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Antidepressant Toxic
Pearls
Dr.S.A.Q
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ObjectivesReview of significant pathophysiologic,
diagnosticand managementissues in
managingthe patient poisoned withthe
following:
- Tricyclicantidepressants
- SSRIs
- MAOIs
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Tricyclic
AntidepressantsMOSTcommoncause ofRx drug-
related deaths; esp. youngadolescents
withintentional ingestions
Less prevalentcurrentlywithcurrent
shiftin AD trends to SSRIs and newerADs
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TCA Toxic Mechanisms?Mild/moderatetoxicityinnave pt. started athightherapeutic doses
Combinations with drugs of similaractivitySlowTCA metabolizers (7% NA pop.)
Concurrent drugs thatinhibitTCA metabolism
Mixed agents thatcontributeto toxicity
Comorbid medical conditions leadingto TCAvulnerability (cardiacconduction, seizures)
Potential serotonin syndromewith SSRIs
Rare NMS
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TCA Toxic EffectsAntihistaminic effects
Peripheral & central antihistamine
inhibition
risk of sedation & coma
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TCA Toxic EffectsAntimuscarinic effects (Notnicotinic)
Central:agitation/delirium,amnesia,
hallucinations,ataxia/speech slurring,sedation/coma
Peripheral: mydriasis, blurryvision,tachycardia,hyperthermia, dryness,ileus,
urine retention,tremor worsewhencombined with otherantimuscarinics
Antimuscariniceffects COMMON but NOT
RESPONSIBLE FOR DEATHS!!
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TCA Toxic Effects-Adrenergic effects
Inhibition of postsynaptic receptors,withgreateraffinity for1 subtypes, resultingin:
- CNS sedation
- orthostatichypoT
- pupillaryconstriction (opposesantimuscariniceffects)
- negation ofantiHTN activity ofclonidineatcentral 2-Rs
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TCA Toxic EffectsInhibited neurotransmitter reuptake
Potentinhibition of NEand serotonin
reuptakein CNS; less effect on
dopamine
augmented NT responses, leadingto
sympathomimeticand serotoninergichyperactivity
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TCA Toxic Effects
Sodium channel blockade
MOSTIMPORTANTMORTALITYMECHANISM
Quinidine-like membrane stabilizerthatblocks fast Nachannels inHis-Purkinjesystem depolarization delays andconduction defects (prolonged phase 0)
Worsewith rapid HR,hypoNa,acidosis
Wide-complex bradycardia suggestsprofound blockade
Risk of spontaneous ventricularectopyandreentry loops
Desipramine most potent blocker
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TCA Toxic EffectsPotassium channel blockade
Inhibited K efflux during repolarization
risk of QTc prolongation/torsades(rareinTCA OD); protected bycommon
tachycardia responses
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TCA Toxic EffectsCentral GABA-A Receptor antagonism
Multiplecentral toxiceffects contribute
to seizures; GABA-A Rinhibition
thoughtto be mostimportant
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TCA PharmacokineticsHighly lipophilic easyBBBcrossing
Limited GIabsorption d/textensive1st
pass metabolism & limited motility
Huge Vd (10-50L/kg) littlevalueindialysis/perfusion, forced diuresis
Hepatic metabolism withvariableactivemetabolites (tertiaryTCAs),enterohepaticcirculation & renal elim.
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TCA Toxic FeaturesLife-threateningadult dose >10mg/kg; usuallyfatal withingestion >1g
Children more susceptibleto antimuscariniceffects
Plasma levels useless clinically d/thigh Vd;may be falselyelevated postmortem
Mostcommon symptom = altered MSMostcommon CVS feature = sinustachycardia (70%)
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Serious TCA Toxicity
Onsetwithin 6 hrs.
Major derangements of:
CNS coma, seizures/SE
CVS conduction defects, SVTs, VT,
hypoT
Other pulmonaryedema,aspiration,
hyperthermia, rhabdo,encephelopathy
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Diagnostic
Dilemnas
Variablenonspecific ?competingclinicalfeatures
Confoundingcoingestions (70%)False positive qualitativetests: CBZ,cyclobenzaprine, Gravol,
phenothiazines
INDEXOFSUSPICION!!!
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ECG UtilityClassic features = sinus tach,RAD,prolonged PR/QRS/QT
classic findings commonin mod/severe ODBUT maynot be presentwithin1st 6hrspostingestion
RAD = largeRinaVR (PPV80%), large S inlead Iinterminal 40 msec of QRS (oftentogether butcan be mutuallyexclusive); PPV66%, NPV 100%
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More ECG Utility?Prognostic features on ECG
Complications more likelywithterminal
RAD>120 or QRS widening
?QRS >100ms
increased seizures (33%pts)
?QRS > 160ms
increaseventricular dysrhythmias(50% pts)
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TCA Toxic ECG
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TCA OD
Mgt. IssuesDecontamination
Ipecacnot recommended; early lavage
can beconsidered if safeto do so
AC recommended early; cautionin
presence ofileus
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TCA OD
Mgt. IssuesCNS Alteration
Comacocktail for unresponsive pts.
Protect from Cspine/TBI possibilityNO REVERSAL AGENTS (Flumazenil,physostigmine)
SeizureRxwithBzds/Barbs/GA NMB;
phenytoin, physo & HCO3 noteffective seizureassoc. with13% risk of CVcollapse,14% death!!
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TCA OD Mgt. Issues
CardiotoxicityHCO3 indicated for: QRS>100ms,refractoryhypoT,ventricular
dysrhythmias (bolus theninfusion)HypoT refractoryto IVF & HCO3requires vasopressors: use NEtodirectlycompeteTCA adr. Effect
NO class Ia/Ic/IIIagents, betablockers/CCBs
Considerhyperventilationif fluid-
intolerant
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TCA Mgt. PitfallsUnrecognized acidosis,hyperthermia or
rhabdo
Inappropriate monitoring (continuous,
serial ECG) for dysrhythmias
Paralysis for seizurewithoutcontinous
EEG monitoring
Inappropriate use of reversal agents
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TCA OD
D
ispositionConsider medical clearanceafter 6-8hrs
observationwithout symptoms and
decontaminationcompleted; mustdemonstratenormal mentation,ECG
and resolved antimuscarinic features
Admitall suicidal ingestions orsymptomatic patients
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SSRIs
Mostcommonantidepressantclass in use
Selectiveinhibition of serotonin reuptakepresynaptically; negligibleeffect on NE & DA
reuptakeRapid complete oral absorption, peakingat 4-8hrs.
Significant1st pass hepatic metabolism, large
Vd,high protein bindingP450 metabolism; interacts withTCAs,antipsychotics,anticonvulsants, opiates,Bzds,theophylline,warfarin,cisapride,
terfenadine
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SSRI Toxicology
Widetherapeuticwindow; pure ODrarely life-threatening (50% adult & 75%peds ODs remainasymptomatic)
CNS effects predominantly depressive;uncommon seizures & antiDA effects(EPS, dystonia, Parkinsonism)
CVS neutral; citalopram (Celexa) assoc.
with QRS widening/QT prolongation(doses >600mg)
Hyponatremia (?SIADH-like)
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SSRI OD Mgt.
CONSERVATIVE!!
Decontaminationwith AC; no role foripecac or lavagein pure OD
ECG CV monitoringif QRS
prolongation; HCO3 indicatedSeizures controlled withBzds,
barbiturates prn
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MAOIs
MAO = degradativeenzymein synapticcleftneeded to breakdownamine NTs
MAOIs irreversiblyinactivateMAOs
increased amine NT levels, prolongedactivity
Biphasictoxic profile:early sympatho-
mimetic features d/texcess NT levels,followed by depressionafter NTsdepleted
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MAOI KineticsRapid GIabsorption, peak levels 1-3hrs.
Large1st pass metabolism
Large Vd,high protein binding
Delayed toxicityevenafter metabolized;
serum levels meaningless
Variableactive metabolites (selegeline)
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MAOI Risk Situations
FOODS:tyramine-containing foods not
broken down bygutMAO increased
circulatingamine levels tyraminecrisis
(sympathomimetic) aged cheese,yeast/meatextracts,
smoked/pickled meats or fish, red wine,
pale beers, fava beans
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MORE MAOIs
DRUG INTERACTIONS (Tint. Tab. 154-1)
Serotonin syndrome:can beprecipitated withconcomitant SSRIs,
Demerol, L-Trp, DextromethorphanHypertensivecrises:coingestions ofindirect sympathomimetics suchasamphetamine,cold remedies
(ephedrines),and dietaids(phenylpropanolamine)
OtherMAO sources: St. Johns wort,antiParkinson/CaRx regimens
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MAOI Toxicity Mgt.
EXPECT DELAYED TOXICITY (12-24hrs), so admit ALL pts.
Supportivecare
Withdrawexogeneous amine sourcesHyperthermia & CNS excitability- RxwithBzds,activecooling
Hypertensivecrises - Rx blockers(phentolamine)
Hypotension Rx direct pressors (NE);POOR prognosis
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