Pharmacology of Antiemetic Drugs

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. Below, we review the pharmacology of the major antiemetic drug classes.

For the purposes of this guide, we will review antiemetic drugs along the following classification:

  • Dopamine antagonists
  • 5-HT3 receptor antagonists
  • H1 receptor antagonists
  • NK1 receptor antagonists
  • Benzodiazepines

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

Dopamine antagonists

We can divide dopamine antagonists into three broad groups:

  1. Phenothiazines – chlorpromazine, prochlorperazine
  2. Butyrophenones – droperidol
  3. Others – metoclopramide, domperidone

The first two classes are typical antipsychotic drugs.

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

METOCLOPRAMIDE, 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.

Mechanism of action – as we have already alluded to, both medicines are 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

Side effects associated with metoclopramide and domperidone include:

  • Diarrhea
  • Fatigue
  • Restlessness
  • Hyperprolactinemia
  • Extrapyramidal symptoms

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 considerations

When we talk about the clinical pharmacology of metoclopramide and domperidone, we need to think about the following factors:

  • 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

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 considerations

When we talk about the clinical pharmacology of phenothiazines and butyrophenones, we need to think about the following factors:

  • 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.

Next, let’s consider the value that 5-HT3 antagonists bring as clinical antiemetics.

5-HT3 receptor antagonists

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

Examples of setrons include:

  • Ondansetron
  • Granisetron
  • Dolasetron
  • Palonosetron

Indications

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 (see below), 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. However, these receptors play little to no role in the vestibular system, meaning triptans are ineffective at treating motion sickness.

Side effects

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 considerations

When we talk about the clinical pharmacology of setrons, we need to think about the following factors:

  • That 5-HT3 are 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.

The next antiemetic drug class to consider is the widely used H1 receptor antagonists.

H1 receptor antagonists

Examples:

  • Cyclizine
  • Meclizine
  • Cinnarizine (UK-only)
  • Promethazine
  • Dimenhydrinate
  • Diphenhydramine

Indications

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

Side effects associated with H1 antagonists include:

  • Drowsiness
  • Anticholinergic effects – dry throat, dry mouth, constipation etc.
  • Sedation
  • Headache
  • Double vision
  • Transient tachycardia after IV use

Cyclizine is the least sedating of the major H1 antagonists.

Clinical considerations

When we talk about the clinical pharmacology of H1 antagonists, we need to think about the following factors:

  • That H1 antagonists 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.

Next, we move onto the NK1 receptor antagonists, our penultimate antiemetic drug class.

NK1 receptor antagonists

Examples: aprepitant, 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

Side effects associated with NK1 receptor antagonists include:

  • Fatigue / weakness
  • Neutropenia
  • Constipation
  • Itch
  • Dizziness
  • Headache
  • Liver enzyme elevation
  • Cough

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

Clinical considerations

When we talk about the clinical pharmacology of NK1 antagonists, we need to think about the following factors:

  • That 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.

That concludes the major drug classes used as antiemetic drugs. However, there are other medicines – such as benzodiazepines – that also have antiemetic properties.

Benzodiazepines

Before we wrap up our study of antiemetics pharmacology, it’s worth considering how some benzodiazepines are also used for their antiemetic properties:

  • Midazolam
  • 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.

Antiemetics pharmacology includes a diverse range of medicines – from H1 antagonists to 5-HT3 antagonists to typical antipsychotics. Nor are they used to treat all causes of nausea and vomiting. This added complexity reinforces the need for the student to consider all necessary factors before making the final clinical decision.

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