1. TCA and Serotonin Re-Uptake Inhibitors Rama B. Rao, MD Bellevue/New York University Medical Center

2. Tricyclic Antidepressants  A patient takes 30 tablets of nortriptylline in a suicide attempt, she calls her family member who summons an ambulance.  On arrival, the paramedics note she is unresponsive, tachycardic, and hypotensive.  She seizes.

4. TCA Toxicity  Anticholinergic/Antihistaminergic –Somnolence, Tachycardia   Adrenergic blockade –Hypotension  GABA Cl - Channel Antagonist –Seizures  Sodium Channel Blockade –Myocardial Depression, dysrhythmias

5. Myocardial Cell: Depolarization Ca 2+ SR Na + 0 1 2 3 4

6. TCA Ca 2+ SR Na + pH TCA 0 1 2 3 4

7. Ca 2+ SR Na + pH TCA 0 1 2 3 4

8. Wide QRS  > 100 msec predictive of seizures  > 160 msec predictive of dysrythmias 0 1 2 3 4 Boehnert M, Lovejoy FH Jr. New Engl J Med 1985;313:474-479

9. I L aV R Myocardium

10. I L aV R With TCA: QRS widening from sodium channel blockade

11. I L aV R R in aV R S in I,L QRS > 100 msec TCA: Terminal Rightward Axis

12. TCA Toxicity  S in I, L  R in aV R  QRS >100 msec  Drowsy/obtunded patient   HR,  BP Boehnert M, Lovejoy FH Jr. New Engl J Med 1985;313:474-479 aV R

13. Sodium bicarbonate*  Place patient on monitor  Run strip  Administer bolus of 1 mEq/kg  Observe for QRS narrowing  Keep pH 7.5-7.55  Intubate/hyperventilate if sodium contraindicated 0 1 2 3 4 NaHCO 3 * Useful for TCA, Cocaine, Type Ia antidysrhythmics

15. After NaHCO 3

16. TCA Toxicity: General Management  2 Large bore intravenous lines  Continuous ECG monitoring  Assessment for QRS widening, terminal RAD, and response to sodium bicarbonate  Aggressive decontamination  Benzodiazepines for seizure management* *Fingerstick blood glucose

17. St John’s Wort

18. Pre-synaptic Post-synaptic DA NE Neuronal Tissue MECHANISM OF ACTION: TCA, SSRI, MAO-I

19. Pre-synaptic Post-synaptic DA NE 5HT Neuronal Tissue

20. Pre-synaptic Post-synaptic DA NE 5HT Propagation Neuronal Tissue

21. Pre-synaptic Post-synaptic DA NE 5HT Propagation C-O-MT MAO

22. Pre-synaptic Post-synaptic DA NE 5HT Propagation TCA, SSRI

23. Pre-synaptic Post-synaptic DA NE 5HT Propagation MAO-I

24. Pre-synaptic Post-synaptic DA NE 5HT Propagation TCA, SSRI MAO-I

25. Serotonin Syndrome  Excessive serotonergic tone 5HT 1A, 5HT 2  Continuum of neuropsychiatric manifestations Serotonin

26. Serotonin Syndrome: Major Criteria*  Confusion  Elevated mood  Coma  Fever  Diaphoresis  Chills  Rigidity  Hyperreflexia  Myclonus  Tremor 4 major, or 3 major and 2 minor Birmes P CMAJ 2003;168:1439-1442

27. Minor Criteria: Serotonin Syndrome  Agitation  Nervousness  Insomnia  Tachypnea  Dyspnea  Tachycardia  High or low BP  Akathisia  Incoordination  Mydriasis  Diarrhea 4 major, or 3 major and 2 minor Birmes P CMAJ 2003;168:1439-1442

28. Fatal Serotonin Syndrome  Abrupt onset  Autonomic instability  Hyperthermia, diaphoresis  Neuromuscular rigidity, movement disorder  Altered mental status  Absence of a neuroleptic or other cause

29. Serotonin Syndrome  Most often iatrogenic  Resolution in 48-96 hours  Death from uncontrolled hyperthermia

30. Serotonin Syndrome: Therapeutic Goals  Rapid identification of Hyperthermia  Continuous core temperature monitoring, aggressive cooling, benzodiazepines for sedation  Rule out other potential etiologies

31. Serotonin Syndrome  Identification of serotonergic factors, particularly the presence of monoamine oxidase inhibitors  ?Role of serotonin antagonists

32. Drugs Implicated in Serotonin Syndrome  MAO-Inhibitors  SSRIs  Clomipramine  Venlafaxine  Lithium  MDMA*  L-Tryptophan*  Meperidine*  Dextromethorphan*  Cocaine*

34. Citalopram  SSRI with toxic metabolite  In overdose can prolong QRS, QT c,  Seizures  Delay in onset Catalano G. Clin Neuropharmacol 2001;24:158-62

35. Citalopram Overdose  Immediate cardiac monitoring for QT c, IV lines  Assess and correct electrolytes, especially K +, Ca 2+, Mg 2+  Decontamination  Use of Mg 2+ for torsade  Admission of minimum 24 hours of cardiac monitoring

36. Myocardial Cell  G AC ATP cAMP 1 2 3 Ca 2+ 4 SR 5