GI Physiology - Nausea and Vomiting

Question 1

Describe the vomiting centre and its inputs

Answer 1

Neurological control centre for vomiting reflex, located in medulla
Though to be a distriuted group of neurones forming a central pattern generator, rather than distinct anatomical site

4 main inputs

Chemoreceptor trigger zone Outside the BBB, senses blood-borne emetics
(D₂, 5HT₃, and μ)

Vestibular system In the cerebellum, inputs from inner ear
(H₁ & M₃ receptors induce motion sickness)

Higher centres Extremes of emotion & stress, disgust (via NK-1)

Solitary tract nucleus In medulla - physical obstruction of pharynx, overdistension of stomach
(ACh and 5HT₃)

Outputs via CNs V, VII, IX, X, XII

NK-1 Neurokinin 1
D₂ Dopamine
5HT₃ Serotonin
μ Mu Opioid
H₁ Histamine
M₃ Muscarinic ACh

Question 2

Explain the steps that happen as part of the vomiting reflex

Answer 2

Complex chain of events
Glottis closes (protect airway
Soft palate lifts (protect nasopharynx)
Excessive salivation (protect from acid)
Tachycardia (increase oxygen supply while glottis closed)
Downwards diaphragmatic contraction
Gastro-oesophageal junction relaxes
Abdominal muscles contract
Retroperistaltic wave from duodenum into pylorus

Increases intraabdominal pressure
Forces stomach contents up the oesophagus.

Question 3

Discuss the solitary tract nucleus

Answer 3

Vagal nucleus, adjacent to chemoreceptor trigger zone

May serve as final common pathway for all inputs to vomiting centre

Inputs:
Stomach & pharynx Chemoreceptors (toxin ingestion, extreme pH changes, irritants)
Mechanoreceptors (overdstension induces vomiting)
Spinal cord
Spino-reticular afferent impulses cause N&V associated with severe physical injury
Heart
Blood pressure & heart rate

Question 4

What is the chemoreceptor trigger zone?

Answer 4

CTZ (AKA area postrema) - circumventricular organ, dorsal surface of medulla oblongata, on floor of fourth ventricle.

Lies outside BBB, receptors for blood borne noxious substances

CTZ receptors:
μ (Opioid)
D2 (Dopamine)
5HT₃ (Serotonin)
Likely also has:
κ (Opiod)
NK1 (Neurokinin-1)
H₁ & H₂ (Histamine)

Question 5

What factors influence PONV, and how is it graded?

APFEL score IMAGE

Answer 5

Anaesthetic factors
Opioids (dose dependent)
Nitrous oxide & volatiles
Neostigmine
Ergometrine
Etomidate

Patient factors
Female
Hx of Motion sickness or PONV
Non-smokers
Rare in < 2yrs of age
Prolonged fasting or full stomach
Anxiety

Surgical factors
Gynaecology
ENT (Especially middle ear)
Breast
Laparoscopy
Laparotomy
Craniotomy
Strabismus repair
Adenotonsillectomy
Hernia repair
Orchidopexy/penile surgery

APFEL score
0 = 10%
1 = 20%
2 = 40%
3 = 60%
4 = 80%

Risk factors (1 point each)
Female gender
Non-smoker
Hx of PONV
Post-op opioids

Question 6

Discuss Serotonin receptor antagonist anti-emetics

Answer 6

Eg. Ondansetron
Originally licenced for chemotherapy N&V, now widely used
Structure synthetic cabazole
Mechanism of action peripheral effects via GI tract serotonin receptors, central effects CTZ
Pharmacokinetics
Absorption: 60% PO bioavailability
Distribution: 75% protein bound
Metabolism: Hepatic, inactive metabolites - reduce dose in hepatic impairment
Excretion: Renal
Dose 4-8mg or 0.1mg/kg in children
Side effects constipation, bradycardia, headache & flushing (if given quickly IV), reported to cause extrapyramidal SE

Question 7

Discuss Histamine receptor antagonist anti-emetics

Answer 7

Eg. Cyclizine
Structure Piperazine derivative
Mechanism of action H₁ antagonism, mainly vestibular & cerebellar, with some antimuscarinic activity
Pharmacokinetics
Absorption: 50% PO bioavailability
Distribution: 75% protein bound
Metabolism: Hepatic
Excretion: Renal
Dose 25-50mg TDS, or 0.1mg/kg in children
Side effects Tachycardia, dry mouth, drowsiness, blurred vision, increased lower oesophageal sphincter tone

Question 8

Discuss Dopamine receptor antagonist anti-emetics

Answer 8

3 Classes:

Phenothiazines
Prochlorperazine - Phenothiazine neuroleptic (antipsychotic)
Chlorpromazine - Propylamine antipsychotic
Mechanism of action D₂ antagonist, mainly on chemoreceptor trigger zone
Pharmacokinetics
Absorption: 12.5-35% PO bioavailability
Distribution: >90% protein bound
Metabolism: Hepatic
Excretion: Renal
Dose 12.5mg IM (adults
Side effects Increased QTc interval, VTE, NMS, lowers seizure threshold, parkinsonism, oculogyric crisis, dry mouth

Butyrophenones
Domperidone (Doesn’t cross BB) & Droperidol (crosses BBB)
Mechanism of action
D₂ receptors gut and CRZ
Increases gut motility
Pharmacokinetics
Absorption: 15% PO bioavailability
Distribution: >90% protein obund
Metabolism: Hepatic CYP3A4
Excretion: 70% faecal 30% renal
Dose 10mg TDS adults
Side effects Ventricular arrhythmias, sedation, hyperprolactinaemia

Benzamides
Metoclopramide
Mechanism of action
D₂ receptor antagonism at CTZ
5HT₃ receptor antagonism
Gastric prokinetic effect
Pharmacokinetics
Absorption: 60-80% PO bioavailability
Distribution: 30% protein bound
Metabolism: Hepatic (hydroxylation & glucuronidation)
Excretion: Renal
Dose 10-20mg TDS
Side effects Extrapyramidal SE, oxculogyric crisis, dystonia (more common young women & elderly, manage with antimuscarinics or antihistamines)

Question 9

Discuss Muscarinic receptor antagonist anti-emetics

Answer 9

Eg. Hyoscine
Structure Only L-hyoscine is pharmacologically active
Mechanism of action Antimuscarinic effects in vomiting centre & vestibular system
Pharmacokinetics
Absorption: 50% PO bioavailability
Distribution: 45% protein bound
Metabolism: Hepatic
Excretion: Renal
Dose 300-600mcg for adults
Side effects Sedation, central anticholinergic syndrome (Often presents as post-op agitation, with drowsiness, hallucinations, ataxia), very dry mouth

Question 10

Discuss Neurokinin 1 receptor antagonist anti-emetics

Answer 10

Eg. Aprepitant
Mechanism of action Central action on Neurokinin-1 receptors, inhibits substance P
Pharmacokinetics
Absorption: 60% PO bioavailability
Distribution: 95% protein bound
Metabolism: Hepatic CYP3A4
Excretion: 95% Faecal
Dose 40mg PO
Side effects Fatigue, hiccups, loss of appetite, alopecia

Question 11

Discuss the anti-emetic effects of dexamethasone

Answer 11

Structure synthetic glucocorticoid
Mechanism of action Acts on nuclear glucocorticoid receptors, exact pathway unclear, potentially stimulation of appetite reducing serotonin release from GI tract
Pharmacokinetics
Absorption: 80% PO bioavailability
Distribution: 75% protein bound
Metabolism: Hepatic
Excretion: Renal
Dose 4-8mg, or 0.1mg/kg
Side effects deranged blood glucose, delirium, immune suppresion