1. Nausea and Vomiting James Hallenbeck, MD Director, Palliative Care Services, Palo Alto VAHCS, Stanford University

2. Objectives Understand the pathophysiology of nausea and vomiting Understand the pathophysiology of nausea and vomiting Utilize the “VOMIT” acronym in identifying causes of nausea Utilize the “VOMIT” acronym in identifying causes of nausea Select antiemetic therapy, based underlying physiology Select antiemetic therapy, based underlying physiology

3. Pearl for the Day… But ferrets do!

4. So WHY do we have this disgusting problem?

5. Consider our Hungry Ancestors… What protects this guy from eating something poisonous?

6. Progressive Failsafe Measures Memory Memory Appearances Appearances What looks gross, is probably gross What looks gross, is probably gross Smell Smell Taste Taste Bitter – bad Bitter – bad Sweet –good Sweet –good GI Track – mechano and chemoreceptors GI Track – mechano and chemoreceptors CNS CNS Chemoreceptor Trigger Zone (CTZ) Chemoreceptor Trigger Zone (CTZ) Vestibular Apparatus Vestibular Apparatus

7. A Central Final Pathway for Nausea CTZCNS VOMIT CENTER VestibularApparatus GI Tract (Dopamine, Serotonin) ??? (Acetylcholine,Histamine) (Acetylcholine,Histamine, Serotonin + mechanoreceptors)

8. Receptor Affinity Common Antiemetics The lower the number, the stronger this agent is at blocking this receptor Drug Dopamine 2 Musc. Chol. Histamine Scopolamine >10,000.08 >10,000 Promethazine 240 21 2.9 Prochlorperazine 15 2100 100 Chlorpromazine 25 130 28 Metoclopramide 270 >10,000 1,000 Haloperidol 4.2 >10,000 1,600 Potency: K1 (nanomolar) Adapted from Perourka, Snyder

9. Causes of Nausea and Vomiting Vestibular Vestibular Obstruction (Opioids) Obstruction (Opioids) Mind (Dysmotility) Mind (Dysmotility) Infection (Irritation) Infection (Irritation) Toxins (Taste and other senses) Toxins (Taste and other senses)

10. V Vestibular Apparatus Complaint of nausea with head movement Complaint of nausea with head movement Mediated by acetylcholine and histamine receptors Mediated by acetylcholine and histamine receptors Doc(s): Doc(s): Promethazine (supp) Promethazine (supp) Scopolamine (patch, injection) Scopolamine (patch, injection) Cyclizine (oral, injection) Cyclizine (oral, injection) Most anticholinergic, antihistiminic drugs will help!

11. O Obstruction Most common cause: constipation Most common cause: constipation May be caused by external or internal obstruction May be caused by external or internal obstruction In advanced malignant bowel obstruction external compression most common In advanced malignant bowel obstruction external compression most common May be mediated through both mechano- and chemoreceptors May be mediated through both mechano- and chemoreceptors DOC(s) DOC(s) True bowel obstruction True bowel obstruction Controversy as to best drugs Controversy as to best drugs Constipation: anti-constipation meds Constipation: anti-constipation meds

12. M Mind Mediates emotional, cognitive aspects of nausea -- anxiety, memory, meaning Mediates emotional, cognitive aspects of nausea -- anxiety, memory, meaning Can be very powerful Can be very powerful Manipulating taste and other senses often helpful Manipulating taste and other senses often helpful DOC(s): DOC(s): Lorazapam (poor solo agent) Lorazapam (poor solo agent) Appetite stimulants Appetite stimulants Megestrol, steroids, Cannibinoids Megestrol, steroids, Cannibinoids

13. M DysMotility Multiple causes Multiple causes Opioids Opioids Anticholinergic drugs Anticholinergic drugs Stomach/bowel compression, infiltration Stomach/bowel compression, infiltration Upper intestinal dysmotility-very common, under appreciated Upper intestinal dysmotility-very common, under appreciated Doc(s): Prokinetics: Doc(s): Prokinetics: Metoclopramide (upper only) Metoclopramide (upper only) Motilin agonists (erythromycin) Motilin agonists (erythromycin) Senna (lower only) Senna (lower only)

14. I Infection/Irritation Mediated through chemoreceptors : acetylcholine, histamine, serotonin Mediated through chemoreceptors : acetylcholine, histamine, serotonin Gut and adjacent organ inflammation can trigger Gut and adjacent organ inflammation can trigger DOC(s): Anticholinergic/antihistaminic agents, such as promethazine DOC(s): Anticholinergic/antihistaminic agents, such as promethazine

15. T Toxins Most important: drugs we give Most important: drugs we give Various mechanisms of inducing nausea Various mechanisms of inducing nausea Local irritant Local irritant NSAIDs NSAIDs Changing blood levels (via CTZ) Changing blood levels (via CTZ) opioids, ? SSRIs opioids, ? SSRIs Toxic blood levels Toxic blood levels digoxin digoxin DOC(s): depends on mechanism of action DOC(s): depends on mechanism of action

16. Opioid Related Nausea Two mechanisms Gut effect: Dysmotility of lower and upper gut Gut effect: Dysmotility of lower and upper gut DOC(s): prokinetics DOC(s): prokinetics Effect on CTZ Effect on CTZ Mediated through D2 receptor Mediated through D2 receptor Related to changing blood levels Related to changing blood levels Improves with steady state blood level Improves with steady state blood level DOC(s): Haloperidol (po, inj.), Prochlorperizine (supp, po) DOC(s): Haloperidol (po, inj.), Prochlorperizine (supp, po) No good evidence, rationale for using promethazine

17. 5HT3 Antagonists Useful for certain forms of chemotherapy related nausea Useful for certain forms of chemotherapy related nausea May have other special uses: May have other special uses: In CTZ related nausea, where dopamine blockade contraindicated In CTZ related nausea, where dopamine blockade contraindicated (Parkinson’s Disease) (Parkinson’s Disease) ? Other refractory CTZ related causes ? Other refractory CTZ related causes ? In certain GI cases ? In certain GI cases ? Bowel Obstruction ? Bowel Obstruction ? Radiation Enteritis ? Radiation Enteritis Currently very expensive Currently very expensive

18. Newer Agents Neurokinin 1 Antagonists