GI - Nausea & Vomiting

Question 1

What is emetic reflex

Answer 1

– contraction of abdominal muscles and diaphragm increasing pressure in stomach
– closure of glottis (prevents vomit entering lungs)

Question 2

which drugs can cause vomiting

Answer 2

cancer drugs

Question 3

Causes of emesis (that you might need to treat)

Answer 3

– motion sickness
– drug induced nausea and vomiting
– post-operative vomiting
– intracranial pathology (eg migraine, increased pressure due to inflammation or haemorrhage)
– emotional causes
– pain
– drugs and radiation eg during cancer therapy

Question 4

The Brain and Vomiting – Control Centres

Answer 4

draw diagram

Question 5

Vomiting reflex

Answer 5

draw diagram

Question 6

Emesis controlled by

Answer 6

• Emesis controlled by two brainstem areas
– Chemo trigger zone (CTZ) – Area Postrema
• Fenestrated capillaries allow detection of circulating chemicals
– Vomiting Centre – Nucleus of the Solitary Tract

Question 7

Emesis - Integrate chemical and neuronal inputs

Answer 7

– Signals from periphery sense “something wrong” • Gut chemo-, mechano-sensation
– Signals from higher brain regions “contextualise” other inputs • Sight and; smell; balance; emotion

Question 8

Emesis - Vomiting reflex

Answer 8

– Co-ordinated motor-pattern

– Retroperistalsis, gastric contraction, abdominal wall contraction

Question 9

What ascends from stomach to brain

Answer 9

Vagal afferents

Question 10

What is very responsive to chemicals in the blood

Answer 10

Chemo Trigger Zone (Area Postrema) D2, 5-HT, NK1

Question 11

Therapy listed by cause of emesis - motion sickness

Answer 11

Anti-histamines, anti-muscarinics

Question 12

Therapy listed by cause of emesis - DI nausea + vomiting

Answer 12

– try minimize gastric irritation with equal spacing of drug; take with food
– otherwise –Dopamine antagonists , antihistamine

Question 13

Therapy listed by cause of emesis - post op vomit

Answer 13

– Dopamine antagonists (phenothiazines)

– 5HT3 antagonist

Question 14

Therapy listed by cause of emesis - migraine

Answer 14

Phenothiazines helpful because also speeds gastric emptying and facilitates absorption of analgesics

Question 15

Therapy listed by cause of emesis - CINV (chemotherapy)

Answer 15

– dexamethasone, 5HT3 antagonist, NK1 antagonist

Question 16

Anti-emetics: anti-histamines (H1)

indications, adr, cautions

Answer 16

– Cinnarizine, (cyclizine, promethazine)
– Promethazine may be used in pregnancy (severe morning sickness)
– act on vestibular apparatus,VC and CTZ

Indications
– travel sickness,
– Vestibular disorders (vertigo)
– Space motion sickness (Promethazine – NASA)
ADR
– Sedation
– anti-cholinergic effects – dry mouth, blurred vision, constipation, urinary retention
– blocks Ca2+ transport so also causes vasodilation Cautions:
– Significant antimuscarinic activity
– use with caution in prostatic hypertrophy, urinary retention, susceptibility to angle-closure glaucoma, and pyloroduodenal obstruction

Question 17

Anti-emetics: anti-muscarinic agents

indications, PK, adr, cautions, contraindications

Answer 17

• Hyoscine hydrobromide (previously called scopolamine)
• Indications
– OTC for motion sickness (both prophylaxis & treatment), GI disorders
• PK
– for motion sickness can use patch on skin behind ear
• ADR/Cautions
– causes less drowsiness than antihistamines but still caution when driving
– can cause typical anticholinergic ADR
• Contraindications
– myasthenia gravis, paralytic ileus, pyloric stenosis, toxic megacolon and prostatic enlargement

Question 18

Anti-emetics: dopamine antagonists (1)

indications, adr, cautions, contraindications

Answer 18

ACT ON CTZ SO NOT USEFUL FOR MOTION SICKNESS/VESTIBULAR DISORDERS

Phenothiazines
– Prochlorperazine, perphenazine, and trifluoperazine (less sedating than chlorpromazine)
• Indications
– N and V associated with diffuse neoplastic disease, radiation sickness, and emesis caused by drugs such as opioids, general anaesthetics, and cytotoxics
• ADR
– resulting from DA antagonism (“extrapyramidal” motor effects), Sedative, dizziness
– Prochlorperazine can cause anti-cholinergic effects
• Cautions
– avoid prochlorperazine (also cholinergic antagonist) in patients with urinary retention or glaucoma
– prochlorperazine prolongs QT and promotes hypotension
• Contraindications
– Parkinson’s disease
– Phaeochromacytoma – can cause hypertensive crisis
• Interactions
– prochlorperazine potentiates effects of other sedatives
– increases effect of other drugs that lower bp or prolong QT

Question 19

MHRA/CHM advice - Domperidone:

Answer 19

risk of cardiac side- effects
– Domperidone should only be used for the relief of the symptoms of nausea and vomiting;
– Domperidone should be used at the lowest effective dose for the shortest possible duration (max. treatment duration should not normally exceed 1 week);
– Domperidone is contra-indicated for use in conditions where cardiac conduction is, or could be impaired, or where there is underlying cardiac disease, when administered concomitantly with drugs that prolong the QT interval or potent CYP3A4 inhibitors, and in severe hepatic impairment

Question 20

HRA/CHM advice Metoclopramide:

Answer 20

risk of neurological adverse effects
– in adults over 18 years, metoclopramide should only be used for prevention of postoperative nausea and vomiting, radiotherapy-induced nausea and vomiting, delayed (but not acute) chemotherapy-induced nausea and vomiting, and symptomatic treatment of nausea and vomiting, including that associated with acute migraine (where it may also be used to improve absorption of oral analgesics)
– Metoclopramide should only be prescribed for short-term use (up to 5 days)

Question 21

5HT3 antagonists

Indications, PK, ADR

Answer 21

• Ondansetron, Granisetron, Palonosetron
– decrease sensitivity of 5HT receptors: • inVC
• in vagal afferent nerve that detect cytotoxic damage to gut
• Indications
– chemotherapy induced nausea
– post operative nausea
• PK
– short t1/2 4hr
– schedule depends on indication
• ADR
– headache and constipation are common (reduce peristalsis) – dizziness

Question 22

Neurokinin Receptor Antagonists

Indications, PK, ADR

Answer 22

• Aprepitant (p.o.), Fosaprepitant (i.v.), Rolapitant (p.o. – launched 2017)
– Netupitant – only in combination with Palonosetron
• Indications
– Adjunct therapy to dexamethasone and 5HT3 antagonists for prevention of chemotherapy-induced N and V
• PK
– Fosaprepitant prodrug of aprepitant
– Allows single i.v. infusion to replace 3-day oral regime
– Aprepitant/fosaprepitant induce cyp3A4, rolaprepitant does not
• ADR
– GI side effects (constipation, diarrhoea, dyspepsia) are common, as is dizziness and headache

Question 23

Olanzapine – Off-label use for CINV

Answer 23

• Antagonist at multiple receptors
– D1, D2, D3 receptors, serotonin 5-HT2a, 5-HT2c, 5-HT3 and 5-HT6 receptors, α1 adrenergic receptors, muscarinic receptors and histamine H1 receptors
• Used off-label for control of chemotherapy-induced N and V
– Growing body of evidence
• Side effects include sedation at a higher level than with other agents

Question 24

Why Does Chemotherapy Induce CINV?

Answer 24

• Chemotherapy administration -> free radical formation -> 5HT release from enterochromaffin cells in
small intestine
• 5HT
– acts directly on chemoreceptor trigger zone, and
– Stimulates sensory receptors on vagal afferents -> CTZ
• CTZ activates vomiting centre
• Dopamine/D2 and substance P/Neurokinin NK1 are also important signalling mechanisms in this pathway

Question 25

Risk Factors for CINV

Answer 25

• Being female
• Previous nausea and vomiting during pregnancy
• Previous history of motion sickness
• Younger age (typically <50 years)
• Previous uncontrolled CINV
• A history of low alcohol intake

Question 26

Pharmacology of CINV

Answer 26

• 5HT3 antagonists
– Ondansetron, Palonosetron (p.o.) granisetron (i.v.)
– Work well for acute CINV; less effective for delayed CINV (hence only used for 2-3 days after chemotherapy)
• Dopamine D2 antagonist
– Metoclopromide (also weak 5HT3 antagonist)
– Risk of extrapyrimidal side effects (because of high dose)
• NK1 antagonists
– Aprepitant (p.o.), fosaprepitant (i.v.), netupitant (combination with palonosetron)
– Improves antiemetic control of 5HT3 antagonists
• Corticosteroids
– Dexamethasone – works in combination with other antiemetics
– MoA unclear – decrease prostaglandin synthesis?

Question 27

What is the rationale for prescribing ondansetron,

dexamethasone and metoclopromide?

Answer 27

• Ondansetron and dexamethasone given alongside chemotherapy to control acute CINV
• Metocloporomide and dexamethasone given to control delayed CINV
• Palonosetron and netupitant combination given as a more efficacious (but more expensive) alternative to odansetron
– As prophylaxis to reduce anticipatory CINV, and allow Mrs DM to make it to her next cycle of treatment
– Alongside chemotherapy to reduce acute CIMV

Question 28

How is chemotherapy-induced nausea

and vomiting classified?

Answer 28

• Not all chemotherapy has the same emetogenic risk.
Classified according to risk of vomiting in absence of
antiemetic prophylaxis:
– Level 1: minimal risk (<10%)
– Level 2: low risk (10-30%)
– Level 3 moderate risk (30-90%)
– Level 4: High risk (>90%)
• Carboplatin is level 3; pemetrexed is level 2.

• Classification:
– Acute CINV occurs within 24-hours of chemotherapy
– Delayed CINV occurs >24 hours after chemotherapy
– Anticipatory CINV occurs before chemotherapy; it is a
conditioned response; previous stimuli (such as sights or smells) associated with the chemo cycle can stimulate it

Question 29

2 further examples of dopamine antagonists: D

indications, PK

Answer 29

Domperidone
• also pro-kinetic – speed gastric emptying
• Indications
– N and V induced by chemotherapy, DA receptor agonists/levoDOPA
• PK
– dose adjustment usually not required with hepatic or renal insufficiency
– poor brain penetration:
• few extrapyramidal effects
• doesn’t antagonise anti-Parkinson’s effects of DA agonists (CTZ has poor BBB)

Question 30

2 further examples of dopamine antagonists: M

indications, PK, ADR, cautions, Contraindications

Answer 30

Metoclopramide
• Indications
– N andV induced by drugs, post-operatively or migraine
• PK
– metoclopramide metabolized by cyp- reduce dose in hepatic insufficiency
• ADR
– resulting from DA antagonism (“extrapyramidal” motor effects)
• Cautions
– avoid metoclopramide in patients with GI obstructions or haemorrhage (prokinetic)
• Contraindications
– Parkinson’s disease
– Phaeochromacytoma –can cause hypertensive crisis