Antiemetics
Last updated 20th December 2017 - Tom Heaton
The physiology of nausea and vomiting is discussed elsewhere.
The pharmacology of antiemetics primarily relates to the well recognised neurotransmitters that are involved in this physiology.
In particular these are:
The pharmacology of antiemetics primarily relates to the well recognised neurotransmitters that are involved in this physiology.
In particular these are:
- Dopamine - at D2 receptors
- Serotonin - at 5HT3 receptors
- Histamine - at H1 receptors
- Acetylcholine
Dopamine
The classes of antidopaminergic drug used are:
Phenothiazines
These are also antipsychotic in action (the neuroleptics).
The mechanism of action is the same, but the antiemetic effect is achieved at a lower dose than the neuroleptic ones.
Chlorpromazine
Whilst it has a significant action at D2 receptors, there is also a wide range of other receptor antagonism - muscarinic, noradrenergic, histaminic, 5HT3.
The brand name Largactil, hints at the wide ranging effects of the drug.
It has a potent antiemetic effects but also a number of adverse effects.
Although it can be used in PONV, it is also an antiemetic of choice in palliative care where other drugs have failed
It has good oral absorption but a high rate of first pass metabolism (oral bioavailability approx 30%). It can be often be given parenterally.
The large number of metabolites are excreted in the urine and bile.
Side effects include:
Prochlorperazine
Another antipsychotic agent used at lower dose for its antiemetic effect.
Very poor oral bioavailability due to high hepatic first pass metabolism so often given parenterally.
Side effects include:
Butyrophenones
Droperidol is the main one of this class in anaesthetic practice.
These are also neuroleptic in nature, and again achieve their antiemetic effect via the same mechanism - via potent D2 receptor antagonism.
It is given parenterally (more commonly IV).
It is highly protein bound with extensive hepatic metabolism.
Its clinical effect appears to last beyond its rapid clearance.
An IV bolus dose of 0.625 - 1.25mg is commonly used.
It has a NNT of 5 to prevent PONV.
It has a NNT of 3 for preventing N&V with PCA use
Side effects include:
Haloperidol has also been described in this role.
It is used in lower doses than for its sedative effects, at an IV or IM dose of 0.5-2mg.
At these doses it has an NNT of between 4 and 6 for PONV.
It is otherwise very similar to droperidol.
Benzamides
Metoclopramide is the common benzamide, but is perhaps used more as a prokinetic.
A number of studies have described the antiemetic effect as being similar to placebo.
The action is again through D2 receptor antagonism, but may also have some gut 5HT3 antagonism.
It is well absorbed orally but hepatic first pass metabolism can vary significantly affecting bioavailability.
It is conjugated in the liver then excreted in the urine and bile, with an amount also being excreted unchanged.
The common IV and oral dose is 10mg, but it seems that higher doses are needed to achieve an antiemetic effect.
Side effects include:
- Phenothiazines
- Butyrophenones
- Benzamides
Phenothiazines
These are also antipsychotic in action (the neuroleptics).
The mechanism of action is the same, but the antiemetic effect is achieved at a lower dose than the neuroleptic ones.
Chlorpromazine
Whilst it has a significant action at D2 receptors, there is also a wide range of other receptor antagonism - muscarinic, noradrenergic, histaminic, 5HT3.
The brand name Largactil, hints at the wide ranging effects of the drug.
It has a potent antiemetic effects but also a number of adverse effects.
Although it can be used in PONV, it is also an antiemetic of choice in palliative care where other drugs have failed
It has good oral absorption but a high rate of first pass metabolism (oral bioavailability approx 30%). It can be often be given parenterally.
The large number of metabolites are excreted in the urine and bile.
Side effects include:
- Extrapyramidal effects e.g. acute dystonias
- Neuroleptic malignant syndrome has been reported
- Anticholinergic effects e.g. dry mouth
- Vasodilation (from antiadrenergic effects) with hypotension and heat loss
- Sedation is a fairly common feature
- Class specific reactions: cholestatic jaundice, skin sensitization, hyperprolactinaemia.
Prochlorperazine
Another antipsychotic agent used at lower dose for its antiemetic effect.
Very poor oral bioavailability due to high hepatic first pass metabolism so often given parenterally.
Side effects include:
- Extrapyramidal - acute movement disorders (e.g. acute dystonia) appear to more common with this drug
- Mild sedation
- Class specific reactions as above
Butyrophenones
Droperidol is the main one of this class in anaesthetic practice.
These are also neuroleptic in nature, and again achieve their antiemetic effect via the same mechanism - via potent D2 receptor antagonism.
It is given parenterally (more commonly IV).
It is highly protein bound with extensive hepatic metabolism.
Its clinical effect appears to last beyond its rapid clearance.
An IV bolus dose of 0.625 - 1.25mg is commonly used.
It has a NNT of 5 to prevent PONV.
It has a NNT of 3 for preventing N&V with PCA use
Side effects include:
- Sedation - more common than the phenothiazines
- Extrapyramidal effects
- Hyperprolactinemia
- Hypotension (alpha adrenoceptor blockade)
- QTc prolongation - resulted in ‘black-box warning’ but seems to have no significant role at the low doses for antiemetic effect.
Haloperidol has also been described in this role.
It is used in lower doses than for its sedative effects, at an IV or IM dose of 0.5-2mg.
At these doses it has an NNT of between 4 and 6 for PONV.
It is otherwise very similar to droperidol.
Benzamides
Metoclopramide is the common benzamide, but is perhaps used more as a prokinetic.
A number of studies have described the antiemetic effect as being similar to placebo.
The action is again through D2 receptor antagonism, but may also have some gut 5HT3 antagonism.
It is well absorbed orally but hepatic first pass metabolism can vary significantly affecting bioavailability.
It is conjugated in the liver then excreted in the urine and bile, with an amount also being excreted unchanged.
The common IV and oral dose is 10mg, but it seems that higher doses are needed to achieve an antiemetic effect.
Side effects include:
- Extrapyramidal effects - more common in young females
- Cardiovascular disturbance can occur with rapid IV administration e.g. hypotension, bradycardia
Serotonin
The 5HT3 receptor antagonists are probably the most used and well recognised antiemetics for PONV.
5HT has been found to be increased in patients with PONV, and the 5HT3 receptor is of particular interest.
It is ligand gated ion channel found throughout the body, including the vomiting related areas of the CNS and in the GI tract.
The highly specific nature of the 5HT3 receptor antagonists appears to provide these drugs with a good side effect profile, as well as impressive efficacy for PONV.
Ondansetron
This is the most common 5HT3 receptor antagonist in the UK.
It is a carbazole that is similar in structure to serotonin.
It is available as an IV preparation, tablets, suppository and a lyophilisate to dissolve on the tongue.
It is well absorbed orally with a bioavailability of about 60%.
It has significant hepatic metabolism to inactive metabolites.
Its plasma half life is around 3 hours.
The usual dose is 4mg IV, or 8mg oral.
The IV dose has a NT of 6 to prevent vomiting and 7 to prevent nausea and is seen as the gold standard for antiemetics.
Side effects are usually only transient and mild but include:
5HT has been found to be increased in patients with PONV, and the 5HT3 receptor is of particular interest.
It is ligand gated ion channel found throughout the body, including the vomiting related areas of the CNS and in the GI tract.
The highly specific nature of the 5HT3 receptor antagonists appears to provide these drugs with a good side effect profile, as well as impressive efficacy for PONV.
Ondansetron
This is the most common 5HT3 receptor antagonist in the UK.
It is a carbazole that is similar in structure to serotonin.
It is available as an IV preparation, tablets, suppository and a lyophilisate to dissolve on the tongue.
It is well absorbed orally with a bioavailability of about 60%.
It has significant hepatic metabolism to inactive metabolites.
Its plasma half life is around 3 hours.
The usual dose is 4mg IV, or 8mg oral.
The IV dose has a NT of 6 to prevent vomiting and 7 to prevent nausea and is seen as the gold standard for antiemetics.
Side effects are usually only transient and mild but include:
- Headache (NNH 36)
- Constipation (NNH 23)
- Elevated liver enzymes (NNH 31)
- Flushing
- QT prolongation at high doses (16mg)
Histamine
The mechanism of action is through antagonism of H1 receptors.
Cyclizine is the main antihistamine antiemetic used and it also exhibits some anticholinergic properties.
It is used perioperatively but because of the higher number of histamine receptors involved in the labyrinthine pathways of nause, it is quite effective for motion sickness and Meniere’s disease.
It is a piperazine derivative and is stored at a pH of 3.2 (IV and especially IM injection can be painful).
It is well absorbed orally with a bioavailability of about 75%.
The usual dose is 50mg 8 hourly and can be given by the IV, IM or oral route.
Side effects include:
Cyclizine is the main antihistamine antiemetic used and it also exhibits some anticholinergic properties.
It is used perioperatively but because of the higher number of histamine receptors involved in the labyrinthine pathways of nause, it is quite effective for motion sickness and Meniere’s disease.
It is a piperazine derivative and is stored at a pH of 3.2 (IV and especially IM injection can be painful).
It is well absorbed orally with a bioavailability of about 75%.
The usual dose is 50mg 8 hourly and can be given by the IV, IM or oral route.
Side effects include:
- Anticholinergic - particularly a tachycardia with rapid IV injection
- Pain on injection - due to low pH
Acetylcholine
The effects are from antagonism at central muscarinic acetylcholine receptors.
Hyoscine is the only real agent used as an antiemetic because of the cardiovascular effects of many of the other preparations e.g. atropine.
It is a racemic mixture with only the L isomer active.
Oral absorption is variable, and it is commonly administered transdermally via a patch.
It has a very short plasma duration and is broken down by liver esterases.
Side effects include:
Hyoscine is the only real agent used as an antiemetic because of the cardiovascular effects of many of the other preparations e.g. atropine.
It is a racemic mixture with only the L isomer active.
Oral absorption is variable, and it is commonly administered transdermally via a patch.
It has a very short plasma duration and is broken down by liver esterases.
Side effects include:
- Sedation
- Amnesia
- Central anticholinergic syndrome
Other Agents
Dexamethasone
This has become well recognised as a useful antiemetic agent for PONV as well as with chemotherapy.
The mechanism of action is not really understood, but is shared by other corticosteroids too.
Dexamethasone is also described as providing additional general postoperative benefits, including reducing pain and fatigue, and generally improved well being.
A dose of between 4 and 8mg has been described.
Although effective individually, it appears to have an augmenting effect on coadministered antiemetics.
Side effects include:
Aprepitant
This is a neurokinin-1 receptor antagonist.
It is a relatively new drug but with some promising trial results.
This has become well recognised as a useful antiemetic agent for PONV as well as with chemotherapy.
The mechanism of action is not really understood, but is shared by other corticosteroids too.
Dexamethasone is also described as providing additional general postoperative benefits, including reducing pain and fatigue, and generally improved well being.
A dose of between 4 and 8mg has been described.
Although effective individually, it appears to have an augmenting effect on coadministered antiemetics.
Side effects include:
- Impaired glucose control - this is a particular problem with labile diabetic patients
- The evidence of increased wound infection rates is unclear
- Can produce a very odd sensation if given as an IV bolus when awake
Aprepitant
This is a neurokinin-1 receptor antagonist.
It is a relatively new drug but with some promising trial results.
Links & References
- Pierre, S. Whelan, R. Nausea and vomiting after surgery. CEACCP. 2013. 13(1): 28-32. Available at: https://academic.oup.com/bjaed/article/13/1/28/281153
- Gan, T. et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesthesia & Analgesia. 2014. 118(1): 85-113. Available at: http://journals.lww.com/anesthesia-analgesia/Fulltext/2014/01000/Consensus_Guidelines_for_the_Management_of.13.aspx
- Peck, T. Hill, S. Williams, M. Pharmacology for anaesthesia and intensive care (3rd ed). 2008. Cambridge University Press.
- Scholz et al. Antiemetics, in: Evers, A. et al (eds). Anesthetic pharmacology: basic principles and clinical practice (2nd ed). Cambridge University Press. 2011
