Postmortem drug distribution
One of the most important factors to affect the interpretation of postmortem drug concentrations is the phenomenon of ‘postmortem redistribution’. The term has been used to describe the movement of drugs within the body after death with the result that the blood concentration of a drug is significantly higher at autopsy than that immediately after death. Postmortem redistribution is a complex phenomenon, and probably involves at least three mechanisms to a greater or lesser degree. The first, and probably the major contributor in most cases, is the release and diffusion of the drug after death from tissues or organs that contain high concentrations (usually the lungs and liver) into nearby cardiac and pulmonary blood vessels. This mechanism has been clearly identified for several drugs, including amitriptyline, for which the concentration in the liver or lungs may be 20–100 times that in the blood. The exact mechanism at a molecular level has not been identified, but it is known that changes in pH and protein structure occur after death, and thereby disrupt the protein binding characteristics of drugs. Therefore, drugs such as the tricyclic antidepressants, which concentrate in the major organs through binding to protein and other molecules, are more likely to undergo redistribution by diffusion along nearby blood vessels. It is worth noting that, although toxicologists have referred to postmortem redistribution from the heart, the bulk of the redistribution occurs from the lungs and liver (Hilberg et al. 1994). In contrast to the tricyclic antidepressants, the benzodiazepines undergo very little postmortem redistribution because they are not highly concentrated in the major organs relative to blood. In one case study in which blood was collected from ten separate ligated venous and arterial sites, the marked site dependence in the concentrations of some drugs, but not others, was demonstrated clearly (Jones and Pounder 1987). Figure 1 shows the marked site dependence of imipramine and desipramine in the case study, and Figure 2 shows the relative lack of site dependence of acetaminophen in the same case. The second mechanism is simple diffusion after death from a drug depot such as the gastric contents. This is unrelated to release from the major organs because of changes in protein binding. At least two, and possibly three, situations have been identified where this can occur: diffusion or traumatic release from the stomach, agonal aspiration of the stomach contents into the lungs, and continued release from a drug delivery system. If a drug is present in sufficient concentration in the stomach, diffusion through the stomach wall can occur. Such diffusion can potentially elevate concentrations of drugs in the abdominal blood vessels, such as the abdominal aorta and iliac vein, as well as in tissue such as the liver and kidney (Parker et al. 1971). The extent of postmortem diffusion is directly related to both the concentration and total amount of drug in the stomach. Rupture of the stomach in a traumatic accident or suicide can cause artificially elevated drug concentrations by allowing gastric contents to spill into the chest cavity. Under such circumstances even the residue of a single therapeutic dose could produce an erroneous chest blood concentration equivalent to 10 to 100 times that expected after therapeutic doses. In many jurisdictions an autopsy is not performed if the cause of death is obvious, and a less experienced medical examiner might attempt to draw blood from the heart by a blind stick through the chest wall (Logan and Lindholm 1996). Agonal or postmortem move ment of the gastric contents into the trachea and lungs can occur after vomiting at the time of death, or as a consequence of handling of the body after death. Marked increases in the concentration of ethanol and drugs can occur through this mechanism, especially into the pulmonary and aortic blood (Pounder and Yone mitsu 1991). In the third situation, markedly increased blood concentrations can occur with at least two different drug delivery devices.
Figure 1 Comparison of concentrations of imipramine and the metabolite desipramine in several specimens from the same case. Lu, lung tissue; Li, liver tissue; Ht, heart tissue; PV, pulmonary vein blood; PA, pulmonary artery blood; Ao th, thoracic aorta blood; Ao sr, suprarenal aorta blood; Ao ir, infrarenal aorta blood; IVC sr, suprarenal inferior vena cava blood; IVC ir, infrarenal vena cava blood; SV l, left subclavian vein blood; FV l, left femoral vein blood; FV r, right femoral vein blood. (Based on data from Jones and Pounder 1987.)
Transdermal patches left on a body after death give rise to locally high concentrations of the drug (e.g. fentanyl, nicotine). Transdermal devices rely on passive diffusion across a rate limiting membrane for drug delivery and, if they are not removed, concentration of the medication in the local area of the patch continues to rise after death, albeit at a slower rate. As there is no blood circulation through the skin after death, the drug is no longer transported away (except by diffusion), which results in a local accumulation of the drug. The concentration gradient between the gel that contains the medication in the patch and the skin is so high that even modest postmortem diffusion can raise postmortem tissue and blood concentrations up to several centimetres away from the patch. The magnitude of such effects depend on the proximity of the patch to the site from which blood was drawn and the postmortem interval. Perhaps more obvious is the situation in which someone dies while receiving analgesics or other medica tion from an intravenous delivery device (e.g. syringe driver). Intravenous solutions may continue to be pumped into the patient after death, and potentially cause a large local increase in blood concentration (Jenkins et al. 1999). While most of these devices are external and readily switched off, some are internal and not obvious until the autopsy is conducted. The third mechanism is in complete distri but ion at the time of death. Even for drugs for which littleorno redistribution is thought to occur, marked site-to-site differences in blood drug concentration can occur following an overdose. Since clinical pharmacokinetic studies have shown that a significant arterial–venous difference in concentrations can occur after therapeutic doses, it is reasonable to conclude that even larger differences are likely after massive oral or even intravenous overdoses. In the case of an oral overdose, localised high concentrations are likely in the portal vein, inferior vena cava and right heart and pulmonary vessels. The existence of this Phenomenon has been suggested as an explanation for site-to-site differences in unconjugated blood morphine concentrations in diamorphine related deaths, even though morphine was shown by the same work not to undergo redistribution per se (Logan and Smirnow 1996). It is therefore important to bear in mind that demonstrating site-to-site differences in the blood concentrations of a particular drug does not necessarily prove that the drug undergoes postmortem redistribution. The distinction Isan important one. By the nature of postmortem redistribution and postmortem diffusion, increases in blood concentration are time dependent. However, simply to demonstrate that blood samples from two different sites in the body contain different concentrations of a particular drug does not prove that redistribution is likely to occur for that drug in all circumstances.
Figure 2 Comparison of concentrations of acetaminophen in several specimens from the same case as in Fig. 1. Lu, lung tissue; Li, liver tissue; Ht, heart tissue; PV, pulmonary vein blood; PA, pulmonary artery blood; Ao th, thoracic aorta blood; Ao sr, suprarenal aorta blood; Ao ir, infrarenal aorta blood; IVC sr, suprarenal inferior vena cava blood; IVC ir, infrarenal vena cava blood; SV, subclavian vein blood; FV, femoral vein blood. (Based on data from Jones and Pounder 1987.)
