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