Tricyclic Antidepressant Overdose

Tricyclic antidepressants are weak bases typically used for depression and as an adjunct for analgesia. They have a complex mechanism of action, competitively inhibiting noradrenaline and serotonin reuptake, and also blocking muscarinic receptors, histaminergic receptors, α-adrenoreceptors, GABA-a receptors, and fast sodium channels.

Toxicity

In overdose, toxicity is predominantly due to cardiac and central effects, though there are effects on most of the major organ systems.

Cardiac toxicity

Cardiac toxicity is due to antagonism of α-adrenoreceptors use-dependent blockade of fast sodium channels.

α-antagonism results in vasodilatation and subsequent hypotension. Hypotension may also be due to myocardial depression from sodium channel blockade.

Blockade of fast sodium channels occurs in the His-Purkinje system, as well as the atrial and ventricular myocardium. This results in decreased myocardial impulse conduction. They block channels in the inactivated state, resulting in a use-dependent blockade such that the effect is greater at faster heart rates. This results in an increased depolarisation and repolarisation time. ECG findings are consistent with this and are essentially pathognomnic:

  • Widened QRS
  • Right axis deviaiton of the terminal QRS
    >3mm terminal R wave in aVR

Additional ECG findings include:

  • Tachycardia
  • Any degree of heart block
  • Ventricular arrythmias

Central toxicity

Central toxicity is predominantly due to anticholinergic effects, though antihistamingergic effects contribute.

Anti-cholinergic effects tend to occur prior to cardiac effects, and include:

  • Confusion
  • Agitation
  • Seizures
  • Pupillary dilatation and blurred vision
  • Seizures

Antihistaminergic effects include obtundation.

Management

Standard management of poisoning applies. TCAs are not dialysable and as they are weak bases are not amenable to urinary alkalinsation.

Cardiac toxicity

NaHCO3 and hyperventilation to a pH >7.5 is used to manage cardiac toxicity. There are a number of proposed mechanisms of action for the benefit of alkalinsation:

  • Plasma alkalosis results in less ionised drug and increases distribution into tissues
  • Plasma alkalosis increases protein binding of drug
  • Intracellular alkalosis results in less bound intracellular drug, favouring its movement out of cells
  • Extracellular alkalosis results in reduced H+/K+ exchange, increasing intracellular potassium and hypopolarising the cell.

  • In addition to the alkalinising effects, sodium load from the NaHCO3 improves the sodium concentration gradient into cells

α-adrenoreceptor antagonism can be countered with use of an α-agonist such as noradrenaline.

Arrythmias should be managed with drugs that do not prolong the action potential - so amiodarone and beta-blockers are contraindicated. Initial management should be using NaHCO3, though MgSO4 and lignocaine can be considered in refractory cases.

Central toxicity

Seizures should be managed with benzodiazepines, phenytoin, propfol, and phenobarbital. Avoid agents which result in QRS prolongation.


References

  1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
  2. Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale's Pharmacology. 6th Ed. Churchill Livingstone.
  3. CICM July/September 2007
  4. Salhanick SD, Traub SJ, Grayzel J. Tricyclic Antidepressant Poisoning. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2017.
  5. Nickson, C. Toxicology Conundrum 22. LITFL.
  6. Nickson, C. Tricyclic Antidepressant Toxicity. LITFL.
  7. UpToDate. Tricyclic antidepressant poisoning
Last updated 2017-10-08

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