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Treatment of Emesis (Vomiting)

Timothy C. Hain, MD of Chicago Dizziness and Hearing Page last modified: September 23, 2017

Emesis English Vomiting Taxi
(From Nasa Symposium) The English are familiar with vomiting (source: http://www.drugs.smd.qmul.ac.uk/drugs/html5/Anti-emetics/AN-FEF54A37-6289-402B-E208-9284E183608A.html) In Chicago, we are so familiar with vomiting that our taxi fares include a clean up fee.

Overview:

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:

Events involved in vomiting (emesis)

A. Vomiting (Emesis)

The act of vomiting is produced by a series of coordinated changes in GI 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.

 

Vomiting is not universal in the animal kingdom.

(Borison et al, 1981)

Interestingly, there are some antiemetics used in animals that are not widely available in human medicine. For example, Maropitant (an NK1 receptor antagonist) is used routinely for cats, but the human approved drug (Aprepitant, Emend), approved in 2003, is prohibitively expensive. Maropitant is highly effective in cats, without any substantial side effects. We are not sure why Maropitant is not used in humans, but there are no published studies in humans.

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).

Cyclic vomiting. Spells of uncontrollable vomiting, typically every two or three months. The cause of this syndrome may be migraine. Treatment with migraine prevention medications is sometimes useful.

B. The reflex mechanism.

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.

C. Pharmacology of emetic and antiemetic drugs.

1. Drugs causing emesis.

a. Drugs acting on CTZ.

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".

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.

2. Classes of antiemetic drugs

a. Muscarinic receptor antagonists (i.e. anticholinergics). Good for prevention of motion sickness.

Many of the anticholinergics can cause hallucinations in large doses. In too large doses they also can cause dry mouth, blurry vision, can affect the pulse and cause urinary retention among other serious side effects.

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. Marzine

Oddly enough, meclizine sometimes marketed as "non-drowsy dramamine", and ginger is marketed as "non-drowsy naturals Dramamine". This is confusing to say the least. One cannot count on a rational match between the name of a drug and the contents of the package.

c. Antidopaminergic drugs. Most of these drugs are also used as antipsychotic agents. They have antimuscarinic action.

Droperidol has a "black box" warning and for this reason should not be used lightly for control of emesis. We think there are many safer drugs. It is peculiar that droperidol has a black box warning and haloperidol does not, as they are close relatives.

Domperidone (not "dom perignon"), is a largely peripheral acting dopamine blocker. As its effect is largely confined to the periphery, it may be safer than the above (Robbins et al, 2016)

d. Benzodiazepines. Good for anticipatory nausea and vomiting before cancer therapy. Also useful for vestibular disorders.

e. Corticosteroids. Mechanism of action not clear. May be related to the inhibition of arachidonic acid release. Dexamethasone is reportedly as effective as ondansetron for prevention of PONV (Wattwil et al. 2003)

f. Cannabinoids. Acts on higher centers in the cortex. -- dronabinol and relatives. These are rarely used until all else has failed.

g. 5-HT3 receptor antagonists. This class of drugs is probably the most effective treatment available for prevention of severe vomiting due to cancer chemotherapy and cause little toxicity; about 85% of patients attain complete control of emesis and nausea. The main competitor to the 5-HT3 drugs are the NK-1 antagonists (see below), but these drugs are prohibitively expensive.

For chemotherapy, the 5-HT3 drugs are usually given in combination with dexamethasone. Also widely used for PONV, but less effective (20% reduction, Tramer et al, Anesthesiology 87:1277-89, 1997). Although animal studies suggest it should not work for vestibular problems, empirically it is also often effective in this context. Constipation is the main side effect (not regular, but possible).

Pricing comment: Antiemetics used for cancer chemotherapy are often priced in the "nose bleed" realm; evidently drug companies have discovered that when one has cancer, no drug is considered too expensive. This makes it difficult for the rest of the population who do not have cancer to use these drugs. Price comparisons are very logical here - -these drugs all do the same thing.

In recent years (e.g. 2010) ondansetron has become generic and can be obtained at a reasonable price. Ondansetron can be taken as a branded sublingual preparation (either the "ODT" form) for a markup of about 10 fold over the non-sublingual preparation. You pay a lot for some artificial flavoring.   According to our patients and web surveys, Costco pharmacy is by far the most reasonable place to find generic Ondansetron. RiteAid is the worst by a gigantic margin. Unless your health insurance is very good, the brand name versions of ondansetron will likely be prohibitively priced.

h. Miscellaneous.

3. Potency of antiemetic drugs.

c. Minimally active.

  • antihistamines (e.g. meclizine)
  • muscarinic receptor antagonists (e.g. meclizine)
  • benzodiazepines (e.g. lorazepam)

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.

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).

Case 2. A 30 year old man who was otherwise normal complained of spells of vomiting for several weeks following airplane travel. Generally a trip was followed several days later by hospital admission for rehydration and antiemetic therapy. Uses of any particular antiemetic by itself were ineffective. Eventually fair control was obtained using a combination of daily verapamil, phenergan, domperidone, and as needed diazepam. For flare-ups, ondansetron and steroids are added.


References

Treatment of Vomiting
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