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 –α adrenergic 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 α 1 –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. 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

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▪ 1 st 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 –2 nd 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 NaHCO 3 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 1 st line drug is bicarbonate therapy 2 nd 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 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

34. 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

35. Questions 3.All of the following medicines are indicated in the treatment of TCA overdoses: a.Syrup of Ipecac b.B-blockers c.Calcium channel blockers d.Type IA, IC and III antiarrhythmics e.Flumazenil f.Physostigmine g.None of the above are indicated

36. Questions 4.Which of the following matched symptom- treatments in incorrect: a.QRS widening-NaHCO 3 b.Seizure-Benzodiazepine & Phenobarbital c.Hypotension-IV crystalloids d.Ventricular tachycardia-Amiodarone e.Unstable rhythm-Synchronized cardioversion

37. Questions 5.For the TCA overdose in status epilepticus, which of the following is effective a.Phenytoin b.Benzodiazepines c.Sodium bicarbonate d.Phenobarbital e.Physostigmine f.Both B & D

38. 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-1 st line is benzodiazepines followed by phenobarbital and may eventually need chemical paralysis