Drugs 11

• toxicant 


  substance that produces adverse biological effects - chemical, physical, biological
• toxicity 


  the extant to which toxicant produces harmful effects
• 4 key factors that influence toxicity

  magnitude of exposure, route and site of exposure, duration and frequency and exposure, latency of toxic response
• LD50


  the amount of toxicant in a single dose required to kill half the test population (smaller value = greater toxicity)
• what can cause deviation from dose-response relationship

  genetic factors - abnormal response or metabolism, hypersensitivity evoking immune response
• distribution of responses to dose curve shape

  bell shape, most respond the same, some susceptible and others resistant
• how is dose response relationship obtained

  data from cells, animals, human studies = sigmoidal curve
• NOAEL


  no adverse effect level, threshold before get some toxic response
• TD50


  dose at which 50% individuals show toxic response
• what does slope of dose relationship curve tell us

  rate toxic effects build up
• routes of exposure for drugs

  inhalation, ingestion, topical, parenteral
• how ADME apply to toxicants

  drugs lower LD, less toxic when exposed via oral route then i.v as have first pass metabolism by gut wall and liver
• acute toxicity 


  less than 24 hrs
• subacute toxicity 


  longer than 24 hours less than 1 month
• subchronic toxicity 


  longer than 1 month, less than 3 months
• chronic toxicity 


  greater than 3 months
• alcohol acute toxicity 


  CNS depression, depending on BAC
• alcohol chronic toxicity 


  alcohol related liver disease
• dose fractionation 


  reduces toxic effects, multiple smaller doses over time period, used in radiotherapy
• dose fractionation exception 


  carcinogens, mutagens (smoking) build up over time so doesn't reduce toxic effects
• exposome 


  complete profile of environment (non genetic) exposure of individual from conception to death
• conventional models of testing drugs problems

  interspecies differences limit use of animal models and in vitro models lack dynamic 3D tissue environment
• why organ on a chip model is better

  use human cells eliminates interspecies differences, has a dynamic 3D environment mimics in vivo physiological conditions
• non covalent mechanisms of toxicity

  lipid peroxidation (radicals attack membrane), production of reactive oxygen species (cell death), depletion of glutathione (can't protect from oxidative stress)
• covalent mechanisms of toxicity

  formation of DNA (mutagenesis) or protein (antigen) adducts
• types of mutagenesis 


  carcinogenesis - caner and tetratogenesis - structural malformations
• diethylstilbestrol (DES)


  a synthetic non steroidal estrogen treatment for treated miscarriage, latent toxic response was clear cell adenocarcinoma of vagina in female offspring of treated mothers
• thalidomide 


  a non addictive sedative for morning sickness, early reports of peripheral neuropathy and induced severe birth defects
• TOCP


  an organophosphate used a lubricant or plasticiser, caused delayed neuropathy, degradation of axons of spinal cord and peripheral neurons causing ataxia and muscle weakness
• TOCP mechanism


  metabolised by CYP450 enzymes and forms reactive metabolite that irreversibly binds acetylcholinesterase, Act cannot be broken down and continues to stimulate muscles so become unresponsive