Pharmacological and toxicological profiling Flashcards
what can molecular biology, in vitro studies and computer technology not do
- integrate response- molecule to man
- reveal the unexpected
- determine therapeutic index
- assess importance of multiple mediators
- determine pharmacokinetics
- assess safety and toxicology
- set clinical dose range
what is pharmacodynamics
- the study of biochemical and physiochemical effects of drugs
- infomation obtained includes
- lead optimisation: improve target specificity and selectivity
- efficacious dose range and therapeutic window
- specificity
what is pharmacokinetics
the determination of the fate of substances administered externally to a living organism
- ADME
what is absorption and how does it vary
- process by which drug proceeds from site of administration to site of measurement in body
- varies due to administration
- IV drug is immediate and complete
- oral drug is delayed and incomplete - relies on passage through membranes to reach blood
what is distribution determined by
- partitioning across various membranes
- binding to tissue components
- binding to blood components
- physiological volumes
what is metabolism determined by
- location of metabolism enzymes
- 1st pass metabolism
- induction of drug metabolising enzymes
- development of prodrug
what is elimination and how does it occur
- either by excretion unchanged or drug metabolites excreted
- drug metabolism is associated with a chemical modification of the drug with the overall goal of getting rid of the drug
- main process by which body eliminates unwanted substances
what is toxicology
concerned with the adverse effects of chemicals on living organisms
what does a toxicological profile consist of
- single dose toxicity
- repeat dose toxicity
- genotoxicity
- carcinogenicity
- reproductive and developmental toxicity
- local tolerance
- environmental issues
outline the molecular mechanisms of toxicity
- allergic response- can lead to anaphylactic shock, deplete blood cell types
- receptor, ion channel and enzyme mediated- animal toxins can block ion channels
- biochemical pathways- inhibition of mitochondrial function
- organ directed toxicity- hepatotoxicity, nephrotoxicity
- changing glomerular filtration rate - mutagenesis and carcinogenesis
- teratogenicity- thalidomide
what is involved in preliminary toxicity testing
- maximum non toxic dose given for 28 days to 2 species before tissue damage assessment
- LD50 test- the dose of the drug which kills 50% of treated animals within a specified short amount of time
describe what is involved in single dose studies/acute toxicity studies
- effect of single dose
- carried out on 2 different animal species
- effects of dose observed for 14 days with any mortality recorded
- morphological, biochemical, pathological and histological changes are investigated
describe what is involved in repeated dose/ sub acute or chronic studies
- 2 mammalian species
- long duration of studies
- dose is dependent on dose escalating studies
- high dose 10x max clinical dose
- low dose 2x clinical dose - drug administered by clinical route
- behavioural, physiological, biochemical and histological parameters monitored
what are local toxicity studies and give examples
- route of administration dependent
- eg. dermal toxicity studies- local signs (oedema), histological studies
- eg. parenteral drugs- IV, IM, SC, ID
- sites of injection examined
give examples of allergenicity/hypersensitivity toxicological studies
- guinea pig maximisation test- evaluation of erythema and oedema and determination of max non irritant or minimum irritant dose
- local lymph node assay- drug given on mouse ear skin
- 5 days treatment followed by auricular lymph node dissection
what are carcinogenicity studies
- lifetime bioassays
- drug used for >6 months or frequent intermittent use for chronic diseases
- chemical structure of drug indicates carcinogenic potential
- therapeutic class of drugs which have produced positive carcinogenicity
what are the clinical signs of toxicity
- respiratory- dyspnea, abnormal breathing
- motor activity- ataxia, tremors
- reflexes- pineal, light
- ocular signs
- CV signs- bradycardia
- autonomic signs
- other signs- salivation, GIT signs
what are the 2 categories of preliminary toxicity testing
- NOAEL- no observed adverse effects level
- highest concentration that doesnt produce toxic response - LOAEL- lowest observed adverse effects level
- lowest concentration that produces a toxic response
describe how NOAEL is used
- determine NOAEL
- convert to a human equivalent dose (HED)
- adjust for anticipated exposure in humans
- adjust for interspecies difference in affinity and potency - apply a >10 fold safety factor
explain how to convert NOAELs to HED
- based on body surface area
HED (mg/kg)= NOAEL (mg/kg) x animal Km/human Km
- Km= body weight kg/m2
what is the therapeutic index
the ratio of the dose of the drug that produces an unwanted effect to that producing a therapeutic effetc
what can be used to identify target related safety
- tissue distribution- if target is highly expressed in organs other than those intended for therapeutic modulation
- KO animals- phenotypes observed in genetically manipulated animals are valuable in identifying potential issues
- siRNA approach- silencing the target in specific organs can identify toxicities
- inactive enantiomers- determines that the target is the cause of toxicity
what can be used to identify chemistry related safety
- chemical series- identify structural features associated with adverse effects
- metabolites- is the drug metabolised into a chemical that causes adverse effects
- isomers- does the drug have an isomer which shows the same toxicity
- impurities
what physiological parameters can be used to identify clinical monitoring of potential adverse effects
- adverse effects in animals for specific organs
- tissue expression of target
- target itself
describe what is involved in hazard integration and risk assessment
- regarding patient safety
- comorbidities, medications, age - risk vs benefit
