Dr. D. K. BrahmaAssociate Professor

Department of PharmacologyNEIGRIHMS, Shillong

Emetic Response: Relaxation of fundus, body of stomach and also the oesophageal sphincter and oesophagus – but contraction of pylorus and duodenum – then rythmic contraction of diaphragm and abdominal muscles - expulsion via mouth

Centre: Medulla Oblongata

Relay Centers: chemoreceptor trigger zone (CTZ) and nucleus tractussolitarius (NTS)

Afferent impulses: GIT, throat and other viscera

Triggering agents: Blood borne drugs, mediators, hormones and toxins etc. – clinically cytotoxic drugs and radiation

Transmitter: 5-HT (enterochromaffin cells) – via 5HT3 receptor of ENS – to vagal and spinal visceral neurones ----- to CTZ and NTS

Spilling of 5-HT due to massive release – acts on CTZ

Other mediators: H1, D2, 5HT3, Muscarinic M and opioid µ etc. – expressed in CTZ and NTS

Vestibular apparatus: generates impulses◦ Body equilibrium disturbed

◦ Ototoxic drugs

Mainly relayed by cerebellum to vomiting centre – Muscarinic and H1 receptors

Directly in higher centres: Bad smell, ghastly sight, pain, fear etc. – drug cisplatin

Drugs which induce vomiting Acts on CTZ: Apomorphine Acts reflexly and on CTZ: Ipecacuanha Apomorphine: Morphine derivative – semi-

synthetic – Dopaminergic agonist in CTZ◦ 6 mg IM/SC – acts within 5 minutes◦ Respiratory depression◦ Orally – not recommended (large dose – slow

inconsistent)◦ Parkinsonism

Ipecacuanha: Cephaelais ipecacuanha◦ Syrup ipecac – 15 to 30 ml (10 to 15 in child)◦ Action takes 15 minutes◦ MOA: Irritation of Gastric mucosa and directly on CTZ

Salt water• Warm water – mild emetic

• 2 spoonful of common salt in 1 pint of warm water

Mustard seed• 1 table spoonful ground mustard seeds in half-pin

of warm water

• Strong coffee is one of the best domestic stimulants, especially after a narcotic poison

In Corrosive poisoning – acid and alkali (why?)

In CNS stimulant poisoning

To unconscious patients

In Morphine and Phenothiazine poisoning

1. Anticholinergics: Hyoscine, Dicyclomine2. H1 antihistaminics: Promethazine,

Diphenhydramine, Doxylamine, Cyclizine, Meclizine and Cinnarazine

3. Neuroleptics (D2 blockers): Chlorpromazine, Prochlorperazine and Haloperidol

4. Prokinetics: Metoclopramide, Domperidone, Cisapride, Mosapride and Tegaserod

5. 5HT3 antagonists: Ondansetron, Granisetron6. Others: Dexamethasone, Benzodiazepines and

Cannabinoids7. Newer Ones: NK1 receptor antagonist -

Aprepitant

Hyoscine: Motion Sickness (0.2 to 0.4 mg IM)◦ Used IM/SC, but short duration of action

◦ MOA: Blocking of cholinergic link of vestibular apparatus to the vomiting centre – does not work in vomiting due to other aetiology

◦ ADRs: Sedation, dry mouth and other anticholinergic effects

◦ Transdermal delivery system (1.5 mg)

Dicyclomine: Prophylaxis of motion sickness and morning sickness

Primarily used in motion sickness, morning sickness and some other vomiting in lesser extent – also anticholinergic, antihistaminic and antidopaminergic actions

Promethazine (Phenothiazine), diphenhydramine: 4 – 6 Hours protection◦ Combined with metoclopramide in CINV: additive effect plus counters

extra pyramidal effects

Promethazine theoclate (Avomine) – motion sickness

Doxylamine: Sedative H1 antihistaminic – marketed in combination with Pyridoxine – specifically for morning sickness –duration of action 10 Hours (at bed time) – drowsiness, dry mouth, vertigo

Meclizine: Long duration of action – sea sickness Cinnarizine: anti vertigo action – inhibits Ca++ influx in

endolymph

Motion Sickness: Anticholinergics are preferred – followed by H1 Antihistaminics –antidopaminergics do not work

Morning Sickness: Preferably drugs should be avoided – reassurance and dietary modification◦ Dicyclomine, promethazine or metoclopramide are

preferred at low doses

Uses:◦ Useful in drug induced post anaesthetic nausea and

vomiting◦ Disease induced vomiting – Gastroenteritis, uraemia,

liver disease◦ Cancer chemotherapy◦ Radiation sickness (less)◦ Morning sickness

ADRs: Sedation, acute muscle dystonia –diagnose the cause first before administering

Prochlorperazine (Stemetil) – D2 blocking agent -labyrinthine suppressant – antivertigo and antiemetic action. Effective in CINV with vertigo◦ EPS and muscle dystonia

Actions on GIT: On upper GIT - Increases gastric peristalsis◦ Relaxes pylorus and 1st part of duodenum – better

gastric emptying◦ LES tone increased – also increases Intestinal

peristalsis

Actions on CNS: Acts on CNS – can counter Apomorphine induced vomiting◦ Gastrokinetic action contributes◦ No antipsychotic property, but has extra pyramidal

and prolactin secreting effects (Promethazinecontext)

1. D2 antagonism: Dopamine is inhibitory transmitter via D2 receptor – delays gastric emptying – also relaxation of LES – nausea and vomiting –Metoclopramide causes opposite effect• Also central antidopaminergic action

2. 5-HT4 agonism: enhanced Acetylcholine release in myenteric plexus – gastric hurrying and increased LES tone

3. 5-HT3 antagonism: at high concentration• Blocks at inhibitory myenteric interneurones and CTZ

/NTS

Pharmacokinetics: Absorbed orally, crosses BBB and placenta and secreted in milk. Conjugated in liver, t1/2 = 4 – 6 Hrs.

Stimuli – cause 5-HT release Stimulates extrinsic and intrinsic

pathway Via peripheral 5-HT3 receptors Extrinsic pathway – via vagus

and dorsal root ganglia – CNS -vomiting stimulation –ondansetron

Intrinsic pathway – excitatory and inhibitory interneurones co-ordinates peristalsis◦ Contraction of proximal and

relaxation of distal gut muscles◦ Ach/CGRP and NANC (NO)◦ Prokinetics (Meto and Csprd) –

activates prejunctional 5-HT4 –promote release of Ach/CGRP –contractile activity

◦ Also weak 5-HT3 blocking action (inhibitory neurones)

◦ Meto and Csprd also inhibits D2 action normally D2 acts as releaser of Ach – more contraction with Meto

ADRs: Sedation, dizziness, loose stool and muscle dystonia◦ Long use: Parkinsonism, galactorrhoea, gynaecomastia◦ Safe in pregnancy but in lactating mother children may have

loose stool, dystonia etc. DI – abolishes levodopa action

Uses: ◦ Antiemetic: Postoperative, drug induced, disease

associated, radiation induced etc. but not effective in motion sickness. Still preferred in vomiting due to anticancer drug – in combination with Promethazine

◦ Gastrokinetic: To accelerate gastric emptying – Emergency GA, gastroparesis (post vagotomy), duodenal intubation etc.

◦ Dyspepsia: stops hiccup◦ GERD: Does not aid in healing, PPIs are preferred – used as

adjuvant

Chemically related to haloperidol but action like Metoclopramide D2 antagonist – in upper GIT (not attenuated by atropine) Rarely EP side effect – does not cross BBB, but

hyperprolactinemia occurs Acts mainly through CTZ – outside BBB Does not abolish action of levodopa Kinetics: absorbed orally but 15% bioavailability – high 1st pass

metabolism, completely metabolized and excreted in urine. T1/2 – 7 – 8 Hrs

ADRs: Less than Metoclopramide – dry mouth, loose stool, headache, galactorrhoea etc. Arrhythmia on injection

Uses: Similar as Metoclopramide but milder spectrum of action –not effective in chemotherapy

Read yourself (Prokinetics) – Cisapride, mosapride, Itopride etc.

Developed for Chemotherapy/radiotherapy induced vomiting – also effective in others (PONV)

MOA: Acts peripherally as well as centrally - Blocks depolarizing action of 5-HT3 receptors in vagus at GIT and CTZ/NTS◦ No action on Dopamine receptor – does not block Apomorphine

induced vomiting and mild gastrokinetic effect

Kinetics: 60 – 70% bioavailability – first pass metabolism. Metabolized as glucoronide and sulfate. Eliminated in urine and faeces. T1/2 life 5-7 Hrs

Dose: 8 mg slow IV for 15 minutes ½ hr before chemotherapy. Followed by 2 such doses 4 hours apart. Then 8 mg orally twice daily for 1 week. For others 4 – 8 mg IV followed by every 8 hourly.

80% success – better/equal to Metoclopramide – no dystonia or sedation. Adjuvant improve response.

ADRs: Headache and dizziness. Mild constipation and abdominal discomfort. Hypotension, allergic reactions, chest pain and bradycardia etc.

Other Drugs: Granisetron, Palonosetron and Ramosetron etc. – READ YOURSELF

Aprepitant: Newer antiemetic

MOA: Emetogenic chemotherapy releases Substance P – stimulates CTZ and NTS by acting on NK1 -blocking of NK1 receptors causes emesis blocking◦ Little effect on 5-HT3 or D2 receptor◦ GIT motility not affected

Uses: 125 mg + 80 mg + 80 mg for 3 days with IV Ondansetron and Dexamethasone – for cisplatininduced vomiting – useful in multiple cycle patients –Orally 40 mg can be used for PONV

Kinetics: well absorbed orally, metabolized in liver, excreted in faeces and urine. T1/2 10 – 13 Hrs

ADRs: Weakness, fatigue, flatulence etc.

Corticosteroids, Benzodiazepines and cannabinoides