Chemicals as Emetogenic Stimuli

Very few drugs or chemicals are administered to humans to purposefully induce emesis. However, chemoreceptor stimulation caused by concentrated saline solutions taken orally have a nauseous taste and may be given in an attempt to cause emesis and remove toxic substances from the stomach. (The insertion of a finger down the throat has a similar effect, irritating the mechanoreceptors in the pharynx.) The alkaloid ipecacuanha has well-known emetic effects and acts by stimulating chemoreceptors in the area postrema. It has also been used in subemetic doses in some paracetamol tablets to prevent self-poisoning; a person taking an excessive number of tablets would finally receive an emetic dose of ipecacuanha, which would expel the paracetamol from the stomach. A different use was found for disulfiram in the treatment of alcoholism. If taken with alcohol, it leads to an accumulation of acetaldehyde, which induces nausea and sickness. It was used as an aversion therapy for drug abuse; apomorphine was used as an alternative treatment. With these exceptions, drug-induced emesis is unwanted but occurs with many different types of medical treatments. It can vary from a transient effect of little consequence to a persistent and chronic effect to severely reduce the quality of life.

The nausea and emesis induced by cancer chemotherapy (and radiation) are correctly perceived as the most severe emetogenic stimulus induced by any drug treatment. However, it is emphasized that the potential emetogenicity of chemotherapy is rated as absent, low,

Periodic Nausea
Figure 3 The causes and incidence of nausea and vomiting from an otherwise healthy population in the United Kingdom. The percentage of respondents in each group who reported nausea and vomiting at least once during the previous 12-month period.

moderate, or severe, depending on the drug used, regime of drug administration, dose, and patient variables. For example, all patients receiving cisplatin would be predicted to be very sick, whereas metho-trexate causes little if any effect. Nausea and vomiting induced by radiation are also related to the dose used and to the area and extent of the body irradiated. Both the cytotoxic therapy and radiation treatment frequently cause tissue disruption to the gastrointestinal tract. This damage may cause the release of toxic products from the tissue destruction and may induce a local inflammatory response influencing vagal afferent nerve endings within the gut to trigger the emetic reflex. This will depolarize the vagus nerve, and this chemically induced response mimics the effects of electrical stimulation of the vagus nerve, which is known to cause vomiting. The release of 5-hydroxy-tryptamine from damaged enterochromaffin cells within the gut provides just one important example whereby an endogenous substance may stimulate the 5-HT3 receptor subtype located on the vagal nerve (see Fig. 2). Additionally, substances such as 5-HT or other agents released as a consequence of cell damage may be transported in the blood system (with cytotoxic agents themselves and also the products of tumor breakdown) to directly stimulate the central components mediating the emetic reflex within the area postrema and perhaps the nucleus tractus solitarius.

A second group of therapeutic agents that inevitably cause nausea as the dose is increased is the dopamine agonist anti-Parkinson drugs, apomorphine, L-dopa, and the ergot derivatives. A major effect is to directly stimulate the dopamine receptors located in the central chemoreceptor mechanisms, with a lesser action to induce gastric stasis.

A third group of drugs that invariably induce nausea or emesis is the opiate analgesics. The acute administration of morphine and related drugs to opioid-naive patients frequently induces nausea and sometimes vomiting. However, tolerance rapidly develops to such effects, and indeed the first treatment may antagonize the emetic effects to a second opioid injection or other emetogens. The emetic effect may be mediated in the chemoreceptor trigger zone, whereas the antiemetic effect may be mediated closer to the vomiting center. The antiemetic effect may relate to an endogenous inhibitory tone exerted by opioids from the enkephalin or related series. The ability of narcotic antagonists such as naloxone to precipitate nausea or vomiting would support this hypothesis.

A fourth group of drugs is those enhancing 5-HT function, for example, 5-hydroxytryptophan, the precursor of 5-HT, or 5-HT re-uptake inhibitors, e.g., fluoxetine and paroxetine, which have been reported to induce nausea and occasionally vomiting as a side

Figure 4 (A) A scanning electron micrograph showing the human area postrema (AP) on the caudal floor of the fourth ventricle (IV) looking toward the central canal (CC; GT, gracile tubercle). The arrowheads indicate the abrupt transition between the area postrema and underlying cells. (B) Section through the medulla oblongata of a ferret that had been given cisplatin to reveal an increase in cellular activity using Fos-like immunoreactivity. This appears as dark dots (indicated by the arrowheads) is visible throughout the area postrema, and extends into the nucleus tractus solitarius (NTS; DMX, dorsal motor nucleus of the vagus nerve).

effect. This may relate to an increased 5-HT activity in both central and gut tissues.

Numerous other drugs also induce nausea and emesis. For example, cardiac glycosides such as digoxin, at doses only slightly greater than the therapeutic dose, induced abdominal pains, nausea, and vomiting. This probably relates to a central action at the chemoreceptor trigger zone and an irritant action within the gastrointestinal tract, which may be exacerbated by cardiac dysrhythmia. Also, the gastrointestinal irritation caused by antibiotic treatment or nonsteroidal anti-inflammatory agents frequently causes gastrointestinal distress, nausea, or vomiting, triggering the emetic reflex via the vagal and splanchnic nerves.

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