhesive form of scopolamine (Trans-derm Scop) provides up to 72 hours of antiemetic pro-tection when applied to the postauricular area. Side ef-fects are similar to those of oral scopolamine  but milder.

 

Benzodiazepines

 

Benzodiazepines and their congeners may help prevent central cortical-induced vomiting. A prominent side ef-fect is drowsiness. They are frequently used in combina-tion with other antiemetics for treating chemotherapy-related nausea and vomiting.

 

Cannabinoids

 

The antiemetic site of action of tetrahydrocannabinol (THC) (Marinol) is unknown, although it appears to af-fect the central cerebral cortex axis. Relief may occur in individuals refractory to other antiemetics. It is less ef-fective in the elderly, primarily because of its side ef-fects. The antiemetic effect is associated with a high, and this appears to be better tolerated in the young. Sedation is seen in approximately 30% of patients. Ataxia, drowsiness, dry mouth, or orthostatic hypoten-sion may be seen in up to 35% of the older patient pop-ulation. GI absorption is variable, though blood levels correlate with efficacy. The bioavailability is not as vari-able if the agent is smoked. The coadministration of prochlorperazine may prevent some of the central nerv-ous system side effects seen with the use of tetrahydro-cannabinol.

 

 

Dopamine Antagonists

 

Metoclopramide is a dopamine antagonist that centrally inhibits stimulation of the CTZ. By improving gastric emptying, it can decompress the stomach, thereby de-creasing a peripherally associated stimulation of the emetic center. Metoclopramide may precipitate ex-trapyramidal reactions and sedation. For further details, see earlier section, Drugs that Increase GI Motility.

 

Phenothiazine Derivatives

 

Phenothiazine derivatives, which include prochlorper-azine (Compazine) and promethazine (Phenergan), act at the CTZ by inhibiting dopaminergic transmission. They also decrease vomiting caused by gastric irritants, suggesting that they inhibit stimulation of peripheral vagal and sympathetic afferents. Sedation will fre-quently occur following their administration. Patients also may have problems with acute dystonic reactions, orthostatic hypotension, cholestatic hepatitis, and blood dyscrasias.

 

5-HT3 Receptor Antagonists

 

Ondansetron (Zofran) and granisetron (Kytril) are po-tent antagonists of 5-HT3 receptors, which are found pe-ripherally on vagal nerve terminals and centrally in the CTZ. During chemotherapy that induces vomiting, mu-cosal enterochromaffin cells in the GI tract release sero-tonin, which stimulates 5-HT3 receptors. This causes va-gal afferent discharge, inducing vomiting. In binding to 5-HT3 receptors, ondansetron and granisetron block serotonin stimulation, hence vomiting, after emetogenic stimuli such as cisplatin. Headache is the most fre-quently reported adverse effect of these medications.

 

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