Tricyclic Antidepressant Cardiotoxicity: Understanding Mechanisms and Clinical Correlates

1. Tricyclic Antidepressant Cardiotoxicity:Beyond ABC to pH Andrew Dawson South Asian Clinical Toxicology Research Collaboration

2. The Case • A 70 kg man presents on 1-2 hours following a TCA overdose (3000 mg Amitryptilline) • Unconscious • Seizure • BP 60 Systolic

3. TRICYCLIC ANTIDEPRESSANTS • Revise the pharmacology and mechanisms • Relate this to the clinical picture • Advanced Treatment Options

4. KINETICS • Highly lipid soluble weak bases • Rapidly absorbed • Anticholinergic effects may prolong absorption • High volume of distribution • Death and toxicity mainly before redistribution (toxic compartment) • Clinical Correlates • asymptomatic at 3 hours remain well • Liebelt EL, et al Ann Emerg Med 1995; 26(2):195-201 • >15 mg/kg associated major toxicity

5. KINETICS • Protein binding > 95% • May saturate increasing free fraction • pH dependent • P450 Hepatic metabolism • Saturable: long elimination half life • Active metabolites • Clinical Correlates • Toxicity increase with acidosis • Prolonged clinical course

6. Pharmacodynamically Promiscuous • Block re-uptake of noradrenaline and serotonin • Antagonists to H1 and H2 receptors,GABA • Alpha antagonists • Anticholinergic effects • Clinical Correlate • Anticholinergic effects • Hypotension

7. Anticholinergic Syndrome • Anticholinergic Syndrome: • Hot as hell • Blind as a bat • Red as a beet • Dry as a bone • Mad as a hatter • A sensitive indicator for ingestion, but poor predictor for toxicity. • Full syndrome is rare

8. CNS Toxicity • Anticholinergic psychosis • Coma • Myoclonus and seizures • Seizures are strongly associated with arrhythmia and acute deterioration and increased mortality • Lancet 1994;343:159-62 • J Tox - Clin Tox. 33(3):199-204, 1995

9. Fast Sodium Channel blockers & pH • Slowing of the 0 phase of depolarisation • Rate dependent block • Ionized drug binds with the greatest affinity • Clinical Correlates • Increasing conduction defects • Impaired myocardial contractility

10. Predicting Major Complication • QRS > 100 milliseconds or more in a limb lead is as good as TCA concentration • Ventricular arrhythmia • Sensitivity 0.79 (95% CI 0.58- 0.91) • Specificity 0.46 (95% CI 0.35- 0.59) • Seizures • Sensitivity 0.69 (95% CI 0.57- 0.78) • Specificity 0.69 (95% CI 0.58- 0.78) • Bailey et al J Tox ClinTox 2004 • RaVR > 3 mm • Sensitivity 0.81 • R/SaVR >.7 • Sensitivity 0.75

11. CVS toxicity • Tachycardia: • Good indicator of TCA ingestion • Caused by cholinergic blockade • Catecholamine • Anxiety • Hypotension • Vasodilation, hypovolaemia, alpha receptor blockade • Serious myocardial depression (normally wide QRS) • Bradycardia: • generally associated major conduction block • severe toxicity

12. HA H+ +A- • Drugs and Receptors can be considered to be weak acids or bases. • Equilibrium influenced by external pH • The balance of the equilibrium can be expressed by pKa • The pKa is the pH where [ionised] = [non-ionised]

13. HA H+ +A- Henderson-Hasselbach • For basic compounds: • pH = pKa + log (non-ionised/ionised) • ionised/non-ionised = 10 (pKa – pH)

14. TCA: pH = 7.1

15. TCA: pH= 7.3 • 200 mEq bicarbonate

16. TCA: pH =7.4 • 200 mEq bicarbonate

17. pH: Local anesthetics Sodium Channel Blocker • Non-ionised form to diffuse • Preferential binding of ionised form in the channel • Narahashi T, Fraser DT. Site of action and active form of local anesthetics. Neurossci Res, 1971, 4, 65-99 • Demonstration pH sensitivity • pH 7.2 to 9.6 unblock the channel • Ritchie JM, Greengard P. On the mode of action of local anesthetics. Annu Rev Pharmacol. 1966, 6, 405-430

18. TCA & pH • Sodium channel Binding • Ionisation trapping in the channel • Receptor preferentially binds ionised drug • Other mechanisms • Protein Binding • Phospholipid barrier • non-ionised diffusion = more rapid redistribution • Sodium Loading

19. Protein Binding • Therapeutic concentrations • pH shift 7.1 to 7.5 • 95% to 96% protein binding • Toxic concentrations protein binding is saturated • pH change is effective in the absence of protein • Sasyniuk B ,Jhamandas V. J Pharmacol Exp Ther 1984;231:387-394 • Wang R,Schuyler J,Raymond R.The role of the cell membrane bicarbonate exchanger in NaHCO3 therapy of imipramine cardiac dysfunction J Toxicol Clin Toxicol 1997;35:533.

20. pH or sodium • Sodium loading has an additive effect • Hypertonic saline (15meq/kg) > NaHCO3 > Hyperventilation • McCabe. Ann Emerg Med.1998;32:329-333. • Bicarbonate via cell membrane exchanger • block exchanger you lose the bicarbonate effect • Wang R,Schuyler J,Raymond R J Toxicol Clin Toxicol. 1997;35:533.

21. Risk? • Shift oxygen desaturation curve • Cerebral blood flow & hypocapnoea • CBF varies linearly with PaCO2 ( 20 - 80 mmHg) • CBF change is 4% per mmHg PaCO2 • Sodium loading and hypertonicity

22. Management CVS Toxicity • ABC • Avoid acidosis • Volume replacement often large • Ventilation to a low normal CO2 • Decontamination • Activated charcoal is indicated….mostly in the same patients who intubation is indicated

23. Na Bicarbonate (AHA ACLS 2a) • Dose: Repeated 3-5 minutes • 1-3 meq/kg bolus (if not in shock) • 1-3 mls/kg of 8.4% solution • 3-6 meq bolus (if in shock) • Titrated by ECG • Monitored ABG target pH 7.55 -7.6

24. ? Refractory Hypotension • Intropes with alpha effects: adrenaline • 3 Case reports of hypertonic saline • Cardiopulmonary bypass • Complex Ventricular Tachycardia • Consider Magnesium • Overdrive pacing

25. Conclusion • Manipulation of pH alters the kinetics and dynamics of TCA • Recommendations are for bolus NaHCO3 • Resuscitation should not be ceased until the pH is corrected