toxicology and therapeutic windows

week 4 specialist topics in biomed

what is a drug

• a medicine or other substance which has a physiological effect when ingested or otherwise introduced to the body

• a substance capable of causing illness/death in living organism when absorbed

toxicology

• science dealing with properties, actions, toxicity, fatal dose

forensic toxicology

• study of chemical/physical properties of toxic substances and their physiological effect on living organisms

• deals with medico-legal aspects of harmful effects of chemicals on human beings

• clinical toxicology: diagnosis and treatment of human poisoning

therapeutic index

• compares therapeutically effective dose to toxic dose of pharmaceutical agent

• TI is a statement of relative safety of a drug

• dose needed to produce therapeutic response

therapeutic index formula

TI = TD50 / ED 50

therapeutic index issues

• varies from species to species

• reliable only when LD50 and ED50 are determined in same strain of same species

• use of ED50 and TD50 may be misleading about drug’s safety

drugs with high TI

• NSAIDs

  • aspirin

  • tylenol

  • ibuprofen

• sedative

• antibiotics

• beta blockers

drugs with a low TI

• lithium

• neuroleptics

• some antibiotics

• digoxin

• immunosuppressives

margin of safety

the ratio of the toxic dose to 1% of the population to dose that is 99% effective to population

MOS= TD01 / ED99

why margin of safety is not always possible

• cannot always be achieved

• some drugs must be used even if arrow MOS

• warfarin (prevent blood clots) can cause bleeding

  • people who take warfarin need frequent check ups

blood samples

• anti mortem: provides closest correlation to dose

• 2 samples at post mortem (1% NaF should be submitted)

• post mortem redistribution

• may contain clots, large fatty deposits

• blood collection site will influence concentrations detected

urine sample

• 99% water

• results don’t always correlate to drug effects at time of collection

• determining past use

• large sample volume

• useful for POCT

urine: post mortem

advantages:

• longer detection window

• post mortem ethanol production

• large sample volume

disadvantages:

• only available in 50% of deaths

• parent compound may not be detectable

• poor correlation with blood

oral fluid

• consists of saliva, gingival crevicular fluid, cellular debris

• detection window relates to administration

• anti mortem sample- used in POCT

vitreous humour

• advantages

  • analyte stability

  • remains sterile for days after death

  • strong correlation between blood alcohol concentrations

• disadvantages

  • small sample volume

  • not all drugs cross blood retina barrier

  • interpretation of drugs can be difficult

stomach contents

• stomach wash out in hospital

• post mortem samples

• can identify fungi and plants

• care must be taken when removing stomach contents

• quantification rare

hair analysis

• hair consists of keratin (65%), water (15%) and lipids (1%)

• drugs incorporated via

  1. blood

  2. sweat/sebum

  3. external

ELISA assay

• enzyme linked immunosorbent assay: uses antibodies to detect presence of a substance

• results produced based on enzymatic colour change