SCREENING METHOD EMETIC AND ANTIEMETICS

1. PADMASHREE DR.D.Y.PATIL
COLLEGE OF PHARMACYAKURDI
TOPIC NAME- PRECLINICAL METHOD
OF EMETIC AND ANTIEMETIC METHODS
SUBJECT NAME – PHARMACOLOGY AND
TOXICOLOGICAL SCREENING METHODS
GUIDED BY- DR. ASHISH. V. KULKARNI
PRESENTED BY – DHANASHRI PRAKASH SONAVANE

2. CONTENT
1. Introduction
2. Pathogenesis of vomiting
3. Classification of antiemetic drug
4. Choice of animal and emetogen
5. Parameter observed
6. In vivo model
7. In vitro model
8. Human model

3. INTRODUCTION
• NAUSEA: • Nausea is an uneasiness of the stomach and non
observable subjective feeling that often accompanies the urge to
vomit, but doesn't always lead to vomiting.
• EMESIS: Vomiting or emesis is clinically defined as the oral eviction
of gastrointestinal contents, due to contractions of the gut and the
muscles of the thoracoabdominal wall. Recommender.
• ACUTE EMESIS (occurs within minutes and resolves within 24 hrs.
• DELAYED EMESIS (occurs after 2-3 days) BREAKTHROUGH
EMESIS (emesis occurring after the prophylactic antiemetic
treatment)

4. • RETCHING: It is a labored movement of abdominal and thoracic
muscles for attempting to vomit w/o expulsion of vomitus (without
bringing any food up up from stomach).
• EJECTION: Expulsion of vomitus forcefully through mouth and
nose.

5. HOW VOMITING IS OCCURE
• The fourth ventricle of the brain hosts the
vomiting centre called the chemoreceptor
trigger zone (CTZ). It is also called the
area postrema. When the CTZ is
stimulated, vomiting may occur. The CTZ
contains receptors for dopamine,
serotonin, opioids, acetylcholine and the
neurotransmitter substance P. When
stimulated, each of these receptors gives
rise to pathways leading to vomiting and
nausea.

6. BLOOD AND
CSF
CTZ IN AREA
POSTREMA
VOMITING
CENTER IN CTS
VOMITING
DRUGS, MOTION
VESTIBULAR
LABYRINTH
VISCERAL
AFFERENTS
SYMPATHETIC &
PARASYMPATHETIC
CORTICAL
AFFERENTS
SENSORY STIMULI
CORTEX
LIMBIC SYSTEM
CEREBELLUM
PATHOGENESIS OF VOMITING: DRUGS, RADIATION, METABOLIC
PRODUCTS

7. PATHOPHYSIOLOGY OF EMESIS
Anticipatory emesis
Cerebral cortex
Smell Sight
Thought
Cancer chemotherapy
(cytotoxic drug). Opioids,
digoxin, morphine
Drugs in blood and
CSF
Chemoreceptor Trigger Zone
(CTZ) (Outside BBB) Dopamine
Dopamine D2 5 HT3 Opioid
Receptors, substance P
Chemo & radio therapy
Gastroenteritis
Pharynx & GIT
(enterochromafin cell)
Release 5 HT3,
Substance P
Vestibular nuclei (in pons of brain
stem Muscarinic Histaminic H1
Vestibular labyrinth
Motion sickness
Vomiting Centre (medulla
oblongata) Have receptors of
Muscarinic, 5 HT3, Histaminic
H1, substance P

8. Vomiting Centre (medulla
oblongata) Have
receptors of Muscarinic,
5 HT3, Histaminic H1.
substance P
• Relaxation of lower
oesophageal sphincter
• Contraction of and
diaphragm abdominal
muscle
stimulus
Vomiting

9. ANTIEMETIC DRUG
1. 5HT3 antagonists: Ondansetron, Palanosetron, Granisetron
2. Centrally acting dopamine receptor antagonists: Prochlorperazine,
Chlorpromazine
3. H1 receptor antagonists: Cyclizine, Hydroxyzine, Promethazine,
Diphenhydramine
4. Muscarinic antagonists: Scopolamine
5. Proinetic agents: Metoclopramide, Domperidone, Cisapride, Mosapride
6. Neurokinin receptor antagonists: Aprepitent
7. Cannabinoid receptor antagonists: Dronabinol, Nabilone
8. Corticosteroids and NSAIDS Benzodiazepines: Alprazolam, Diazepam

10. MECHANISM OF ACTION OF ANTIEMETIC
DRUG
Cerebral cortex
Smell Sight
Thought
Cancer chemotherapy
(cytotoxic drug). Opioids,
digoxin, morphine
Drugs in blood and
CSF
Chemoreceptor Trigger Zone
(CTZ) (Outside BBB) Dopamine
Dopamine D2 5 HT3 Opioid
Receptors, substance P
Chemo & radio therapy
Gastroenteritis
Pharynx & GIT
(enterochromafin cell)
Release 5 HT3, Substance
P
Vestibular nuclei (in pons of brain
stem Muscarinic Histaminic H1
Vestibular labyrinth
Motion sickness
Vomiting Centre (medulla
oblongata) Have receptors of
Muscarinic, 5 HT3, Histaminic
H1, substance P
5 HT3 Receptor
antagonists
(ondansetron)
antihistaminic H
2(promethazine) ,
Muscarinic
antagonist.
Muscarinic
Receptor
antagonists
(Scopolamine)
D2 Receptor
antagonists
(chlorpromazine,
metaclopromide)

11. CHOICE OF ANIMAL USED
• COMMONLY USED ANIMAL
DOG
GERBILS
PIGEON
LEAST SHREW
(CRYPTOTIS
PARVA)
CAT
FERRET
HOUSE
MUSKSHRE
W (SUNCUS
MURINUS).
MONKEY

12. CHOICE OF EMETOGENS:
Emesis can be induced by motion, ionising radiation and drugs used for
cancer chemotherapy in several animal species as discussed earlier.
Several experimentally model scan be employed for testing or
evaluating anti-emetic activity of drugs, which are described as follows:
1. Drug Induced
2. Radiation Stimulus
3. Motion Stimulus

13. PARAMETER OBSERVED:
• Behavioral changes
• Latency to first retching and vomiting
• Number of vomiting episodes
• Conditioned flavor avoidance (PICA) in rats and mouse

14. 1. DRUG INDUCED EMESIS MODELS
Cisplatin-induced emesis mode
Apomorphine-induced emesis model
• CuSO4-induced emesis model
Methotrexate-induced emesis model

15. A. Cisplatin induced emesis in pigeons:
Cisplatin cause acute and delayes emesis.
Used for ematogen for acute emesis.
• PIGEONS: (250-500 g)
1. Control groups are given an oral dose of normal saline (0.9%),
2. while the test groups are given a test drug body weight in a volume of 10 ml/kg
in 0.9% saline.
3. Cisplatin (4 mg/kg, iv.) are used to induce behavior or retching.
4. The emesis observation period generally showed acute and delayed emesis, 3 hr
for early and 72 hr of observation for delayed emesis.
• Interpretation: Number of retching episodes is recorded after 15 min
immediately administration of cisplatin or test compound up to the observation
period. The test compound decreases the retching episodes against control group
(cisplatin) as well as inhibition of emesis by antiemetic drug after high dose of
emetic compound.

16. B. Apomorphine Induced Emesis:
Vomiting induced by apomorphine, an agonist at dopamine D2 receptors, in dogs
has been largely used for screening anti-emetics. Apomorphine induces emesis via
activation of D2 receptors in the chemoreceptor trigger zone located in the area
postrema.
Dog: Male dog,(7-14 kg),
1. Dog are housed single in per cage with free access to rationed food (25-300
g/day) and water. The animal room is maintained on a 12-hr light/dark cycle at
an ambient temperature of 21 ±2 dog ºC.
2. Animals are first orally administered with vehicle or test compound or a placebo
administration, 30 min before being fed with half their daily ratio of food.
3. After a further 30 min, they received a s.c. administration of apomorphine (0.03
to 0.1 mg/kg, iv.).
4. Then observed for a period of 60 min to record general behavior, as well as the
latency to first retching or vomiting event, retching (number of retches),
vomiting (number of vomits), number of emetic periods.

17. Interpretation:
Number of vomiting and retching episodes is recorded for 1 hr immediately
administration of apomorphine or test compound, the test compound decreases then
number of emetic episodes, number of retches, and number of vomits against
control group(apomorphine).

18. C. Copper sulphate induced emesis in dogs:
• Each Beagle dogs (15-20 kg)
• Given 200-300 g food 30 min before treatment. The animals are divided into
different groups each group carries 5-6 animals.
• The emetic dose of copper sulphate 3 - 4mg / kg i.v. or 100 mg/kg p.o. is
employed to induce emesis.
• and in another group, the animals receive an equivalent volume of vehicle or test
compound under similar conditions in order to detect the presence of emetic
response.
• It is possible that copper sulphate might cause of gastrointestinal irritation
resulting in the release of serotonin, and evoke emesis by activation of abdominal
visceral afferents through 5-HT4receptors. Thus, the activation of 5-HT4 receptors
in copper sulphate induced emesis seems to be cardinal.
• Vomiting and retching episodes are recorded during the first hour of iv. route or
po route after copper sulphate treatment.

19. • Interpretation: Number of vomiting and retching episodes is recorded for 1 h
immediately iv. or pa administration of copper sulphate and test agent. The test
compound decreases number of emetic episodes, number of retches, and number
of vomits as compared to copper sulphate.

20. D.Morphine induced emesis:
Method: Young healthy albino or Fitch ferrets (600-2000 g) of either sex, are used
for emesis model.
The animals are divided into different groups each group carries 5-6 animals.
The emetic dose of morphine (0.3 mg/kg, s.c.) is used to induce emesis and in
another group, the animals receive an equivalent volume of vehicle or test
compound under similar conditions in order to detect the presence of emetic
response.
Vomiting and retching episodes are recorded during the first 30 min (observation
time) of s.c. administration of morphine. Emesis is characterized by rhythmic
abdominal contractions associated with retching and vomiting.
Interpretation: Number of vomiting and retching episodes is recorded for 30 min
immediately administration of morphine and test compound. The test agent
decreases number of emetic episodes, number of retches, and number of vomits as
compared to morphine.

21. OTHER REPORTED IN VIVO MODELS TO
INDUCE EMESIS:
1. Yohimbine induced emesis in Ferret.
2. X-irradiation induced emesis in mink on exposure to radiation of 18
Gy.
3. Methotrexate induced emesis in dog
4. Reserpine induced emesis in pigeon
5. Zacopride induced emesis
6. Cyclophosphamide induced emesis in ferret

22. 2.RADIATION INDUCED EMESIS
MODEL:
• Dog model
• Ferret model
• Ferrets are most sensitive to radiations followed by dogs.
• Cats are resistant to radiations.

23. 3. ACTIVITY AGAINST MOTION INDUCED
EMESIS
• The house musk shrew (Suncus murinus) is a small insectivore that has been
shown to exhibits emesis when exposed to linear reciprocation motion.
• PROCEDURE
1. House musk shrew adult male (55-90 g) and female (35-50 g) are used.
2. The animals receive a dose of the test drug or vehicle in a volume of 4 ml/kg 15
min before motion testing.
3. The animals are placed in a Perspex chamber (11 cm wide x 22 cm long x 11 cm
high) that is attached to the platform of a shaker set to execute a linear
horizontal movement of 4 cm at a frequency of 1 Hz along the long axis of the
chamber.

24. 4. The animals are allowed approximately 3 min to become accustomed to the
chamber before exposure to motion for a period of 5 min, during which the
number and timing of emetic episodes are recorded.
5. An emetic episode usually consists of a short period of rapid retching followed
by a vomit.
6. A cross-over design is used for the experiment, with animals exposed to motion
testing following treatment with vehicle control on one occasion, and following
treatment with test drug on another An interval of 12 days is allowed between
treatments.