Tricyclic ToxicityTricyclic Toxicity

Joshua Rocker, MDJoshua Rocker, MD

Pediatric Emergency MedicinePediatric Emergency Medicine

Schneider Children’s HospitalSchneider Children’s Hospital

TricyclicsTricyclics

33 aromatic rings aromatic ringsMechanism of action:Mechanism of action: Blocks re-uptake of Norepinephrine and Blocks re-uptake of Norepinephrine and

Serotonin- Serotonin- primary therapeutic effectprimary therapeutic effect Anticholinergic- Anticholinergic- considered to be side effectconsidered to be side effect

Used in treatment of:Used in treatment of: Depression, Chronic pain, Enuresis, ADHD, Depression, Chronic pain, Enuresis, ADHD,

OCD, School phobia, Separation AnxietyOCD, School phobia, Separation Anxiety

TCAs and trade namesTCAs and trade names

Amitriptyline (Elavil) Amitriptyline (Elavil)

Nortriptyline (Aventyl or Pamelor)Nortriptyline (Aventyl or Pamelor)

Imipramine (Tofranil)Imipramine (Tofranil)

Desipramine (Norpramin) Desipramine (Norpramin)

Clomipramine (Anafranil) Clomipramine (Anafranil)

Doxepin (Prudoxin, Sinequan, Zonalon)Doxepin (Prudoxin, Sinequan, Zonalon)

EpidemiologyEpidemiology

Bimodal frequencyBimodal frequency Accidental toddler/childAccidental toddler/child Intentional adolescentIntentional adolescent

EpidemiologyEpidemiology

1998 Poison Control Center study1998 Poison Control Center study 68k antidepressant exposure, 16k TCAs68k antidepressant exposure, 16k TCAs

4k <19yrs, 2k <6 y/o4k <19yrs, 2k <6 y/o 1-2% Mortality1-2% Mortality

Cardiac in natureCardiac in natureusually presented within first hour of ingestionusually presented within first hour of ingestion

2004 Poison Control Center2004 Poison Control Center 33rdrd leading cause of toxic exposures (1 leading cause of toxic exposures (1stst- analgesics, - analgesics,

22ndnd- sedatives)- sedatives) 12k cases, similar number of deaths12k cases, similar number of deaths

As you can see…As you can see…

Decrease usage (Decrease usage (↓↓16k to 12k, in 6 yrs)16k to 12k, in 6 yrs)

Secondary to adverse events and Secondary to adverse events and increased popularity with SSRIsincreased popularity with SSRIs

ToxicityToxicity

Low toxicity thresholdLow toxicity threshold

Therapeutic Dose 2-4 mg/kg/dTherapeutic Dose 2-4 mg/kg/dToxic Dose seen at 10-20 mg/kgToxic Dose seen at 10-20 mg/kg

Example: Example: Pincer grasp- 8-12 months, 8-11 kgs.Pincer grasp- 8-12 months, 8-11 kgs.1 tablet 50 mg, 2 tablets 100mg1 tablet 50 mg, 2 tablets 100mg

PharmokineticsPharmokinetics

Rapidly absorbed by GI tractRapidly absorbed by GI tract

The anticholinergic effects may impair The anticholinergic effects may impair gastric emptying and delay peak serum gastric emptying and delay peak serum levels up to 12 hours levels up to 12 hours

Tissue levels of TCAs far exceed those Tissue levels of TCAs far exceed those found in plasmafound in plasma

Therefore, dialysis clinically ineffective at Therefore, dialysis clinically ineffective at enhancing elimination enhancing elimination

ToxicologyToxicologyAnticholinergicAnticholinergicReuptake InhibitorReuptake Inhibitor Initially hyperadrenergic and then catecholamine Initially hyperadrenergic and then catecholamine

depletedeplete

Alpha adrenergic blockadeAlpha adrenergic blockade Vasodilation then subsequent hypotensionVasodilation then subsequent hypotension

Blocks cardiac myocyte fast sodium channels Blocks cardiac myocyte fast sodium channels

Direct myocardial toxicity + catecholamine Direct myocardial toxicity + catecholamine depletion + alpha-adrenergic blockade can depletion + alpha-adrenergic blockade can produce profound cardiovascular dysfunction. produce profound cardiovascular dysfunction.

PresentationPresentation

Usually within 2 hoursUsually within 2 hours

Consistent with presumed peak Consistent with presumed peak concentrationconcentration

PresentationPresentation

AnticholinergicAnticholinergicDry mouthDry mouth

Flushed/dry skinFlushed/dry skin

Blurred visionBlurred vision

Urinary retentionUrinary retention

ConstipationConstipation

DizzinessDizziness

EmesisEmesis

Altered Mental Altered Mental StatusStatus

Sinus Sinus TachycardiaTachycardia

MydriasisMydriasis

FeverFever

PresentationPresentation

CardiacCardiac Palpitation, chest pain, hypotension, Palpitation, chest pain, hypotension,

arrhythmiaarrhythmia

CNSCNS AMS to coma, Sz, respiratory depressionAMS to coma, Sz, respiratory depression

Peripheral AutonomicPeripheral Autonomic Dry mouth/skin, urinary retention, blurry Dry mouth/skin, urinary retention, blurry

vision, mydriasis, ileusvision, mydriasis, ileus

ArrhythmiaArrhythmia

TCAs inhibit the fast sodium channel, TCAs inhibit the fast sodium channel, thereby slowing phase O depolarization in thereby slowing phase O depolarization in His-Purkinje and ventricular myocytes His-Purkinje and ventricular myocytes Slows conduction (Slows conduction (↑ ↑ QRS)QRS) Impairs contractility (impaired calcium entry)Impairs contractility (impaired calcium entry)

The sodium channel blockade is mitigated The sodium channel blockade is mitigated by larger concentrations of extracellular by larger concentrations of extracellular sodium (overcome competitive blockade) sodium (overcome competitive blockade) and alkalemiaand alkalemia

Work upWork up

Toxic labs, alcohol level, anion gap (co-Toxic labs, alcohol level, anion gap (co-ingestions)ingestions)

CBC, Lytes with LFTs, D-stickCBC, Lytes with LFTs, D-stick If If ↓Ca, Mg or Phos ↓Ca, Mg or Phos - may exacerbate cardiac - may exacerbate cardiac

and CNS disturbancesand CNS disturbances

pHpH

EKGEKG

EKGEKG

Sinus tachycardia most common findingSinus tachycardia most common finding Anti-muscarinic effectAnti-muscarinic effect

Measure QRS interval- if >100msec, treatMeasure QRS interval- if >100msec, treat If > 100 msec- If > 100 msec-

Chance of seizures 34% Chance of seizures 34%

Chance of life-threatening cardiac arrhythmia 14% Chance of life-threatening cardiac arrhythmia 14% If > 160 msecIf > 160 msec

Chance of ventricular arrythmia 50%Chance of ventricular arrythmia 50%

EKGEKG

The amplitude of the R wave in lead aVR The amplitude of the R wave in lead aVR and the ratio of the R/S waves in aVR are and the ratio of the R/S waves in aVR are greater in patients who developed greater in patients who developed seizures or dysrhythmias seizures or dysrhythmias

When the R wave in aVR > 3 mm, the When the R wave in aVR > 3 mm, the sensitivity of subsequent development of sensitivity of subsequent development of seizures or arrhythmias are 81% and 73%, seizures or arrhythmias are 81% and 73%, respectively respectively

TreatmentTreatment

The greatest risk of seizures and The greatest risk of seizures and arrhythmias occurs within the first 6-8 arrhythmias occurs within the first 6-8 hours hours If asymptomatic - supportive therapy. If asymptomatic - supportive therapy.

For all patients with possible cyclic For all patients with possible cyclic antidepressant toxicity: airway protection, antidepressant toxicity: airway protection, ventilation and oxygenation, intravenous ventilation and oxygenation, intravenous fluids, cardiac monitoring, and obtaining fluids, cardiac monitoring, and obtaining ECGs are all essential measures ECGs are all essential measures

TreatmentTreatment

ABCsABCsGastric decontamination- Gastric decontamination- charcoal vs lavage charcoal vs lavage

Benzodiazepines (seizures- which are Benzodiazepines (seizures- which are often self-limited)often self-limited) Lidocaine, to treat ventricular arrhythmia, Lidocaine, to treat ventricular arrhythmia, should be administered with caution to should be administered with caution to avoid precipitating seizuresavoid precipitating seizuresFoley catheterization Foley catheterization

IV Sodium BicarbonateIV Sodium Bicarbonate

Dose 1-2 meq/kgDose 1-2 meq/kgProlonged QRS is most often the Prolonged QRS is most often the indication for serum alkalinization indication for serum alkalinization Evidence exists demonstrating the Evidence exists demonstrating the reversal of toxic effects of CA such as reversal of toxic effects of CA such as QRS prolongation and myocardial QRS prolongation and myocardial depression following serum alkalization depression following serum alkalization and sodium loading with sodium and sodium loading with sodium bicarbonate. bicarbonate.

(hyperventilation for alkalination has also been proposed but not (hyperventilation for alkalination has also been proposed but not universally accepted)universally accepted)

PhysostigminePhysostigmine

Cholinesterase inhibitorCholinesterase inhibitor

Has been used in past for anti-muscarinic Has been used in past for anti-muscarinic effects but is no longer used secondary to effects but is no longer used secondary to cases of asystole cases of asystole

OKAYOKAY

What is Ciguatera Fish What is Ciguatera Fish Poisoning and where does it Poisoning and where does it

occur?occur?

CiguateraCiguatera

A common foodborne disease related to A common foodborne disease related to the consumption of subtropical and the consumption of subtropical and tropical marine finfish which have tropical marine finfish which have accumulated naturally occurring toxins. accumulated naturally occurring toxins.

The concerned –ciguatoxic -fish are either The concerned –ciguatoxic -fish are either feeding on small algae species known as feeding on small algae species known as dinoflagellates or feeding on toxic dinoflagellates or feeding on toxic herbivore fish. herbivore fish.

CiguateraCiguatera

Symptoms within 10 minutesSymptoms within 10 minutes

GI- N/V, salivationGI- N/V, salivation

CNS- CNS- tingling and numbness in the mouth and the tingling and numbness in the mouth and the

extremities, muscle cramping and sensation extremities, muscle cramping and sensation of temperature reversalof temperature reversal

headache, vertigo, hallucinations, headache, vertigo, hallucinations,

CiguateraCiguatera

TreatmentTreatment SupportiveSupportive GI decontaminationGI decontamination Anti-emeticAnti-emetic Antihistamine if pruritisAntihistamine if pruritis Some studies have shown mannitol works Some studies have shown mannitol works

wellwell

CaseCase

I just had some Mahi-mahi and I feel like I just had some Mahi-mahi and I feel like hell. V/D, flushed, dysphagia, perioral hell. V/D, flushed, dysphagia, perioral tingling.tingling.

What do I got?What do I got?

How do you treat it?How do you treat it?

ScombroidScombroid

After eating spoiled mahi-mahi, amber jack After eating spoiled mahi-mahi, amber jack (both non-scombroid fish) or fish in the (both non-scombroid fish) or fish in the scombroidea family- tuna, albacore, scombroidea family- tuna, albacore, bonito, mackerel and skipjack.bonito, mackerel and skipjack.

After spoiling histamnie levels on the fish After spoiling histamnie levels on the fish increase by a factor of 100 within 12 increase by a factor of 100 within 12 hours.hours.

ScombroidScombroid

The histamine is converted to saurine by The histamine is converted to saurine by bacteria and the saurine is what casues bacteria and the saurine is what casues the symptoms.the symptoms.

ScombroidScombroid

Tx- anti-histaminesTx- anti-histamines