Briefly outline the mechanism of effectiveness of sodium bicarbonate in the management of tricyclic antidepressant overdose.
Increased serum pH, TCAs are weak bases and therefore increasing serum pH will increase the proportion of non-ionised drug thus causing a greater proportion of drug to be distributed throughout the body away from the heart.
Increased serum Na also overcomes the Na receptor blockade
Alkalinisation also accelerates recovery of sodium channels by neutralizing the protonation of the drug receptor complex.
The indication for the use of bicarbonate in tricyclic overdose is the widening of the QRS interval, rather than the metabolic acidosis (which may or may not accompany TCA poisoning).
Exactly how this works is a topic of some debate. In general, the QRS prolongation in TAC overdose seems to result from voltage-gated sodium channel blockade
Some authers have been able to demonstrate that amitryptilline enjoys greater protein binding in a more alkaline environment, which decreases the fraction of free drug.
Other authors have correctly identified sodium (rather than bicarbonate) as the more important ion in sodium bicarbonate; the administration of hypertonic saline seemed to have greater antiarrhytmic effect than sodium bicarbonate!
The last part of the college answer I could find no evidence for, at least not in the way it was worded. A good paper on the molecular mechanisms of sodium channel blockade by imipramine seems to report that intracellular alkalosis seems to favour the unbinding of imipramine from the voltage-gated sodium channel, which vaguely sounds like the thing that the college said.
In summary, bicarbonate in TCA overdose works in the following ways:
- Increased protein binding of TCAs in an alkaline bloodstream, thus decreasing the biologically active free fraction.
- Increased availability of sodium in sodium bicarbonate, as a substrate for the voltage-gated channels.
- Decreased binding of TCAs to the voltage gated sodium channel
- Correction of metabolic acidosis
- Volume expansion because of the dilutional effect on TCA concentration
- Cellular membrane hypopolarisation results from bicarbonate-induced intracellualr shift of potassium.
Hoffman, J. R., and C. R. McElroy. "Bicarbonate therapy for dysrhythmia and hypotension in tricyclic antidepressant overdose." Western Journal of Medicine134.1 (1981): 60.
Kerr, G. W., A. C. McGuffie, and S. Wilkie. "Tricyclic antidepressant overdose: a review." Emergency Medicine Journal 18.4 (2001): 236-241.
Brown, T. C., et al. "The use of sodium bicarbonate in the treatment of tricyclic antidepressant-induced arrhythmias." Anaesthesia and intensive care 1.3 (1973): 203-210.
McCabe, James L., et al. "Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation." Annals of emergency medicine 32.3 (1998): 329-333.
Bou-Abboud, Elias, and Stanley Nattel. "Molecular mechanisms of the reversal of imipramine-induced sodium channel blockade by alkalinization in human cardiac myocytes." Cardiovascular research 38.2 (1998): 395-404.