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

Systemic alkalinisation does shift the oxygen dissociation curve to the left and hypocapnoea reduces cerebral blood flow by about 4% for each mmHg reduction in pCO2. For these reasons we would normally aim for pH of about 7.50 - 7.55 and aim to keep the pCO2 around 30 mmHg.