pH Manipulation in Toxicology

Manipulation of pH has an established role in clinical toxicology for a few limited indications.

The basis of its effect relates to the fact that drugs and receptors can be considered to be weak acids or bases. As such they exist in an equilibrium of ionised and non-ionised forms. This equilibrium is influenced by external pH. The pH where the concentration of ionised drug equals the concentration of non- ionised drug is called the pKa.

The relationship between pH, pKa and the ionised/non-ionised ratio is described by the Henderson-Hasselbach equation.

For acidic compounds:
pH = pKa + log (ionised/non-ionised)

For basic compounds:
pH = pKa + log (non-ionised/ionised)/ionised)

This can be transformed to: non-ionised/ionised/ionised = 10 P(pH – pKa)P
Thus: pH change of X produces a 10PXP change in the ratio

Clinically this may become important if the changes in pH are physiologically tolerated and have significant effect on ionisation.

Altering ionisation has potential effects at multiple targets and the effect should be considered complex rather than simple.

Targets include:

• Distribution
• Protein: carriers, enzymes, receptors
• Ion channels
• Intracellular organelles

For many drugs distribution requires passive diffusion through charged phospholipid membranes. Movement of ionised drug is slower effectively causing trapping of the drug on that side of the membrane. This can affect effect the rate and sites of redistribution both in tissues and at a cellular level (i.e. Intra- vs Extra-cellular). These factors may effect concentrations at the drug’s target. It can also affect the rate of excretion. For example, see salicylates later in this module.

For some drugs changes in protein binding can occur although this is only likely to have a significant impact when drugs have >90% binding.

At the target, binding affinity is affected by the charge of both the receptor and the drug. For example, the fast sodium channel in cell walls preferentially binds ionised drugs (such as the sodium channel blockers Lignocaine, cocaine, and tricyclic antidepressants). This is very important when the dose concentration response curve is steep as a relatively little change in concentration significantly affects response.

There are many ways to alter pH and they appear to not be interchangeable.. The method we choose of altering pH may depend upon which ‘compartment’ we are trying to effect, eg altering pH at the heart requires a different strategy to alkalinising urine. Animal work suggests that hyperventilation has little effect in reversing cardiac dysfunction; this may relate to the rate of change in pH or the absence of additional factors seen when using hypertonic sodium bicarbonate (such as sodium loading and volume expansion).

The two most common methods of alkalisation are using hypertonic Sodium Bicarbonate or Hyperventilation. Sodium bicarbonate can be given as either a bolus (generally for reversal of cardiac conduction problems) or by infusion (normally for enhancing elimination).

• Proudfoot AT, Krenzelok EP, Vale JA. Position Paper on urine alkalinization.J Toxicol Clin Toxicol. 2004;42(1):1-26. (fulltext)
• McCabe JL, Cobaugh DJ, Menegazzi JJ, Fata J. Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Annals of Emergency Medicine 1998;32(3 pt1):329-333.
• Seger DL, Hantsch C, Zavoral T, Wrenn K. Variability of recommendations for serum alkalinization in tricyclic antidepressant overdose: a survey of U.S. poison centre medical directors. Clinical Toxicology 2003;41(4)331-338.
• Blackman K, Brown SGA, Wilkes GJ. Plasma alkalinization for tricyclic antidepressant toxicity: a systematic review. Emergency Medicine 2001;13:204-210. (Internet access to University of Newcastle Library required.)

Figure. Oxygen partial pressure mm/Hg

• Shift oxygen desaturation curve (see Figure 1)
• Cerebral blood flow (CBF) is altered by hypocapnoea. CBF varies linearly with PaCOB2B (20-80 mmHg). In effect CBF reduces by 4% for each per mmHg reduction in PaCOB2B
• Sodium loading and hypernatraemia

Alkalinisation is an important part of treatment for both salicylate and tricyclic antidepressant poisoning, but the method and rationale are different.

1. Understand the mechanism and treatment of salicylate and tricyclic antidepressant poisoning
2. Understand effects of alkalinisation and the rationale for the different approaches

Now explore salicylate poisoning. It is a poisoning that produces a complex metabolic disturbance.

• Wikitox: Salicylates monograph
  • Salicylate Problem

Then explore tricyclic poisoning.

• Wikitox: Cyclic antidepressant monograph

• Tricyclic Problems