Post-mortem clinical pharmacology

Abstract

Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that the effects are related to the measured concentration. Post-mortem changes render the assumptions of clinical pharmacology largely invalid, and make the interpretation of concentrations measured in post-mortem samples difficult or impossible. Qualitative tests can show the presence of substances that were not present in life, and can fail to detect substances that led to death. Quantitative analysis is subject to error in itself, and because post-mortem concentrations vary in largely unpredictable ways with the site and time of sampling, as a result of the phenomenon of post-mortem redistribution. Consequently, compilations of 'lethal concentrations' are misleading. There is a lack of adequate studies of the true relationship between fatal events and the concentrations that can be measured subsequently, but without such studies, clinical pharmacologists and others should be wary of interpreting post-mortem measurements.

Figure 1

The relationship between the extent of post-mortem redistribution and the volume of distribution. The extent of post-mortem distribution is measured by the central : peripheral concentration ratio, taken from reference [8]. The volume of distribution is taken from [64]. The regression coefficient, r = 0.247, P > 0.1

Figure 2

The relationship between the extent of post-mortem redistribution and log octanol : water partition coefficient. The extent of post-mortem distribution is measured by the central : peripheral concentration ratio, taken from reference [8]. The octanol : water partition coefficient is taken from [65]. The regression coefficient, r = 0.035, P > 0.1

Figure 3

A scheme of the relationship between ante-mortem dose–response curve for a lethal drug and the definition of lethal concentration by reference to the observed post-mortem concentration

Figure 4

(a) Deductions made from concentrations of drug measured during life. If the relationship between concentration (or dose) and effect is known, then in some circumstances the likely effect can be deduced. Even in life, there are difficulties with drugs, such as ethanol, where responses are very variable; opiates, whose dose–response curve is substantially altered by repeated dosing; and penicillin, where a subset of patients is hypersusceptible to adverse effects. (b) Deductions made from concentrations of drug measured after death. It is now impossible to establish the administered dose, and the effect of a measured concentration cannot be deduced from dose–response curves determined in living subjects

Figure 5

The proportion of patients having a specified post-mortem concentration of some hypothetical drug, and for two groups of subjects: those with drug-induced death (DID); and those with death not due to drugs (DID-not), allowing for likely variability between individuals. The two distributions may differ in shape, and may be skewed, but it is very likely that they will overlap considerably: those in whom concentration A was found may have died from the effects of the drug, whereas those in whom concentration B was found may not. There is no clear ‘lethal concentration’