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.

 

List:

·     Diagramme

·     Chemoreceptor trigger zone

·     Table of drugs, MoA, side effects

 

Diagramme:

 

Chemoreceptor trigger zone:

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

·    ↑QTC

·    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

·    ↑QTC, 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, 5HT4a
(↓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