SCREENING

ANTIEMETIC DRUGS

Dr. Prashant ShuklaJunior ResidentDept. of Pharmacology

INTRODUCTIONPATHOGENESIS OF VOMITINGCLASSIFICATION OF ANTI EMETIC DRUGSCHOICE OF ANIMALS AND EMETOGENSPARAMETERS OBSERVEDINVIVO MODELSINVITRO MODELSHUMAN MODELS

Contents

INTRODUCTIONNAUSEA: Non observable

subjective feeling of having an urge to vomit.

EMESIS ACUTE EMESIS (occurs within minutes

and resolves within 24 h) DELAYED EMESIS (occurs after 2-3 days) BREAKTHROUGH EMESIS (emesis

occurring after the prophylactic antiemetic treatment)

RETCHING: Attempt to vomit w/o expulsion of vomitus.

EJECTION: Expulsion of vomitus forcefully through mouth and nose.

DRUGS,RADIATION,METABOLIC PRODUCTS

MOTIONVESTIBULAR LABYRINTH

SENSORY STIMULICORTEX

LIMBIC SYSTEM

SYMPATHETIC & PARASYMPATHETIC

CEREBELLUM

VOMITING CENTRE IN NTS

CTZ IN AREA POSTREMA

BLOOD & CSF

VOMITING

PATHOGENESIS

CORTICAL AFFERENTS

VISCERAL AFFERENTS

CLASSIFICATION OF ANTIEMETICS

1. 5HT3 antagonists: ondansetron, tropisetron, palanosetron, granisetron

2. Centrally acting dopamine receptor antagonists: prochlorperazine, chlorpromazine

3. H1 receptor antagonists ex: Cyclizine, hydroxyzine, promethazine, diphenhydramine

4. Muscarinic antagonists ex:Scopolamine

5. Proinetic agents: Metoclopramide, Domperidone, Cisapride,Mosapride

6.Neurokinin receptor antagonists ex: Aprepitent

7. Cannabinoid receptor antagonists ex: Dronabinol, Nabilone

8. Corticosteroids and NSAIDs9. Benzodiazepines ex: Alprazolam, Diazepam

10. Phosphorated carbohydrate solutionsEx: Aqueous solutions of glucose,

fructose and phosphoric acid

CHOICE OF ANIMALSAnimals normally used-not useful

Degenerate vomiting reflex – rodents

Commonly used animals:Dogs House musk shrew (Suncus murinus)

Cats Least shrew (Cryptotis parva)Ferrets GerbilsMonkeys Pigeons

CHOICE OF EMETOGENSDRUG INDUCED RADIATION STIMULUSMOTION STIMULUS

PARAMETERS ASSESSEDBehavioral changesLatency to first retching and

vomitingNumber of vomiting episodesConditioned flavor avoidance

(PICA) in rats and mouse

DRUG INDUCED EMESIS MODELS

1. •Cisplatin- induced emesis model

2. •Apomorphine- induced emesis model

3. • CuSO4- induced emesis model

4. •Methotrexate- induced emesis model

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

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.

CONTROL GROUP: Vehicle is administered.Ten mins later, cisplatin is administered IV at a dose of 3.2mg/kg/ml.

Cisplatin-induced dog model

Cisplatin-induced cat modelDescribed by John et al.

Cats of either sex, 2-6 kg.

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.

OBSERVATION FOR 4

HOURS FOR EMETIC EPISODES

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.

Animals are subjected to overnight fasting.

Cisplatin-induced ferret model

TEST GROUP

Test drug and Cisplatin (IV at a dose of 10 mg/kg/ml) are administered.

If Test drug is given orally, give cisplatin 30 mins later.

OBSERVATION FOR 4

HOURS FOR EMETIC EPISODES

CONTROL GROUP

Vehicle and Cisplatin (IV at a dose of 10 mg/kg/ml) are administered.

Pigeon model

S. murinus model

Rat model

4 mg/kg IV 20 mg/kg IP 3-10 mg/kg IP

Duration between administration of drug/ vehicle and cisplatin depends upon expected time of drug action

Duration between administration of drug/ vehicle and cisplatin is 30 mins.

Cisplatin is administered 30 mins after rats have been pre-treated with drug/ vehicle.

Observed for emetic episodes

Observed for 2h for behavioral changes as well as emetic episodes (latency & frequency)

Observe for pica (ingestion of non-food substances)

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.

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.

Dog model Ferret model Rat model

0.3 mg/kg SC 0.25 mg/kg SC 10 mg/kg IP

Duration between administration of drug and apomorphine depends upon expected time of drug action

Duration between administration of drug and apomorphine is 30 mins.

Apomorphine is administered to rats pre-treated with drug/ vehicle.

Observed for emetic episodes

Observed for 60 mins for behavioral changes as well as emetic episodes

Observe for pica (ingestion of non-food substances)

Copper sulfate-induced emesis modelCOPPER 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

Dog model Cat model

100 mg/kg via an orogastric tube

40 mg/kg orally

Observed for 1 hour for emetic episodes

Cats are administered test drug/ vehicle followed by oral administration of threshold dose of CuSO4.

Dogs with no obvious toxicity are retested after an interval of 2 weeks.

Observed for emetic episodes

Ferret model Sun murinus model

Chick model

40 mg/kg orally 40 mg/kg intragastric

50 mg/kg orally

Drug/ vehicle pretreated ferrets are administered CuSO4.

Duration between administration of drug and CuSO4 is 30 mins.

Duration between administration of drug and CuSO4 is 10 mins.

Observed for latency and frequency of emetic episodes

Observed for 60 mins for emetic episodes

Observed for latency and frequency of emetic episodes

MTX- induced Delayed emesis modelAnimals: 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

Motion-induced emesis modelo Dogs are probably as sensitive to

motion-induced emesis as man.

COMMONLY USED MODELSo CAT MODELo SUNCUS MURINUS MODELo RAT MODEL

Cat model Suncus murinus model

Rat model

Vertical oscillations at 0.3 Hz through a distance of 75 cm

Horizontal oscillations of 4 cm at 1 Hz for 10 min

60 min double rotations

Repetitive licking, salivation often dripping out of mouth, or vomiting

Emetic episodes are noted during motion as well as after motion cease

↑ kaolin intake indicates motion sickness

↑ latency/ ↓frequency of emesis in cats pretreated with drug indicates antiemetic action

* Animal can be exposed only twice in 1 week d/t adaption to motion stimuli

↓ kaolin intake in rats pretreated with drug indicates antiemetic action

Radiation- induced emesis model

RADIATION INDUCED EMESIS MODEL

oDOG MODELoFERRET MODELoRAT MODEL

Ferrets are most sensitive to radiations followed by dogs. Cats are resistant to radiations.

Dog model Ferret model Rat model60Co; 8 Gy administered to total body surface

60Co; 201 cGy 4Gy of total body irradiation (abdominal > head irradiation)

One group gets drug & other group gets no medications

Emesis incidence of 100% is reported at 201 cGy in ferret

Exposure to radiation induces pica in rats

↑ latency/ ↓frequency of emesis in cats pretreated with drug indicates antiemetic action

↑ latency/ ↓frequency of emesis in cats pretreated with drug indicates antiemetic action

↓ kaolin intake in rats pretreated with drug indicates antiemetic action

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.

S. murinus model

•Either sex, 20-50 g•Weaned at 20 days•Housed in transparent cages•Obs. Chamber well illuminated

LiCl 100 mg/kg IPVehicleObserved (45 min); 2nd /3rd conditioning trial

after 72 h, 144h

Test group

Control group

6 days later

LiCl 100 mg/kg IPVehicle

Test drug or vehicle is administered

Physiological saline is given Observe for emetic episodes

Rat model

4 conditioning trials (using LiCl) 72 hours apart

Drug/ vehicle is given to the rats

72 hours after 4th conditioning trial

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)

GAPING

In vitro modelsUsed 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 methods.

5-HT3 Receptor antagonists

1. Distal colon (20mm) of GP

2. Krebs-Henseleit solution

3. 2-methyl-5-HT (Agonist)

4. Tropisetron (Antagonist)

5. Temp: 37˚C6. Vol. (Inner bath) 10

mL7. pH: 7.3- 7.5

↑TROPISETRON

↑ ↑↑ conc./doses of 2-methyl-5-HT

No effect of 2-methyl-5-HT

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Human ModelsApomorphine induced: Apomorphine, 0.05 mg/kg, SC is an appropriate

challenge dose for testing compounds for antiemetic activity in normal human volunteers.

Ipecac inducedHealthy 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.

RECENT ADVANCES IN ANTI-EMETIC DRUGS

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 2015Netupitant + Palonosetron

NK-1# + 5-HT3 #

CINV Oct 2014

Doxylamine succinate + Pyridoxine HCl DR

H1# Nausea and vomiting of pregnancy

Apr 2013

REFERENCESDrug 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.