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Antiemetic Drugs

Definition

Vomiting is a protective reflex frequently associated with nausea controlled


and integrated by different CNS nuclei in order to reduce absorption of toxic substances
Patologic Vomiting

Pregnancy
Kinetosis
Dispepsia
Liver diseases
Renal failure
Stroke
Surgery (abdominal, ear, eye)
Radiotherapy
Chemotherapy (!!!)
Anatomy of the neuronal pathways controlling emesis
The bulbar center of the Vomiting Reflex
The Brain stem - posterior view , the cerebellum was removed.

1. Middle cerebellar peduncle


2. Superior cerebellar peduncle
3. Inferior cerebellar peduncle
4'.The medullary vestibular area
4''.The pontine vestibular area
5. Medial eminence
6. Facial colliculus
7. Hypoglossal trigone
8. Vagal trigone
9. Area postrema (chemoreceptor trigger zone)
10. Cinereum tubercle
11. Cuneate tubercle
12. Gracile tubercle
13. Posterolateral sulcus
14. Posterior intermediate sulcus
15. Posteromedian sulcus
16. Obex
17. Fovea inferior
18. Striae medullares
19. Sulcus limitans
20. Fovea superior
21. Locus coeruleus
22. Trochlear nerve
23. Frenulum veli
24. Superior medullary velum
Myoenteric Plexus
The neuronal network regulating peristalsis
Peripheral and Brain centers regulating the Vomiting Reflex- I
Peripheral and Brain centers regulating the Vomiting Reflex- II
Neurotransmitters and receptors regulating the Vomiting Reflex

Glu, GABAA

D2, M1, 5HT3 D2, M1, 5HT3

H1, M1

5HT3, D2
Drugs used to induce the Vomiting reflex
Ipecacuana syrup
Drugs used to induce the Vomiting reflex
Apomorphine
Drugs used to induce the Vomiting reflex
CuSO4
Overview of the Antiemetic Drugs

Antimuscarinic scoplamine Glucocorticoids prednisone


atropine dexametasone

Antihistaminic dinenidramine Cannabinoids dronabinole (THC)


ciclizine nabilone
prometazine
dimedrinate Benzodiazepine lorazepam
diazepam
Antidopaminergic proclorpromazine
droperidole Vitamin B6 piridossal phosphate
metoclopramide
domperidone
tietilperazina
levosulpiride

Antiserotoninergicondansetron
granisetron
tropisetron
Sites of action of Antiemetic Drugs
Pharmacodynamic profile of the antiemetic drugs
Chemotherapy Induced Nausea and Vomiting
(CINV)
The aetiology and risk factors for CINV and radiotherapy-induced nausea and vomiting
Not all patients receiving chemotherapy or radiotherapy will experience nausea and vomiting but it has been estimated that
(untreated) it occurs in up to 70% of patients receiving cancer chemotherapy[2].

There are three types of nausea and vomiting associated with chemotherapy and radiotherapy, each with different aetiologies:
1-Acute nausea and vomiting. This lasts for 12-24 hours.
2-Delayed nausea and vomiting. This may occur up to 5 days after chemotherapy. It is less apparent in the case of
radiotherapy.
3-Anticipatory nausea and vomiting. This conditioned response results from the patient's expectation (anticipation) of
nausea and vomiting.

Patient risk factors


Age. Children are more likely to develop nausea and vomiting than adults
Gender. The prevalence of nausea and vomiting is higher in women
History of nausea and vomiting. Patients with a history of motion sickness may have a lower threshold to nausea and
vomiting than the rest of the population. This can be exacerbated by patient anxiety and by a prior history of nausea and
vomiting associated with chemotherapy or radiation therapy
History of heavy alcohol use. This is associated with a lower risk of nausea and vomiting.
Chemotherapy Induced Nausea and Vomiting
(CINV)
SEROTONIN 5-HT 3 ANTAGONISTS
Selective 5-HT 3 -receptor antagonists have potent antiemetic
properties that are mediated in part through central 5-HT 3
receptor blockade in the vomiting center and chemoreceptor
trigger zone but mainly through blockade of peripheral 5-HT 3
receptors on extrinsic intestinal vagal and spinal afferent
nerves. The antiemetic action of these agents is restricted to
emesis attributable to vagal stimulation (eg, postoperative)
and chemotherapy; other emetic stimuli such as motion
sickness are poorly controlled.
Five agents are available in Italy:
1. Ondansetron
2. Granisetron
3. Dolasetron
4. Tropisetron
5. Palonosetron.
CLINICAL USES
A. Chemotherapy-Induced Nausea and Vomiting
5-HT 3 -receptor antagonists are the primary agents for the prevention
of acute chemotherapy-induced nausea and emesis.
When used alone, these drugs have little or no efficacy for the
prevention of delayed nausea and vomiting (ie, occurring > 24 hours
after chemotherapy). The drugs are most effective when given as a
single dose by intravenous injection 30 minutes prior to
administration of chemotherapy in the following doses: ondansetron,
8 mg; granisetron, 1 mg; dolasetron, 100 mg; or palonosetron, 0.25
mg.
A single oral dose given 1 hour before chemotherapy may be equally
effective in the following regimens: ondansetron 8 mg twice daily or
24 mg once; granisetron, 2 mg; dolasetron, 100 mg.
Although 5-HT 3 -receptor antagonists are effective as single agents for
the prevention of chemotherapy-induced nausea and vomiting, their
efficacy is enhanced by combination therapy with a corticosteroid
(dexamethasone) and NK 1 -receptor antagonist (see below).
B. Postoperative and Postradiation Nausea and
Vomiting
5-HT 3 -receptor antagonists are used to prevent or
treat postoperative nausea and vomiting.
Because of adverse effects and increased restrictions
on the use of other antiemetic agents, 5-HT 3
receptor antagonists are increasingly used for this
indication.
They are also effective in the prevention and
treatment of nausea and vomiting in patients
undergoing radiation therapy to the whole body or
abdomen.
ADVERSE EFFECTS
The 5-HT 3 -receptor antagonists are well-tolerated agents
with excellent safety profiles.
The most commonly reported adverse effects are
headache, dizziness, and constipation.
All agents cause a small but statistically significant
prolongation of the QT interval, but this is most
pronounced with dolasetron. Although cardiac
arrhythmias have not been linked to dolasetron, it should
not be administered to patients with prolonged QT or in
conjunction with other medications that may prolong the
QT interval.
NEUROKININ-1 RECEPTOR
ANTAGONISTS
Neurokinin 1 (NK 1 )-receptor antagonists have
antiemetic properties that are mediated through
central blockade in the area postrema.
Aprepitant (an oral formulation) is a highly selective NK
1 -receptor antagonist that crosses the blood-brain
barrier and occupies brain NK 1 receptors. It has no
affinity for serotonin, dopamine, or corticosteroid
receptors.
Fosaprepitant is an intravenous formulation that is
converted within 30 minutes after infusion to
aprepitant.
CLINICAL USES
Aprepitant is used in combination with 5-HT 3 -receptor
antagonists and corticosteroids for the prevention of acute
and delayed nausea and vomiting from highly emetogenic
chemotherapeutic regimens.
Combined therapy with aprepitant, a 5-HT 3 receptor
antagonist, and dexamethasone prevents acute emesis in 80
90% of patients compared with less than 70% treated without
aprepitant.
Prevention of delayed emesis occurs in more than 70% of
patients receiving combined therapy versus 3050% treated
without aprepitant.
NK 1 -receptor antagonists may be administered for 3 days as
follows: oral aprepitant 125 mg or intravenous fosaprepitant
115 mg given 1 hour before chemotherapy, followed by oral
aprepitant 80 mg/d for 2 days after chemotherapy.
ADVERSE EFFECTS & DRUG
INTERACTIONS
Aprepitant may be associated with fatigue, dizziness, and
diarrhea.
The drug is metabolized by CYP3A4 and may inhibit the
metabolism of other drugs metabolized by the CYP3A4
pathway. Several chemotherapeutic agents are metabolized
by CYP3A4, including docetaxel, paclitaxel, etoposide,
irinotecan, imatinib, vinblastine, and vincristine.
Drugs that inhibit CYP3A4 metabolism may significantly increase
aprepitant plasma levels (eg, ketoconazole, ciprofloxacin,
clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and
quinidine).

Aprepitant decreases the international normalized ratio (INR) in


patients taking warfarin.
CORTICOSTEROIDS
Corticosteroids (dexamethasone, methylprednisolone) have
antiemetic properties, but the basis for these effects is
unknown.
These agents appear to enhance the efficacy of 5-HT 3
-receptor antagonists for prevention of acute and delayed
nausea and vomiting in patients receiving moderately to
highly emetogenic chemotherapy regimens.
Although a number of corticosteroids have been used,
dexamethasone, 820 mg intravenously before
chemotherapy, followed by 8 mg/d orally for 24 days, is
commonly administered.
DOPAMINE-RECEPTOR
ANTAGONISTS
MECHANISM of ACTION
The exact mechanism of action of the dopamine
antagonists prochlorperazine and metoclopramide
as anti-emetic drugs is unclear, but
prochlorperazine inhibits apomorphine induced
vomiting by blocking dopamine D2 receptors
[DRD2] in the CTZ.
Also metoclopramide has shown to directly affect
the CTZ in the area postrema by blocking DRD2.
The drug increases the CTZ threshold and
decreases the sensitivity of visceral nerves that
transmit afferent impulses from the gastrointestinal
tract to the vomiting center in the lateral reticular
formation.
BENZODIAZEPINES
The anti-emetic mechanism of action of
benzodiazepines, for example lorazepam, is related
to the combination effects of sedation, reduction in
anxiety, and possibly depression of the vomiting
centre.
Benzodiazepines bind to plasma protein, varying
from 7099%, and undergo extensive metabolism
by CYP enzymes. The CYP2C19 and CYP3A4/5,
CYP2C9 and CYP1A2 contribute to the metabolism
of benzodiazepines.
CANNABINOIDS
Cannabinoids have an anti-emetic effect at the enterochromaffin cells
in the gastrointestinal tract and an anti-cholinergic effect on
cholinergic terminals and Auerbachs plexus and possibly
mediate the prostaglandin cyclic nucleotide system.
Two cannabinoid drugs have been approved for chemotherapy
induced nausea and vomiting (CINV):
1. Dronabinol
2. Nabilone
Although there are conflicting data, cannabinoids can be used for
refractory emesis.
Nabilone showed superior efficacy compared to prochlorperazine and
also the combination of the two agents were better than was
used alone.
The use of these agents is limited because of their slow elimination
from the body and because of adverse effects such as sedation,
dysphoria, vertigo, euphoria, dizziness, and dry mouth.
Further, cannabinoids are prone to pharmacodynamic and/or
pharmacokinetic interactions with other drugs. The interaction of
cannabinoids with chemotherapeutic agents that are sensitive to
the alteration of CYP3A function should be closely monitored.
GUIDELINES
According to the guideline of the American Society of Clinical Oncology on
prevention of CINV, the combination of neurokinin-1 receptor antagonist, 5-
HT3RA and dexamethasone is the regimen of choice in patients receiving
highly emetogenic chemotherapy.
Moreover, addition of lorazepam or alprazolam, or substitution the 5-HT3RA
with high dose intravenous of metoclopramide or adding dopamine
antagonist is recommended in patients with suboptimal response.
MUSCARINIC ANTAGONISTS
In the treatment of post operative NV, the muscarinic receptors present in the hindbrain medulla are important targets.
The two muscarinic antagonists used as anti-emetics in anaesthesia are:
1. hyoscine
2. atropine.
Both are lipid soluble and penetrate the brain to reach the vomiting centre.
Intramuscular administration of hyoscine is generally more effective as an anti-emetic than intramuscular atropine but
was associated with increased drowsiness and delayed recovery from anaesthesia. To increase its duration of action,
hyoscine has also been used as a transdermal preparation. The patch needs to be applied several hours before the
emetic stimulus to enable an adequate plasma concentration to be obtained.
Muscarinic receptors are found in the periphery, associated with the effector organs of the parasympathetic nervous
system. Thus, typical antimuscarinic adverse effects such as dry mouth and blurred vision are common, though not
usually serious.
HISTAMINE H1-RECEPTOR ANTAGONISTS

Both histamine H1 and muscarinic receptors are present in the vomiting centre and the
vestibular nucleus.
The antihistamine drugs that are used to treat nausea and vomiting also have
antimuscarinic activity, therefore it is unclear which property is more important for their
anti-emetic action.
Cyclizine has been used extensively to treat PONV and most reports demonstrate
efficacy with few side effects such as sedation.
Promethazine is a markedly sedative drug and has been used by anaesthetists to
premedicate children, but whether this is for its sedative effect or anti-emetic effect is
debatable.
Oral dimenhydrinate given at least 1 hour before surgery has also been used to
prevent PONV.
Second-generation antihistamines (e.g. terfenadine, astemizole) are not effective anti-
emetics because they do not cross the bloodbrain barrier.
Antiemetic Drugs Summing Up

Anticholinergic
Kinetosis (scopolamine transdermic)
Diziness, sedation, cycloplegia, dry mouth
Rapid effects

Antihistaminic
Kinetosis, Meniere Syndrome, vertigo
sedation

Antidopaminergic
Vertigo, chemotherapy, dispepsia
Prolonged effect
Extrapiramidal symptoms, hyperprolattinemia

Antiserotonergic
Chemotherapy
Headache stipsis

Corticosteroids
Chemotherapy

Vit B6
Pregnancy

Cannabinoids
Chemotherapy
Sedation, dysphoria, vertigo,

Benzodiazepin
Anticipation Emesis

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