Tricyclic Antidepressant Overdose

1
Tricyclic Antidepressant Overdose

• Manav Bhavsar
• 27th April 2007, ICM Study Day

2
Introduction

• 1st case 1959- 2 years after start of clinical
  use (BMJ 1959 13389)
• One of the commonest cause of overdose (Med J
  Aust 19951641903)
• On average 268 die each year TCA overdose
• Dothiepin amitriptyline gt toxicity than others
  (BMJ 19953102214)
• SSRIS most commonly prescribed now days
• TCA cheaper most effective acc to some

3
Pharmacokinetics

• Rapidly abs GIT first pass metabolism
• Highly protein bound high vol distribution
• Longer half life of elimination gt 24 hours
• Metabolised hepatic enzyme
• Some metabolites pharm active
• Conjugated and excreted by the kidneys
• Amitriptyline can take up to 31 to 46 hours
  (Psychopharmacol Bull 19912754150)

4
Pharmacokinetics - Overdose

• Altered with ingestion of large quantities TCA
• GI absorption inhibited by gastric emptying
• Enterohepatic recirculation final elimination
• Protein binding ? - resp depression acidosis
• Toxic effect TCA caused 4 main pharm effect
• Inhibition of norepinephrine reuptake n.
  terminals
• Direct alpha adrenergic block
• Membrane stabilising or quinidine-like effect on
  the myocardium
• Anticholinergic action

5
Clinical Features Complications

• Dose ingested, poor predictor outcome
• Doses lt 20 mg/kg unlikely fatal but
• Individual variation abs, prot binding met
  (JAMA 1976236171112)
• Clinical features TCA overdose 3 main effects
• Anticholinergic
• Cardiovascular
• Central nervous system

6
Anticholinergic Effects

• Common aid in diagnosis
• Dry mouth, blurred vision, dilated pupils
• Urinary retentions, absent bowel sounds
• Pyrexia, myoclonic twitching
• Usually not serious but cases of
• Toxic megacolon and intestinal perforation
  (Postgrad Med J 1989659489
• (Am Surg 1998642424)
• Central effect can alter thermoregulation
  (Intensive Care Med 19962245355)

7
Cardiovascular System

• Sinus tachycardia most common
• Prolonged PR/QRS/QT inhibition Na current
  slowing depolarisation (Am J Cardiol 1980)
• Heart block
• Hypotension common 14-15 (Am J Emerg Med
  1988643942)
• ST/T wave changes
• Cardiogenic shock
• Ventricular fibrillation/tachycardia asytole
  low incidence (Acta Med Scand 1983 2132758)

8
Central Nervous System

• Drowsiness
• Coma one series 316 present 53 pt
  (Q J Med 1980493349)
• Convulsions
• Pyramidal signs
• Rigidity
• Delirium
• Respiratory depression
• Ophthalmoplegia

9
Investigations

• Plasma TCA levels not reliable guide
• Higher in tissue - high vol dist protein
  binding does not measure metabolites
• QRS duration (Acta Med Scand 1983 2132758)
• Decreased R-R variation (Intensive Care Med
  199521598601)
• Terminal R wave gt 3mm in lead aVR (Ann Emerg Med
  199526195201)
• Mixed metabolic acidosis
• Hypokalemia 9

10
Management

• Reduce absorption gastric lavage charcoal
• Alkalinisation sodium bircarbonate
• Management of complications
• antiarrhythmic treatment
• hypotension
• cardiac arrest
• Central nervous system
• Drug elimination antibody fragments

11
Reducing Absorption

• Gastric lavage consensus statement European
  toxicologist only effective if done 1 hour within
  ingest (Clin Toxicol 19973571119)
• Activated charcoal reduce absorption of TCA
• Benefits both single multiple dose described
  (Lancet 1977ii12035)
• (J Clin Psychopharmacol 1984433640)
• But overall evidence remains poor

12
Alkalinisation

• Sodium bicarbonate therapy
• Treat arrhythmias (Anaesth Inten Care 1973
  120310)
• Treat hypotension and correct prolonged QRS (Am J
  Emerg Med 19931133641)
• Mechanism of action subject to debate
• Increase prot binding of TCA and ? pharm active
• Correcting acidosis improves myocardial contr
• Hyperventilation
• Hypertonic saline - ? extracellular Na
• (Ann Emerg Med 19983232933)

13
Antiarrhythmia Treatment

• Avoid antiarrhythmics
• Correct hypoxia,?BP, acidosis
• Avoid class Ia,Ib and 3 prolong QT
• Lignocaine and phenytoin evidence poor
• ß blocker would correct arrhythmia but ?BP
• Magnesium sulphate

14
Hypotension

• Caused by ? myo contr per vasodil
• IV fluids, if refractory than inotropes
• Nor adrenaline
• Dopamine not much useful
• Experimental study combined adr NaHCO3
• (Crit Care Med 19972566974)
• Extracorporal circulation resistant to inotropes
• (Ann Emerg Med 1994234806)

15
Cardiac Arrest CNS complications

• Cases of recovery 3 5 hrs cardiac massage
• (BMJ 198128311078) (BMJ 1974450)
• Seizures usually self limiting benzodiazepine
• If comatose intubation ventilation
• Tricyclic specific antibody fragments large
  dose needed (Lancet 1999354161415)
• Forced diuresis, peritoneal dialysis and
  haemodialysis no benefit seen large Vd

16
Monitoring

• Major complications usually seen within 6 hrs
• (J Emerg Med 199084514)
• Incidence of late complications extremely low
  (Clin Toxicol 198185438)
• Arrhythmias do not occur after CVS toxicity has
  resolved (JAMA 198525417725)
• Cardiac monitoring till ECG normal 12-24 hrs
  (Med Toxicol 1986110121)

17
Summary

• Assess and treat ABCs as appropriate
• Examine for clinical features
• Check urea and electrolyteslook for low pot
• Check arterial blood gaseslook for acidosis
• Perform ECG - look for QRSgt0.16 seconds
• Consider gastric lavage only if within one hour
• Give 50 grams of charcoal if within one hour
• Give sodium bicarbonate (50 ml of 8.4) if
• pH lt7.1, QRS gt0.16 sec, arrhythmias, ? BP

18
Summary

• Arrhythmias
• Avoid antiarrhythmics
• Correct hypoxia, ?BP, acidosis, hypokalemia
• Hypotension IV fluids, inotropes
• Cardiac arrest prolonged resuscitation
  successful
• Monitoring 12 hours sign of toxicity