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) Neurokinin1 receptor 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.

Radiographic dose‐dependency study of loperamide effects on gastrointestinal motor function in the rat. Temporal relationship with nausea‐like behavior

“…Bedding intake was transient and reached similar maximum values for Lop 0.1 at 1 hour and Lop 10 at 2 hours after administration. Two main pathways may be involved in drug‐induced nausea and vomiting/pica: direct activation, by circulating drugs, of neurons within the area postrema (without blood‐brain barrier and known as the chemoreceptor trigger zone); activation of vagal afferents located in the stomach and small intestine, sensitive to distension and to the chemical nature of the luminal environment. Distension of the gastric antrum and duodenum, and dysrhythmic gastric movements can induce nausea and vomiting but paradoxically, gastric motor quiescence is also associated with nausea .…”

“…Distension of the gastric antrum and duodenum, and dysrhythmic gastric movements can induce nausea and vomiting but paradoxically, gastric motor quiescence is also associated with nausea . Inhibition of gastric motility (with relaxation of the proximal stomach, gastric dysrhythmia, and delayed gastric emptying) has been included amongst the physiological changes often referred to as “prodromata of vomiting” . However, whether gastrointestinal motor changes and nausea are a co‐consequence of activation of emetic pathways or whether nausea is a consequence of disordered gastrointestinal motility is still debated .…”

“…72,73 Inhibition of gastric motility (with relaxation of the proximal stomach, gastric dysrhythmia, and delayed gastric emptying) has been included amongst the physiological changes often referred to as "prodromata of vomiting". 71,72,74 However, whether gastrointestinal motor changes and nausea are a co-consequence of activation of emetic pathways or whether nausea is a consequence of disordered gastrointestinal motility is still debated. 71 In our hands, nausea-like behavior was transient whereas gastric dysmotility, comprising gastric emptying delay (as shown from the X-rays and ex vivo studies), and gastric distension (ex vivo) were much longer lasting.…”

“…71,72,74 However, whether gastrointestinal motor changes and nausea are a co-consequence of activation of emetic pathways or whether nausea is a consequence of disordered gastrointestinal motility is still debated. 71 In our hands, nausea-like behavior was transient whereas gastric dysmotility, comprising gastric emptying delay (as shown from the X-rays and ex vivo studies), and gastric distension (ex vivo) were much longer lasting. Thus, like nausea-like behavior in rats, nausea in humans might occur during an early phase in which distension-sensitive afferents increase signaling to the brainstem and not necessarily later on.…”

Functional brain networks and neuroanatomy underpinning nausea severity can predict nausea susceptibility using machine learning

“…). Although nausea is a common clinical symptom, anti‐emetics have limited efficacy against nausea and treatments targeted specifically against nausea, irrespective of cause, are lacking (Sanger & Andrews, ).…”