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Tricyclic Antidepressants Intoxication 新光急診 林立偉醫師 100.10.18 History & Epidemiology First TCA for depression in the late 1950s: Imipramine 1960-1980: TCAs were the major pharmacologic treatment for depression 1980-1990: newer CAs (maprotiline) due to serious toxicity of older TCAs Last 10 years: SSRI History & Epidemiology 1993-1997 in England and Wales: 95% of poisoning death, esp. amitriptyline and dothiepin. Leading cause of poisoning fatalities in US until 1993. 12-13% all CA exposures during the last 10 years < 6 y/o; second most commonly used Most lethal unintentional drug ingestions in younger children Pharmacology & Pharmacokinetics CAs inhibit presynaptic reuptake of NE and/or serotonin Chemical structure classification: Tertiary Amines Secondary Amines Amitriptyline Clomipramine Doxepin Imipramine Trimipramine Desipramine Nortriptyline Protriptyline Amoxapine Maprotiline More potent inhibitors in NE More potent inhibitors in serotonin Pathophysiology & Manifestations Tri-blocker Muscarinic acetylcholine receptors Peripheral α 1 - adrenergic receptor Sodium channel GABA receptor-chloride-ionophore complex in brain Low toxicity threshold 10-20 mg/kg: significant manifestations 2-4 mg/kg/d: therapeutic dose > 1 g: life-threatening in adult Progression is unpredictable and rapid 4C Conduction Contractility Confusion Convulsion

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  • Tricyclic Antidepressants Intoxication

    100.10.18

    History & Epidemiology

    First TCA for depression in the late 1950s: Imipramine1960-1980: TCAs were the major pharmacologic treatment for depression1980-1990: newer CAs (maprotiline) due to serious toxicity of older TCAsLast 10 years: SSRI

    History & Epidemiology

    1993-1997 in England and Wales: 95% of poisoning death, esp. amitriptyline and dothiepin.Leading cause of poisoning fatalities in US until 1993.12-13% all CA exposures during the last 10 years < 6 y/o; second most commonly usedMost lethal unintentional drug ingestions in younger children

    Pharmacology & Pharmacokinetics

    CAs inhibit presynaptic reuptake of NE and/or serotoninChemical structure classification:

    Tertiary Amines Secondary AminesAmitriptylineClomipramineDoxepinImipramineTrimipramine

    DesipramineNortriptylineProtriptylineAmoxapineMaprotiline

    More potent inhibitors in NE

    More potent inhibitors in serotonin

    Pathophysiology & Manifestations

    Tri-blockerMuscarinic acetylcholine receptorsPeripheral 1- adrenergic receptorSodium channel

    GABA receptor-chloride-ionophore complex in brainLow toxicity threshold

    10-20 mg/kg: significant manifestations2-4 mg/kg/d: therapeutic dose> 1 g: life-threatening in adult

    Progression is unpredictable and rapid

    4CConductionContractilityConfusionConvulsion

  • Pathophysiology & Manifestations

    Acute cardiovascular toxicityAcute cardiovascular toxicityPrimarily responsible for morbidity and mortalityConduction delay: RBBB; PR, QRS, QTcThe most common dysrhythmia in overdose: sinus tachycardia (aberrantly conducted)Wide-complex tachy: potentially life-threateningBlocks are rare Torsades is more likely in bradycardia; VT/VF only 4% of all cases

    Pathophysiology & Manifestations

    Acute cardiovascular toxicityAcute cardiovascular toxicityThe most common cause of death: refractory hypotension prolong CPRHypotension is multifactorial:

    Impairing myocardial contractilityBlunted responses to catecholaminesPeripheral vasodilationHypoxia, acidosis, volume depletion, seizure

    Pathophysiology & Manifestations

    Acute CNS toxicityAcute CNS toxicityAgitation, delirium anticholinergic effectsSeizure

    GABA-chloride complexGeneralized and briefWithin 1-2 hours of ingestion4% in patients; 13% in fetal casesRisks: HI, history of seizure, other drug withdrawal

    Uncontrolled seizures are uncommonMA, hyperthermia, rhabdomyolysis, ARF

    Pathophysiology & Manifestations

    Other complicationsOther complicationsAcute lung injury, ARDS, aspiration pneumonitisIschemia bowelPancreatitis

    Death in the first several hours due toLate deaths (>1-2 days) due to complications

    Diagnostic testing

    ECGECGMaximal limb lead QRS is a sensitive indicator of toxicity (dysrhythmia, coma, hypotension, seizure)

    QRS>100 msec: 33% seizures; 14% VT/VFQRS>160 msec: 50% VT/VF

    Terminal 40-ms QRS right side deviationMore sensitive than QRSPPV and NPV for TCA ingestion: 66% & 100%

  • Managements

    ABCD, O2-IV-monitorEarly intubationEKG for all patientsLab tests: CBC, BCS, ABG, drug levelKeep vital signs

    Managements

    GI decontamination GI decontamination Benefits against risks be weighedOrogastric lavage up to 12 hrs after ingestionMay intubation firstMay not performed in young childActivated charcoal for all cases (1 g/kg)Additional dose after hrs is reasonable (0.5 g/kg)Monitor ileus induced complications

    Managements

    Conduction delays correctionConduction delays correctionHypertonic sodium: undefinedHyperventilation: not effective as single useAlkalinization: most beneficial

    Any conduction delay (QRS>100 msec; R aVR3 msec; new RBBB)Keep pH: 7.50-7.55No evidence for prophylactic useContinuous use until clinically and EKG improvement, not necessarily normalizationWatch for complications-fluid, sodium, chloride

    Managements

    AntidysrhythmicAntidysrhythmicContraindication:

    Class IA (quinidine, procainamide, disopyramide)Class IC (flecainide, propafenone)Class III (amiodarone, bretylium) [unstudied]

    Lidocaine: most commonly usedMagnesium sulfate: not routinePhysostigmine: not routinePhenytoin: not recommended used

    Managements

    All patients should be monitored for 6 hrsAdmission criteriaAdmission criteria

    QRS > 100msec, cardiac dysrhythmias, altered mental status, seizures, respiratory depression, hypotension within 6 hrs of ingestion100% sensitive in identifying significant toxicityHR > 120 + QTc > 480 msec: major toxicity

    ICU admission criteria is dependantSinus tachycardia may persist for 1 week

    TCA Treatment SummaryConduction DelaysQRS>100 msecRaVR3 mmT40-ms axis >130

    NaHCO3:1-2 meq/kg IV bolus at 3-5 min intervals to reverse the abnormality or to a target serum pH no greater than 7.55

    Controlled ventilation (if clinically indicated for hypoventilation)

    DysrhythmiasSinus tachycardiaWide QRS Tachycardia/VT

    Torsades de pointes

    No treatmentNaHCO3: 1-2 meq/kg IV bolus at 3-5 min intervals to reverse the

    abnormality or to a target serum pH no greater than 7.55Correct hypoxia, acidosis, hypotensionConsider lidocaine: 1mg/kg IV bolus followed by infusion of 20-50

    g/kg/minConsider hypertonic saline(3% NaCl)Consider magnesium sulfate 25-50 mg/kg (Max 2g) IV for 2 minControlled ventilation (if clinically indicated for hypoventilation)Magnesium sulfateOverdrive pacing

  • TCA Treatment SummaryHypotension Isotonic saline (0.9% NaCl) boluses (up to 30 mL/kg)

    Correct hypoxia, acidosisNaHCO3: 1-2 meq/kg IV bolus at 3-5 min intervals to reverse the

    abnormality or to a target serum pH no greater than 7.50- 7.55NorepinephrineConsider extracorporeal mechanical circulation (ECMO,

    cardiopulmonary bypass)

    Seizures Benzodiazepines, propofolSecure airway with intubation if necessaryCorrect hypoxia, acidosisBarbituratesContinuous infusion of midazolam or propofol if barbiturates failConsider neuromuscular paralysis/general anesthesia if all other

    measures fail

    Sedative-Hypnotics

    History

    Bromide, the first available sedative-hypnotics agent in 1853The barbiturates were introduced in 1903Chlordiazepoxide, the first commercially available benzodiazepines was synthesized in 1955 and marketed in 1960.Zolpidem, zaleplon and eszoplicone have replaced BZDs recently

    Pharmacokinetics

    Most sedative-hypnotics are rapidly absorbed in GI tractMost drugs are eliminated by hepatic metabolismBut phenobarbital can be eliminated increased from kidney by urine alkalization

    Sedative-hypnotics

    Targets of Toxicity

    Body Componets Primary Targets

    Airway

    Breathing X

    Cardiovascular

    Disability (nervous system) X

    Elimination (Liver &kindney)

    Sedative-hypnotics Toxidrome

    Coma with normal vital signs

    Vital Signs Pupil

    Bow

    elA

    ctivity

    SkinBP P R T Mental Status

    / Depressed

  • Clinical clue for Sedative-hypnotics overdose

    Clinical signs Sedative-HypnoticsHypothermia Barbiturates, bromides, ethchlorvynolUnique odors Chloral hydrate, ethchlorvynolCardiac dysrhythmias Meprobamatebradycardia GHBtachydysrhythmias Chloral hydrate

    Muscular twitching GHB, methaqualone, propofol, etomidateAcneiform rash BromidesFluctuation coma Glutethimide, meprobamateGI bleeding Chloral hydrate, methaqualoneDiscolored urine Propofol (green/pink)Anticholinergic signs Glutethimide

    Diagnostic Evaluation

    Not all BZDs are detected by screen test

    Poisoning Treatment Paradigm

    A=Alter absorptionGastric lavageActivated charcoal

    A=AntidoteFlumazenil for BZD

    B=BasicsContinually reassess the patients ABC and treat accordingly

    Poisoning Treatment Paradigm

    B=BasicsSupplemental oxygen, respiratory support, and prevention of aspiration are the cornerstonesVolume expansion 1st and vasopressor 2nd for hemodynamic instability

    C=Change metabolism D=Distribute DifferentlyE=Enhance Elimination

    Not applicable

    Antidotes in Detail:Flumazenil

    Flumazenil

    IndicationsPure BZD overdose in a nontolerant individual who has

    CNS depressionNormal vital signs, including SaO2Normal ECGOtherwise normal neurologic exam

  • Flumazenil

    ContraindicationsPrior seizure history or current treatment of seizuresHistory of ingestion of a xenobiotic capable of provoking seizures or cardiac dysrhythmiasLong term use of benzodiazepinesECG evidence of cyclic antidepressantsAbnormal vital signs; hypoxia

    Flumazenil

    DosageSlow IV titration (0.1 mg/min ) to a total dose 1mg.

    Onset 1-2 min

    Half life53 min

    Mechanism of ActionA competitive benzodiazepine receptor antagonist

    Serotonin Reuptake Inhibitors Intoxication

    History & Epidemiology

    Serotonin reuptake inhibitors:Citalopram, escitalopram, fluoxetine, luvoxamine, paroxetine, sertraline-lopramine; -xetine

    Atypical antidepressant:Venlafaxine, Reboxetine,bupropion, trazodone

    1980s, first-line therapy for depressionOCD, panic disorder, alcoholism, obesity, migraine headache, chronic painSafer than TCAs, MAOIs when overdose

    Acute Overdose

    Nausea, vomiting, dizziness, blurred vision, depression and sinus tachycardiaSeizure, QRS complex prolongation, life-threatening effects

    Rarely occur even after large overdosesCitaloparam/escitalopram: QTc widening and seizure in dose-related; >600 mg

  • Managements

    Largely supportiveOrogastric lavage is not generally indicated due to rarely lifethreateningOral activated charcoal (1g/kg)Citalopram or escitalopram: 24hrs monitorSmall ingestion can be observed at home

    Libby Zion Law

    Serotonin SyndromeSerotonin Syndrome

    Syndrome v.s. ToxicityClinical triad

    Mental-status changesAutonomic hyperactivityNeuromuscular abnormalities

    Combined serotonergic drug overdose (SSRI and MAOI)Single serotonergic drug overdose (Ecstasy)

    Drugs that Can Produce SSDrugs that Can Produce SSNEUROLOGIC EMERGENCY

    Mechanism of Action Related Drugs

    Increased serotonin synthesis L-tryptophan

    Decreased serotonin breakdown MAOIs(including linezolide), ritonavir

    Increased serotonin release Amphetamines, MDMA, cocaine, Fenfluramine

    Decreased serotonin reuptake SSRIs, TCAs, dextromethorphan, meperidine, fentanyl, tramadol

    Serotonin receptor agonists Lithium, sumitriptan, buspirone, LSD

    PathophysiologyPathophysiologyNEUROLOGIC EMERGENCY

    Boyer, N Engl J Med 2005

  • Boyer, NEJM 2005

    Clinical Findings of SSClinical Findings of SS

    Boyer, N Engl J Med 2005

    Spectrum of FindingsSpectrum of Findings

    Boyer, N Engl J Med 2005

    Algorithm for SS DiagnosisAlgorithm for SS Diagnosis

    Boyer, NEJM 2005

    ManagementManagement

    Removal of the precipitating drugsThe provision of supportive care

    IVF and correct vital signs The control of agitation

    Give BZD, avoid physical strainThe administration of 5-HT2A antagonistsThe control of autonomic instability

    Use NE, Epi, avoid dopamine for hypotensionShort-acting agents (nitroprusside/esmolol) for HTN

    The control of hyperthermiaUse NDMBs, avoid succinylcholine

    ManagementManagement

    Administration of 5-HT2A antagonistsCyproheptadine

    Oral form onlyInitial dose 12mg, followed by 2mg q2hMaintenance dose 8mg q6h

  • ManagementManagement

    Severity Clinical Presentation Supportive care Interventions

    Mild Hyperreflexia and tremor but no feverABCs, removal of the precipitating drugs Benzodiazepines

    Moderate ABCs, removal of the precipitating drugsBenzodiazepines5-HT2A antagonists

    Severe BT>41C ABCs, removal of the precipitating drugs

    Benzodiazepines5-HT2A antagonistsNeuromuscular paralysisIntubation

    Antipsychotics

    History & Epidemiology

    AntipsychoticsMajor tranquilizersNeuroleptics

    Introduction of chlorpromazine in 1950, dramatically reduced the symptoms of schizophrenia.Atypical antipsychotic

    ClozapineSynthesized in 1959, but be used until early 1970sFree of EPS, improvement of negative symptoms of schizophreniaArgaulocytosis

    Clinical Manifestations

    AntipsychoticsAcute Overdose

    Targets of Toxicity

    Body Componets Primary Targets

    Airway

    Breathing

    Cardiovascular X

    Disability (nervous system) X

    Elimination (Liver &kindney)

  • Antipsychotics OverdoseToxidromes

    CNSSomnolence to frank coma

    CVTachycardia, hypotension

    Anticholinergic manifestations

    Diagnostic Evaluation

    Hx+PEEKG

    Similar to TCA toxicityWide ES, rightward deflection of terminal 40 msec of the QRS in aVR, QTc prolongation

    Poisoning Treatment Paradigm

    A=Alter absorptionActivated charcoal

    A=AntidoteNone

    B=BasicsContinually reassess the patients ABC and treat accordinglyHypotension

    NSPreferred NE or phenylephrine over dopamine

    Poisoning Treatment Paradigm

    B=BasicsVentricular dysrhythmias or QRS >0.12 sec

    1st line Sod. Bicarbonate 1-2 mEq/kg, avoid hypoK2nd line lidocaineIV MgSO4 for TdP

    SeizureIV BZD

    Central antimuscarinic syndromephysostigmine

    C=Change metabolism D=Distribute DifferentlyE=Enhance Elimination

    Not applicable

    NeurolepticNeuroleptic Malignant SyndromeMalignant Syndrome

    NMS is a rare idiosyncratic reactionTypically occurring in persons taking neurolepticsor after the sudden withdrawal of dopamine agonists.

    Most NMS cases begin to appear 24 to 72 hours after the onset of drug therapy, almost are apparent in the first 2 weeks of drug therapy.The prevalence of NMS is between 0.02% and 2.44% for patients taking neuroleptics

    Drugs Implicated in NMSDrugs Implicated in NMS

    Ongoing Drug intake

    Antipsychotic agentButyrophenones (eg, Haloperidol), phenothiazines, clozapine, olanzapine, respiradone

    Antiemetic agent Metoclopramide, droperidol, prochlorperazine

    Discontinued Drug Intake

    Dopaminergic drug Amantidine, bromocriptine, levodopa

  • NMS NMS PathophysiologyPathophysiology

    Strawn, Am J Psychiatry 2007

    NMS Clinical FeaturesNMS Clinical Features

    4 clinical syndromeHyperthermia

    The key diagnostic featuresAltered mental status

    Delirium, somnolence, coma, and mutismSkeletal muscle rigidity

    Lead-pipe rigidityAutonomic dysfunction

    Tachycardia, hyper- or hypotension, and diaphoresis

    NMS Laboratory StudyNMS Laboratory Study

    CPK level should be higher than 1000 U/LLeukocytosis with left shiftLow serum iron

    NMS DSMNMS DSM--IV CriteriaIV Criteria

    A. The development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication.

    B. Two (or more) of the following:DiaphoresisDysphagiaTremorIncontinenceChanges in level of consciousness ranging from confusion to comaMutismTachycardiaElevated or labile blood pressureLeucocytosislaboratory evidence of muscle injury (e.g., elevated CPK)

    C. The symptoms in Criteria A and B are not due to another substance (e.g., phencyclidine) or a neurological or other general medicalcondition (e.g., viral encephalitis).

    D. The symptoms in Criteria A and B are not better accounted for by a mental disorder (e.g., Mood Disorder With Catatonic Features).

    NMS ManagementNMS Management

    Immediate removal of the offending drug.Supportive therapy is the key of treatment. BenzodiazepinesDopaminergic AgentsDantrolene

    NMS ManagementNMS Management

    Dopaminergic AgentsBromocriptine

    Oral form5 to 20 mg q6hSide effects: hypotension, dyskinesia, erythematous, tender lower extremitiesOther agents: carbidopa/levodopa, L-dopa, amantadine

  • NMS ManagementNMS Management

    DantroleneSingle dose of 2-3mg/kg/day, increases to a total dose of 10 mg/kg/day IVOral dantrolene 50 to 200 mg daily in divided dosed every 6 to 8 hoursSide effects: hepatic toxicity

    Features differentiating SS and NMSFeatures differentiating SS and NMS

    Serotonin syndrome NMS

    Etiology Serotonergic drugs Neuroleptics

    Pathophysiology Serotonin excess (toxicity) Idiosyncratic reaction

    Onset Rapid onset and progression Slow onset and

    progression

    Prominent symptoms

    Hyperkinesia and hyperreflexia / clonus Bradykinesia

    Rigidity Pyramidal rigidity, terminal development

    Extrapyramidalrigidity, a prodromal

    symptom

    Whyte, Medical Toxicology, 3rd ed.