Serotonin Syndrome. Learning Objectives. Serotonin syndrome is. What is serotonin? Demographics and Incidence. What does serotonin do?

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1 Serotonin Syndrome Ma# Neukirch Pharm.D., BCPS Iowa Physician Assistant Society Fall CME 2016 Coralville, IA Learning Objectives Discuss the pathophysiology of serotonin syndrome (SS) Discuss the medicaions and interacions that may cause SS Discuss the diagnosis of SS Discuss the differenial diagnosis 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 problemaic effects of excess serotonergic acivity Most ooen results from an overdose or when a combinaion of medicaions increase serotonin acivity It can occur with a single therapeuic dose of one medicaion Monoamine neurotransmiper Metabolized by the monoamine oxidase enzyme Also known as 5-hydroxytryptamine (5-HT) Source: What does serotonin do? CNS roles APenIon Behavior ThermoregulaIon Peripheral nervous system roles GastrointesInal moility VasoconstricIon Uterine contracion BronchoconstricIon Platelet aggregaion Demographics and Incidence SS has been documented in every age group Poison center and post-markeing surveillance data report Tens of thousand of SSRI exposures are reported every year ~15 % of those cases lead to SS ~2-12% of severe SS cases lead to death SuscepIbility to serotonergic excess seems to vary between individuals Bronstein AC, Spyker DA, Cantilena LR Jr. et al Annual report of the American Association of Poison Control Center s National Poison Data System (NPDS): 29 th Annual Report. Clin Toxicol 2012;50:911. 1

2 Serotonin syndrome Mental status changes Classic clinical triad Mental status changes Neuromuscular abnormaliies Autonomic hyperacivity AgitaIon Anxiety DisorientaIon Restlessness Excitement Symptoms may include Neuromuscular abnormalities Symptoms may include Tremors Clonus Hyperreflexia Muscle rigidity Bilateral Babinski Signs Akathisia Autonomic Hyperactivity Tachypnea Tachycardia Hyperthermia Mydriasis Diaphoresis Dry mucous membranes Flushed skin Symptoms may include Shivering VomiIng Diarrhea HyperacIve bowel sounds Arrhythmias What is serotonin syndrome? Diagnosis Serotoninergic excess causes toxicity on a spectrum This is a clinical diagnosis based on MedicaIon history Physical exam Neurological exam Timing of symptoms Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:

3 Medication History Should include all medicaions and recent changes PrescripIon meds Illicit drugs Over-the-counters AlternaIve medicaions/herbals Dietary supplements Dose or dosing interval changes FormulaIon changes Immediate release, extended release, etc Causative Medications MedicaIons with the following serotonergic effects Impairs reuptake from the synapic cleo Direct serotonin receptor agonism Inhibit serotonin metabolism Increase release of serotonin Increase sensiivity of serotonin receptor Increase serotonin synthesis MedicaIon combinaions can increase serotonin acivity by AddiIve effects Altering the metabolism of serotonergic drugs Meds that impair reuptake from the synaptic cleft SelecIve serotonin reuptake inhibitors (SSRIs) Citalopram, escitalopram, fluoxeine, fluvoxamine, paroxeine, and sertraline Serotonin-norepinephrine reuptake inhibitors (SNRIs) Desvenlafaxine, duloxeine, milnacipran, and venlafaxine Dopamine-norepinephrine reuptake inhibitors Bupropion Serotonin modulators Nefazodone, trazodone, and vilazodone Meds that impair reuptake from the synaptic cleft Tricyclic anidepressants (TCAs) Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maproiline, nortriptyline, protriptyline, trimipramine 5-HT3 receptor antagonists Dolasetron, granisetron, ondansetron, palonosetron CerIan opiods Fentanyl, meperidine, tapentadol, methadone, and tramadol Pentazocine Robles LA. Serotonin syndrome induced by fentanyl in a child: a case report.clin Neuropharmacol 2015; 38:206. Meds that impair reuptake from the synaptic cleft Meds with direct serotonin receptor agonism St. John's wort (Hypericum perforatum) Metoclopramide Valproate Carbamazepine Sibutramine Dextromethorphan Cyclobenzaprine MDMA (Ecstasy) Cocaine Buspirone Triptans Sumatriptan, rizatriptan, others Ergot derivaives Dihydroergotamine, methylergonovine Fentanyl Lysergic acid diethylamide (LSD) 3

4 Meds that inhibit serotonin metabolism Meds that increase release of serotonin Monoamine oxidase inhibitors (MAOIs) Phenelzine, tranylcypromine, isocarboxazid, moclobemide, selegiline, rasagiline, procarbazine, Syrian rue (Peganum harmala/harmine) Linezolid Tedizolid Methylene blue Amphetamines Dextroamphetamine, methamphetamine, and others Amphetamine derivaives Fenfluramine, dexfenfluramine, phentermine Cocaine MDMA (Ecstasy) Levodopa Lithium Meds that increase sensitivity of serotonin receptor Meds that increase serotonin formation Tryptophan Source: UptoDate and Google Images Drug Interactions Combining muliple serotonergic agents increases risk Be aware of long acing meds, like fluoxeine, which may exhibit serotonergic effects for weeks aoer the last dose Always consider how medicaions may alter the metabolism of serotonergic agents Most interacions involve the cytochrome P450 enzyme system More than 50 different isoforms responsible for the metabolism of many medicaions Ex: CPY3A4, CPY2C9, CYP2D9 and so forth Cytochrome P450 enzymes Substrate a drug that is metabolized by a paricular enzyme Ex) Venlafaxine is substrate of CYP3A4 Inducer a drug that increases the acivity of a paricular enzyme Ex) Carbamazepine is an inducer of CYP1A2, 2C9, and 3A4 Inhibitor a drug that decreases the acivity of a paricular enzyme Ex) Ciprofloxacin inhibits CPY1A2 4

5 Physical exam Kindings Neurological exam Kindings AgitaIon Akathisia Anxiety Diaphoresis Dry mucus membranes Flushed skin Hyperthermia Increased bowel sounds Mydriasis Shivering Tachycardia Neuromuscular findings may be more pronounced in the lower extremices Bilateral Babinski Signs Deep tendon hyperreflexia Inducible or spontaneous clonus Muscle rigidity Ocular clonus Tremor Diagnostic criteria Hunter Criteria Two criteria exist for aiding SS diagnosis Must be exposed to a serotonergic agent and have at least one below Sternbach s criteria - older 75% sensiive and 96% specific for diagnosing SS Hunter criteria - newer and most commonly used 84% sensicve and 97% specific for diagnosing SS Gold standard is the diagnosis by a medical toxicologist Spontaneous clonus Inducible clonus with agitaion or diaphoresis Ocular clonus with agitaion or diaphoresis Tremor and hyperreflexia Hypertonia 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. QJM 2003; 96:635. 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. 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:

6 What is serotonin syndrome? Serotoninergic excess causes toxicity on a spectrum Mild cases to moderate cases DisconInue serotonergic agents Provide supporive cares SedaIon with benzodiazepines Treat autonomic instability and abnormal vital signs Consider giving a serotonin antagonist if abnormaliies persist Severe cases including hyperthermic paients (>41⁰C) Endotracheal intubaion Paralysis Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:1112. DisconInue serotonergic agents Signs and symptoms generally start to resolve within 24 hours for short acing agents Some drugs have longer half lives and/or duraion of effect and thus toxicity may persist for days Provide supporive cares Supplemental 02 to keep sats above 94 % Crystalloid fluids for volume depleion Cardiac monitoring SedaIon with benzodiazepines to address AgitaIon Tachycardia Hyperthermia Titrate dose to achieve sedaion and normal vital signs Treat autonomic instability and abnormal vital signs Use short acing agents like esmolol or nitroprusside Avoid long acing agents like propranolol Hypotension most ooen seen with MAOI induced SS Use direct acing agents like norepinephrine, epinephrine, or phenylephrine Avoid dopamine Consider giving a serotonin antagonist Cyproheptadine is a 5-HT1A and 5-HT2A receptor antagonist IniIal dose is 12 mg followed by 2 mg Q2H unil response OpImal dosing is not established Available as 4 mg tablets and 2mg/5mL oral syrup Tablets can be crushed and given via nasogastric tube It is not known if cyproheptadine affects paient outcomes Chlorpromazine and olanzapine are not recommended for use a serotonin antagonists Undesirable side effect profiles 6

7 PaIents with temperatures greater than 41.1⁰C Endotracheal intubaion SedaIon Paralysis Reduce temperature with external cooling Do not use acetaminophen or dantrolene Thank You QuesIons? 7