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Tricyclic Antidepressant Cardiotoxicity: Beyond ABC to pH Andrew Dawson South Asian Clinical Toxicology Research Collaboration The Case A 70 kg man presents on 1-2 hours following a TCA overdose (3000 mg Amitryptilline) – Unconscious – Seizure – BP 60 Systolic TRICYCLIC ANTIDEPRESSANTS Revise the pharmacology and mechanisms Relate this to the clinical picture Advanced Treatment Options 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 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 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 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 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 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 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) RaVR > 3 mm Bailey et al J Tox ClinTox 2004 Sensitivity 0.81 R/SaVR >.7 Sensitivity 0.75 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 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] Henderson-Hasselbach HA + H +A For basic compounds: – pH = pKa + log (non-ionised/ionised) – ionised/non-ionised = 10 (pKa – pH) pKa 8.5 pH 6.9 7 7.1 ratio I/U 39.8 31.6 25.1 7.2 20.0 7.3 7.4 7.5 15.8 12.6 10.0 TCA: pH = 7.1 TCA: pH= 7.3 200 mEq bicarbonate TCA: pH =7.4 200 mEq bicarbonate 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 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 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. 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. 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 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 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 ? Refractory Hypotension – Intropes with alpha effects: adrenaline – 3 Case reports of hypertonic saline – Cardiopulmonary bypass Complex Ventricular Tachycardia – Consider Magnesium – Overdrive pacing 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