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
- SSRI’s
- MAOI’s
 Tricyclic
Antidepressants
MOST common cause of Rx drug-
related deaths; esp. young adolescents
with intentional ingestions

Less prevalent currently with current

shift in AD trends to SSRI’s and newer
ADs
TCA Toxic Mechanisms?
Mild/moderate toxicity in naïve 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 SSRI’s
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-R’s
 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 fluid-intolerant
 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
 SSRI’s
Most common antidepressant class in use
Selective inhibition of serotonin reuptake
presynaptically; negligible effect on NE & DA
reuptake
Rapid complete oral absorption, peaking at 4-
8hrs.
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 OD’s 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
 MAOI’s
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 sympatho-
mimetic 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 SSRI’s, Demerol, L-Trp,
Dextromethorphan
Hypertensive crises: coingestions of indirect
sympathomimetics such as amphetamine, cold
remedies (ephedrines), and diet aids
(phenylpropanolamine)
Other MAO sources: St. John’s wort,
antiParkinson/Ca Rx regimens
 MAOI Toxicity Mgt.
EXPECT DELAYED TOXICITY (12-
24hrs), 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