pharmacology of nausea and vomiting Flashcards
vomiting centre
multiple distributed nuclei in the brainstem
located within the lateral medullary reticular formation
coordinates complex act of vomiting
four sources of afferent input into the vomiting centre
- chemoreceptor trigger zone
- vestibular system
- vagal and spinal afferent nerves from GI tract
- CNS
chemoreceptor trigger zone
caudal end of the forth ventricle within the area postrema, outside the blood brain barrier
responds to etoogenic stimuli from blood or CSF (drugs/toxins)
vestibular system
semicircular canals
motion sickness via CN 8
muscarinic and histamine receptors
vagal and spinal afferent nerves from GI tract
rich in 5-HT3 receptors
irritation to the mucosal results in release of mucosal serotonsis by enterochroomaffin (EC) cells
afferents to vomiting centre as well as CTZ
CNS inputs to vomiting centre
raised intracranial pressure
anxiety/stress
nausea
conscious recognition of the excitation of an area closely related to the vomiting centre
often prodrome of vomitting - not always
vomiting is created by
motor impulses that originate in the vomiting centre
peristalsis in the upper GI tract is reversed and halted in the lower GI tract
cranial nerves close epiglottis
diaphragm and abdominal muscles also required
non-pharmacological considerations of avoiding nausea and vomiting
avoiding strong odours
open area with air movement
diet - small amount to prevent distention,
- avoid spicy, rich, fatty and very sweet foods
- ginger thought to prevent vomiting
metoclopramide
metoclopramide
- multiple mechanisms of action
- enhances response to acetylcholine in the upper GI tract which slows peristalsis
- blocks dopamine receptors in the CTZ
- at higher doses also blocks CTZ serotonin receptors
- multiple routes of administration PO/SV/IV/IM
adverse effects of metoclopramide
extrapyramidal symptoms - more common in younger patients and female patients
rarely causes tardive dyskinesia, higher risk with longer treatment
tardive dyskinesia
repetitive jerking movements that occur in the face neck and tongue
metoclopramide should not be used in patients with
Parkinson’s disease
suspected complete mechanical bowel obstruction duet to pro kinetic effects
prochlorperazine
a piperazine phenothiazine antipsychotic
antiemetic effects via dopamine and muscarinic receptor antagonism
subcutaneous administration not recommended due to irritation
risk of extrapyramidal side effects and it should not be used in Parkinson’s disease
what are extrapyramidal symptoms
involuntary movements, tremors or muscle contractions
prochlorperazine side effects
extrapyramidal side effects
should not bemused in Parkinson’s
domperidone
dopamine antagonist
- active peripherally
- still effective at the CTZ because it lies outside the blood brain barrier
- blocks dopamine receptos in the upper GI tract resulting in increased motility
- oral
- generally well tolerated
domperidone side effects
- increased prolactin levels
- may be confused for a cancer
blood brain barrier
a monolayer of endothelial cells that are joined by tight junctions with a thick basement membrane and astrocytic end feet
multiple control mechanisms
control mechanisms in the BBB
- transmembrane diffusion - lower molecular weight, lipid soluble, no charge
transport systems - both influx and efflux pumps, receptor mediated transcytosis, carrier mediated
transcellular pathway
5HT3 antagonists
ondansetron, granisetron, palonosetron
peripheral and central mechanism of action
- major effect is to block released serotonin in the upper GI tract
- micro effect is at the vomiting centre and CTZ
- mainly work on causes that relate too irriatation of the upper GI tract eg. post-operative, radiotherapy, and chemotherapy
5HT3 antagonists side effects
constipation, headache, fatigue
glucocorticoids
eg. dexamethasone
most commonly used in chemotherapy and peri-operative setting, usually in combination with other drugs
- exact method of anti-emetic effect unknown
- reduced peri-tumoural oedema in cases of raised intracranial pressure secondary to brain tumour
- oral and IV doses are equivalent
side effects of glucocorticoids
short term - increased blood sugar levels, hunger, increased blood pressure
neuropsychiatric irritability and psychosis
long term - osteoporosis, steroid induced diabetes mellitus, proximal myopathy, thin skin
aprepitant
highly selective neurokinin receptor NK-1 antagonist which readily crosses the BBB
- blocks the effects of substance P which normally binds this receptor
- oral- used in combination with 5HT3 antagonists and dexamethosome in the prevention of nausea and vomiting from mod-highly emetogenic chemotherapy
- three day regimen
side effects of aprepitant
associated with fatigue, dizziness and diarrhoea
fosaprepitant
- IV formulation is a prodrug
- rapidly metabolised to aprepitant by many tissue types in vitro
hyoscine
anticholinergic at muscarinic receptor
- minor histamine and serotonin antagonism
- PO/IV/transdermal formulations
- can be used as a patch for the prevention of motion sickness - less side effects
side effects of hyoscine
anticholinergic side effects
- dry mouth, blurred vision, tachycardia, urinary retention, confusion
hyoscine butyl bromide (buscopan) vs hyoscine hydrobromide (kwellen)
hyoscine hydrobromide is derived from plant sources, not charged and therefore able to cross the BB, where is has effect
hyoscine butyl bromide is not an effective antiemetic
cyclizine
primarily a histamine antagonist
- main action is at the CTZ
- some central anticholinergic (muscarinic) effects have been noted
- available in PO, SC, IV
- useful when histamine pathway is involved eg. motion sickness or brain metastasis
cyclizine side effects
tremulousness, hallucinations and drowsiness
dry mouth and other anticholinergic S+E are less common
- generally well tolerated
Lorazepam
high potency, intermediate acting benzodiazepine used as an anxiolytic
- binds to benzodiazepine receptor at multiple sites within the CNS
PO or sublingual formulations
used for anticipatory nausea and vomiting associated with chemotherapy
Lorazepam side effects
sedation, dizziness, unsteadiness
hyperemesis gravidarum
morning sickness
drugs from morning sickness
metoclopramide, pyridoxine - Cat A
ondansetron - Cat B1
prochloperazine - cat C(still commonly used)
drugs for children
common presentation is acute gastroenteritis
main focus is oral rehydration therapy with avoidance of medications
high rate of extrapyramidal side effects from dopamine antagonists
if required ondansetron is safer and more effective
