Antiemetic Drugs Pharmacology

Antiemetic drugs are medicines used to treat and prevent nausea and vomiting. Some drugs are
used entirely as prophylactics, whereas other are used to directly treat nausea and vomiting.

Antiemetic drug that includes;

 Dopamine antagonists

 5-HT3 receptor antagonists

 H1 receptor antagonists

 NK1 receptor antagonists

 Benzodiazepines

For each class, we review its members, indications, mechanism of action, side effect profile and
notable drug interactions.

Dopamine antagonists
There are three broad classes of antiemetic dopamine antagonist:

1. Phenothiazines – chlorpromazine, prochlorperazine

2. Butyrophenones – droperidol

3. Others – metoclopramide, domperidone

The first two classes are typical antipsychotic drugs.

The third class is not antipsychotic drugs, but they share a common mechanism of action with
those drugs – namely, antagonism of dopamine, D2 receptors.

 Metoclopramide and Domperidone

Indications – prophylaxis and treatment of nausea and vomiting in a variety of contexts.

However, they are particularly effective in cases of reduced gut motility. In addition these drug
used for management of dyspepsia, heartburn, epigastric pain and Diabetic gastroparesis.

Mechanism of action, both medicines is antagonists at dopamine, D2 receptors. These receptors

are found throughout the brain, including the chemoreceptor trigger zone (CTZ). D2 receptors
are also found in high concentrations in the gut, leading to a prokinetic effect, further aiding their
antiemetic, clinical effect.
Side effects associated with metoclopramide and domperidone include:

 Diarrhea

 Restlessness

 Hyperprolactinemia

 Extrapyramidal symptoms

 galactorrhea, gynecomastia, and menstrual irregularities

Extrapyramidal side effects are associated with metoclopramide, not domperidone. This is
because domperidone does not cross the blood-brain barrier and, given that the CTZ is largely
outside this barrier; domperidone can exert its antiemetic effect without causing more central
extrapyramidal effects.

Clinical pharmacology
 That the risk of movement disorders with metoclopramide is higher in patients under
the age of 20 or who are on high-doses / prolonged therapy.

 That due to their prokinetic effects, metoclopramide and domperidone should be avoided
in patients with gastrointestinal obstruction and perforation.

 That the risk of extrapyramidal side effects with metoclopramide increases when these
medicines are taken alongside antipsychotics or dopaminergic drugs used to treat
Parkinson’s disease. These interactions do not apply to domperidone.

 CYP3A4 inhibitors – such as ketoconazole and macrolide antibacterials – increase the

risk of domperidone toxicity.

ANTIPSYCHOTICS
Examples:

 droperidol

 chlorpromazine

 prochlorperazine

Indications – used to treat and prevent nausea and vomiting in a wide variety of contexts.
Prochlorperazine is particularly effective at treating nausea and vomiting caused by vertigo.
Mechanism of action – as with metoclopramide and domperidone, these three medicines work
by antagonising D2 receptors found in the chemoreceptor trigger zone (CTZ). They are also
typical antipsychotic drugs, their antipsychotic effects most likely due to their antagonism of
D2 receptors in the mesolimbic pathway.

Side effects associated with droperidol, chlorpromazine and prochlorperazine include:

 Postural hypotension

 Drowsiness

 Extrapyramidal side effects – dystonia, akathisia, Parkinsonism (rigidity)

 Neuroleptic malignant syndrome

 Tardive dyskinesia

 QT prolongation

Clinical factors of phenothiazines and butyrophenones include:

 That dosage should be reduced in vulnerable populations, such as the elderly.

 That antipsychotics increase the risk of death in patients with dementia.

 That they should be avoided in patients with Parkinson’s disease due to their
extrapyramidal side effect profile.

 That antipsychotics should be avoided with other drugs that prolong the QT
interval such as amiodarone, quinine, macrolides and SSRIs.

 That haloperidol decreases the effects of levodopa.

5-HT3 receptor antagonists

The next class to review in antiemetic drugs pharmacology is 5-HT3 receptor antagonists, also
known as “setrons”.

Examples of setrons include:

 Ondansetron

 Granisetron

 Dolasetron

 Palonosetron
5-HT3 receptor antagonists are particularly effective in the treatment of:

 Chemotherapy-induced nausea and vomiting (CINV)

 Radiation-induced nausea and vomiting (RINV)

For CINV, setrons are often given alongside another antiemetic medicine – such as
dexamethasone or an NK1 receptor antagonist, such as aprepitant – to boost their antiemetic
effects.

Mechanism of action – as with dopamine, D2 receptors, there is a high concentration of

serotonergic receptors in the chemoreceptor trigger zone (CTZ). In addition, there is a high
concentration of these receptors found in the gastrointestinal tract, the primary neurotransmitter
released in that part of the body. When 5-HT3 receptors are activated, a stimulus passes onto the
CTZ via the vagus nerve and solitary tract nucleus, triggering nausea and vomiting.

Side effects associated with 5-HT3 receptor antagonists include:

 GI effects – including constipation and diarrhea

 Headache

 Dizziness, Generally, setrons are very well tolerated medicines.

Clinical pharmacology

 That 5-HT3 is tentatively linked to QT prolongation. Avoid medicines which are known
to increase this risk – macrolides, quinine, amiodarone, SSRIs and antipsychotics.

 That setrons are ineffective at treating motion sickness.

 That not all setrons are antiemetic drugs. For example – alosetron – is used in the
treatment of irritable bowel syndrome.

H1 receptor antagonists
Examples:

 Cyclizine

 Meclizine

 Promethazine

 Dimenhydrinate

 Diphenhydramine
H1 receptor antagonists are particularly effective at treating nausea and vomiting whose cause
is motion sickness or vertigo.

Mechanism of action – histamine is an essential link between the vestibular system and the
chemoreceptor trigger zone. Acetylcholine is another important link. H1 antagonists work by
blocking this neuronal pathway – meaning they become particularly effective at alleviating
nausea and vomiting in motion sickness or vertigo. However, many H1 antagonists, such as
cyclizine, are useful for other causes – such as postoperative or drug-induced nausea and
vomiting.

Side effects associated with H1 antagonists include:

 Drowsiness Sedation, Headache, Double vision

 Anticholinergic effects – dry throat, dry mouth, constipation etc.

 Transient tachycardia after IV use

Cyclizine is the least sedating of the major H1 antagonists.

Clinical pharmacology of H1 antagonists,

 That H1 antagonist should be avoided in patients for whom anticholinergic effects can
prove problematic – for example, in patients with benign prostatic hypertrophy.

 That the risk of sedation increases when H1 antagonists are taken alongside other
sedating medicines – such as benzodiazepines or Z-drugs or opioids. Alcohol, too,
increases this risk.

 That the risk of anticholinergic effects increases when H1 antagonists are taken alongside
other drugs with anticholinergic effects – for example, in patients taking antipsychotic
medicines.

NK1 receptor antagonists

Examples: Aprepitant and rolapitant

Indications:

 Prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV)

Aprepitant and rolapitant are not used in isolation. Instead, they are administered alongside
another antiemetic drug – most commonly a 5-HT3 receptor antagonist or a steroid, such as
dexamethasone – augmenting their antiemetic properties.
NK1 antagonists are effective in treating both the acute and delayed forms of CINV. While 5-
HT3 antagonists are highly effective at treating the acute phase, they are not as effective treating
the delayed CINV phase. NK1 antagonists have been shown to be effective at treating both
phases.

Mechanism: NK1 is a G-coupled protein receptor (GPCR) found in the central and peripheral
nervous systems. The dominant ligand of this receptor is Substance P; an 11-amino acid
neuropeptide that is found in high concentrations in the chemoreceptor trigger zone (CTZ) of the
brain. By binding to and antagonising these receptors, Substance P cannot trigger its nerve
impulses to the CTZ – reducing the vomiting reflex.

Side effects associated with NK1 receptor antagonists include:

 Fatigue / weakness

 Neutropenia

Constipation, Itch, Dizziness, Cough

 Liver enzyme elevation

More rarely, NK1 antagonists have been linked to hypertension, palpitations and blood alkaline
phosphatase increase.

Clinical pharmacology of NK1 antagonists

 Those NK1 antagonists enhance the antiemetic effects of 5-HT3 antagonists and
dexamethasone.

 NK1 antagonists are mostly metabolised by CYP3A4, though some is metabolised by

CYP2C19 and CYP1A2. Aprepitant is a moderate inhibitor of CYP3A4, meaning it can
increase concentrations and risk of toxicity of drugs metabolised by CYP3A4, such as
oxycodone.

Benzodiazepines

Benzodiazepines commonly used for their antiemetic properties include:

 Midazolam and Lorazepam

In the case of lorazepam, it has been used to treat nausea and vomiting caused by the patient’s
belief that they may be sick. Lorazepam reduces anxiety in affected patients, reducing the risk of
nausea and vomiting. Lorazepam has also been used, in combination with other medicines, to
treat cyclic vomiting syndrome. In the case of midazolam, it has been used in patient’s pre-
surgery to prevent nausea and vomiting.