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Tricyclic Antidepressants

Tricyclic Antidepressants. Presented by Dr. Bloxdorf Prepared by A. Hillier. Case.

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Tricyclic Antidepressants

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  1. Tricyclic Antidepressants Presented by Dr. Bloxdorf Prepared by A. Hillier

  2. 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.

  3. 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

  4. Pathophysiology • All TCA’s structurally similar • Cyclobenzaprine structurally similar to TCA’s • Many have active metabolites • Multiple toxicologic effects • Antihistaminic • Anticholinergic • αadrenergic blockade • Sodium channel blockage • GABA-A receptor antagonist

  5. 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

  6. 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

  7. Pathophysiology • Amine Uptake Inhibition • Mechanism by which TCA’s are efficacious in depression • In overdose likely produces early sympathomimetic effects including some dysrhythmias

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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 ▪ SMA-20 ▪ Urine tox ▪ Acetaminophen ▪ Salicylate ▪ Ethanol ▪ ABG* ▪ Serum osmolality* * If unknown ingestion or possible coingestants

  22. 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

  23. Treatment • Sodium Bicarbonate Therapy • Indications • Widened QRS >100ms • Refractory hypotension • Terminal R >3mm in aVR • Ventricular dysrhythmias • Improves ▪ Conduction ▪ Contractility ▪ Suppresses ventricular ectopy

  24. 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

  25. 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

  26. 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

  27. Treatment • Seizures • If status continues • Repeat bolus with phenobarbital 5mg/kg • Neuromuscular paralysis to prevent ▪ Rhabdomyolysis ▪ Metabolic acidosis ▪ Hyperthermia ▪ Renal failure • Phenytoin, Physostigmine and NaHCO3 do not affect seizures

  28. 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

  29. 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 ▪ β-blockers ▪ Class III antiarrhythmics ▪ Calcium channel blockers

  30. 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

  31. 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

  32. 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

  33. Questions • Concerning tricyclic antidepressants all of the following are true except: • TCA’s have more intentional fatalities associated with them than any other prescribed drugs • They have antihistaminic, anticholinergic and quinidine-like properties • They are easily managed overdoses • There most fatal symptoms are due to cardiac effects • They have characteristic ECG changes

  34. Questions • With tricyclic antidepressants which of the following are true: • TCA’s are easily cleared by hemodialysis, hemofiltration and forced diuresis • Due to negative cardiac inotrophy, pulmonary edema is common • Aggressive sodium bicarbonate therapy is the treatment of choice for widened QRS/QTc • You should avoid all antiarrhythmics except Class IB’s • All of the above are true

  35. Questions • All of the following medicines are indicated in the treatment of TCA overdoses: • Syrup of Ipecac • B-blockers • Calcium channel blockers • Type IA, IC and III antiarrhythmics • Flumazenil • Physostigmine • None of the above are indicated

  36. Questions • Which of the following matched symptom-treatments in incorrect: • QRS widening-NaHCO3 • Seizure-Benzodiazepine & Phenobarbital • Hypotension-IV crystalloids • Ventricular tachycardia-Amiodarone • Unstable rhythm-Synchronized cardioversion

  37. Questions • For the TCA overdose in status epilepticus, which of the following is effective • Phenytoin • Benzodiazepines • Sodium bicarbonate • Phenobarbital • Physostigmine • Both B & D

  38. Answers • C-This class of overdose may be one of the most serious you may treat • E-All of the above are true • G-None of the above are indicated, in fact all of the above are absolutely contraindicated • D-All are correct therapies except Amiodarone. Amio is a Class III antiarrhythmic which is absolutely contraindicated • F-1st line is benzodiazepines followed by phenobarbital and may eventually need chemical paralysis

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