Opioid pharmacokinetics in relation to their effects

The chemical structure of drug molecules determines their fundamental pharmacological properties by 'fit' to the receptor, but the physicochemical properties, particularly lipid solubility and fraction un-ionised, dominate in determining distribution in the body and the rate of access to the biophase containing the drug receptors. For example, fentanyl appears much more potent than morphine because similar effective biophase concentrations are achieved with much smaller doses. Pharmacokinetic and pharmacodynamic investigations of the relationships between dose and the time-courses of blood concentrations and pharmacological effects of opioid drugs have helped explain the commonly observed variability between patients and have been useful in deriving effective dosage regimens of opioids such as pethidine, morphine, fentanyl and methadone where blood concentrations are a determinant of pharmacological response and 'target' analgetic blood opioid concentrations have been identifiable. However, there are instances when blood opioid concentrations are not determinants of the analgetic response. Examples include opioids, such as buprenorphine, for which the drug-receptor dissociation rate determines the duration of action, heroin which first has to be metabolised to become an agonist, pentazocine which is an agonist at some opioid receptors and an antagonist at others, and opioids placed intra-spinally acting on receptors in the spinal cord.