Emetics ,Antiemetics Prokinetic Agents

Dr. Akshil Mehta

Physiology of Vomiting

• Stimulation of vomiting centre in medulla oblongata

• It receives afferents from CTZ vestibular apparatusGI tractCentres in the Brain

Physiology of Vomiting Cytotoxic drugs / radiation

Damage cells , irritate the gut mucosa

Release mediators from gut mucosa

Activation of vagal afferents in the gut

Emetogenic impulses to NTS,CTZ

Stimulate Emetic centre

Vomiting

Emetics

Apomorphine : • Derivative of morphine• Given SC/IM• Produces vomiting in 5-10 min• Stimulates dopaminergic Rs in CTZ• Depresses Respiration ..so should be avoided

in presence of respiratory depression

Emetics contd.

Ipecacuanha• Obtained from the dried roots of Cephalis

Ipecacuanha which contains an alkaloid emetine .• Given as syrup 15- 20 ml vomiting in 15 minutes • Acts

Directly on CTZReflexly by irritating the gastric mucosa

• Safe in Children

Drugs that produce Emesis

• Most cancer drugs• Levodopa , bromocriptine, other dopamine

agonists• Morphine and opioids• Cholinomimetic drugs• Metronidazole • Ergot alkaloids • Chloroquine, emetine

Antiemesis

• Vomiting is a protective mechanism.

• Aimed at eliminating the unwanted harmful material from the stomach .

• In dehydration , weakness and electrolyte imbalance .. Vomiting needs to be suppressed with drugs

Antiemetic Classification • Dopamine D2 antagonists – ( prokinetics )

Metaclopromide , domperidone , trimethobenamide• 5HT3 antagonists

Ondansetron, granisetron, dolasetron Tropisetron, palanosetron

• Antimuscarinics Hyoscine, Promethazine Cyclizine , diphenhydramine

• Neuroleptics Chlorpromazine, prochlorperazine Haloperidol

• Neurokinin Rs antagonists Aprepitant Forprepitant

• Other Agents Cisapride , corticosteriods Cannabinoids – dronabinol, nabilone

Dopamine D2 Antagonists

• Metoclopramide and domperidone act centrally by blocking dopamine D2 Rs in the CTZ and thereby prevent vomiting .

They enhance the tone of the LES and increase gastric peristalsis … Prokinetics

• Trimethobenzamide has antihistaminic activity in addition to dopamine blockade

5HT3 Antagonists

• Blocks 5 HT3 rs in the gut , CTZ and NTS.• Efficient Antiemetics • Effective both orally and parenterally • Largely safe – no sedation or other CNS/

autonomic side effects . • Adverse effects negligible – headache , GI

disturbances .• Drugs of choice in postoperative and anticancer

drug- induced vomiting

Pharmacokinetics

• 5 HT3 are well absorbed from the gut • Metabolised by the liver by microsomal

enzymes • Excreted by the kidneys and partly through

the gut . • They can be given orally , IM and IV .• Dose reduction may be required in liver

dysfunction

Adverse Effects

• Headache• Constipation • Abdominal discomfort • Rashes • Dolesetron prolongs QT interval and so should

be avoided in patients with prolonged QT interval .

Uses• To control vomiting induced by anticancer

drugs or radiotherapy .IV 30 min before or orally 1 hr before starting

chemotherapy . ( ondansetron 8 mg infusion over 15 min. From 2 nd day.. 8mg orally for 3-7 days ).

• Postoperative vomiting and other drug induced vomiting (but not in motion sickness )In pov 4-8mg ondansetron before induction and

the dose may be repeated after 8 hr or as required

Ondansetron • Oral bioavailability is 60 – 70 %• T ½ of 3- 5 hr and a duration of action of 4 -12 hr. • Dose 4-24 mg in one / 2 divided doses • Emset , Osteron 4, 8 mg tab 2mg/ml inj.

Palanosetron has a higher affinity for the 5 HT3 rs longer t ½

Granisetron • More potent than ondansetron as an

antiemetic • Though Granisetron , Dolasetron and

Topisetron have longer t ½, their biological t ½ remains the same .

Dose: Granisetron 1-2 mg OD . 10 μg /kg IV .GRANISET 1,2 mg tab . 1mg /ml/inj.

Drugs for vomiting due to various causesConditions Drugs

Motion sickness Hyoscine , cyclizine , Promethazine , Cinnarizine

Vomiting due to cytotoxic drugs

1. Ondansetron + Dexamethsone + aprepitant

2. Metoclopramide + dexamethasone + diphenhydramine + lorezepam

Vomiting due to other drugs

Chlorpromazine , Metoclopramide

Postoperative vomiting

Ondansetron , Metoclopramide

Vomiting in Pregnancy

Doxylamine , Dicyclomine , pyridoxine , cyclizine , meclizine , Metoclopramide

The stimuli , pathways and centre mediating emetic reflex and Rs involved

Fear emotion, Anticipation , Smell, sight Higher Centres

Emetic Centre Cerebellum

Inner Ear

NTS, 5 HT3 , D2, M3, H1

CTZ, (Area postrema ), 5 HT3, D2 , M1

Pharynx Stomach , Small intestines ( 5 HT3)

Toxins , Drugs , Irritants

Anti Muscarinics Hyosine • It is a labyrinthine sedative very effective in motion

sickness( due to over stimulation of vestibular apparatus along with psychological environmental factors ).

• It relaxes the gastrointestinal smooth muscle. • Taken 30 min before journey ,( 0.4 – 0.6 mg oral) acts

for 6 hrs and the dose should be repeated if the journey is longer than that .

• A transdermal patch delivers hyoscine constantly over 3 days and is to be applied behind the ear .

• Sedation and dry mouth are common side effects .

• Dicyclomine : is used to control vomiting in morning sickness and motion sickness – orally in the dose of 10 -20 mg .

• H1 antihistamine : Like promethazine , diphenhydramine , doxylamine , cyclizine and cinnarizine have ant cholinergic properties .Antihistamines block H1 rs in the area postrema as well as muscarinic rs in the CNS .they also act in GIT. Useful in motion sickness and post operative vomiting .

Doxylamine • Available in combination with pyridoxine for

morning sickness . • Free of teratogenic potential but its safety is

not proved .• Dose : 10 mg + pyridoxine 10mg GRAVIDOX.

DOXINATE 10 mg tab.

Neuroleptics • Blocks D2 rs in the CTZ • Useful in vomiting due to most causes except

motion sickness • Common side effects :Sedation and extra

pyramidal symptoms .• Prochlorperazine is anti emetic as well useful

in vomiting with vertigo.Dose ( 5- 25 mg . STEMETIL 5 , 25mg tab , 12.5 mg /ml Inj.

Neurokinin Rs AntagonistsThese drugs bind to Neurokinin (nk1) rs in the

area postrema and act as anti emetics .

Aprepitant available for oral use while fosaprepitant is given IV and gets converted to aprepitant in the body .Has a t ½ of 12 hr . It is metabolised in the liver by microsomal enzymes CYP3A4 and may compare with other drugs metabolised by the same pathways .

NK1 antagonist may cause dizziness , weakness and diarrhoea .

NK1 antagonist used for prevention of chemotherapy induced vomiting in combination with 5 HT3 antagonists and a glucocorticoid.

Dose : Aprepiant 125mg 1 hr before chemotherapy followed by 80mg daily for next days .

Corticosteroids • used in combination with other antiemetics like

ondansetron or metoclopramide .• Controls delayed vomiting following anti cancer

drug therapy .• Act by activating the glucocorticoid rs in the NTS .Pyridoxine ( Vitamin B6 ) • Used as prevention of vomiting in pregnancy

without any known pharmacological basis .• Serves as a co factor in GABA synthesis and GABA

acting as the inhibitory neurotranmitter at CTZ may suppress vomiting .

• Dose 20 – 60 mg

Sedatives hypnotics :• Barbiturates and benzodiazipines may raise

the threshold for vomiting by depressing the CNS .

• Their anxiolytic and sedative properties also help.

• Used as a adjuvants to other antiemetics in treating anticancer drug – inducing vomiting .

Cannabinoids :• Dronabinol , a cannabiniod is 9 tetra

hydrocannabinol. • It has antiemetic properties • Acts by the stimulation of the Cannabinoid rs

(CB1 ) in the vomiting centre .• It also increases appetite Dronabinol is orally effective and almost

completely absorbed on oral administration Dose 5mg/ m2, 2 hr before chemotherapy and the

dose may be repeated every 4 hr

• Dronabinol : causes hallucinations , euphoria , dysphoria , behavioural abnormalities , dependence , incresed appetite , dryness of mouth and hypotension .

• Can be used as an alternative in the prevention of anticancer drug induced vomiting in combination with other anti emetics – when the other drugs are ineffective .

Also usedas an appatite stimulant.