Antidepressant Toxicology

8/6/2019 Antidepressant Toxicology

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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!!


7/31

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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Antidepressant Toxicology