Introduction
Nausea and vomiting are protective mechanisms designed
to :
Rid the body
of toxic substances
Prevent their
further ingestion.
Phases of vomiting
Vomiting may be divided into three phases:
It is accompanied by
loss of gastric tone and peristalsis
with contraction of the duodenum and reflux of intestinal contents into
the stomach.
Additional symptoms
such as increased perspiration, salivation, tachycardia, anorexia and headache
occur simultaneously.
Phases of vomiting
Retching which is characterized by contraction of
abdominal and intercostal muscles and diaphragm against a closed glottis.
Vomiting (emesis, ejection phase) which is the forceful expulsion of GI contents
through the mouth.
It is associated with
descent of the diaphragm, powerful sustained contractions of the abdominal muscles
and relaxation of the upper esophageal sphincter.
Mechanisms that trigger nausea and vomiting
Two brainstem sites have key roles in the vomiting
reflex pathway.
The chemoreceptor trigger zone, which is located in
the area postrema (a circumventricular structure at the caudal end of the
fourth ventricle).
It is located outside the blood-brain barrier.
Thus, it can respond directly to chemical
stimuli in the blood or cerebrospinal fluid.
Mechanisms that trigger nausea
and vomiting
The second important site is the vomiting center,
It is located in the lateral reticular formation
of the medulla,
Coordinates
the motor mechanisms of vomiting.
The vomiting center
also responds to afferent input from the vestibular system, the periphery
(pharynx and gastrointestinal tract), and higher brainstem and cortical
structures.
The vestibular system
functions mainly in motion sickness.
Area postrema and CTZ
This is located
on the floor of the fourth ventricle and contains the chemoreceptor trigger
zone(CTZ).
The CTZ is a
special sensory organ rich in dopaminergic, serotonergic, histaminergic and
muscarinic receptors.
It is located outside the blood brain barrier
Therefore
chemicals, toxins, drugs and neurotransmitters in the CSF and bloodstream interact directly with this
area to cause nausea and vomiting.
Central pathways:The vomiting centre and NTS .
This is located in the dorsolateral reticular
formation close to the respiratory centre and receives impulses from higher
brain centres, visceral efferents, the eighth cranial nerve and from the CTZ.
The visceral efferents
and the eighth cranial nerve transmit their impulses through the nucleus
tractus solitarius (NTS).
The vomiting centre and NTS .
The vomiting centre coordinates the motor mechanisms
of vomiting
It includes a
number of brainstem nuclei required to
integrate the responses of the GIT,
pharyngeal muscles, respiratory muscles and somatic muscles to result in a
vomiting episode.
The vomiting centre and NTS
The vomiting reflex can be elicited either directly
via afferent neuronal connections
especially from the GIT which is dependent on the integrity of the NTS.
Vomiting can
also occur as a result of humoral factors which is dependent on the integrity
of the area postrema.
The sequence of muscle excitation and inhibition
necessary for the act of vomiting is
controlled by a central pattern generator located in the NTS and
information from the CTZ and vagus nerve converges at this point.
Causes of vomiting
Central causes of nausea and vomiting include:
Increased intracranial pressure,
Dilation of cerebral arteries during migraine
Stimulation of labyrinthine mechanism or of the senses of
sight, smell and taste.
Causes of vomiting
Peripheral causes of nausea and vomiting include:
Motion sickness,
Delayed gastric emptying and gastric mucosal
irritation e.g. due to NSAIDs.
All these mechanisms are mediated through the vagal
afferent neurones.
Vomiting associated
with distension or obstruction of the GIT is mediated through both the
sympathetic and vagal afferent neurones.
The vestibular system
functions mainly in motion sickness.
Chemotherapy induced nausea
and vomiting
Nausea and vomiting
may also be produced by many
chemotherapeutic agents.
Nearly 70 -80% of all
patients who undergo chemotherapy experience nausea or vomiting.
Chemotherapy induced nausea and vomiting (CINV)
requires effective management
Chemotherapy induced nausea and vomiting
Several factors influence the incidence and severity
of chemotherapy-induced emesis.
These include the specific chemotherapeutic drug,
dose, route, schedule of administration, and patient variables.
For example, the young
and women are more susceptible than older patients and men,
10 to 40% of patients
experience nausea or vomiting in anticipation of their chemotherapy
(anticipatory vomiting).
Chemotherapy induced nausea and vomiting
Emesis not only affects the quality of life but can
lead to rejection of potentially curative antineoplastic treatment.
In addition,
uncontrolled vomiting can produce dehydration, profound metabolic imbalances,
and nutrient depletion.
Emetic potential of anticancer drugs
Emetic actions of chemotherapeutic agents
Chemotherapeutic agents (or their metabolites) can
directly activate the medullary CTZ or
vomiting center;
Several
neuroreceptors, including dopamine receptor Type 2 and serotonin Type 3
(5-HT3), play critical roles.
Emetic actions of chemotherapeutic agents
Often, the color or smell of chemotherapeutic drugs
(and even stimuli associated with chemotherapy, e.g. cues in the treatment room
or the physician or nurse who
administers the therapy) can activate higher brain centers and trigger
emesis.
This is referred to as anticipatory nausea and vomiting
Emetic actions of chemotherapeutic agents
Chemotherapeutic drugs can also act peripherally by
causing cell damage in the GI tract and releasing serotonin from the
enterochromaffin cells of the small intestinal mucosa.
The released serotonin activates 5-HT3 receptors on
vagal and splanchnic afferent fibers, which then carry sensory signals to the
medulla, leading to the emetic response.
Pharmacological targets in
emesis
The CTZ and NTS contain several types of receptors for
various neurotransmitters and neuromodulators.
These include:
Dopamine (D2), histamine (H1), cholinergic
(muscarinic M1), serotonergic (5HT3) and neurokinin -1 (NK1) receptors.
These are the targets for drugs used in treatment of
nausea and vomiting.
Drugs used in nausea and vomiting
Antiemetics generally are classified according to the
predominant receptor on which they act.
However, these mechanisms overlap considerably,
particularly for the older agents .
For treatment and prevention of CINV, several antiemetic agents from
different pharmacological classes may be combined.
5-HT3-Receptor Antagonists
Serotonin plays an important role in nausea and
vomiting.
5-HT3 receptors which mediate the vomiting pathway are
located peripherally on vagal nerve endings in the GIT and centrally in the
brain, with high concentrations in the area postrema and NTS.
The specific antagonists of 5-HT3-receptor antagonists are the most
widely used drugs for CINV.
5-HT3-Receptor Antagonists
Ondansetron is
the prototypical drug in this class.
Other
agents include granisetron ,
dolasetron , palonosetron ( IV use only) and tropisetron.
Differences among these agents relate mainly to their
chemical structures, 5-HT3 receptor affinities, and pharmacokinetic profiles .
5-HT3-Receptor Antagonists: Therapeutic uses
All the agents
are equally efficacious in CINV and in treating nausea secondary to upper
abdominal irradiation
They also are
effective against hyperemesis of pregnancy, and to a lesser degree,
postoperative nausea, but not against motion sickness.
Unlike other agents in this class, palonosetron also
may be helpful in delayed emesis .
5-HT3-Receptor Antagonists:
Therapeutic uses
These agents are available as tablets, oral solution,
and intravenous preparations for injection.
For patients on cancer chemotherapy, these drugs can
be given in a single IV dose infused over 15 minutes, beginning 30 minutes
before chemotherapy, or in 2-3 divided doses, with the first usually given 30
minutes before and subsequent doses at various intervals after chemotherapy.
The drugs also
can be used intramuscularly or orally.
These drugs generally are very well tolerated, with
the most common adverse effects being constipation or diarrhea, headache, and
light-headedness.
Dopamine Receptor Antagonists:
Phenothiazines and butyrophenones
Drugs such as haloperidol, block dopamine (D2)
receptors in the CTZ
They also have cholinergic (M1) and histaminergic (H1)
receptor antagonist activity.
Consequently, they share adverse effects with antihistamines and anticholinergics e.g. drowsiness.
In addition,
dopamine blocking effects may be associated with acute dystonia, tardive
dyskinesia and parkinsonism when used for prolonged periods.
Therapeutic uses
Phenothiazines and butyrophenones are sometimes used for drug associated emesis including CINV
However, they have
been replaced by more effective agents
e.g. metoclopramide and 5-HT3 receptor antagonists.
These agents also possess antihistaminic and
anticholinergic activities which are of value in other forms of nausea such as
motion sickness.
Dopamine Receptor Antagonists:
Metoclopramide
Antiemetic actions of metoclopramide are dose-related.
At low doses, it acts
as a selective D2 antagonist at CTZ and produces pharmacological effects
similar to those of phenothiazines and butyrophenones.
It also exerts D2
antagonism in the GIT at these doses resulting in stimulation of cholinergic
receptors in GI smooth muscle thus enhancing gastric emptying.
For this reason,
metoclopramide may be more effective than phenothiazines and butyrophenones
when nausea is related to intestinal or biliary disease.
At higher doses, it may exert 5-HT3 receptor
antagonism
However,at these doses
the high incidence of acute dystonic reactions may limit its usefulness in CINV.
Dopamine Receptor Antagonists:
Domperidone
Although domperidone does not readily cross the BBB, it is a selective
antagonist of D2 dopamine receptors at the CTZ which lies outside BBB in the
area postrema.
It also has
effects in the GIT which result in increased motility and enhanced gastric
emptying.
Dopamine Receptor Antagonists: Domperidone
It is used in drug-associated vomiting and is
relatively non-sedating.
Acute dystonic
reactions occur less frequently than with metoclopramide.
It prevents
nausea and vomiting during treatment with dopamine agonists used in Parkinson’s
disease
It is also useful in vomiting associated with
emergency hormonal contraception.
Antihistamines
Histamine H1-receptor antagonists act by blockade of H1 receptors in the CTZ
and vestibular afferents.
They are
primarily used for motion sickness and postoperative nausea and vomiting.
Examples include cyclizine, hydroxyzine, promethazine,
and diphenhydramine .
Some antihistamines such as cyclizine have additional
anticholinergic effects that may be useful for patients with abdominal cancer.
Sedation is their main side effect
However, the newer non-sedating antihistamines e.g. fexofenadine are of limited value in
nausea and vomiting.
Anticholinergic Agents
These are antagonists at muscarinic (M1) receptor both
centrally and peripherally.
Anticholinergics such as atropine, hyoscine and
glycopyrronium are used preoperatively to inhibit salivation and excessive
respiratory secretions during anaesthesia.
Anticholinergics act by inhibition of cholinergic
transmission from the vestibular nuclei to higher centres within the cerebral
cortex
They are
therefore predominantly used in
the treatment of motion sickness.
Anticholinergic agents
The most commonly used muscarinic receptor antagonist
is scopolamine (hyoscine)
It is
principally used in the prevention and treatment of motion sickness
It also has some activity in postoperative
nausea and vomiting.
In general, anticholinergic agents have no role in
CINV.
Anticholinergic agents:Adverse
effects
Inhibition of peripheral muscarinic receptors can
cause:
Drowsiness ,
Dry mouth,
Dilated pupils and blurred vision,
Decreased GI motility and secretions
Difficulty with micturition.
Cannabinoids
Antiemetic activity of cannabinoids is thought to be
due to stimulation of central and peripheral cannabinoid (CB1) receptors.
They have
modest antiemetic activity that is of
similar magnitude to prochlorperazine in CINV
However they can cause a wide range of CNS adverse
effects e.g. drowsiness and behavioural
disturbances which can be severe at times.
Cannabinoids: Dronabinol
Dronabinol (MARINOL) is a naturally occurring
cannabinoid that can be synthesized chemically or extracted from the marijuana
plant, Cannabis sativa.
The antiemetic action of dronabinol results from stimulation of the CB1 subtype of cannabinoid
receptors on neurons in the vomiting
center.
Cannabinoids:Dronabinol
It is a useful
prophylactic agent in patients receiving cancer chemotherapy when other
antiemetic medications are not effective.
It also can stimulate appetite and has been used in
patients with AIDS and anorexia.
Cannabinoids:Dronabinol
As an antiemetic agent, it is administered at an
initial dose of 5 mg/m2 given 1–3 hours before chemotherapy and then
every 2–4 hours afterward for a total of four to six doses.
If this is not
adequate, incremental increases in dose can be made up to a maximum of 15
mg/m2.
For other indications, the usual starting dose is 2.5
mg twice a day;
This can be titrated up to 20 mg a day.
Dronabinol: Adverse effects
Dronabinol has complex effects on the CNS,
These include a prominent central sympathomimetic
activity that can lead to:
Palpitations
Tachycardia
Vasodilation
Hypotension
Conjunctival injection (bloodshot eyes).
Dronabinol: Adverse effects
Patient supervision is necessary because
marijuana-like “highs” (e.g., euphoria, somnolence, detachment, dizziness,
anxiety, nervousness, panic, etc.) can occur
Other
disturbing effects include
paranoid reactions and thinking abnormalities.
After abrupt withdrawal of dronabinol, an abstinence
syndrome manifest by irritability, insomnia, and restlessness can occur.
Dronabinol: Cautions
Because of its high affinity for plasma proteins,
dronabinol can displace other plasma protein-bound drugs, whose doses may have
to be adjusted as a consequence.
Dronabinol should be prescribed with great caution to
persons with a history of substance abuse because it also may be abused by
these patients.
Cannabinoids:Nabilone
This is a synthetic cannabinoid indicated for nausea
and vomiting associated with cytotoxic chemotherapy unresponsive to
conventional antiemetics.
It is recommended that it should be used under close
supervision, preferably in a hospital setting.
Neurokinin 1 (NK1) receptor
antagonists
Substance P is a
peptide that plays an important role as a neurotransmitter in vomiting,
pain and other inflammatory processes.
It binds to the
NK1 receptors which are found in the area postrema and NTS.
Aprepitant is a selective NK1 receptor antagonist
which is used as an adjunct to dexamethasone and 5-HT3 antagonists in
preventing, but not treating nausea and vomiting associated with highly
emetogenic chemotherapy e.g. cisplatin.
Neurokinin 1 (NK1) receptor
antagonists
The nausea and vomiting associated with cisplatin has
two components:
An acute phase within 24 hours after
chemotherapy that universally is experienced
Delayed phase on days 2–5 that affects only some
patients.
5-HT receptor antagonists are not very effective
against delayed emesis.
Neurokinin 1 (NK1) receptor antagonists
Antagonists of the NK1 receptors for substance P, such
as aprepitant (EMEND), have antiemetic effects in delayed nausea
They improve the efficacy of standard antiemetic
regimens in patients receiving multiple cycles of chemotherapy.
Neurokinin 1 (NK1) receptor antagonists
Aprepitant is well tolerated but is an inhibitor of
CYP3A4 and an inducer of CYP2C9 and glucuronidation.
Therefore it has
potential for drug interactions with chemotherapeutic agents as well as other
concomitantly administred agents.
The recommended adult
dosage of aprepitant is 125 mg administered 1 hour before chemotherapyon day
one, followed by 80 mg once daily in the morning on days 2 and 3 of the
treatment regimen.
Corticosteroids
Dexamethasone and methylprednisolone used alone, are
effective against mildly to moderately emetogenic chemotherapy.
Most frequently,
however, they are used in combination with other agents.
Their antiemetic mechanism is not known, but it may
involve blockade of prostaglandins.
These drugs can cause insomnia as well as
hyperglycemia in patients with diabetes mellitus.
Benzodiazepines
The antiemetic potency of lorazepam and alprazolam is
low.
Their beneficial effects may be due to their sedative,
anxiolytic, and amnesic properties.
These properties make benzodiazepines useful in
treating anticipatory vomiting.
Combination antiemetic
regimens
Antiemetic drugs are often combined to increase
antiemetic activity or decrease toxicity.
Corticosteroids, most
commonly dexamethasone, increase antiemetic activity when given with high-dose
metoclopramide, a 5-HT3 antagonist, phenothiazine, butyrophenone, a
cannabinoid, or a benzodiazepine.
Combination antiemetic
regimens
Antihistamines, such as diphenhydramine, are often
administered in combination:
With high-dose metoclopramide to reduce
extrapyramidal reactions or
With corticosteroids
to counter metoclopramide-induced diarrhoea.
Potency of antiemetic drugs
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