Antiemetics

This is an overview of drugs used to control nausea and vomiting. This presentation was for 2nd year pharmacy students as part of a pharmacology & toxicology course and accompanies Goodman & Gilman's (12e) chapter 46.

1. Antinauseants & Antiemetic Agents Brian J. Piper, Ph.D., M.S. October 16, 2012

2. Learning objectives Pharmacy students should be able to: 1. Explain emesis pathway(s) 2. Identify drug targets for antiemetic agents 3. Describe mechanism of action of antiemetic agents 4. Recognize adverse effects of antiemetic agents Ibn Bultan (1531)

3. Emesis A protective reflex that serves to rid the stomach and intestine of toxic substances and prevent their further ingestion. Vomiting is a complex process that consists of: Pre-ejection phase : gastric relaxation & retroperistalsis Retching : rhythmic action of respiratory muscles preceding vomiting and consisting of contraction of abdominal and intercostal muscles and diaphragm against a closed glottis Ejection : intense contraction of the abdominal muscles and relaxation of the upper esophageal sphincter

4. Importance Vomiting is an adverse effect of many clinically useful drugs: c ancer chemotherapy & radiation o pioids g eneral anesthetics Nausea may be a component of: m igraines p regnancy

5. Area Postrema s urrounds 4 th ventricle o utside blood brain barrier & monitors blood Miller & Leslie (1994). Frontiers in Neuroendocrinology, 15(4 ), 301-320.

6. Activity of Area Postrema Following Chemotherapy Neuronal activation (c- fos , arrowheads) in the area postrema (AP) following cisplatin administration (10 mg/kg) to an adult ferret. CC: Central Canal (4 th ventricle); NTS: nucleus of the solitary tract; DMX dorsal motor nucleus of vagus nerve. Miller & Leslie (1994). Frontiers in Neuroendocrinology, 15(4 ), 301-320.

7. Area Postrema & Nausea Rats (non-retching) got saccharine, injection (saline or lithium chloride), then two-bottle choice Bernstein et al. (1992). Brain Research, 575 , 132-137.

8. Area Postrema & Nausea Rats (non-retching) got saccharine, injection (saline or lithium chloride), then two-bottle choice Lesion of the area postrema eliminated this response. Bernstein et al. (1992). Brain Research, 575 , 132-137.

9. Area Postrema (AP) & Nausea Rats ( + AP lesioned ) got saccharine, injection (saline or lithium chloride) Behavioral ratings of response to lithium ( Lieing on Belly) were made Pre- inections , a meal was consumed. Stomach contents were examined. Area Postrema = chemoreceptor trigger zone Bernstein et al. (1992). Brain Research, 575 , 132-137. * *

10. Anatomy of Emesis Chemoreceptor trigger zone (CTZ) in the area postrema (AP) at the bottom of the fourth ventricle has high concentration of: 5-HT 3 (?) D 2 M 1 NK 1 opioid The CTZ has connections to the Nucleus of the T ractus Solitarius (NTS) & Reticular Formation (aka vomiting center) which contains: 5-HT 3 (?) M 1 NK 1

11. M 1 D 2 Krakauer et al. (2005). New England Journal of Medicine, 352 , 817.

12. Classification of antiemetics † some peripheral activity at 5-HT 3 receptor; ‡ some antihistamine and anticholinergic activity

13. Ondansetron MOA : 5-HT 3 antagonist Indications : radiation, chemotherapy, postoperapative Dosing : 1x/day Adverse Effects : constipation & headache

14. 5-HT 3 Antagonists (- etron ) Compared Granisetron Ondansetron Dolasetron Brand name Kytril , Sancuso Zofran Anzemet FDA Approval 1988 1991 G 1997 Indications chemotherapy radiation chemotherapy radiation chemotherapy radiation Half-life (hours) 9 4 8 Routes of administration oral, iv, transdermal oral, iv oral, iv Adverse effects constipation & headaches constipation & headaches headache tachy / bradycardia G generic form available

15. 5-HT 3 Antagonists (- etron ) Compared Granisetron Ondansetron Palonosetron Brand name Kytril , Sancuso Zofran Aloxi FDA Approval 1988 1991 G 2003 (delayed nausea) Indications chemotherapy radiation chemotherapy radiation chemotherapy post-operative Half-life (hours) 10 4 40 Routes of administration oral, iv, transderm oral, iv oral, iv Adverse effects constipation & headaches constipation & headaches headache, constipation, QT

16. 5-HT3 Antagonists Compared: Efficacy Chemotherapy patients (N = 563) randomized to receive ondansetron versus palonosetron Treatment failure = emetic response or rescue medication % of Patients Gralla et al. (2003). Annals of Oncology, 14 , 1570-1577.

17. 5-HT3 Antagonists Compared: Safety Chemotherapy patients (N = 563) randomized to receive ondansetron versus palonosetron Gralla et al. (2003). Annals of Oncology, 14 , 1570-1577.

18. Pathway of Emesis 2 1 3 5 4

19. 19 Pavlov’s Experiments During conditioning, the neutral stimulus (tone) and the US (food) are paired, resulting in salivation (UR). After conditioning, the neutral stimulus (now Conditioned Stimulus, CS) elicits salivation (now Conditioned Response, CR)

20. Classical Conditioning & Nausea Pre-Conditioning Neutral Stimulus: hospital environment Unconditioned Stimulus: chemotherapy Unconditioned Response: nausea & vomiting Post-Conditioning Conditioned Stimulus: hospital environment Conditioned Response: nausea & vomiting

21. Metoclopramide MOA : D 2 antagonist, 5-HT 3 antagonist Indications : chemotherapy , post-operative Adverse Effects : restlessness, Parkinsonian symptoms Pronunciation: http ://dictionary.reference.com/browse/metoclopramide?s=t 1 min: http://www.youtube.com/watch?v=dum81RdFrhM

22. Olanzapine MOA: D 2 antagonist + others Indications: acute & delayed CINV Adverse Effects: Stahl (2008). Essential Psychopharmacology , p. 411.

23. Synthetic delta-9-tetrahydrocannabinol  ( Δ 9 - THC) Schedule: III MOA: Cannabinoid receptors? AE: dysphoria , postural hypotension Dronabinol

24. Density of Cannabinoid Receptor 1 (Increased Darkness = more receptors labeled with [ 3 H]CP-55,940) Hekenham et al. (1991) J Neurosci, 11 , 563-583.

25. A prepitant MOA: substance P binds to N eurokinin A receptors Arg -Pro- Lys -Pro- Gln - Gln - Phe - Phe - Gly - Leu - Met N eurokinin A antagonist Indications: CINV, PONV Adverse Effects: a sthenia, constipation, hiccups

26. Neurokinin A Antagonist: Efficacy Abdominal surgery patients (N=750) randomized to receive oral Aprepitant or Ondansetron Hours until vomiting or rescue medication Gan et al. (2007). Anesthesia & Analgesia, 104(5) , 1082-1089.

27. Neurokinin A Antagonist: Safety Abdominal surgery patients (N=750) randomized to receive oral Aprepitant or Ondansetron Gan et al. (2007). Anesthesia & Analgesia, 104(5) , 1082-1089.

28. Summary High Therapeutic Index 5-HT 3 antagonists NK 1 antagonists c orticosteroids (combo) Low Therapeutic Index cannabinoids d opamine antagonists benzodiazepines Hesketh (2008). New England Journal of Medicine, 358 , 2482-2494.

29. Abbreviations CB 1 Cannabinoid 1 CINV Chemotherapy-induced nausea and vomiting CTZ Chemoreceptor trigger zone DA Dopamine NK 1 Neurokinin 1 PONV Post-operative nausea and vomiting STN Solitary tract nucleus VC Vomiting center