Antidepressant Toxic Pearls

Dr.S.A.Q

Objectives
Review of significant pathophysiologic, diagnostic and management issues in managing the patient poisoned with the following: - Tricyclic antidepressants - SSRIs - MAOIs

Tricyclic Antidepressants
MOST common cause of Rx drugrelated deaths; esp. young adolescents with intentional ingestions
Less prevalent currently with current shift in AD trends to SSRIs and newer ADs

TCA Toxic Mechanisms?

Mild/moderate toxicity in nave pt. started at high therapeutic doses Combinations with drugs of similar activity Slow TCA metabolizers (7% NA pop.) Concurrent drugs that inhibit TCA metabolism Mixed agents that contribute to toxicity Comorbid medical conditions leading to TCA vulnerability (cardiac conduction, seizures) Potential serotonin syndrome with SSRIs Rare NMS

TCA Toxic Effects

Antihistaminic effects
Peripheral & central antihistamine inhibition risk of sedation & coma

TCA Toxic Effects

Antimuscarinic effects (Not nicotinic) Central: agitation/delirium, amnesia, hallucinations, ataxia/speech slurring, sedation/coma Peripheral: mydriasis, blurry vision, tachycardia, hyperthermia, dryness, ileus, urine retention, tremor worse when combined with other antimuscarinics Antimuscarinic effects COMMON but NOT RESPONSIBLE FOR DEATHS!!

TCA Toxic Effects

-Adrenergic effects
Inhibition of postsynaptic receptors, with greater affinity for 1 subtypes, resulting in: - CNS sedation - orthostatic hypoT - pupillary constriction (opposes antimuscarinic effects) - negation of antiHTN activity of clonidine at central 2-Rs

TCA Toxic Effects

Inhibited neurotransmitter reuptake Potent inhibition of NE and serotonin reuptake in CNS; less effect on dopamine augmented NT responses, leading to sympathomimetic and serotoninergic hyperactivity

TCA Toxic Effects

Sodium channel blockade MOST IMPORTANT MORTALITY MECHANISM Quinidine-like membrane stabilizer that blocks fast Na channels in His-Purkinje system depolarization delays and conduction defects (prolonged phase 0) Worse with rapid HR, hypoNa, acidosis Wide-complex bradycardia suggests profound blockade Risk of spontaneous ventricular ectopy and reentry loops Desipramine most potent blocker

TCA Toxic Effects

Potassium channel blockade
Inhibited K efflux during repolarization risk of QTc prolongation/torsades (rare in TCA OD); protected by common tachycardia responses

TCA Toxic Effects

Central GABA-A Receptor antagonism
Multiple central toxic effects contribute to seizures; GABA-A R inhibition thought to be most important

TCA Pharmacokinetics
Highly lipophilic easy BBB crossing Limited GI absorption d/t extensive 1st pass metabolism & limited motility Huge Vd (10-50L/kg) little value in dialysis/perfusion, forced diuresis Hepatic metabolism with variable active metabolites (tertiary TCAs), enterohepatic circulation & renal elim.

TCA Toxic Features

Life-threatening adult dose >10mg/kg; usually fatal with ingestion >1g Children more susceptible to antimuscarinic effects Plasma levels useless clinically d/t high Vd; may be falsely elevated postmortem Most common symptom = altered MS Most common CVS feature = sinus tachycardia (70%)

Serious TCA Toxicity

Onset within 6 hrs. Major derangements of: CNS coma, seizures/SE CVS conduction defects, SVTs, VT, hypoT Other pulmonary edema, aspiration, hyperthermia, rhabdo, encephelopathy

Diagnostic Dilemnas
Variable nonspecific ?competing clinical features Confounding coingestions (70%) False positive qualitative tests: CBZ, cyclobenzaprine, Gravol, phenothiazines
INDEX OF SUSPICION!!!

ECG Utility
Classic features = sinus tach, RAD, prolonged PR/QRS/QT classic findings common in mod/severe OD BUT may not be present within 1st 6hrs postingestion
RAD = large R in aVR (PPV80%), large S in lead I in terminal 40 msec of QRS (often together but can be mutually exclusive); PPV 66%, NPV 100%

More ECG Utility?

Prognostic features on ECG Complications more likely with terminal RAD>120 or QRS widening
?QRS >100ms increased seizures (33%pts) ?QRS > 160ms increase ventricular dysrhythmias (50% pts)

TCA Toxic ECG

TCA OD Mgt. Issues

Decontamination Ipecac not recommended; early lavage can be considered if safe to do so AC recommended early; caution in presence of ileus

TCA OD Mgt. Issues

CNS Alteration Coma cocktail for unresponsive pts. Protect from Cspine/TBI possibility NO REVERSAL AGENTS (Flumazenil, physostigmine) Seizure Rx with Bzds/Barbs/GA NMB; phenytoin, physo & HCO3 not effective seizure assoc. with 13% risk of CV collapse, 14% death!!

TCA OD Mgt. Issues

Cardiotoxicity HCO3 indicated for: QRS>100ms, refractory hypoT, ventricular dysrhythmias (bolus then infusion) HypoT refractory to IVF & HCO3 requires vasopressors: use NE to directly compete TCA adr. Effect NO class Ia/Ic/III agents, beta blockers/CCBs Consider hyperventilation if fluidintolerant

TCA Mgt. Pitfalls

Unrecognized acidosis, hyperthermia or rhabdo Inappropriate monitoring (continuous, serial ECG) for dysrhythmias Paralysis for seizure without continous EEG monitoring Inappropriate use of reversal agents

TCA OD Disposition
Consider medical clearance after 6-8hrs observation without symptoms and decontamination completed; must demonstrate normal mentation, ECG and resolved antimuscarinic features Admit all suicidal ingestions or symptomatic patients

SSRIs
Most common antidepressant class in use Selective inhibition of serotonin reuptake presynaptically; negligible effect on NE & DA reuptake Rapid complete oral absorption, peaking at 48hrs. Significant 1st pass hepatic metabolism, large Vd, high protein binding P450 metabolism; interacts with TCAs, antipsychotics, anticonvulsants, opiates, Bzds, theophylline, warfarin, cisapride, terfenadine

SSRI Toxicology
Wide therapeutic window; pure OD rarely life-threatening (50% adult & 75% peds ODs remain asymptomatic) 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)

SSRI OD Mgt.
CONSERVATIVE!! Decontamination with AC; no role for ipecac or lavage in pure OD ECG CV monitoring if QRS prolongation; HCO3 indicated Seizures controlled with Bzds, barbiturates prn

MAOIs
MAO = degradative enzyme in synaptic cleft needed to breakdown amine NTs MAOIs irreversibly inactivate MAOs increased amine NT levels, prolonged activity Biphasic toxic profile: early sympathomimetic features d/t excess NT levels, followed by depression after NTs depleted

MAOI Kinetics
Rapid GI absorption, peak levels 1-3hrs. Large 1st pass metabolism Large Vd, high protein binding Delayed toxicity even after metabolized; serum levels meaningless Variable active metabolites (selegeline)

MAOI Risk Situations

FOODS: tyramine-containing foods not broken down by gut MAO increased circulating amine levels tyramine crisis (sympathomimetic) aged cheese, yeast/meat extracts, smoked/pickled meats or fish, red wine, pale beers, fava beans

MORE MAOIs
DRUG INTERACTIONS (Tint. Tab. 154-1) Serotonin syndrome: can be precipitated with concomitant SSRIs, Demerol, L-Trp, Dextromethorphan Hypertensive crises: coingestions of indirect sympathomimetics such as amphetamine, cold remedies (ephedrines), and diet aids (phenylpropanolamine) Other MAO sources: St. Johns wort, antiParkinson/Ca Rx regimens

MAOI Toxicity Mgt.

EXPECT DELAYED TOXICITY (1224hrs), so admit ALL pts. Supportive care Withdraw exogeneous amine sources Hyperthermia & CNS excitability - Rx with Bzds, active cooling Hypertensive crises - Rx blockers (phentolamine) Hypotension Rx direct pressors (NE); POOR prognosis