GI - Nausea & Vomiting Flashcards
What is emetic reflex
– contraction of abdominal muscles and diaphragm increasing pressure in stomach
– closure of glottis (prevents vomit entering lungs)
which drugs can cause vomiting
cancer drugs
Causes of emesis (that you might need to treat)
– 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
The Brain and Vomiting – Control Centres
draw diagram
Vomiting reflex
draw diagram
Emesis controlled by
• 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
Emesis - Integrate chemical and neuronal inputs
– Signals from periphery sense “something wrong” • Gut chemo-, mechano-sensation
– Signals from higher brain regions “contextualise” other inputs • Sight and; smell; balance; emotion
Emesis - Vomiting reflex
– Co-ordinated motor-pattern
– Retroperistalsis, gastric contraction, abdominal wall contraction
What ascends from stomach to brain
Vagal afferents
What is very responsive to chemicals in the blood
Chemo Trigger Zone (Area Postrema) D2, 5-HT, NK1
Therapy listed by cause of emesis - motion sickness
Anti-histamines, anti-muscarinics
Therapy listed by cause of emesis - DI nausea + vomiting
– try minimize gastric irritation with equal spacing of drug; take with food
– otherwise –Dopamine antagonists , antihistamine
Therapy listed by cause of emesis - post op vomit
– Dopamine antagonists (phenothiazines)
– 5HT3 antagonist
Therapy listed by cause of emesis - migraine
Phenothiazines helpful because also speeds gastric emptying and facilitates absorption of analgesics
Therapy listed by cause of emesis - CINV (chemotherapy)
– dexamethasone, 5HT3 antagonist, NK1 antagonist
Anti-emetics: anti-histamines (H1)
indications, adr, cautions
– 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
Anti-emetics: anti-muscarinic agents
indications, PK, adr, cautions, contraindications
• 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
Anti-emetics: dopamine antagonists (1)
indications, adr, cautions, contraindications
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
MHRA/CHM advice - Domperidone:
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
HRA/CHM advice Metoclopramide:
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)
5HT3 antagonists
Indications, PK, ADR
• 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
Neurokinin Receptor Antagonists
Indications, PK, ADR
• 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
Olanzapine – Off-label use for CINV
• 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
Why Does Chemotherapy Induce CINV?
• 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
Risk Factors for CINV
- 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
Pharmacology of CINV
• 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?
What is the rationale for prescribing ondansetron,
dexamethasone and metoclopromide?
• 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
How is chemotherapy-induced nausea
and vomiting classified?
• 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
2 further examples of dopamine antagonists: D
indications, PK
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)
2 further examples of dopamine antagonists: M
indications, PK, ADR, cautions, Contraindications
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
