Timothy C. Hain, MD,
Last updated: 10/21/2001. Please read our disclaimer.
Nausea and vomiting are not diseases, but are only indications of altered physiological functions. Rational therapy depends on diagnosis of the underlying disorder and may or may not include drugs. The drugs that are currently used to prevent and treat vomiting belong to the following classes:
The act of vomiting is produced by a series of coordinated changes in G-I activity and in respiratory movements: salivation; sharp and deep inspiration; increase in intra-abdominal pressure; contraction of abdominal muscles; closure of the epiglottis and raising of the soft palate; forceful contractions of the stomach pylorus; and relaxation of the fundus, cardiac sphincter and esophagus.
Gastric contents are propelled into the mouth and are expelled, usually accompanied by pallor and cold sweat. If retroperistalsis of the small intestine occurs, a greenish vomitus is produced. Other types of emesis or variations of the theme:
Vomiting can be triggered by a variety of stimuli: stimulation of the sensory nerve endings in the G-I tract and pharynx; drugs; endogenous emetic substances produced as a result of radiation damage or disease; disturbance of vestibular apparatus; stimuli to the sensory nerves of the heart and viscera; endocrine factors; a rise in intracranial pressure; nauseating smells; repulsive sights; disgusting experience.
Nausea and vomiting may occur in: cancer; cancer chemotherapy; radiation therapy; gastroenteritis; consequence of surgery and general anesthesia (PONV = post-operative nausea and vomiting); alcohol binge; drug side effects; cerebral edema; severe pain; flu; vertigo; pregnancy; emotional stress ("sick to the stomach"); poisoning (e.g., anticholinesterases), etc.
1. The central neural regulation of vomiting is vested in two separate units in the medulla:
VC receives many excitatory inputs from: nerve endings of vagal sensory fibers in the G-I tract; the labyrinths via the vestibular nuclei; higher centers in the cortex (when vomiting is produced by disgusting experience or in anticipation of such occurrence); CTZ; and intracranial pressure receptors.
The schematic diagram below summarizes the reflex mechanism of emesis (H1 = histaminic H1; M = muscarinic; D2 = dopaminergic D2 receptors).
|Receptors and neurotransmitters involved in mediating vomiting:|
N. tractus solitarius
|Vagal sensory nerve
a. Drugs acting on CTZ.
- emetine (when given parenterally and only at large doses)
- estrogens (morning sickness of pregnancy)
- ergot alkaloids
- cardiac glycosides
- cancer chemotherapeutic agents
- cardiac glycosides
NOTE: Morphine can either induce or block emesis; both actions can be blocked by naloxone. Emetic effect is mediated by delta or kappa receptors, whereas antiemetic effect by mu receptors.
b. Drugs acting locally on the G-I tract. They activate enterochromaffin cells in the mucosa of the G-I tract, causing the cells to secrete serotonin which acts on the 5-HT3 receptors at the nerve endings of the vagal sensory fibers. The afferent fibers transmit excitation to the N. tractus solitarius, which in turn activates the VC. These drugs are traditionally called "local irritants".
- ipecac (the most useful household emetic is syrup of ipecac; emetine is one of its active ingredients)
- zinc salts
- copper sulfate
- antimony salts ("tartar emetic" is antimony potassium tartrate)
c. Cancer chemotherapeutic agents and radiation therapy produce free radicals which act on the enterochromaffin cells to release serotonin. The chemotherapeutic agents or their metabolites may also stimulate CTZ receptors. Anticancer drugs that cause vomiting are listed below. Note that antineoplastic agents are often given in combination (e.g., MOPP). Dose, route and schedule of administration also affect the incidence and intensity of nausea and vomiting. Cisplatin is the most highly emetogenic agent.
a. Muscarinic receptor antagonists. Good for prevention of motion sickness.
- scopolamine (Transderm-Scop®), presently not available (11/97)
b. H1 antihistamines. For motion sickness. Most antihistamines have additional anticholinergic action. Typical side effects of H1 antihistamines include drowsiness and loss of coordination. The newer antihistamines (e.g., Hismanal, Claratin, Allegra) which do not cross the blood-brain barrier would not be useful.
- dimenhydrinate (Dramamine)
- several clizines (e.g., cyclizine)
- diphenhydramine (Benadryl)
c. Antidopaminergic drugs. Most of these drugs are also used as antipsychotic agents. They have antimuscaranic action.
- droperidol (Inapsine)
- metoclopramide (used as antiemetic)
- domperidone (used as antiemetic)
d. Benzodiazepines. Good for anticipatory nausea and vomiting before cancer therapy. Also useful for vestibular disorders.
- diazepam (Valium)
- lorazepam (Ativan)
e. Corticosteroids. Mechanism of action not clear. May be related to the inhibition of arachidonic acid release.
f. Cannabinoids. Acts on higher centers in the cortex. -- dronabinol
g. 5-HT3 receptor antagonists. This class of drugs are the most effective treatment available for prevention of severe vomiting due to cancer chemotherapy and causes little toxicity; about 85% of patients attain complete control of emesis and nausea. Usually given in combination with dexamethasone. Also widely used for PONV, but less effective (20% reduction, Tramer et al, Anesthesiology 87:1277-89, 1997). Expensive. Probably not useful for vestibular disorders.
- granisetron (approved for IV injection only)
- dolasetron (investigational)
- trimethobenzamide (Tigan)
a. Active against highly emetogenic chemotherapy.
- 5-HT3 receptor antagonists, substituted benzamide (high dose).
b. Active against mildly or moderately emetogenic chemotherapy.
c. Minimally active.
- muscarinic receptor antagonists
Case study. A 63-year old man with bone metastases from lung cancer experienced nausea before treatment, despite regular use of prochlorperazine. He received radiotherapy to the lumbar spine which produced emesis almost immediately, with 4 episodes of emesis in the first 2 hrs. following radiotherapy. A domperidone (30 mg) suppository failed to stop the emesis. However, a single IV dose of ondansetron (8 mg) abolished emesis immediately. The patient therefore received regular oral doses of ondansetron and was able to continue his palliative course of radiotherapy with no further ill effects. (From Roberts/Priestman, 1993: Ondansetron in radiation-induced emesis. Oncology 50:178).
Combinations of antiemetic drugs. Various types of antiemetic drugs can be combined, with the goal of increasing antiemetic efficacy or decreasing associated drug toxicity (by reducing dosage). Corticosteroids are the agents most commonly used in combination therapy. Antihistamines, anticholinergic drugs, benzodiazepines, cannabinoid, and antidopaminergic agents are also used as secondary antiemetic agents.
Delayed vomiting. Occurs 2-5 days after the administration of cisplatin in about 60% of patients. Mechanisms of emesis are probably different from those that cause acute vomiting. Particularly difficult to control with standard antiemetic drugs. Combination therapy using oral dexamethasone and oral metoclopramide has been reported to decrease the frequency of delayed vomiting.
Anticipatory vomiting. This is a learned response conditioned by the severity and duration of previous reactions to chemotherapy. Aggressive antiemetic therapy during early courses of cancer chemotherapy is the key to prevent this condition. Antiemetic therapy may also include hypnosis, behavioral modification, anxiolytic agents (benzodiazepine).