ANTIEMETIC MODELS

DR PRUTHVI D2ND YEAR PG

• INTRODUCTION• PATHOGENESIS OF VOMITING• CLASSIFICATION OF ANTI EMETIC DRUGS• CHOICE OF ANIMALS AND EMETOGENS• PARAMETERS OBSERVED• INVIVO MODELS• INVITRO MODELS• HUMAN MODELS

INTRODUCTION• NAUSEA• EMESIS

• ACUTE EMESIS• DELAYED EMESIS• ANTICIPATORY EMESIS• BREAKTHROUGH EMESIS

• PRE EJECTION• RETCHING• EJECTION

DRUGS,RADIATION,METABOLIC PRODUCTS

MOTIONVESTIBULAR LABYRINTH

SENSORY STIMULICORTEX

LIMBIC SYSTEM

SYMPATHETIC & PARASYMPATHETIC

VISCERAL AFFERENTS

CORTICAL AFFERENTS

CEREBELLUM

VOMITING CENTRE IN NUCLEUS

TRACTUS SOLITARIUS

CTZ IN AREA POSTREMA

BLOOD & CSF

VOMITINGPATHOGENESIS

CLASSIFICATION OF ANTIEMETICS1. 5HT3 antagonists: ondonsetron, tropisetron, palanosetron2. Centrally acting dopamine receptor antagonists:

prochlorperazine, chlorpromazine3. H1 receptor antagonists ex: Cyclizine, hydroxyzine,

promethazine, diphenhydramine4. Muscarinic antagonists ex:Scopolamine5. Neurokinin receptor antagonists ex: Aprepitent6. Cannabinoid receptor anatgonists ex: Dronabinol, Nabilone7. Corticosteroids and Nsaids8. Benzodiazepines ex: Alprazolam, Diazepam9. Phosphorated carbohydrate solutions

1. Ex:Aqueous solutions of glucose, fructose and phosphoric acid

CHOICE OF ANIMALS• Animals normally used-not useful• Degenerate vomiting reflex – rodents• Commonly used animals:

• Dogs• Cats• Ferrets• Monkeys• House musk shrew(suncus murinus)• Least shrew(cryptotis parva• Gerbils• Pigeons

SUNCUS MURINUS

FERRET

LEAST SHREW

GERBIL

CHOICE OF EMETOGENS

• CANCER CHEMOTHERAPEUTIC AGENTS• APOMORPHINE• COPPER SULPHATE• RADIATION STIMULUS• MOTION STIMULUS

PARAMETERS ASSESSED

• BEHAVIOURAL CHANGES• LATENCY TO FIRST RETCHING AND VOMITING• NUMBER OF VOMITING EPISODES• CONDITIONED FLAVOUR AVOIDANCE IN RATS

DRUG INDUCED EMESIS MODELSCISPLATIN INDUCED EMESIS MODEL:Causes Both Acute And Delayed EmesisUsed as emetogen to evaluate acute emesis.Solvent normal saline at 70oC followed by slow cooling to 40oC

o DOG MODEL: described by Gylys et al. IV dose of 3.2mg/kg/mlo CAT MODEL: described by John et al.IV dose of 3- 7.5 mg/kgo FERRET MODEL: IV 10 mg/kgo PIGEON MODEL: IV 4 mg/kgo SUNCUS MURINUS MODEL: 20 mg/kg IPo RAT MODEL: 3 to 10 mg/kg IP

APOMORPHINE INDUCED EMESIS MODELDogs most sensitive. Cats controversialSuncus murinus unresponsive

o DOG MODEL: 0.3 mg/kg SC o FERRET MODEL: 0.25 mg/kg SCo RAT MODEL: 10 mg/kg IP

COPPER SULFATE INDUCED EMESIS MODELPowerful oxidizing agentSolvent distilled water

o DOG MODEL:100 mg/kg orogastric tubeo CAT MODEL:40 mg/kg orallyo FERRET MODEL:40 mg/kg orallyo SUNCUS MURINUS MODEL:40 mg/kg orally

MOTION INDUCED EMESIS MODELo CAT MODEL: vertical osscillations @ 0.3Hzo SUNCUS MURINUS MODEL: horizontal osscillations @ 1 Hz

for 10 mntso RAT MODEL:

RADIATION INDUCED EMESIS MODELo DOG MODEL: Co 60 and 8 Gyo FERRET MODEL: Co 60 and 201cGyo RAT MODEL: 4 Gy

MODEL FOR ANTICIPATORY NAUSEA AND VOMITINGEmetic stimuli used are horizontal motion(1 Hz,4 cm,10

min),nicotine(4mg/kg sc),lithium chloride 100 mg/kg IP

DELAYED EMESIS MODEL- METHOTRAXATE INDUCED MTX prepared in 5% dextrose

• INVITRO MODELS• ISOLATED GUNIEA PIG COLON PREPERATION

• HUMAN MODELS• APOMORPHINE INDUCED• IPECAC INDUCED

REFERENCES• Drug screening methods by SK Gupta• The Pharmacological Basis of Therapeutics Goodman &

Gilman- 12th edition.• Basic and clinical Pharmacology Betram G Katzung- 12 th

Edition• J Clin Pharmacol. 1978 Feb-Mar;18(2-3):95-9.An

apomorphine-induced vomiting model for antiemetic studies in man Proctor JD, Chremos AN, Evans EF, Wasserman AJ.

• Clin Pharmacol Ther. 1993 Jul;54(1):53-7.Ipecacuanha-induced emesis: a human model for testing antiemetic drug activity.Minton N1, Swift R, Lawlor C, Mant T, Henry J.