Alkalinisation may decrease the toxicity of tricyclic antidepressants through a number of mechanisms; for all of the mechanisms a change in ionisation status is important. In effect, a shift in pH towards the pKa (approximately 8.5) causes a decrease in ionised drug and an increase in un-ionised drug.
- receptor binding in the sodium channel prefers ionised drug
- drug lipid solubility is increased for the un-ionised drug. This allows drug to diffuse quickly back into the cell membrane partition, it may also increase redistribution into fat
- the free fraction of TCA may be reduced by about 20% this is probably due to non-specific uptake into circulating lipids as the other carrier proteins (albumin and alpha glycoproteins) are normally saturated at toxic concentrations of TCA