2016B15 Briefly describe the pharmacodynamics of agents used in the treatment of post-operative
nausea and vomiting (PONV) with particular reference to their site of action and side effects.

What is it

·     Region in area postrema outside blood-brain body

·     Purpose to protect against ingested toxins

·     Stimulated CTZ activates vomiting centre (VC)

Emetogenic receptors

·     Serotonin

·     Histamine

·     Muscarinic

·     Opioid

·     Dopamine

(Sarah hates men on drugs)

Drug

Mechanism of anti-emesis

Side effects

Dexamethasone

·     Not well understood

·     For PONV prevention, not rescue
(onset 2 hours)

·     Receptor: transcription factor in cytosol -> affects 25% of genome

·     Location: ? nucleus tractus solitarius (NTS)

·     ↑BSL (especially if diabetic)

·     Anxiety/depression, psychosis, insomnia

·     Peri-anal pain if rapid IV injection (due to phosphate esters)

·     ? ↑Infection (PADDI trial in progress)

5-HT₃ antagonist

e.g. ondansetron

·     Central: ↓afferent CTZ -> VC

·     Peripheral: ↓CNX afferent to CTZ via NTS

·     Headache

·     Sedation

·     Constipation

·     Allergy/anaphylaxis rare

·     ↑QT_C

·     Inhibit analgesic effect of tramadol (serotonin reuptake inhibition)

DA₂ antagonist:

-Butyrophenone

e.g. droperidol

·     ↓Afferent from CTZ to VC

·     Sedation

·     Extra-pyramidal side effects (EPSE)

o Parkinsonism

o Akathisia

o Dystonia

o Tardive dyskinesia

·     Avoid in Parkinson’s disease

·     Neuroleptic malignant syndrome

·     ↑QT_C, TdP

·     Mild hypotension (α₁ antagonist)

DA₂ antagonist:

-Phenothiazine e.g. prochlorperazine

·     ↓Afferent CTZ -> VC

·     Sedation

·     EPSE

DA₂ antagonist:

-Benzamide

e.g. metoclop

·     Central: DA₂i, 5HT₃i
(↓afferents from CTZ to VC)

·     Peripheral: DA₂i, 5HT_4a
(↓afferent from CNX to CTZ via NTS)

·     Anti-emetic and prokinetic

·     EPSE

·     ↑PRL: galactorrhoea, depression, headache

Anti-histamine first generation

e.g. cyclizine

·     ↓Afferent from CTZ to VC

·     ↓Afferent from vestibular apparatus to CTZ

·     Strong anti-muscarinic

·     Weak anti-DA

·     Sedation

Anti-muscarinic

e.g. atropine

·     mAChRi

·     Central: CTZ, vestibular

·     Peripheral: CNX afferent

·     Central anticholinergic

·     ↑HR

·     Mydriasis, blurred vision

·     Dry skin, flushing, hyperthermia

Propofol

·     Central 5HT₃i

·     ↓Afferent from CTZ to VC

·     Minimal at tiny dose e.g. 20mg

Benzodiazepines e.g. midazolam

·     Positive modulator at GABA-A

·     ? ↓cortical afferent to CTZ

·     Antegrade amnesia

Cannabinoids

·     Cannabinoid receptor in GIT

·     Especially cancer-associated N&V

·     Psychosis

NK-1 antagonist

e.g. aprepitant

·     Substance P antagonist at NK-1R

·     Peripheral: ↓CNX afferent to CTZ via NTS

·     Esp cancer-associated N&V

·     Inhibit CYP3A4