9 Nausea and Vomiting.docx

Nausea, Vomit and Motion Sickness Objectives Demonstrate understanding of the anatomical areas, neurotransmitters and receptors responsible for N/V/MS Describe mechanisms of action of the drugs used to treat nausea, vomit and motion sickness Demonstrate an understanding of the pharmacokinetics of t...

Nausea, Vomit and Motion Sickness Objectives Demonstrate understanding of the anatomical areas, neurotransmitters and receptors responsible for N/V/MS Describe mechanisms of action of the drugs used to treat nausea, vomit and motion sickness Demonstrate an understanding of the pharmacokinetics of the drugs used to treat nausea, vomit and motion sickness Describe adverse effects of the drugs used to treat nausea, vomit and motion sickness The tight junctions of endothelial cells - BBB Pharmacologist's view of emetic stimuli. Myriad signaling pathways lead from the periphery to the emetic center. Stimulants of these pathways are noted in italics. These pathways involve specific neurotransmitters and their receptors (bold type). Receptors are shown for dopamine (D2), acetylcholine (muscarinic, M), histamine (H1), cannabinoids (CB1), substance P (NK1), and 5-hydroxytryptamine (5-HT3). Some of these receptors also may mediate signaling in the emetic center. Serotonin Serotonin is released by the enterochromaffin cells of the small intestine in response to blood-borne emetics and local irritants. Serotonin stimulates vagal afferents by binding to 5HT3 receptors (5HT3R) to initiate the vomiting reflex. The 5HT3R are present on sites involved in emesis including vagal afferents and the solitary tract nucleus (STN) (which receives signals from vagal afferents and the area postrema) The highest concentrations of 5HT3R in the CNS are found in the STN and CTZ (chemoreceptor trigger zone) Antagonists of 5HT3R also may suppress nausea and vomiting by acting at these sites. 5-HT3 Receptor Antagonists Antiemetic 5-HT3 Receptor Antagonists 5-HT3 Receptor Antagonists Trade Name Ondansetron Zofran (most commonly used) Granisetron Kytril Dolasetron Anzemet Palonosetron Aloxi (delayed CINV) Mechanism of Action - 5-HT3R Antagonists Mechanism not fully characterized Ondansetron, Granisetron, Dolasetron and Palonosetron are selective 5-HT3R antagonists 5-HT3R antagonists have different chemical structures and receptor binding affinity. 5-HT3R antagonists binds to 5-HT3Rs in the periphery and in the CNS, with primary effects in GI tract Ondansetron Is rapidly absorbed after oral administration Extensive hepatic metabolism by CPY1A2, CPY2D6 and CPY3A4 Bioavailability ~60% T1/2 is 3-6 h Plasma clearance is decreased with increasing aging with hepatic failure (80% reduction in severe failure) females cleared more slowly that males Metabolic studies showed the drug is excreted in urine. Granisetron Complete absorption from the GI tract following oral dosing Bioavailability reduced by first-pass metabolism (extensively metabolized by liver CPY3A4 enzyme) Extensive distribution Extensive inter-subject variability T1/2 is 6-9 h Excreted in urine and feces after both intravenous and oral dosing Dolasetron Dolasetron is a pro-drug - converted in vivo by carbonyl reductase to its active metabolite, hydrodolasetron Hydrodolastron t½ is 6-8 h Hydrodolastron is metabolized in the liver by CYP2D6 and CYP3A4 Hydrodolastron is excreted in urine (mostly) and feces Palonosetron (Aloxi) Higher receptor-binding affinity to 5-HT3R and longer half-life (40 h after intravenous injection).  Metabolized by CYP2D6 (and to a lesser extent, CYP3A4 and CYP1A2) Eliminated in urine Adverse Effects EVENT ALOXI 0.25 MG (N=633) ONDANSETRON 32 MG I.V. (N=410) DOLASETRON 100 MG I.V.  (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 ( < 1%) 4 (1%) 4 (2%) Abdominal Pain 1 ( < 1%) 2 ( < 1%) 3 (2%) Insomnia 1 ( < 1%) 3 (1%) 3 (2%) Neurokinin-1 (NK1R) Receptor Antagonist Substance P belongs to a group of neurokinins (NKs), small peptides distributed in CNS and PNS exerts its effect on the NK-1 receptors causing nausea and vomiting. Aprepitant and fosaprepitant dimeglumine (intravenous prodrug) block NK1 receptor thereby, preventing nausea and vomiting. Used in conjunction with a 5-HT3 receptor antagonist and dexamethasone in highly emetogenic chemotherapy. Aprepitant Metabolism Aprepitant after absorption aprepitant is bound to plasma protein t1/2 is 9–13 h is metabolized by CYP3A4 excreted in feces Aprepitant inhibits CYP3A4 Therefore, there are drug interactions with CYP3A4- metabolized medications, including oral contraceptives, warfarin and dexamethasone. Because of this, the dexamethasone dose should be decreased by 50% when given with aprepitant or fosaprepitant. Netupitant and Palonesetron Combination A combination NK1 receptor antagonist, netupitant (ne too pi tent) plus 5HT3 receptor antagonist, palonesetron (Akynzeo) was recently approved for use by the FDA (~2014) Combination is well absorbed Long t ½ (netupitant, ~ 80 h; palonesetron, ~ 48 h). Netupitant is extensively metabolized by CYP3A4 (major) and CYP2C9 and CYP2D6 (minor) to active metabolites.  Palonesetron metabolized by CYP2D6 (and to a lesser extent, CYP3A4 and CYP1A2) They are excreted in the feces and urine Neurokinin-1 Receptor Antagonist- Side Effects Common side effects include: headache anorexia abdominal pain hiccups mild transaminase elevations Glucocorticoids Dexamethasone Binds to the glucocorticoid receptor (localized mainly in the solitary tract nucleus) Useful as adjuncts (with Aprepitant & Ondansetron) May suppress inflammation and prostaglandin production Metabolized by CYP3A4 Dopamine Receptor Antagonists Dopamine receptor antagonists (works by blocking dopamine receptors (D2) centrally in the CTZ): Phenothiazines (prochlorperazine and chlorpromazine) also have anticholinergic and antihistaminic activities Benzamide (metoclopramide) Metoclopramide works by blocking dopamine receptors (D2) centrally in the CTZ Dopamine Receptor Antagonists- Side effects Toxicities include sedation and extrapyramidal side effects (hypotension and cardiac effects) A black box warning has been added for metoclopramide warning of tardive dyskinesia (muscle movement disorders) with high doses or long-term use (>3 months). These dyskinesias may continue after the metoclopramide is discontinued (irreversible) . Cannabinoids - Dronabinol – Antiemetic Cannabinoids – CNS and GI tract – binds to cannabinoid receptor 1 (CB1). Active metabolite 11-OH-delta-9-tetrahydrocannabinol Lipid soluble – readily absorbed after oral administration, onset of actions occur within an hour Bioavailability low because of extensive first pass metabolism Detectable levels of metabolites for several weeks Excreted by urine and feces (mostly) Side effects include: sedation dysphoria dizziness dry mouth Anticholinergic Agent Scopolamine transdermal patch- (to prevent systemic side effects) Is a competitive and nonselective muscarinic antagonist Is the most effective drug for the prophylaxis and treatment of motion sickness. Is excreted in the urine. Anticholinergic Agent - Side effects drowsiness disorientation dry mouth blurred vision dilated pupils confusion hallucinations difficulty urinating rash Histamine (H1R) antagonists Histamine (H1R) antagonists are used for motion sickness and postoperative emesis (among other uses) Examples cyclizine (anticholinergic effects) hydroxyzine, (low affinity for the muscarinic receptors) Promethazine (has affinity for cholinergic receptors) Diphenydramine (potent muscarinic antagonists ) Reduce activity of receptor and compete with histamine binding to the receptor The H1R antagonists are well absorbed from the GI tract The drug is distributed widely throughout the body, including the CNS. Following oral administration, peak plasma concentrations are achieved in 1-3 hours, and effects usually last 4-6 hours; however, some of the drugs are much longer acting Metabolized in liver and excreted in urine Antihistamines - Adverse Effects Most frequent – sedation Ingested with alcohol or CNS depressants = additive effect = impaired motor skills The next most frequent side effects involve the digestive tract and include loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea Sample Study Questions What are the stimuli that activate the Area postrema (chemo receptive area)? What areas are stimulated by neurotransmitters from the area postrema? Which areas would be or not be associated with motion sickness? What areas would be affected (directly and indirectly) by blood-borne emetics and local irritants? Where are the serotonin receptors localized and how do they influence the emetic center? How do stimuli from the CNS or periphery influence the emetic center? What receptor (s) would be directly affected by local irritants bacteria, radiation and cytotoxic drugs? What are the names of the 5-HT3 receptor antagonists? How are 5-HT3 receptor antagonists excreted from the body? What are some of the common characteristics among them? What event in the body results most often as a side effect of 5-HT3 use? Why are 5-HT3 receptor antagonists used? What are the nerves associated with emesis? Name NK-1 receptor antagonists What are the ligands for NK-1 receptors? When using NK-1 receptor antagonists why is it important to be careful about other medications that utilize the CYP3A4 and CPY2C9 systems? Name some examples. Name the receptors localized at the CTZ? What ligands bind to these receptors? Name the antagonists that block these receptors. Why should metoclopramide not be given at high doses or used long-term? What are the properties of cyclizine and other H1 receptor antagonist that would allow them to prevent motion sickness and cause dry mouth? Name some antihistamine drugs What are some side effects of antihistamines and anticholinergics? Which areas in the CNS would be most associated with motion sickness? Which areas in the CNS could be most associated with gagging? What are the neurotransmitters associated with motion sickness? What are the neurotransmitters associated with gagging?