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Transcript
Tricyclic Antidepressants
Presented by Dr. Bloxdorf
Prepared by A. Hillier
Case
A 16 year old female had an argument with
boyfriend and ingested 10 of her Mom’s
antidepressants. She presents one hour
after ingestion with parents. At triage she
is crying and upset. Vitals: 158/93, 112,
16, 98%. After changing patient into
gown, the nurse yells out that the patient
has collapsed. You go in to find the
patient now with agonal respirations and in
profound coma.
Epidemiology
•
•
•
•
18,000 exposures over past decade
60% likely intentional
Narrow therapeutic index
More drug-related deaths than any other
prescription medication
• Used for depression, OCD, chronic pain
and migraine prophylaxis
Pathophysiology
•
•
•
•
All TCA’s structurally similar
Cyclobenzaprine structurally similar to TCA’s
Many have active metabolites
Multiple toxicologic effects
– Antihistaminic
– Anticholinergic
– α adrenergic blockade
– Sodium channel blockage
– GABA-A receptor antagonist
Pathophysiology
• Antihistamine Effects
– Potent inhibitors of histamine receptors
– Manifested as CNS sedation
• Anticholinergic Effects
– Due to antimuscarinic receptor blockade
▪ Dilated pupils
▪ Blurred vision
▪ Dry skin
▪ Tachycardia▪ Hypertension
▪ Hyperthermia
▪ Urinary retention ▪ Ileus
▪ Dry mouth
▪ Agitation
▪ Delirium
▪ Confusion
▪ Hallucinations
▪ Slurred speech
▪ Coma
Pathophysiology
• α-Adrenergic Receptor Antagonism
– Inhibits both central and peripheral receptors
– Greater affinity for α1
– No β-blockade
– Effects
- Sedation
- Orthostatic hypotension
- Pupillary constriction
▪ Usually negated by antimuscarinic effect
Pathophysiology
• Amine Uptake Inhibition
– Mechanism by which TCA’s are efficacious in
depression
– In overdose likely produces early
sympathomimetic effects including some
dysrhythmias
Pathophysiology
• Sodium Channel Blockade
– Quinidine-like effect
– Single-most important factor relating to
mortality in TCA toxicity
– Inhibits fast sodium channels in His-Purkinje
cells
– Impairs sodium entry into myocardial cells
– Prolongs depolarization (Phase 0), decreases
contractility
– More pronounced effects with rapid heart
rates, hyponatremia and acidosis
Pathophysiology
• Sodium Channel Blockade
– Prolonged PR
– Widens QRS
– Right axis deviation
- Manifested by terminal R-wave in aVR and
S-wave in I
– Bradycardia
- May be attenuated by antimuscarinic effect
- Indicates profound sodium channel blockade
Pathophysiology
• Sodium Channel Blockade
– May develop reentry ventricular dysrhythmias
– Hypotension
– Negative inotropic effect
– Cardiac ectopy
• GABA-A Receptor Antagonist
– Major cause of seizure in TCA toxicity
Pathophysiology
• Potassium Channel Blockade
– Prevents efflux during repolarization
– QT interval prolongation
– More pronounced with bradycardia
– Tachycardia prevents severe QT prolongation
– Torsades de pointes may develop, but is rare
in TCA toxicity
Pharmacokinetics
•
•
•
•
Highly lipophilic
Readily crosses blood-brain barrier
Peak levels occur 2-6 hours post ingestion
Decreased gut motility may prolong
absorption
• Highly protein bound
• Tissue levels up to 100 times plasma level
• Only 1-2% total-body TCA in plasma
Pharmacokinetics
• Hemodialysis, hemoperfusion and forced
diuresis are ineffective
• Hepatic metabolization
• Renal excretion
• Most have active metabolites
– Toxicity from tertiary TCA’s last longer than
secondary TCA’s
• Half life
– Therapeutic: on average 24 hours
– Overdose: up to 72 hours
Toxicity
• Life threatening
– Ingestions greater than 10mg/kg in adults
– Pediatrics more susceptible to antimuscarinic
effects
– Manifest symptoms within 6 hours
– High risk for TCA toxicity
▪ Coingestion with other cardiac or CNS depressants
▪ Prior heart disease
▪ Geriatrics
Toxicity
• Most fatalities ingest more than 1 gram
• Fatalities occur in initial hours usually
before arrival to hospital
• Desipramine
– Most potent Na-channel blocker
– Twice the fatality rate of other TCA’s
– May precipitate cardiotoxicity without
significant antimuscarinic symptoms
Toxicity
•
•
•
•
Drug levels unhelpful to EP’s
Serious toxicity rarely occurs if <300ng/mL
Most fatalities have levels >1000ng/mL
Clinical toxicity often does not correlate
with serum levels
• Urine qualitative may help to rule out TCA
toxicity in unknown ingestion
Clinical Features
• Varies from mild antimuscarinic to severe
cardiovascular collapse
• Up to 70% will have coingestants
• May have rapid progression of coma and
cardiovascular collapse
Clinical Features
– Mild/Moderate Toxicity
•
•
•
•
•
•
•
•
•
•
Drowsiness
Confusion
Slurred speech
Ataxia
Dry skin/mucous membranes
Tachycardia
Urinary retention
Myoclonus
Hyperreflexia
Hypertension
– Severe Toxicity
•
•
•
•
•
•
•
•
Coma
Conduction delays
SVT
Hypotension
Respiratory depression
PVC’s
Ventricular tachycardia
Seizures
– Status occasionally
• Pulmonary edema
• High degree AVB
Clinical Features
• Life threatening complications are more
likely with
– QRS >100ms
• Greater likelihood of seizures
– Positive terminal R-wave in aVR and negative
S-wave in lead I
– QRS >160ms
• Greater likelihood of ventricular dysrhythmias
Diagnosis
• Suspect in:
– Rapidly presenting coma
– Cardiovascular collapse
– Anticholinergic toxidrome
– Generalized seizure
– Characteristic ECG findings
▪ RAD aVR
▪ 1st degree AVB
▪ Widened QRS
▪ Prolonged QTc
▪ Ventricular ectopy
▪ Usually develop within 6 hours of ingestion
Treatment
• Initial treatment
– Evaluate immediately for
• Alterations in consciousness
• Hemodynamic instability
• Respiratory compromise
– Two large bore IV’s
– Cardiac monitoring
– Electrocardiogram
– Routine toxicologic lab tests
▪ CBC
▪ Acetaminophen
▪ ABG*
▪ SMA-20
▪ Urine tox
▪ Salicylate
▪ Ethanol
▪ Serum osmolality*
* If unknown ingestion
or possible coingestants
Treatment
• GI Decontamination
– DO NOT use syrup of ipecac!!!
– Gastric lavage if performed within first few
hours after toxic ingestion
• Performed lying flat in left lateral decubitus position
• Obtunded patients need intubation prior to lavage
– Activated Charcoal 1gm/kg PO/NG
Treatment
• Sodium Bicarbonate Therapy
– Indications
•
•
•
•
Widened QRS >100ms
Refractory hypotension
Terminal R >3mm in aVR
Ventricular dysrhythmias
– Improves
▪ Conduction
▪ Contractility
▪ Suppresses ventricular ectopy
Treatment
• Sodium Bicarbonate Therapy
– Dosage
• Initially 1-2 mEq/kg IV bolus until patient
improvement or blood pH of 7.50-7.55
• Continuous infusion
– 3 ampules in 1L D5W at 2-3mL/kg per hour
– Further adjustments based on blood pH
– Hypokalemia is an expected complication
• Supplementation usually required
Treatment
• Altered Mental Status
– Usually soon after a toxic overdose
– Due to histamine, muscarinic and α-receptor
blockade
– Administer “DONT” therapy for potentially
reversible causes
– Consider occult head or neck trauma
– Flumazenil and physostigmine contraindicated
due to increased risk of seizures
Treatment
• Seizures
– Most occur within 3 hours of ingestion
– Usually single, but may be multiple in up to 30%
– May develop status epilepticus with maprotiline
and amoxapine
– Benzodiazepines are drug of choice
– 2nd line is phenobarbitol 15mg/kg
• Side effects
▪ Hypotension
▪ Respiratory depression
Treatment
• Seizures
– If status continues
• Repeat bolus with phenobarbital 5mg/kg
• Neuromuscular paralysis to prevent
▪ Rhabdomyolysis
▪ Hyperthermia
▪ Metabolic acidosis
▪ Renal failure
– Phenytoin, Physostigmine and NaHCO3 do
not affect seizures
Treatment
• Hypotension
– Initial treatment with 10 mL/kg incremental
boluses
– Due to the negative inotropic effects,
pulmonary edema is common
– Poor response to crystalloids is an indication
for bicarbonate therapy
– Norepinephrine is drug of choice if
unresponsive to bicarbonate therapy
– May need ECMO or IABP
Treatment
• Dysrhythmias
– Prolonged QRS or ventricular dysrhythmias
• 1st line drug is bicarbonate therapy
• 2nd line drug is lidocaine
– Unstable rhythms
• Synchronized cardioversion
– Torsade de pointes
• Magnesium sulfate 2 gm IV bolus
– Contraindicated
▪ Class IA and IC antiarrhythmics
▪ Class III antiarrhythmics
▪ β-blockers
▪ Calcium channel
blockers
Disposition
• Patients asymptomatic for 6 hours
– No medical reason for hospitalization
• Will need psychiatric admission if
intentional ingestion
• Symptomatic
– Monitored bed
• Moderate-severe toxicity
– Intensive care unit
Summary
• TCA ingestions are one of the worst
overdoses you will see
• Initial management focused on ABC’s
• Activated charcoal
• QRS prolongation-sodium bicarbonate
• Dysrhythmias-sodium bicarbonate and
lidocaine
Summary
• Hypotension-crystalloids, bicarbonate,
norepinephrine
• Seizures-benzodiazepines and phenobarbital
• Contraindicated
▪ Syrup of Ipecac
▪ Physostigmine
▪ β-blockers
▪ Calcium channel blockers
▪ Class IA, IC, III antiarrhythmics
▪ Flumazenil
Questions
1. Concerning tricyclic antidepressants all of the
following are true except:
a. TCA’s have more intentional fatalities associated
with them than any other prescribed drugs
b. They have antihistaminic, anticholinergic and
quinidine-like properties
c. They are easily managed overdoses
d. There most fatal symptoms are due to cardiac
effects
e. They have characteristic ECG changes
Questions
2. With tricyclic antidepressants which of the
following are true:
a. TCA’s are easily cleared by hemodialysis,
hemofiltration and forced diuresis
b. Due to negative cardiac inotrophy, pulmonary edema
is common
c. Aggressive sodium bicarbonate therapy is the
treatment of choice for widened QRS/QTc
d. You should avoid all antiarrhythmics except Class IB’s
e. All of the above are true
Questions
3. All of the following medicines are indicated in
the treatment of TCA overdoses:
a.
b.
c.
d.
e.
f.
g.
Syrup of Ipecac
B-blockers
Calcium channel blockers
Type IA, IC and III antiarrhythmics
Flumazenil
Physostigmine
None of the above are indicated
Questions
4. Which of the following matched symptomtreatments in incorrect:
a.
b.
c.
d.
e.
QRS widening-NaHCO3
Seizure-Benzodiazepine & Phenobarbital
Hypotension-IV crystalloids
Ventricular tachycardia-Amiodarone
Unstable rhythm-Synchronized cardioversion
Questions
5. For the TCA overdose in status epilepticus,
which of the following is effective
a.
b.
c.
d.
e.
f.
Phenytoin
Benzodiazepines
Sodium bicarbonate
Phenobarbital
Physostigmine
Both B & D
Answers
1. C-This class of overdose may be one of the
most serious you may treat
2. E-All of the above are true
3. G-None of the above are indicated, in fact all
of the above are absolutely contraindicated
4. D-All are correct therapies except Amiodarone.
Amio is a Class III antiarrhythmic which is
absolutely contraindicated
5. F-1st line is benzodiazepines followed by
phenobarbital and may eventually need
chemical paralysis