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.
> Acupuncture
• Acustimulation to point P6
(pericardium 6, which is 2.5–5 cm proximal
to the distal crease of the wrist)
has been shown to reduce the
incidence of PONV.
• Studies have shown that it can provide a
further 30% reduction in
PONV when used in
combination with ondansetron.
• Special wrist bands that exert
pressure at this point can be purchased
to reduce the incidence of travel sickness.
Which drugs increase gastric motility and how do they exert their effects? 5
> Metoclopramide:
> Domperidone:
> Erythromycin:
> Neostigmine:
> Cisapride:
> Metoclopramide:
> Metoclopramide:
This D2 receptor antagonist also exerts prokinetic effects by stimulation of muscarinic, 5-HT3 and 5-HT4 receptors in the GIT.
It causes relaxation of the pyloric sphincter,
leads to increased peristalsis in the jejunum
and duodenum,
and increases stomach emptying, which may contribute to its antiemetic actions.
It crossesthe BBB and therefore can cause extrapyramidal side effects.
Metoclopramide is often used on ICU
for the treatment
of gastric stasis
and ileus.
> Domperidone:
This D2 receptor antagonist is
primarily an antiemetic but
it also increases gastrointestinal motility.
It is used in the treatment
of postprandial bloating,
reflux and belching.
Unlike metoclopramide, it does not cross the BBB
therefore it has minimal central side effects.
The intravenous form was
withdrawn following reports of significant
cardiovascular arrhythmias.
Erythromycin
Mimics the effect of the gut peptide
motilin
and acts as an agonist
at the motilin receptors found
mainly in the gastric antrum
and proximal duodenum.
It increases gastric emptying
and can be used for the
short-term treatment of gastroparesis.
It is more effective when
given orally compared with intravenously.
Side effects include abdominal cramps, diarrhoea, nausea and vomiting, and rarely, tornado de pointes.
Neostigmine
This acetylcholinesterase inhibitor
increases the availability of acetylcholine
(ACh) at the myenteric plexus,
resulting in increased gut motility,
salivation,
gastric secretions
and sphincter tone.
It is occasionally used on the
ICU to treat refractory constipation.
Cisapride
This prokinetic agent acts at
5-HT4 receptors enhancing
ACh release at the myenteric plexus.
This increases sphincter tone
and
peristalsis and the drug used
to be prescribed for reflux oesophagitis.
It has now been withdrawn in the UK because it causes long Q-T syndrome, VT, VF and torsades de pointes.
Which drugs inhibit gastric
motility and how do they exert
their effects?
> Antimuscarinic agents (e.g. atropine and hyoscine):
• An increase in parasympathetic tone
in the GIT promotes
‘resting and digesting’.
Antimuscarinic drugs antagonise the
muscarinic M3 receptors,
decreasing GIT motility,
saliva production, gastric secretions
and lower oesophageal sphincter tone.
> Opioids:
• Morphine and other opioids
are agonists at the MOP receptors
in the myenteric plexus.
Stimulation of MOP receptors
leads to
hyperpolarisation of cells,
which reduces stomach emptying,
decreases gut motility and
increases intestinal transit time.
They also decrease gastric,
biliary and pancreatic secretions.
Opioids cause constipation
and commonly
cause nausea and vomiting by their
stimulation of opioid receptors at the CTZ.
CYCLIZINE
Prep
Dose
MOA
Uses
Antihistamine
• Tablets: 50 mg
• Solution: 50 mg/mL
DOSE
• 50 mg 8 hourly (adult)
• 1 mg/kg 8 hourly (children)
MOA
• Competitive
antagonist at H1 and
muscarinic receptors
USES
• Antiemetic
• Ménière’s disease
Cyclizine
ADME
Effects
METABOLISM AND EXCRETION • Hepatic metabolism • Decrease dose in liver failure • Excreted in urine ABSORPTION/ DISTRIBUTION • Well absorbed orally • Oral bioavailability 75% • t½ 10 hours
EFFECTS
GI
• ↑ Lower oesophageal sphincter tone
CVS
• Tachycardia
OTHER
• Pain on injection because pH of solution is 3.2
• Mild sedation
CHLORPROMAZINE
Prep
Dose
MOA
USes
Phenothiazine • Tablets: 10/25/50/100 mg • Syrup: 5 mg/mL • Suppositories: 100 mg • Solution (IM): 25 mg/mL DOSE • Oral: 10–50 mg 8 hourly • IM: 25–50 mg 8 hourly • PR: 100 mg 8 hourly
MOA • Antagonises • D2 • Muscarinic • a1 and a2 • H1 • 5-HT receptors
• Inhibits uptake 1
USES
• Treatment of nausea and vomiting mostly in
terminally ill (because although it is effective, its
side-effects limit its use)
- Treatment of hiccoughs
- Antipsychotic
CHLORPROMAZINE
ADME
METABOLISM
AND EXCRETION
- Hepatic metabolism
- Excreted in urine and bile
ABSORPTION/
DISTRIBUTION
- Well absorbed orally
- Significant first-pass metabolism
- Oral bioavailability 30%
- Protein binding > 90%
EFFECTS
CVS
• Vasodilation and hypotension
CNS
• Sedation
• Extrapyramidal side effects (D2 antagonist)
• Neuroleptic malignant system (rare)
- ↑ Growth hormone
- ↑ Prolactin
• Hypothermia and
impaired temperature regulation
GI
• Antiemetic
• ↑ Weight
OTHER • Agranulocytosis • Haemolytic anaemia • Leucopenia • Cholestatic jaundice • Antimuscarinic effects
DOMPERIDONE
Prep
Dose
MOA
ADME
USES
effects
DOMPERIDONE
DOMPERIDONE Butyrophenone • Tablets: 10 mg • Suspension: 1 mg/mL • Suppositories: 30 mg • Solution (IM): 12.5 mg/mL
DOSE
• 10–20 mg 8 hourly PO
• 60 mg 8 hourly PR
MOA
• Antagonises D2 receptors
• Does not cross BBB so fewer extrapyramidal
side-effects
ABSORPTION/ DISTRIBUTION • Extensive first-pass metabolism • Oral bioavailability 15% • Protein binding 92% • t½ 7½ hours
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in faeces and urine
USES
• Nausea and vomiting,
especially following
chemotherapy
EFFECTS
GI
• ↑ Tone of lower oesophageal sphincter
OTHER
• ↑ Prolactin secretion causing
gynaecomastia and galactorrhoea
CHEMICAL PROPERTIES
• Nil
METOCLOPRAMIDE
Prep
dose
MOA
METOCLOPRAMIDE
Benzamine
- Tablets/Slow release capsules: 10/15 mg
- Syrup: 1 mg/mL
- Solution: 5 mg/mL
DOSE
• 10 mg 8 hourly
MOA
• Antagonises D2 receptors
at chemoreceptor-trigger zone (CTZ)
• Antagonises 5-HT3 receptors
• Agonist at muscarinic receptors so
increases gut motility
USES
• Antiemetic
• Prokinetic
CHEMICAL PROPERTIES
• Nil
Metoclopramide
ADME
effects
METABOLISM AND EXCRETION
- Hepatic metabolism
- Metabolites and unchanged drug excreted in urine
ABSORPTION/
DISTRIBUTION
- Well absorbed orally
- Significant first-pass metabolism
- Oral bioavailability 30–90%
EFFECTS
GI
• ↑ Tone of lower oesophageal sphincter
- ↓ Tone of pyloric sphincter
- Prokinetic
CNS
• Crosses BBB so can cause extrapyramidal side-effects
- Oculogyric crisis – usually in females < 21 years old
- Neuroleptic malignant syndrome (rare)
- Sedation
- Agitation
CVS • Hypotension (rare) • Tachycardia (rare) ENDOCRINE • ↑ Prolactin causing gynaecomastia and galactorrhoea
• Precipitates porphyria crisis
ONDANSETRON
Prer
ONDANSETRON
Carbazole
- Tablets: 4/8 mg
- Solution: 2 mg/mL
DOSE
- 4–8 mg 8 hourly (adult)
- 100 μg/kg 8 hourly (children > 2 years old)
MOA
• Antagonises peripheral and central 5-HT3 receptors
USES
• Antiemetic - not effective motion sick
• Effective in PONV & chemotherapy
induced N & V (CINV)
Ondansetron
effects
METABOLISM
AND EXCRETION
- Hepatic metabolism
- Decrease dose in liver failure
- Excreted in urine
ABSORPTION/
DISTRIBUTION
• Well absorbed orally
- Oral bioavailability 60%
- Protein binding 75%
- t½ 3 hours
EFFECTS
GI
• Constipation
CNS
• Headache
CVS
• Bradycardia
• Flushing
• Caution in patients with risk factors for
prolonged QT interval/ cardiac arrhythmias.
Dose dependent prolongation of QT interval &
cardiac arrhythmias including torsades de
pointes.
For CINV a dose limitation is now set & all doses
should be diluted prior to administration in
patients > 65 years.
PROCHLORPERAZINE
PROCHLORPERAZINE
Phenothiazine
- Tablets: 3/5/25 mg
- Syrup: 1 mg/mL
- Suppositories: 5/25 mg
- Solution (IM): 12.5 mg/mL
DOSE
• 5–20 mg 8–12 hourly
MOA
• Antagonises D2 receptors
USES
• Nausea and vomiting
- Vertigo and motion sickness
- Psychosis
- Premedication
PROCHLORPERAZINE
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in bile and urine
ABSORPTION/
DISTRIBUTION
• Variable oral absorption
- Significant first-pass metabolism
- Oral bioavailability low
EFFECTS
CNS
• Extrapyramidal symptoms
- Acute dystonias and akathesia in young patients
- Mildly sedating
GI
• Cholestatic jaundice
OTHER
• Haematological abnormalities
• Skin sensitivity
↑Prolactin
- Neuroleptic malignant syndrome
- Pruritis
- Antiandrogen
