PM redistribution Flashcards
What is PM redistribution
After death – drugs undergo passive diffusion down conc gradients resulting in increased PM drug conc
Release from drug reservoirs
Diffusion into adjacent tissues
“reservoirs”: liver, lung, and heart
Cell death: changes in pH and breakdown of cell walls
Increase vascular permeability
Unabsorbed drugs in the stomach
Passively diffuse from stomach into mediastinal vessels and surrounding organs
Vasculature and proximal organs
Cardiac chambers, aorta, and inferior vena cava
Lower lobe of left lung
Left lobe of liver and heart
First discovery of PM redistruntion and studies
Curry and Sunshine [1960] reported a large difference in Barb conc
Central vs peripheral blood
Advocated for use of peripheral blood and advocated research
Gee et al [1972]
Corroborated Curry and Sunshine data
Cautioned that area/site of collection is important consideration for interpretation
How did they discover PM redistrubtion after first
Different sites in one body contained different conc of digoxin
Speculated that the drug may have been redistributed in the body after death
Conc difference for digoxin between HB/FB/SB
HB the highest
“Special Case”
Digoxin highly bound to myocardium
No extrapolation to other drugs
Extent of postmortem redistribution depends on many factors
site and time and PM interval
site and time
Brandt (1980) presented a study at the AAFS describing the results of a study involving TCAs
Concluded conc of the drug [TCA] was a function of the origin of the blood sample
heart blood concentrations are usually greater than blood from peripheral sites; such as femoral blood
PM interval
concentration incerease as the PM interval increase
Sentinel case- desipramine
63 year old female hospitalized in state facility
Pt died at night found next morning
Autopsy: large brain tumor
Sufficient size and location prob COD
Routine toxicology
Desipramine detected
Blood conc in range considered lethal
Medications controlled – administered by staff
Intensive investigation undertaken
Pharmacy records reviewed
No evidence of over dispensing
Pharmacokinetic calculations suggested massive amount of drug ingested
Est dose: 6,600 mg
264 [25 mg] tablets
Indication that PMR occurred
Also prob 2D6 deficiency – given liver conc
Prouty and Anderson and published in 1990
Serial study of changes in conc over time
Leaking fluid after first collection
Multiple draws potential for contamination
Continual collection of peripheral blood – conc approached the conc of a more central sample [IVC]
Site and temporal dependence on conc
Weakly basic drugs
Rate of increase nor magnitude not predictable
HB generally greater than FB
SB similar to HB
PMR with IV and oral
Independent of gastric conc
Factors that may influence postmortem redistribution
Condition of body
Chemical characteristics of the drug
Collection induced
Postmortem interval
Condition of body
Proximity to high conc depots
Heart
Lung
Liver
Physical barriers – decomp and/or trauma
pH of tissues
residual enzymatic activity
microbial invasion
movement of blood
induced by putrefaction and rigor mortis
gravity dependent blood flow
valves in femoral veins
Chemical characteristics of the drug
Apparent volume of distribution
High Vd > 3 L/kg
Weakly basic in chemical nature [pKa > 7]
Octanol: water partition coefficient
Lipophilic drugs more liable to redistribute
Sample passive diffusion from high to low conc
Organs close proximity to the heart and major vessels
Liver [left lobe],Stomach, Lungs, Intestine, Myocardium
Drugs with large Vd – high conc in these tissues
Collection induced
Peripheral blood specimens usually obtained from femoral vein
Leg vein preferred over veins of head and neck
Due to anatomical presence of a larger number of valves that resist blood movement from more central compartments
Do not milk: overcome physical barrier
