History & Epidemiology - disaster.org.t · Pathophysiology & Manifestations ... QRS > 100msec, cardiac dysrhythmias, altered mental status, seizures, ... History & Epidemiology

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


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


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


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


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


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


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


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


Spectrum of FindingsSpectrum of Findings


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


Administration of 5-HT2A antagonistsCyproheptadine

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


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


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


A=Alter absorptionActivated charcoal

A=AntidoteNone

B=BasicsContinually reassess the patients ABC and treat accordinglyHypotension

NSPreferred NE or phenylephrine over dopamine


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


Dopaminergic AgentsBromocriptine

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


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.

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History & Epidemiology - disaster.org.t · Pathophysiology & Manifestations ... QRS > 100msec, cardiac dysrhythmias, altered mental status, seizures, ... History & Epidemiology