9 Nausea and Vomiting- Pathophysiology and Pharmacology.pdf

Nausea, Vomit and Mo0on Sickness Objec&ves o Demonstrate understanding of the anatomical areas, neurotransmi4ers and receptors responsible for N/V/MS o Describe mechanisms of ac<on of the drugs used to treat nausea, vomit and mo<on sickness o Demonstrate an understanding of the pharmacokine<cs of th...

Nausea, Vomit and Mo0on Sickness Objec&ves o Demonstrate understanding of the anatomical areas, neurotransmi4ers and receptors responsible for N/V/MS o Describe mechanisms of ac<on of the drugs used to treat nausea, vomit and mo<on sickness o Demonstrate an understanding of the pharmacokine<cs of the drugs used to treat nausea, vomit and mo<on sickness o Describe adverse effects of the drugs used to treat nausea, vomit and mo<on sickness The &ght junc&ons of endothelial cells - BBB Pharmacologist's view of eme<c s<muli. Myriad signaling pathways lead from the periphery to the eme<c center. S<mulants of these pathways are noted in italics. These pathways involve specific neurotransmi4ers 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 eme<c center. Serotonin o Serotonin is released by the enterochromaffin cells of the small intes<ne in response to blood-borne eme<cs and local irritants. o Serotonin s<mulates vagal afferents by binding to 5HT3 receptors (5HT3R) to ini<ate the vomi<ng reflex. o 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) o The highest concentra<ons of 5HT3R in the CNS are found in the STN and CTZ (chemoreceptor trigger zone) o Antagonists of 5HT3R also may suppress nausea and vomi<ng by ac<ng at these sites. 5-HT3 Receptor Antagonists An&eme&c 5-HT3 Receptor Antagonists 5-HT3 Receptor Antagonists Ondansetron Granisetron Dolasetron Palonosetron Trade Name Zofran (most commonly used) Kytril Anzemet Aloxi (delayed CINV) Mechanism of Ac&on - 5-HT3R Antagonists o Mechanism not fully characterized o Ondansetron, Granisetron, Dolasetron and Palonosetron are selec<ve 5-HT3R antagonists o 5-HT3R antagonists have different chemical structures and receptor binding affinity. o 5-HT3R antagonists binds to 5-HT3Rs in the periphery and in the CNS, with primary effects in GI tract Ondansetron o Is rapidly absorbed a\er oral administra<on o Extensive hepa<c metabolism by CPY1A2, CPY2D6 and CPY3A4 o Bioavailability ~60% o T1/2 is 3-6 h o Plasma clearance is decreased • with increasing aging • with hepa<c failure (80% reduc<on in severe failure) • females cleared more slowly that males o Metabolic studies showed the drug is excreted in urine. Granisetron o Complete absorp<on from the GI tract following oral dosing • Bioavailability reduced by first-pass metabolism (extensively metabolized by liver CPY3A4 enzyme) o Extensive distribu<on o Extensive inter-subject variability • T1/2 is 6-9 h o Excreted in urine and feces a\er both intravenous and oral dosing Dolasetron o Dolasetron is a pro-drug - converted in vivo by carbonyl reductase to its ac<ve metabolite, hydrodolasetron o Hydrodolastron t½ is 6-8 h o Hydrodolastron is metabolized in the liver by CYP2D6 and CYP3A4 o Hydrodolastron is excreted in urine (mostly) and feces Palonosetron (Aloxi) o Higher receptor-binding affinity to 5-HT3R and longer half-life (40 h a\er intravenous injec<on). o Metabolized by CYP2D6 (and to a lesser extent, CYP3A4 and CYP1A2) o Eliminated in urine Adverse Effects 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%) Cons&pa&on 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fa&gue 3 ( < 1%) 4 (1%) 4 (2%) Abdominal Pain 1 ( < 1%) 2 ( < 1%) 3 (2%) Insomnia 1 ( < 1%) 3 (1%) 3 (2%) EVENT Neurokinin-1 (NK1R) Receptor Antagonist o Substance P • belongs to a group of neurokinins (NKs), • small pep<des distributed in CNS and PNS • exerts its effect on the NK-1 receptors causing nausea and vomi<ng. o Aprepitant and fosaprepitant dimeglumine (intravenous prodrug) block NK1 receptor thereby, preven<ng nausea and vomi<ng. o Used in conjunc<on with a 5-HT3 receptor antagonist and dexamethasone in highly emetogenic chemotherapy. Aprepitant Metabolism o Aprepitant • a\er absorp<on aprepitant is bound to plasma protein • t1/2 is 9–13 h • is metabolized by CYP3A4 • excreted in feces o Aprepitant inhibits CYP3A4 o Therefore, there are drug interac<ons with CYP3A4- metabolized medica<ons, including oral contracep<ves, warfarin and dexamethasone. o Because of this, the dexamethasone dose should be decreased by 50% when given with aprepitant or fosaprepitant. Netupitant and Palonesetron Combina&on o A combina<on NK1 receptor antagonist, netupitant (ne too pi tent) plus 5HT3 receptor antagonist, palonesetron (Akynzeo) was recently approved for use by the FDA (~2014) o Combina<on is well absorbed o Long t ½ (netupitant, ~ 80 h; palonesetron, ~ 48 h). o Netupitant is extensively metabolized by CYP3A4 (major) and CYP2C9 and CYP2D6 (minor) to ac<ve metabolites. o Palonesetron metabolized by CYP2D6 (and to a lesser extent, CYP3A4 and CYP1A2) o They are excreted in the feces and urine Neurokinin-1 Receptor Antagonist- Side Effects o Common side effects include: • headache • anorexia • abdominal pain • hiccups • mild transaminase eleva<ons Glucocor&coids o Dexamethasone • Binds to the glucocor<coid receptor (localized mainly in the solitary tract nucleus) • Useful as adjuncts (with Aprepitant & Ondansetron) • May suppress inflamma<on and prostaglandin produc<on • Metabolized by CYP3A4 Dopamine Receptor Antagonists o Dopamine receptor antagonists (works by blocking dopamine receptors (D2) centrally in the CTZ): • Phenothiazines (prochlorperazine and chlorpromazine) also have an<cholinergic and an<histaminic ac<vi<es • Benzamide (metoclopramide) § Metoclopramide works by blocking dopamine receptors (D2) centrally in the CTZ Dopamine Receptor Antagonists- Side effects o Toxici<es include seda<on and extrapyramidal side effects (hypotension and cardiac effects) o 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 con<nue a\er the metoclopramide is discon<nued (irreversible) . Cannabinoids - Dronabinol – An&eme&c o Cannabinoids – CNS and GI tract – binds to cannabinoid receptor 1 (CB1). o Ac<ve metabolite 11-OH-delta-9-tetrahydrocannabinol o Lipid soluble – readily absorbed a\er oral administra<on, onset of ac<ons occur within an hour o Bioavailability low because of extensive first pass metabolism o Detectable levels of metabolites for several weeks o Excreted by urine and feces (mostly) o Side effects include: • seda<on • dysphoria • dizziness • dry mouth An&cholinergic Agent o Scopolamine transdermal patch- (to prevent systemic side effects) • Is a compe<<ve and nonselec<ve muscarinic antagonist • Is the most effec<ve drug for the prophylaxis and treatment of mo<on sickness. • Is excreted in the urine. An&cholinergic Agent - Side effects o drowsiness o disorienta<on o dry mouth o blurred vision o dilated pupils o confusion o hallucina<ons o difficulty urina<ng o rash Histamine (H1R) antagonists o Histamine (H1R) antagonists are used for mo<on sickness and postopera<ve emesis (among other uses) o Examples • cyclizine (an<cholinergic effects) • hydroxyzine, (low affinity for the muscarinic receptors) • Promethazine (has affinity for cholinergic receptors) • Diphenydramine (potent muscarinic antagonists ) o Reduce ac<vity of receptor and compete with histamine binding to the receptor o The H1R antagonists are well absorbed from the GI tract o The drug is distributed widely throughout the body, including the CNS. o Following oral administra<on, peak plasma concentra<ons are achieved in 1-3 hours, and effects usually last 4-6 hours; however, some of the drugs are much longer ac<ng o Metabolized in liver and excreted in urine An&histamines - Adverse Effects o Most frequent – seda<on • Ingested with alcohol or CNS depressants = addi<ve effect = impaired motor skills o The next most frequent side effects involve the diges<ve tract and include loss of appe<te, nausea, vomi<ng, epigastric distress, and cons<pa<on or diarrhea Sample Study Ques:ons o o o o o o o o o o o o o o o o o o o o o o o o o What are the s<muli that ac<vate the Area postrema (chemo recep<ve area)? What areas are s<mulated by neurotransmi4ers from the area postrema? Which areas would be or not be associated with mo<on sickness? What areas would be affected (directly and indirectly) by blood-borne eme<cs and local irritants? Where are the serotonin receptors localized and how do they influence the eme<c center? How do s<muli from the CNS or periphery influence the eme<c center? What receptor (s) would be directly affected by local irritants bacteria, radia<on 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 characteris<cs among them? What event in the body results most o\en 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 medica<ons that u<lize 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 proper<es of cyclizine and other H1 receptor antagonist that would allow them to prevent mo<on sickness and cause dry mouth? Name some an<histamine drugs What are some side effects of an<histamines and an<cholinergics? Which areas in the CNS would be most associated with mo<on sickness? Which areas in the CNS could be most associated with gagging? What are the neurotransmi4ers associated with mo<on sickness? What are the neurotransmi4ers associated with gagging?