screening of anti emetics drug

1. Presented By:
Department of Pharmacology
I S F College of Pharmacy
Moga, Punjab

2. CONTENTS:
1. Introduction
2. Pathogenesis of Vomiting
3. Classification of Anti Emetic Drugs
4. Choice of Animals and Emetogens
5. Parameters Observed
6. In vivo Models
7. In vitro Models
8. Human Models
9. References.
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3. INTRODUCTION:
NAUSEA: Non observable subjective feeling of having an
urge to vomit.
EMESIS:
1. ACUTE EMESIS (occurs within minutes and resolves
within 24 h)
2. DELAYED EMESIS (occurs after 2-3 days)
3. BREAKTHROUGH EMESIS (emesis occurring after the
pro phylactic antiemetic treatment)
RETCHING: Attempt to vomit without expulsion of vomitus.
EJECTION: Expulsion of vomitus forcefully through mouth
and nose.
3

4. CTZ INAREA
POSTREMA
BLOOD & CSF
VOMITING CENTRE
IN NTS
VOMITING
PATHOGENESIS:
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6. CLASSIFICATION OF ANTIEMETICS:
5HT3 antagonists: Ondansetron, Palanosetron, Granisetron
Centrally acting dopamine receptor antagonists: Prochlorperazine, Chlorpromazine
H1 receptor antagonists : Cyclizine, Hydroxyzine, Promethazine, Diphenhydramine
Muscarinic antagonists : Scopolamine
Proinetic agents: Metoclopramide, Domperidone, Cisapride,Mosapride
Neurokinin receptor antagonists :Aprepitent
Cannabinoid receptor antagonists : Dronabinol, Nabilone
Corticosteroids and NSAIDs
Benzodiazepines : Alprazolam, Diazepam
6

7. COMMONLY USED ANIMALS:
Dogs House musk shrew (Suncus
murinus)
Cats Least shrew (Cryptotis parva)
Ferrets Gerbils
Monkeys Pigeons
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8. CHOICE OF EMETOGENS:
1. Drug Induced
2. Radiation Stimulus
3. Motion Stimulus
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9. PARAMETERSASSESSED:
1. Behavioral changes
2. Latency to first retching and vomiting
3. Number of vomiting episodes
4. Conditioned flavor avoidance (PICA)in rat and mouse
9

10. DRUG INDUCED EMESIS MODELS:
Cisplatin- Induced emesis model
Apomorphine- Induced emesis model
CuSO4- Induced emesis model
Methotrexate- Induced emesis model
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11. CISPLATIN-INDUCED EMESIS MODEL:
Causes Both Acute And Delayed E
Used as emetogen to evaluate acute emesis.
Solvent normal saline at 70oC followed by slow
cooling to 40oC
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12. CISPLATIN-INDUCED DOG MODEL:
Described by Gylys et al.
Used to evaluate antiemetic properties of 5-HT3 receptor
antagonists.
TEST GROUP:
Test drug is administered. Ten mins later, cisplatin is
administered IV at a dose of 3.2mg/kg/ml.
OBSERVATION FOR 5 HOURS:
Dogs with no obvious toxicity are retested after an interval
of 4 weeks.
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13. CISPLATIN-INDUCED CAT MODEL:
TEST GROUP
Cisplatin is administered IV at a dose of 3- 7.5 mg/kg/ml
over 4 m.
Immediately after this, Test drug is administered.
CONTROL GROUP
Cisplatin is administered IV at a dose of 3- 7.5 mg/kg/ml
over 4 m.
Immediately after this, Vehicle is administered.
OBSERVATION FOR 4 HOURS FOR EMETIC EPISODES
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14. RAT MODEL:
3-10 mg/kg IP
Cisplatin is administered 30 mins after rats have been
pre- treated with drug/ vehicle.
Observe for pica (ingestion of non-food substances)
PIGEON MODEL:
4 mg/kg IV
Duration between administration of drug/ vehicle and
cisplatin depends upon expected time of drug action
Observed for emetic episodes 14

15. APOMORPHINE- INDUCED EMESIS MODEL:
Apomorphine is an opiate that acts as a potent central
dopamine agonist directly at the area prostrema via
dopamine receptors.
As the vestibular pathways are also involved in
apomorphine-induced emesis, the active animals
develop emesis readily than sedated and immobile
animals.
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16. Dogs most sensitive followed by ferret.
Use of apomorphine in cats is controversial as
administration of apomorphine can cause excitation
in cats.
Suncus murinus is unresponsive to apomorphine
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17. DOG MODEL:
0.3 mg/kg SC
Duration between administration of drug and apomorphine
depends upon expected time of drug action
Observed for emetic episodes
RAT MODEL:
10 mg/kg IP
Apomorphine is administered to rats pre-treated with
drug/ vehicle.
Observe for pica (ingestion of non- food substances)
17

18. COPPER SULFATE-INDUCED EMESIS MODEL:
COPPER SULFATE (CuSO4)
Powerful oxidizing agent and an irritant to mucosa
membranes. If administered orally, it causes irritation of
gastric mucosa and leads to nausea and vomiting.
Solvent: Distilled water
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19. Ferret model Dog model Cat model
40
mg/kg
orally
100 mg/kg via
an orogastric
tube
40 mg/kg orally
Drug/ vehicle
pre treated
ferrets are
administered
CuSO4.
Observed for 1 hour
for emetic episodes
Cats are administered
test drug/ vehicle
followed by oral
administration of
threshold dose of
CuSO4.
Observed for
latency and
frequency of
emetic episodes
Dogs with no obvious
toxicity are retested
after an interval of 2
weeks.
Observed for
emetic episodes
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20. MTX- INDUCED DELAYED EMESIS MODEL:
Animals: Dogs, cats, ferrets & shrews.
MTX is prepared by dissolving in 5% Dextrose.
Test drug/vehicle is administered at 24, 36, 48 & 60 h after
MTX.
Observed under video camera for 72h.
Animals can be retested with MTX at least 6 weeks later
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21. MOTION-INDUCED EMESIS MODEL:
Dogs are probably as sensitive to motion- induced emesis
as man.
COMMONLY USED MODELS
1. Cat Model
2. Suncus Murinus Model
3. Rat Model
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22. CAT MODEL:
Vertical oscillations at 0.3 Hz through a distance of 75 cm
Repetitive licking, salivation often dripping out of mouth,
or vomiting
↑ latency/ ↓frequency of emesis in cats pre-treated with
drug indicates antiemetic action
SUNCUS MURINUS MODEL:
Horizontal oscillations of 4 cm at 1 Hz for 10 min
Emetic episodes are noted during motion as well as after
motion cease
Animal can be exposed only twice in 1 week d/t adaption
to motion stimuli
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23. RADIATION- INDUCED EMESIS MODEL:
RADIATION INDUCED EMESIS MODEL:
1. Dog Model
2. Ferret Model
3. Rat Model
Ferrets are most sensitive to radiations followed by
dogs. Cats are resistant to radiations.
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24. Dog model
60Co; 8 Gy
administered to
total body
surface
One group gets
drug & other
group gets no
medications
↑ latency/
↓frequency of
emesis in cats
pretreated with
drug indicates
antiemetic action
Rat model
4Gy of total body
irradiation
(abdominal >
head irradiation)
Exposure to
radiation induces
pica in rats
↓ kaolin intake in
rats pretreated
with drug
indicates
antiemetic action
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25. MODEL FOR ANTICIPATORY NAUSEA & VOMITING:
Anticipatory nausea and vomiting is described as
conditioned response to cues present at the time of
exposure to toxins as a result of pairing.
Often ass. with cancer chemotherapy.
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26. RAT MODEL:
4 conditioning trials (using LiCl) 72 hours apart
72 hours after 4th conditioningtrial
Drug/ vehicle is given to the rats
0.1% saccharin sol. is delivered via surgically implanted
cannulae every 5 min for 1 min (6inj in 30m)
Rats are observed for gaping (equivalent to emesis)
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27. INVITRO MODELS:
Used to demonstrate the pharmacological activity of
newer anti-emetic agents.
5-HT3 are the most potent of all anti- emetics.
The experimental drugs can be evaluated for 5-
HT3 receptor antagonist activity using in vitro
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28. HUMAN MODELS:
APOMORPHINE INDUCED:
Apomorphine, 0.05 mg/kg, SC is an appropriate
challenge dose for testing compounds for antiemetic
activity in normal human volunteers.
IPECAC INDUCED:
Healthy men are given single 5-minute infusions of
Ondansetron 30 minutes before oral administration
of 30 ml syrup of ipecacuanha. Emetic episodes and
nausea are assessed over an 8-hour period.
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29. Drug name Class Indication Approval year
Granisetron 5-HT3 # CINV Aug 2016
Dronabinol oral
sol.
CB-1 #,
CB-2 #
CINV Jul 2016
Rolapitant NK-1# CINV Sep 2015
Netupitant +
Palonosetron
NK-1# +
5-HT3 #
CINV Oct 2014
Doxylamine
succinate +
Pyridoxine HCl
DR
H1# Nausea and
vomiting of
pregnancy
Apr 2013
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30. REFERENCES:
Tripathi KD; “Essentials of medical pharmacology”;
Jaypee Brothers Medical Publishers, New Delhi, Edition 6
th, 2009: 599-610.
Grunberg SM; Noonan K; “Perspectives on Recent
Clinical Practice Guideline Updates for the Management
of Chemotherapy-Induced Nausea and Vomiting”; The
Official Publication of the Association for Value-Based
Cancer Care 2012; 3(2):4-6.
Feeney K; “Chemotherapy induced nausea and vomiting”;
Australian Family Physician 2007; 36(9): 702-705.
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