NAUSEA AND VOMITING

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:

 anticholinergic agents
 antidopaminergic agents
 5-HT3 antagonists
 H1 antihistamines
 Cannabinoids (CB)
 corticosteroids
 benzodiazepines
 NK-1 antagonists

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:
  Projectile vomiting: a sudden and particularly forceful vomiting action.
 Retching: a series of weaker and unproductive vomiting movements.
 Nausea: the sensation associated with anticipation of retching or vomiting.

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.

 Man: responds to all known emetics

 Cat: responds to most emetics
 Monkey: responds to selected emetics
 Sheep: vomits rarely
 Horse: vomits very rarely
 Rabbit: does not vomit
 Mouse: does not vomit
 Chicken: develops diarrhea only

(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:

 a. Chemoreceptor trigger zone (CTZ), contained in the area postrema on the floor of the
IV ventricle, is particularly sensitive to chemical stimuli. The blood-brain barrier is
poorly developed in CTZ, hence, it is readily accessible to emetic substances in the
general circulation.
 b. Vomiting center (VC) integrates the emetic response. Located in the dorsolateral
border of the reticular formation of the medulla. Consisting of N. tractus solitarius,
parvicellular reticular formation; and the visceral and somatic motor nuclei coordinating
the act of vomiting.

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.

 apomorphine
 emetine (when given parenterally and only at large doses)
 L-DOPA
 estrogens (morning sickness of pregnancy)
 ergot alkaloids
 cardiac glycosides
 opiates
 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-HT 3 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.

2. Classes of antiemetic drugs

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

sickness.

  scopolamine (Transderm-Scop?)
 There are many others such as several of the antihistamines (see below), and some of the
medications used for IBS (such as hyoscine).

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.

 dimenhydrinate (Dramamine)
 several clizines (e.g., cyclizine -- "Marzine")
 diphenhydramine (Benadryl)
 promethazine
 hydroxyzine (Vistaril)
 meclizine -- typical dose is 25 mg TID

Oddly enough, meclizine sometimes marketed as "non-drowsy dramamine", and ginger is

marketed as "non-drowsy naturals Dramamine" (https://www.dramamine.com/motion-sickness-
medicine);. 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.

 chlorpromazine
 droperidol (Inapsine)
 prochlorperazine, thiethylperazine (Torecan)
 metoclopramide (used as antiemetic) -- typical dose is 10 mg TID.
 fluphenazine
 domperidone (used as antiemetic) typical dose is 10 mg TID.(Barone, 1999)
 haloperidol (Haldol). Typical dose is 5 drops SL.

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.

 diazepam (Valium) -- typical dose is 2 mg to 5 mg, once or twice/day.

 lorazepam (Ativan) -- typical dose is 0.5 mg BID
 klonazepam (Clonapin) -- 0.5 mg prior to nauseating experience.

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)

 dexamethasone (typical dose is 4 mg)

 methylprednisolone (typically given as a "dose pak"

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).

 ondansetron (8 mg QD or BID) -- costs as little as $0.30 per tablet at Costco.

 tropisetron -- these are expensive.
 granisetron (1 mg) -- costs as little as $.50 per tablet.
 dolasetron (Anzemet) -- costs $100/tablet !

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.

 benzquinamide
 diphenidol (Vontrol) -- little used because of side effects (hallucinations)
 trimethobenzamide (Tigan)
 verapamil (Calan) -- useful for migraine associated vertigo and cyclic vomiting.
Typical dose is 120 mg HS (more in persons heavier than 120 lbs)

i. NK1-antagonists.

Aprepitant (Emend) was approved by the FDA in 2003, but it is prohibitively expensive -- in
2016, a single 40 mg capsule of Emend was priced at $97.19. In 2017, it was $121. Online
pharmacies may offer it for as low as $50. Of course, tese nose-bleed prices are tolerated this
drug is used for cancer chemotherapy. Cancer drugs seem to cost quite a bit more than other
drugs.

In animals a similar drug, (Maripitant -- Cerenia) is used routinely for vomiting (priced roughly
$4/capsule). Thus the price differential between animals and people is about 25/1. We can only
hope that a cheaper generic will become available for Emend. We wonder why the drug is so
much cheaper for animals. Maropitant has a half-life of about 4-8 hours in dogs.

NK1 receptor antigonists are also effective in human patients with overactive bladders and in
animal models of cough. Side effects are uncommon. It can be combined with other drugs.
Maropitant can be used in very high doses (i.e. 8 mg/kg PO) to prevent motion sickness in dogs.
We hope that these drugs will become available at more reasonable prices. As it was aprepitant
was FDA approved in 2003, and now it is 2017, it has been "out there" for 14 years. In the US,
drugs are protected by patent for 20 years after the drug was invented. The fosaprepitant patent is
to expire on march 4, 2019.

3. Potency of antiemetic drugs.

a. Active against highly emetogenic chemotherapy.    

o 5-HT3 receptor antagonists (e.g. ondasetron)

o substituted benzamides (high dose -- e.g. metoclopramide).

b. Active against mildly or moderately emetogenic chemotherapy.

 phenothiazines (e.g. thorazine)

 corticosteroids (e.g. decadron)
 butyrophenones (e.g. haloperidol)
 cannabinoids (e.g. marinol)

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

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vomiting.British Journal of Anaesthesia 69 (Supplement 1):60S-62S.
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 Marty, M  (1993) Future trends in cancer treatment and emesis control. Oncology
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 Wattwil M, Thorn SE, Lovqvist A, Wattwil L, Gupta A and Liljegren G (2003).
"Dexamethasone is as effective as ondansetron for the prevention of postoperative nausea
and vomiting following breast surgery." Acta Anaesthesiol Scand 47(7): 823-7.
 Rajoo Sangeetha. Anti-Emetics: Metoclopramide, Domperidone, Ondansetron.
https://www.drugs.smd.qmul.ac.uk/drugs/html5/Anti-emetics/AN-FEF54A37-6289-
402B-E208-9284E183608A.html Accessed 3/21/2016