24. Antiemetics and Prokinetics Flashcards
Which receptors play a role in the stimulation of vomiting?
The vomiting centre is located
within the medulla
and
receives afferent stimuli from
multiple areas including the
chemoreceptor trigger zone (CTZ),
peripheral pain receptors, cerebral cortex (pain, anxiety, vision, taste),
vestibular and
cerebellar nuclei,
and from chemoreceptors
and pressure receptors in the gut.
The CTZ
where
The CTZ lies close to the area postrema
on the floor of the fourth ventricle,
outside the blood–brain barrier.
It is well placed to detect
blood-borne toxins.
It has many receptors including: > Histamine (H1) > Muscarinic (mAChR) > Dopaminergic (D2) > Serotonergic (5-HT3) > Opioid > α1 and α2 adrenoceptors.
Stimulation of any of these receptors
may ultimately lead to the activation of
the vomiting centre and
therefore most anti-emetic drugs act
as antagonists to the receptor sites of the CTZ.
As there are several receptor systems
involved in the physiology of
nausea and vomiting,
it seems obvious that a combination of drugs acting at different receptors would have a greater antiemetic efficacy (i.e. a ‘multimodal’ approach).
What is the incidence of POV
impacts
(PONV)?
PONV is a real concern to
many patients presenting for surgery.
.
The incidence ranges from
12% to 38% (risk factor dependent),
and the effects of PONV can
impact significantly on
recovery time and
hospital length of stay
(and therefore cost).
Strategies to minimise the risk of PONV should
commence pre-operatively and continue into the post-operative period.
> Pre-operative period:
Strategies to reduce PONV
• Patients at risk of PONV should be
identified during the anaesthetic
assessment.
• Anxiolysis –
benzodiazepine premedication to
reduce anxiety has been
shown to reduce PONV in at risk patients.
• Pre-hydration –
oral carbohydrate containing
solutions given 2 hours
pre-operatively reduce PONV (
this forms part of the Enhanced
Recovery Programme for major gastrointestinal surgery).
Keeping starvation times to a minimum
and using peri-operative intravenous
fluid hydration all reduce PONV.
> Intra-operative period:
• Anaesthetic agent –
avoid use of nitrous oxide
and, if feasible, inhalation agents for high-risk patients.
As the duration of anaesthesia increases
(i.e. MAC hours) so does the incidence of PONV.
Total intravenous anaesthetic techniques
using propofol are associated with
a reduction in PONV rates.
• Analgesia –
pain and anxiety both increase
PONV and therefore good
peri-operative analgesia is imperative
at reducing PONV.
Use regional anaesthetic techniques
where possible as this can reduce
opioid and volatile agent requirements.
Multimodal and
pre-emptive analgesic
strategies
(i.e. opioid reducing/sparing)
also reduce PONV.
• Anti-emetic agents –
the use of one or more anti-emetic agents
reduces PONV.
Each additional agent has an additive effect and can
reduce the risk of PONV by 30% (so-called rule of one-third).
Give examples of anti-emetic drugs that act at the major receptor sites.
1
> Histamine receptor antagonists
(e.g. cyclizine and cinnarizine)
2
> Muscarinic receptor antagonist
3
> Dopaminergic receptor antagonists
> Histamine receptor antagonists
(e.g. cyclizine and cinnarizine):
How work
Most effective in
S/E
• Antihistamines exert their antiemetic action
at H1 receptors within the CNS.
The sedative side effect of these
drugs may also contribute to their efficacy.
• Antihistamines are useful in the
treatment of motion sickness, PONV
and vestibular disorders causing vertigo.
• Side effects include dry mouth,
urinary retention, blurred vision and
sedation.
Cyclizine causes tachycardia
if given intravenously,
and more arely can
cause extrapyramidal effects and confusion.
> Muscarinic receptor antagonist
(e.g. hyoscine and atropine)
• The antimuscarinic (or anticholinergic) drugs act as competitive antagonists of muscarinic receptors at the vomiting centre
and
also in the gastrointestinal tract (GIT).
Here, they are anti-spasmodic and
decrease salivary and gastric secretions,
consequently reducing
gastric distension.
• They are the most effective therapy available
for motion sickness, and
are also effective for
opioid-induced nausea.
• Side effects are predictable, and include dry mouth, blurred vision, urinary retention, tachycardia and sedation.
> Dopaminergic receptor antagonists
> Dopaminergic receptor antagonists
(e.g. phenothiazines,
metoclopramide,
domperidone and
butyrophenones)
• Phenothiazines
e.g. prochlorperazine,
chlorpromazine and
promethazine)
act on both the
dopaminergic receptors
at the CTZ
and the
muscarinic receptors
at the vomiting centre.
• Prochlorperazine’s
(Stemetil) side effects include
extrapyramidal symptoms,
especially in children.
• Chlorpromazine is mainly used in the
terminally ill as its use is limited
by its serious side effects
that include extrapyramidal symptoms, sedation, impaired temperature regulation, increased growth hormone and prolactin release, agranulocytosis, haemolytic anaemia and leucopenia.
• Promethazine is also an antihistamine.
It causes profound sedation,
which often precludes its use as an antiemetic.
• Metoclopramide is a dopamine antagonist at the CTZ but also works directly on the GIT causing increased gastric motility.
It is an effective antiemetic in
gastrointestinal and biliary disorders.
its side effects acute dystonic reactions (particularly oculogyric crises in young women and the very elderly), sedation, diarrhoea and neuroleptic malignant syndrome.
• Domperidone is a dopamine antagonist at the CTZ.
It is of particular use in the treatment of
nausea and vomiting associated with
cytotoxic therapy.
It does not cross the blood–brain barrier and so is
relatively free of side effects.
It can rarely cause GIT disturbances and
hyperprolactinaemia.
• Butyrophenones
e.g. droperidol, benperidol and haloperidol)
are dopamine antagonists at the CTZ.
They are also mild histamine antagonists and anticholinergics.
They have many side effects including extrapyramidal symptoms, neuroleptic malignant syndrome, altered temperature regulation, hypotension, tachycardia, arrhythmias and endocrine effects including weight gain and galactorrhoea.
• Droperidol is an effective antiemetic
but it causes dissociation and
dysphoria, which limit its use.
• Benperidol and haloperidol are
prescribed for their anti-psychotic
actions and are not used to treat nausea.
> 5-HT3 receptor antagonists
(e.g. ondansetron and granisetron) • There are four types of serotonergic receptors but 5-HT3 receptors are abundant at the CTZ, and are also found in the GIT.
• The 5-HT3 receptor antagonists are effective in the treatment and prevention of PONV and the nausea and vomiting associated with chemotherapy.
• Side effects include headache, flushing, diarrhoea, constipation, drowsiness, tachycardia, bradycardia and ECG changes.
> Steroids (e.g. dexamethasone and methylprednisolone)
• High doses of dexamethasone and methylprednisolone are
effective in the treatment of nausea
caused by cytotoxic agents and in PONV.
Dexamethasone may be used
alone or in combination for the
prevention and treatment of PONV,
but its mode of action is unclear.
> Propofol
> Propofol • Posseses antiemetic properties when given at sub-hypnotic doses at the end of surgery (e.g. 10–20 mg bolus for an adult)
and also when used to induce and maintain anaesthesia (TIVA regime).
The exact mechanism of action is
unclear but it is thought to
have an effect on
5-HT3 receptors.
> Benzodiazepines (e.g. lorazepam)
• Lorazepam has sedative,
amnesic and
antiemetic properties.
It is used as an antiemetic during chemotherapy.
• It is thought that lorazepam
modulates central pathways involved in
nausea and vomiting.
> Neurokinin-1 receptor antagonists
(anti-NK 1, e.g. aprepitant)•
These are currently being researched
+
may represent the final common pathway
in the stimulation of the vomiting reflex.
Blockade of NK 1 receptors is associated
with broad-spectrum anti-emesis in a
wide range of species.
> Cannabinoids (e.g. nabilone)
> Cannabinoids (e.g. nabilone)
• Nabilone is a synthetic cannabinoid that
mimics an ingredient of cannabis.
It is approved for the
treatment of chemotherapy-induced
nausea and vomiting
and
as an analgesic adjunct for neuropathic pain.
• It causes drowsiness, dizziness, dry mouth and sometimes also psychosis.
