Antiemetics

Antiemetics can be used to treat or prevent nausea and vomiting due to a range of causes. Their use can significantly improve quality of life and prevent complications such as dehydration and electrolyte disturbances.

Several neural pathways are involved in the development of nausea and vomiting. These include dopaminergic, serotonergic, histaminergic, cholinergic, neurokinin and cannabinoid receptor-mediated pathways. No antiemetic is universally effective, as no agent acts on all of these receptors.

The choice of antiemetic is influenced by the cause of nausea and vomiting, severity of symptoms, preferred route of administration, and the patient’s previous response to therapy. If a poor response occurs to one agent, a medication from a different class may be considered. Combination therapy using antiemetics with different mechanisms of action may also be considered.

Dopamine antagonists

Dopamine acts on D2 receptors in the chemoreceptor trigger zone (CTZ) to induce nausea and vomiting. Dopamine antagonists treat and prevent nausea and vomiting by blocking these receptors. Domperidone and metoclopramide also have prokinetic effects, which may be useful if symptoms are due to gastroparesis.

While dopamine is involved in the development of nausea and vomiting, it has a number of other functions in the brain. These include motor control, cognitive function, pleasure/reward, and hormonal control. Therefore, dopamine antagonists are associated with adverse effects, such as extrapyramidal side effects (EPSE) and elevation of prolactin levels.

The risk of EPSE is greatest with high doses and rapid intravenous administration of dopamine antagonists. Caution should be used in patients who are elderly as they may be more sensitive to the adverse effects of this class. These agents should generally be avoided in patients with Parkinson’s disease as they can cause significant exacerbation of parkinsonian symptoms. Of the dopamine antagonists, domperidone is least likely to cause this issue as it does not readily cross the blood-brain barrier.

Domperidone

Domperidone is indicated for the short-term treatment of intractable nausea and vomiting from any cause. Domperidone has been associated with an increased risk of serious ventricular arrhythmias and sudden cardiac death. This risk may be higher in patients taking doses greater than 30mg a day and in those over 60 years of age. Domperidone is contraindicated in patients with pre-existing prolongation of cardiac conduction intervals, significant electrolyte disturbances, or underlying cardiac conditions such as congestive heart failure.

Domperidone is primarily metabolised via CYP3A4. To minimise adverse effects, domperidone is contraindicated with potent inhibitors of CYP3A4 (e.g. azole antifungals, macrolide antibiotics, diltiazem, verapamil, amiodarone, aprepitant, fosamprenavir, ritonavir, saquinavir).

Metoclopramide

Metoclopramide is used to control nausea and vomiting associated with medications, uraemia, radiation sickness, malignancy, labour, infectious disease, and postoperative vomiting.

Metoclopramide is available as an oral tablet and an injection for intramuscular or intravenous use. The onset of effect is 1-3 minutes following an IV dose, 10-15 minutes for an IM dose, and 30-60 minutes following an oral dose; effects persist for 1-2 hours.

To minimise the risk of EPSE, metoclopramide is recommended for short-term use only (up to five days). Children are also at greater risk of EPSE with metoclopramide and it should be avoided in patients younger than 20 years.

Prochlorperazine

Prochlorperazine is used for the treatment of nausea and vomiting due to various causes and is available as a tablet and an injection. In addition to its action on dopamine receptors, prochlorperazine also has antagonist effects at α-adrenoceptors, histamine receptors, and cholinergic receptors, and potentiates noradrenaline. This may result in adverse effects such as orthostatic hypotension, reflex tachycardia, sedation, dry mouth, and constipation.

Droperidol

Droperidol can be used to prevent or treat postoperative nausea and vomiting. It is available as an injectable for IV or IM use. The usefulness of droperidol is limited by its sedating tendency and risk of EPSE.

5HT₃ antagonists

5-HT₃ antagonists block serotonin peripherally (in the gastrointestinal system) and centrally in the CTZ. It is thought that chemotherapeutics and radiotherapy can cause the release of 5-HT in the small intestine to trigger a vomiting reflex. These agents are effective in managing nausea and vomiting associated with cancer therapy and surgery.

The 5-HT₃ antagonists available in Australia are:

• Granisetron;
• Ondansetron;
• Palonosetron; and
• Tropisetron.

All of these agents appear to be similarly effective overall. However, palonosetron is more effective for preventing postoperative vomiting than ondansetron. When used for chemotherapy-induced nausea and vomiting, 5-HT₃ antagonists are more effective for acute rather than delayed symptoms.

5-HT₃ antagonists have a favourable side effect profile; common adverse effects include constipation, headache, and dizziness.

These agents are available in a range of presentations, including tablets/capsules, orally disintegrating tablets, oral liquid, and injections.

Substance P antagonists

Substance P antagonists prevent the binding of substance P to the neurokinin type 1 receptor (NK-1R) in the CTZ. This class includes:

• Aprepitant;
• Fosaprepitant;
• Fosnetupitant (only available in combination with the 5-HT₃ antagonist, palonosetron)
• Netupitant (only available in combination with palonosetron).

Fosnetupitant and fosaprepitant are phosphorylated pro-drugs of netupitant and aprepitant, respectively. This improves their water solubility. Following IV administration, they are rapidly converted to their active form.

Substance P antagonists are indicated for the prevention of acute and delayed nausea and vomiting associated with chemotherapy. For this purpose, they are typically administered in combination with a 5-HT₃ antagonist and a corticosteroid (e.g. dexamethasone). Aprepitant is also indicated for the prevention of postoperative nausea and vomiting.

Common side effects for this class include diarrhoea, fatigue, headache, and dizziness. There are many potential drug interactions with this class due to their effects on cytochrome P450. Aprepitant inhibits, induces and is metabolised by CYP3A4, and is also a moderate inducer of CYP2C9. Caution is required when administering with other medicines metabolised by these enzymes as therapeutic effect may be altered and adverse effects may be increased. Combination with pimozide, terfenadine, astemizole, or cisapride is contraindicated.

Netupitant is metabolised by, and moderately inhibits, CYP3A4. Combined use with a strong CYP3A4 inducer should be avoided as netupitant levels may reduce significantly. Caution should be used when combining netupitant with medicines that rely on CYP3A4 for metabolism as their levels may rise, increasing the risk of adverse effects. It is worth noting that netupitant has a long half-life (~88 hours), so this inhibitory effect may last for four days or more.

Antihistamines

Antihistamines reduce nausea and vomiting by blocking the effects of histamine in the CTZ. Cyclizine and promethazine are the antihistamines typically used for the management of nausea and vomiting in the hospital setting. Agents such as levomepromazine are not marketed in Australia but may be accessed via the Special Access Scheme. Other antihistamines are available over the counter for the management of motion sickness (e.g. dimenhydrinate in a fixed-dose combination with hyoscine).

Antihistamines can cause sedation. Due to their anticholinergic properties, they may also cause side effects such as dry mouth and constipation. Promethazine also has some anti-serotonin effects.

Promethazine is available as tablets and as an injection. It is a known vesicant, and the manufacturer recommends deep intramuscular injection into a large muscle as the preferred method of parenteral administration. Intravenous or inadvertent intra-arterial or subcutaneous administration can result in complications that may be severe (e.g. thrombophlebitis, venous thrombosis, phlebitis, nerve damage, abscess, tissue necrosis, and gangrene). However, care is required wherever injectable promethazine is used, as all administration routes can result in tissue damage. The Institute for Safe Medication Practices (ISMP) strongly advises against the use of injectable promethazine in favour of safer alternatives, such as 5-HT₃ antagonists.

Summary

A summary of commonly used antiemetics is shown in Table 1. If a poor response occurs to one agent, a drug from a different class may be considered. Alternatively, combination therapy using antiemetics with different mechanisms of action may also be considered.

Table 1. Overview of antiemetic agents