PHARMACOKINETICS AND PHARMACODYNAMICS OF OPIOIDS

Humans exhibit substantial intersubject variability in their response to opioids.^[294] This variability is at least three- to fivefold and is a function of both pharmacokinetic and pharmacodynamic parameters ( Fig. 11-11 ). Therefore, opioid dosage regimens should be customized for each patient.

With the advent of modern drug assay technology and the widespread availability of computers, it is now possible to analyze pharmacologic data with combined pharmacokinetic-pharmacodynamic models, which separate drug response into pharmacokinetic and pharmacodynamic components. Pharmacokinetic parameters govern the relationship between opioid dose and the opioid concentrations in the blood (or other body fluid). Pharmacodynamic parameters describe the relationship between opioid concentration in blood (or other fluid) and the opioid's pharmacological effect.

Physicochemical Properties

Opioids are weak bases. When dissolved in solution, they are dissociated into protonated and free-base fractions, with the relative proportions depending on the pH and pKa. The free base fraction is more lipid-soluble than the protonated fraction.

High lipid solubility facilitates opioid transport into the biophase or site of action. Therefore, highly lipid-soluble opioids have a more rapid onset of action. However, because the opioid receptor "recognizes" an opioid molecule in the protonated form, the intensity of opioid effects is closely related to the ionized concentration of drug in the biophase ( Fig. 11-12 ).

All opioids are to some extent bound to plasma proteins, including albumin and α₁ -acid glycoprotein. It is only the un-ionized, unbound fraction that constitutes the diffusible fraction and provides the concentration gradient that promotes diffusion of opioid from the blood to the tissue of interest. Thus, the speed of onset of opioid effect is influenced by both the lipid solubility and the protein binding.