Many drugs are weak electrolytes, i.e. their structural groups ionise to a greater or lesser extent, according to environmental pH. Most such molecules are present partly in the ionised and partly in the unionised state. The degree of ionisation influences lipid-solubility (and hence diffusibility) and so affects absorption, distribution and elimination.
Ionisable groups in a drug molecule tend either to lose a hydrogen ion (acidic groups) or to add a hydrogen ion (basic groups). The extent to which a molecule has this tendency to ionise is given by the dissociation (or ionisation) constant (Ka). This is usually expressed as the pKa, i.e. the negative logarithm of the Ka (just as pH is the negative logarithm of the hydrogen ion concentration). In an acidic environment, i.e. one already containing many free hydrogen ions, an acidic group tends to retain a hydrogen ion and remains un-ionised; a relative deficit of free hydrogen ions, i.e. a basic environment, favours loss of the hydrogen ion from an acidic group which thus becomes ionised. The opposite is the case for a base. The issue may be summarised:
• Acidic groups become less ionised in an acidic environment
• Basic groups become less ionised in a basic
(alkaline) environment and vice versa.
This in turn influences diffusibility since:
• Un-ionised drug is lipid-soluble and diffusible
• Ionised drug is lipid-insoluble and nondiffusible.
The profound effect of environmental pH on the degree of ionisation is best shown when the relation between these is quantified. It is convenient to remember that when the pH of the environment is the same as the pKa of a drug within it, then the ratio of un-ionised to ionised molecules is 1:1. But for every unit by which pH is changed, the ratio of un-ionised to ionised molecules changes 10-fold. Thus when the pH is 2 units less than the pKa, molecules of an acid become 100 times more unionised and when the pH is 2 units more than the pKa, molecules of an acid become 100 more ionised. Such pH change profoundly affects drug kinetics.
pH variation and drug kinetics. Studies of the partitioning of a drug across a lipid membrane according to differences in pH have been developed as the pH partition hypothesis. There is a wide range of pH in the gut (pH 1.5 in the stomach; 6.8 in the upper and 7.6 in the lower intestine). But the pH inside the body is maintained within a limited range (pH 7.46 ± 0.04) so that only drugs that are substantially un-ionised at this pH will be lipid-soluble, diffuse across tissue boundaries and so be widely distributed, e.g. into the CNS. Urine pH varies between the extremes of 4.6 and 8.2; thus the amount of drug reabsorbed from the renal tubular lumen by passive diffusion can be very much affected by the prevailing urine pH.
Consider the effect of pH changes on the disposition of aspirin (acetylsalicylic acid, pKa 3.5). In the stomach aspirin is un-ionised and thus lipid-soluble and diffusible. When aspirin enters the gastric epithelial cells (pH 7.4) it will ionise, become less diffusible and so will localise there. This ion trapping is one mechanism whereby aspirin is concentrated in, and so harms, the gastric mucosa. In the body aspirin is metabolised to salicylic acid (pKa 3.0), which at pH 7.4 is highly ionised and thus remains in the extracellular fluid. Eventually the molecules of salicylic acid in the plasma are filtered by the glomeruli and pass into the tubular fluid, which is generally more acidic than plasma and causes a proportion of salicylic acid to become un-ionised and lipid-soluble so that it diffuses back into the tubular cells. Alkalinising the urine with sodium bicarbonate causes more salicylic acid to become ionised and lipid-insoluble so that it remains in the tubular fluid, and is eliminated in the urine. The effect is sufficiently great for alkalinising the urine to be effective treatment for salicylate (aspirin) overdose. Conversely, acidifying the urine increases the elimination of the base amphetamine (pKa 9.9) (see Acidification of urine, p. 156).
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