Effects of pKa on the Biological Properties of Ionizable Drugs

Acidic drugs (e.g. aspirin) are generally more highly bound to plasma albumin, giving a lower volume of distribution, i.e. they tend to stay in the plasma rather than distribute to the tissues. Basic drugs (including many CNS-acting agents such as phenothiazines) are theoretically more prone to binding to acid glycoprotein, an acute phase inflammatory plasma protein; however, albumin also has binding sites for basic drugs.

Acidic drugs tend to interact by displacement from protein binding. Plasma protein binding reduces the free (unbound) drug plasma concentration, and thus both drug activity and clearance, because it is this fraction that is available equally for pharmacodynamic effect, and also for hepatic extraction and renal excretion.

Interactions may occur intra-renally owing to competition for the special tubular secretory transport mechanisms that exist for weak acids and bases. The pH of the urine can affect clearance: a more acid urine promotes the clearance of basic drugs, and vice versa. This is the basis of forced acid or alkaline diuresis to treat poisoning, e.g. urinary alkalinization for barbiturate or aspirin overdose.

pKa – Effect

<7.4 – Hydrophilic; acidic

  • Absorbed in stomach (fastest)
  • Bound to plasma albumin
  • Reduced solubility in normal urine

About 7.4 – Lipophilic

>7.4 – Hydrophilic; basic

  • Absorbed in ileum (delayed)
  • Bound to plasma acid glycoprotein
  • Increased solubility in normal urine

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