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ANTIEMETIC MODELS
DR PRUTHVI D
2ND 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
MOTION
VESTIBULAR
LABYRINTH
SENSORY STIMULI
CORTEX
LIMBIC SYSTEM
SYMPATHETIC &
PARASYMPATHETIC
VISCERAL AFFERENTS
CORTICAL AFFERENTS
CEREBELLUM
VOMITING CENTRE
IN NUCLEUS
TRACTUS
SOLITARIUS
CTZ IN AREA
POSTREMA
BLOOD & CSF
VOMITING
PATHOGENESIS
Anti emetic models
CLASSIFICATION OF ANTIEMETICS
1. 5HT3 antagonists: ondonsetron, tropisetron, palanosetron
2. Centrally acting dopamine receptor antagonists:
prochlorperazine, chlorpromazine
3. H1 receptor antagonists ex: Cyclizine, hydroxyzine,
promethazine, diphenhydramine
4. Muscarinic antagonists ex:Scopolamine
5. Neurokinin receptor antagonists ex: Aprepitent
6. Cannabinoid receptor anatgonists ex: Dronabinol, Nabilone
7. Corticosteroids and Nsaids
8. Benzodiazepines ex: Alprazolam, Diazepam
9. 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 MODELS
CISPLATIN INDUCED EMESIS MODEL:
Causes Both Acute And Delayed Emesis
Used 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/ml
o CAT MODEL: described by John et al.IV dose of 3- 7.5 mg/kg
o FERRET MODEL: IV 10 mg/kg
o PIGEON MODEL: IV 4 mg/kg
o SUNCUS MURINUS MODEL: 20 mg/kg IP
o RAT MODEL: 3 to 10 mg/kg IP
APOMORPHINE INDUCED EMESIS MODEL
Dogs most sensitive.
Cats controversial
Suncus murinus unresponsive
o DOG MODEL: 0.3 mg/kg SC
o FERRET MODEL: 0.25 mg/kg SC
o RAT MODEL: 10 mg/kg IP
COPPER SULFATE INDUCED EMESIS MODEL
Powerful oxidizing agent
Solvent distilled water
o DOG MODEL:100 mg/kg orogastric tube
o CAT MODEL:40 mg/kg orally
o FERRET MODEL:40 mg/kg orally
o SUNCUS MURINUS MODEL:40 mg/kg orally
MOTION INDUCED EMESIS MODEL
o CAT MODEL: vertical osscillations @ 0.3Hz
o SUNCUS MURINUS MODEL: horizontal osscillations @ 1
Hz for 10 mnts
o RAT MODEL:
RADIATION INDUCED EMESIS MODEL
o DOG MODEL: Co 60 and 8 Gy
o FERRET MODEL: Co 60 and 201cGy
o RAT MODEL: 4 Gy
MODEL FOR ANTICIPATORY NAUSEA AND VOMITING
Emetic 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.
Anti emetic models

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Anti emetic models

  • 2. • INTRODUCTION • PATHOGENESIS OF VOMITING • CLASSIFICATION OF ANTI EMETIC DRUGS • CHOICE OF ANIMALS AND EMETOGENS • PARAMETERS OBSERVED • INVIVO MODELS • INVITRO MODELS • HUMAN MODELS
  • 3. INTRODUCTION • NAUSEA • EMESIS • ACUTE EMESIS • DELAYED EMESIS • ANTICIPATORY EMESIS • BREAKTHROUGH EMESIS • PRE EJECTION • RETCHING • EJECTION
  • 4. DRUGS,RADIATION,METABOLIC PRODUCTS MOTION VESTIBULAR LABYRINTH SENSORY STIMULI CORTEX LIMBIC SYSTEM SYMPATHETIC & PARASYMPATHETIC VISCERAL AFFERENTS CORTICAL AFFERENTS CEREBELLUM VOMITING CENTRE IN NUCLEUS TRACTUS SOLITARIUS CTZ IN AREA POSTREMA BLOOD & CSF VOMITING PATHOGENESIS
  • 6. CLASSIFICATION OF ANTIEMETICS 1. 5HT3 antagonists: ondonsetron, tropisetron, palanosetron 2. Centrally acting dopamine receptor antagonists: prochlorperazine, chlorpromazine 3. H1 receptor antagonists ex: Cyclizine, hydroxyzine, promethazine, diphenhydramine 4. Muscarinic antagonists ex:Scopolamine 5. Neurokinin receptor antagonists ex: Aprepitent 6. Cannabinoid receptor anatgonists ex: Dronabinol, Nabilone 7. Corticosteroids and Nsaids 8. Benzodiazepines ex: Alprazolam, Diazepam 9. Phosphorated carbohydrate solutions 1. Ex:Aqueous solutions of glucose, fructose and phosphoric acid
  • 7. 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
  • 12. CHOICE OF EMETOGENS • CANCER CHEMOTHERAPEUTIC AGENTS • APOMORPHINE • COPPER SULPHATE • RADIATION STIMULUS • MOTION STIMULUS
  • 13. PARAMETERS ASSESSED • BEHAVIOURAL CHANGES • LATENCY TO FIRST RETCHING AND VOMITING • NUMBER OF VOMITING EPISODES • CONDITIONED FLAVOUR AVOIDANCE IN RATS
  • 14. DRUG INDUCED EMESIS MODELS CISPLATIN INDUCED EMESIS MODEL: Causes Both Acute And Delayed Emesis Used 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/ml o CAT MODEL: described by John et al.IV dose of 3- 7.5 mg/kg o FERRET MODEL: IV 10 mg/kg o PIGEON MODEL: IV 4 mg/kg o SUNCUS MURINUS MODEL: 20 mg/kg IP o RAT MODEL: 3 to 10 mg/kg IP
  • 15. APOMORPHINE INDUCED EMESIS MODEL Dogs most sensitive. Cats controversial Suncus murinus unresponsive o DOG MODEL: 0.3 mg/kg SC o FERRET MODEL: 0.25 mg/kg SC o RAT MODEL: 10 mg/kg IP COPPER SULFATE INDUCED EMESIS MODEL Powerful oxidizing agent Solvent distilled water o DOG MODEL:100 mg/kg orogastric tube o CAT MODEL:40 mg/kg orally o FERRET MODEL:40 mg/kg orally o SUNCUS MURINUS MODEL:40 mg/kg orally
  • 16. MOTION INDUCED EMESIS MODEL o CAT MODEL: vertical osscillations @ 0.3Hz o SUNCUS MURINUS MODEL: horizontal osscillations @ 1 Hz for 10 mnts o RAT MODEL: RADIATION INDUCED EMESIS MODEL o DOG MODEL: Co 60 and 8 Gy o FERRET MODEL: Co 60 and 201cGy o RAT MODEL: 4 Gy MODEL FOR ANTICIPATORY NAUSEA AND VOMITING Emetic 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
  • 17. • INVITRO MODELS • ISOLATED GUNIEA PIG COLON PREPERATION • HUMAN MODELS • APOMORPHINE INDUCED • IPECAC INDUCED
  • 18. 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.