Screening of Antiemetic Drugs

Screening of Antiemetic Drugs

1. Definition, rationale & scope of antiemetic screening

• Antiemetic screening = the preclinical, mostly in vivo evaluation of candidate compounds for their ability to suppress experimentally-induced emesis (retching + vomiting) or its non-vomiting surrogates, using species that possess a functional vomiting reflex and standardised emetogenic challenges (SK Gupta 3e Ch.37, pp.546–553).
• Nausea and vomiting are common, distressing symptoms across pregnancy, peptic ulcer, GI infections/obstruction, renal disease, hepatitis, motion sickness, post-anaesthesia/post-operative states, and — most importantly for screening — as an adverse effect of drugs, especially cancer chemotherapeutic agents (SK Gupta 3e Ch.37, p.546).
• Emesis is also a defence mechanism against accidental ingestion of toxins; the vomiting reflex, though not essential for survival, helps the body expel ingested poisons — this is why not all vomiting-competent species are sensitive to all emetic stimuli (SK Gupta 3e Ch.37, pp.546–547).
• Purpose of the models (three-fold): (i) elaborate the pathways generating nausea and reflex vomiting; (ii) identify pharmacological approaches for developing new antiemetics; (iii) understand disease states in which nausea/vomiting are cardinal features (SK Gupta 3e Ch.37, p.547).
• Emesis comparable to man occurs only in a few animal species — this single fact drives the entire species-selection logic of antiemetic screening (Vogel 4e V3 Part XI, p.2469).
• Apomorphine has a dual role in these assays: as a reference emetic standard (against which other emetics are compared) OR as the challenging agent against which candidate antiemetics are evaluated (Vogel 4e V3 Part XI, p.2469).

Terminology of the emetic act (measured endpoints depend on these definitions)

• Nausea — a non-observable, subjective urge to vomit, felt at the back of the throat and epigastrium; may or may not culminate in emesis. Because animals cannot communicate emotional status, nausea is inferred indirectly from behaviour (SK Gupta 3e Ch.37, p.546, p.548).
• Retching — rhythmic inspiratory movements against a closed glottis; an attempt to vomit without expulsion of upper-GI contents; diaphragm and abdominal muscles contract and relax simultaneously (SK Gupta 3e Ch.37, p.546; Vogel 4e V3 Part XI, p.2471).
• Vomiting — sustained abdominal contraction coordinated with intercostal, laryngeal and pharyngeal muscles; glottis closed, soft palate elevated, gastric fundus relaxed → forced expulsion of gastric contents through nose/mouth (SK Gupta 3e Ch.37, p.546; Vogel 4e V3 Part XI, p.2471).
• Emetic episode — where retch frequency is too high to score individually (e.g. Suncus murinus), retching + vomiting are pooled and counted as emetic episodes (SK Gupta 3e Ch.37, p.548).
• The occurrence and frequency of retching and vomiting can be measured objectively — this observability is what makes emesis (unlike nausea) a tractable screening endpoint (SK Gupta 3e Ch.37, p.546).

Temporal classification of emesis (dictates which model to choose)

• Acute emesis — occurs minutes to several hours after emetogen exposure; usually resolves within 24 h (SK Gupta 3e Ch.37, p.546).
• Delayed emesis — >24 h after cancer chemotherapy; peaks at 48–72 h, may continue 6–7 days; does not respond well to 5-HT₃ antagonists (screened with methotrexate, not cisplatin) (SK Gupta 3e Ch.37, p.546, p.549).
• Anticipatory emesis — a conditioned response occurring before the emetic stimulus (e.g. before chemotherapy) due to negative past experience (SK Gupta 3e Ch.37, p.546).
• Breakthrough emesis — emesis occurring despite prophylactic antiemetic treatment, requiring rescue therapy (SK Gupta 3e Ch.37, p.546).