Pharmacological response
Even when it has been established that the measured drug concentration in the blood accurately represents the concentration of drug at the receptor site, it must also be established that the clinical response is a primary consequence of the presence of the drug. For example, drugs with an irreversible biochemical effect, such as reserpine and some monoamine oxidase inhibitors, still have clinical effects long after drug administration has stopped, and when plasma concentrations of the drug are negligible. Similarly, unless the time of ingestion is known with reasonable accuracy, it is almost impossible to relate drug concentrations with the secondary and potentially fatal responses to substances such as paracetamol (liver damage) and paraquat (lung necrosis). Incorporation of drugs or chemicals into endogenous metabolic cycles may result in a toxicity (lethal synthesis) that is not related to blood concentrations of the drug. Finally, interpretation is made difficult or impossible when underlying disease alters the pharma cological action of the drug, or when a patient has died from complications associated with inhalation of vomit.
Active metabolites A number of drugs have been modified such that metabolism is required to produce an active species. This is often done to facilitate oral absorption or to reduce toxicity, although for some drugs the active form was not established until after clinical use. Examples include diamorphine, which is hydrolysed to morphine; the esters of many angiotensin-converting enzyme (ACE) inhibitors (e.g. enalapril, quinapril), which are hydrolysed to potent di-acid forms; azathioprine, which is metabolised to mercaptopurine; and zidovudine which is metabolised to zidovudine triphosphate. When an active metabolite makes an import ant contribution to the overall pharmacological response, the interpretation of toxicological data is further complicated. Toxicological situations that involve such metabolites (e.g. oxazepam, nortriptyline, desipramine and phenobarbital, derived from diazepam, amitriptyline, imipramine and methylphenobarbital, respectively) can be misinterpreted if only the parent drugs are assayed. The concentrations of active metabolites must be taken into account. Although it is unclear what is the best way to evaluate the contribution of metabolites, the individual concentrations of drug and metabolites are often added together to provide an estimate of the total amount of active drug species present in the sample. This assumes that their relative pharmacological activities are equal, which is not generally true.
