A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research

Abstract

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists-originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists-searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H₁) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists-investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D₂) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine₃(5-HT₃) receptor antagonists-metoclopramide was initially assumed to act only via D₂ receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine₄ receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT₃ receptors. The latter led to identification of selective 5-HT₃ receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin₁receptor antagonists-antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.

Keywords: 5-hydroxytryptamine3 receptor antagonists; drug discovery; histamine H1 receptor antagonists; metoclopramide; muscarinic receptor antagonists; nausea and vomiting; neurokinin1 receptor antagonists; olanzapine.

Figure 1

A summary of the levels of defense employed to initially avoid and, if required, to detect and respond to toxins ingested with the food. AP, area postrema (also known as the “chemoreceptor trigger zone” for emesis, but see text for discussion); NTS, nucleus tractus solitarius; the site in the dorsal brainstem where inputs from the vagal afferents and the area postrema are integrated and from which outputs pass to other areas of the brainstem to coordinate the motor outputs for vomiting and from which information is relayed to “higher” brain regions to evoke the sensation of nausea. Figure adapted and modified from Andrews (1993).

Figure 2

Diagram illustrating that nausea and vomiting can be evoked by stimuli ranging from toxins in the food where they may be viewed as an “appropriate” response helping to defend the animal, to diseases and therapeutic interventions where they are viewed as undesirable and are classified as “symptoms” or “side-effects.” Profile of the head from http://getdrawings.com/talking-head-silhouette.

Figure 3

Major players in the pharmaceutical industry responsible for the development of the main anti-emetic drugs over the time course covered by this review. See text for details and references.

Figure 4

A summary of the physical, physiological, and psychological consequences of nausea and vomiting for the person suffering, as well as for any observers including health care professionals. The potential risk of infection from vomiting is also highlighted. Profile of the head from http://getdrawings.com/talking-head-silhouette.

Figure 5

Summary of the pathways responsible for the induction of nausea and vomiting (blue arrows), the integrative regions in the brain stem (blue box indicates dorsal brain stem and nucleus tractus solitarius in particular) and the output pathways for nausea (green) and the motor outputs for vomiting (red box indicates the pathways in the ventral brain stem). See text for details of pathways. CB₁, cannabinoid₁ receptor; D₂, dopamine₂ receptor; H₁, histamine₁ receptor; M_3/5, muscarinic_3/5 acetylcholine receptor; 5-HT₃-5-hydroxytryptamine₃ receptor; 5-HT₄-5-hydroxytryptamine₄ receptor; NK₁, tachykinin neurokinin ₁ receptor. Adapted and modified from Stern et al. (2011).

Figure 6

Photograph of the packaging for Marzine (cyclizine, developed in 1947) indicating its use by NASA during the Apollo moon missions. With permission: Wellcome collection, Wellcome Library (WF/M/PL/191), London, United Kingdom.

Figure 7

Two hypotheses for the relationship between disordered upper gastrointestinal tract motility and the sensation of nausea. These are not mutually exclusive but the efficacy of drugs targeted at sites A and B will differ depending upon which mechanism is in operation. In hypothesis A (left hand panel) the activation of central emetic pathways activates ascending pathways leading to the sensation of nausea, followed by descending autonomic pathways leading to delayed gastric emptying. An anti-nausea drug targeted centrally (site A) would block both nausea and the peripheral motility changes, so there will be a secondary return of gastric emptying to normal. In this hypothesis a drug targeted at site B may only have a small effect by reducing a positive reinforcing feedback from the centrally-driven disruption of motility. In hypothesis B (right hand panel) disordered upper digestive tract motility, usually resulting from disease (e.g., diabetic gastroparesis), is the primary driver for the genesis of nausea, leading to activation of visceral afferents or possibly the release of enteroendocrine agents into the blood for subsequent activity at the area postrema. A drug acting on the upper digestive tract (site B) would normalize gastric motility and remove the primary drive for nausea. Note that in this hypothesis, the “traditional prokinetic drugs” (with an exclusively peripheral action) have generally not been successful; potential alternatives are indicated. In this hypothesis a drug acting at the central site A would also be likely to indirectly reduce nausea by preventing activation of central pathways. ENS, enteric nervous system; ICC, interstitial cells of Cajal.