16.02.3 Emesis with Cytotoxic Drugs and Drugs for

One of the most serious causes of nausea and emesis (vomiting) is cytotoxic drugs (drugs that kill cells), such as the anti-cancer drugs. Some cytotoxic drugs are irritants to the gastro-intestinal tract, and this irritation involves 5-HT₃ receptors (Figure 16.3).

The other route to nausea and vomiting with cytotoxic drugs is when they are carried in the blood, to the chemoreceptor trigger zone in the area postrema of the central nervous system. There is also a neural input after gastrointestinal irritation to the chemoreceptor trigger zone. The chemoreceptor trigger zone or emetic centre has 5-HT₃-receptors, dopamine D₂ receptors, and muscarinic M₁-receptors (Figure 16.3), and consequently drugs that act at these receptors can modify nausea and vomiting.

Figure 16.3 Nausea and vomiting with cytotoxic drugs (Copyright QUT, Sheila Doggrell)

The 5-HT₃-receptor antagonists, the –etrons, such as ondansetron (prototype) act at centrally- and peripherally 5-HT₃ receptors to inhibit emesis. The –etrons, such as ondansetron, are the most effective agents for treating chemotherapy-induced nausea and vomiting, but they are not effective in motion sickness, which involves a different pathway.

The dopamine D₂-receptor antagonists, prochlorperazine and metoclopramide, act as antagonists at the dopamine D₂-receptors in the chemoreceptor trigger zone to inhibit cytotoxic-induced emesis. These drugs used to be standard treatment for cytotoxic-induced emesis, but their use is declining as they are less effective than the 5-HT₃-receptor antagonists.

Prochlorperazine and metoclopramide are also used in the nausea and vomiting associated with pregnancy (morning sickness), where the underlying pathway remains to be clarified.

Substance P is a peptide neurotransmitter in the central nervous system that acts at NK₁-receptors. By stimulating NK­-receptors, substance P has a role in emetic pathways, especially the emesis associated with chemotherapy. Apepitant is an antagonist at NK₁-receptors used to control chemotherapy-induced vomiting. Apepitant is not usually used as the first choice in preventing the emesis associated with chemotherapy, but can be used in combination with ondansetron. Thus, when ondansetron is not effective alone, the addition of apepitant can increase the ability to inhibit the emesis caused by chemotherapy. Apepitant is metabolised by CYP3A4, and consequently can be involved in interactions with numerous drugs.

The glucocorticoids, especially dexamethasone, are used as anti-emetics to prevent emesis with cytotoxic drugs. The anti-emetic properties of the glucocorticoids were a seredipitous discovery. Thus, when dexamethasone was being used in chemotherapy, it was notices that there was less nausea and vomiting. As it was a chance discovery rather than a drug designed for specific target, the mechanism behind the anti-emetic effect of dexamethasone is not clear. The mechanism may be related to inhibition of the synthesis of prostaglandin E₂, as PGE₂ probably has a role on emesis. Dexamethasone is not generally used alone as an antiemetic, but is used with other antiemetics.