9/28/16 Serotonin Syndrome Learning Objectives • Discuss the pathophysiology of serotonin syndrome (SS) Ma# Neukirch Pharm.D., BCPS • Discuss the medicaons and interacIons that may cause SS Iowa Physician Assistant Society • Discuss the diagnosis of SS Fall CME 2016 • Discuss the differenIal diagnosis Coralville, IA • Discuss the management of SS Serotonin syndrome is What is serotonin? • A potenIally life-threatening condiIon • Caused by serotonin toxicity in the central nervous system (CNS) • Serotonin toxicity is a term used to describe the expected and problemac effects of excess serotonergic acIvity • Most oOen results from an overdose or when a • Monoamine neurotransmiPer combinaon of medicaons increase serotonin acIvity • Metabolized by the monoamine oxidase enzyme • It can occur with a single therapeuIc dose of one • Also known as 5-hydroxytryptamine (5-HT) medicaon Source: https://images.google.com What does serotonin do? Demographics and Incidence • CNS roles • SS has been documented in every age group • AenIon • Behavior • Poison center and post-markeIng surveillance data report • Thermoregulaon • Tens of thousand of SSRI exposures are reported every year • ~15 % of those cases lead to SS • Peripheral nervous system roles • ~2-12% of severe SS cases lead to death • GastrointesInal moIlity • VasoconstricIon • SuscepIbility to serotonergic excess seems to vary between • Uterine contracIon individuals • BronchoconstricIon • Platelet aggregaon Bronstein AC, Spyker DA, Cantilena LR Jr. et al. 2001 Annual report of the American Association of Poison Control Center’s National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol 2012;50:911. 1 9/28/16 Serotonin syndrome Mental status changes • Classic clinical triad Symptoms may include • Mental status changes • Agitaon • Neuromuscular abnormaliIes • Anxiety • Autonomic hyperacIvity • Disorientaon • Restlessness • Excitement Neuromuscular abnormalities Autonomic Hyperactivity Symptoms may include Symptoms may include • Tremors • Hypertension • Shivering • Clonus • Tachypnea • Voming • Hyperreflexia • Tachycardia • Diarrhea • Muscle rigidity • Hyperthermia • HyperacIve bowel sounds • Bilateral Babinski Signs • Mydriasis • Arrhythmias • Akathisia • Diaphoresis • Dry mucous membranes • Flushed skin What is serotonin syndrome? Diagnosis Serotoninergic excess causes toxicity on a spectrum This is a clinical diagnosis based on • Medicaon history • Physical exam • Neurological exam • Timing of symptoms Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:1112. 2 9/28/16 Medication History Causative Medications • Should include all medicaons and recent changes • Medicaons with the following serotonergic effects • PrescripIon meds • Impairs reuptake from the synapIc cleO • Illicit drugs • Direct serotonin receptor agonism • Over-the-counters • Inhibit serotonin metabolism • Alternave medicaons/herbals • Increase release of serotonin • Dietary supplements • Increase sensiIvity of serotonin receptor • Increase serotonin synthesis • Dose or dosing interval changes • Medicaon combinaons can increase serotonin acIvity by • AddiIve effects • Formulaon changes • Altering the metabolism of serotonergic drugs • Immediate release, extended release, etc Meds that impair reuptake from the Meds that impair reuptake from the synaptic cleft synaptic cleft • SelecIve serotonin reuptake inhibitors (SSRIs) • Citalopram, escitalopram, fluoxeIne, fluvoxamine, paroxeIne, • Tricyclic anIdepressants (TCAs) and sertraline • Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maproIline, nortriptyline, protriptyline, trimipramine • Serotonin-norepinephrine reuptake inhibitors (SNRIs) • Desvenlafaxine, duloxene, milnacipran, and venlafaxine • 5-HT3 receptor antagonists • Dolasetron, granisetron, ondansetron, palonosetron • Dopamine-norepinephrine reuptake inhibitors • Bupropion • CerIan opiods • Fentanyl, meperidine, tapentadol, methadone, and tramadol • Serotonin modulators • Nefazodone, trazodone, and vilazodone • Pentazocine Source: UpToDate Robles LA. Serotonin syndrome induced by fentanyl in a child: a case report.Clin Neuropharmacol 2015; 38:206. Source: UpToDate Meds that impair reuptake from the Meds with direct serotonin receptor synaptic cleft agonism • St. John's wort (Hypericum perforatum) • Buspirone • Metoclopramide • Triptans • Valproate • Sumatriptan, rizatriptan, others • Carbamazepine • Ergot derivaves • Sibutramine • Dihydroergotamine, methylergonovine • Dextromethorphan • Fentanyl • Cyclobenzaprine • Lysergic acid diethylamide (LSD) • MDMA (Ecstasy) • Cocaine Source: UpToDate Source: UpToDate 3 9/28/16 Meds that inhibit serotonin metabolism Meds that increase release of serotonin • Monoamine oxidase inhibitors (MAOIs) • Amphetamines • Phenelzine, tranylcypromine, isocarboxazid, moclobemide, • Dextroamphetamine, methamphetamine, and others selegiline, rasagiline, procarbazine, Syrian rue (Peganum • Amphetamine derivaves harmala/harmine) • Fenfluramine, dexfenfluramine, phentermine • Linezolid • Cocaine • Tedizolid • MDMA (Ecstasy) • Methylene blue • Levodopa Source: UpToDate Source: UpToDate Meds that increase sensitivity of Meds that increase serotonin formation serotonin receptor • Lithium • Tryptophan Source: UpToDate Source: UptoDate and Google Images Drug Interactions Cytochrome P450 enzymes • Combining mulIple serotonergic agents increases risk • Substrate – a drug that is metabolized by a parIcular • Be aware of long acIng meds, like fluoxeIne, which may exhibit enzyme serotonergic effects for weeks aer the last dose • Ex) Venlafaxine is substrate of CYP3A4 • Always consider how medicaons may alter the • Inducer – a drug that increases the acIvity of a parIcular metabolism of serotonergic agents enzyme • Most interacIons involve the cytochrome P450 enzyme system • Ex) Carbamazepine is an inducer of CYP1A2, 2C9, and 3A4 • More than 50 different isoforms responsible for the metabolism of many medicaons • Ex: CPY3A4, CPY2C9, CYP2D9 and so forth • Inhibitor – a drug that decreases the acIvity of a parIcular enzyme • Ex) Ciprofloxacin inhibits CPY1A2 4 9/28/16 Physical exam indings Neurological exam indings • Agitaon • Hypertension Neuromuscular findings may be more pronounced in the lower • Akathisia • Hyperthermia extremies • Anxiety • Increased bowel sounds • Diaphoresis • Mydriasis • Bilateral Babinski Signs • Dry mucus membranes • Shivering • Deep tendon hyperreflexia • Flushed skin • Tachycardia • Inducible or spontaneous clonus • Muscle rigidity • Ocular clonus • Tremor Diagnostic criteria Hunter Criteria Must be exposed to a serotonergic agent and have at least one • Two criteria exist for aiding SS diagnosis below • Sternbach’s criteria - older • Spontaneous clonus • 75% sensiIve and 96% specific for diagnosing SS • Inducible clonus with agitaon or diaphoresis • Ocular clonus with agitaon or diaphoresis • Hunter criteria - newer and most commonly used • Tremor and hyperreflexia • 84% sensiCve and 97% specific for diagnosing SS • Hypertonia • Gold standard is the diagnosis by a medical toxicologist • Temperature above 38⁰C with ocular clonus or inducible clonus Dunkley EJ, Isbister GK, Sibbrit, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnosIc decision rules for serotonin toxicity. Dunkley EJ, Isbister GK, Sibbrit, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnosIc decision rules for serotonin toxicity. QJM 2003; 96:635. QJM 2003; 96:635. Differential Diagnosis Differential Diagnosis • NeurolepIc Malignant Syndrome (NMS) • Malignant Hyperthermia • SympathomimeIc toxicity • AnIcholinergic toxicity • EncephaliIs Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:1112. 5 9/28/16 What is serotonin syndrome? Management Serotoninergic excess causes toxicity on a spectrum • Mild cases to moderate cases • DisconInue serotonergic agents • Provide supporIve cares • Sedaon with benzodiazepines • Treat autonomic instability and abnormal vital signs • Consider giving a serotonin antagonist if abnormaliIes persist • Severe cases – including hyperthermic paents (>41⁰C) • Endotracheal intubaon • Paralysis Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:1112. Management Management • DisconInue serotonergic agents Sedaon with benzodiazepines to address • Signs and symptoms generally start to resolve within 24 hours for short acIng agents • Agitaon • Some drugs have longer half lives and/or duraon of effect and thus • Tachycardia toxicity may persist for days • Hypertension • Hyperthermia • Provide supporIve cares • Supplemental 02 to keep sats above 94 % • Titrate dose to achieve sedaon and normal vital signs • Crystalloid fluids for volume depleIon • Cardiac monitoring Management Management • Consider giving a serotonin antagonist • Treat autonomic instability and abnormal vital signs • Cyproheptadine is a 5-HT1A and 5-HT2A receptor antagonist • IniIal dose is 12 mg followed by 2 mg Q2H unIl response • Hypertension • OpImal dosing is not established • Use short acIng agents like esmolol or nitroprusside • Available as 4 mg tablets and 2mg/5mL oral syrup • Avoid long acIng agents like propranolol • Tablets can be crushed and given via nasogastric tube • It is not known if cyproheptadine affects paent outcomes • Hypotension – most oOen seen with MAOI induced SS • Use direct acIng agents like norepinephrine, epinephrine, or • Chlorpromazine and olanzapine are not recommended for use a phenylephrine serotonin antagonists • Avoid dopamine • Undesirable side effect profiles 6 9/28/16 Management Thank You • Paents with temperatures greater than 41.1⁰C • Endotracheal intubaon • Sedaon • Paralysis • Reduce temperature with external cooling • Do not use acetaminophen or dantrolene Quesons ? 7 .