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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.

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tricyclic antidepressant cardiotoxicity beyond abc to ph

Tricyclic Antidepressant Cardiotoxicity:Beyond ABC to pH

Andrew Dawson

South Asian Clinical Toxicology Research Collaboration

the case
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
TRICYCLIC ANTIDEPRESSANTS
  • Revise the pharmacology and mechanisms
  • Relate this to the clinical picture
  • Advanced Treatment Options
kinetics
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
kinetics5
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
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
  • 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
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
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
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
cvs toxicity
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
slide12

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-

Henderson-Hasselbach
  • For basic compounds:
    • pH = pKa + log (non-ionised/ionised)
    • ionised/non-ionised = 10 (pKa – pH)
tca ph 7 3
TCA: pH= 7.3
  • 200 mEq bicarbonate
tca ph 7 4
TCA: pH =7.4
  • 200 mEq bicarbonate
ph local anesthetics sodium channel blocker
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
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
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
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.
slide21
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
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
slide23
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
slide24
? Refractory Hypotension
    • Intropes with alpha effects: adrenaline
    • 3 Case reports of hypertonic saline
    • Cardiopulmonary bypass
  • Complex Ventricular Tachycardia
    • Consider Magnesium
    • Overdrive pacing
conclusion
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