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PY367 Licensing a new drug > Pharmacological and toxicological profiling > Flashcards

Pharmacological and toxicological profiling Flashcards

1
Q

what can molecular biology, in vitro studies and computer technology not do

A
  1. integrate response- molecule to man
  2. reveal the unexpected
  3. determine therapeutic index
  4. assess importance of multiple mediators
  5. determine pharmacokinetics
  6. assess safety and toxicology
  7. set clinical dose range
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2
Q

what is pharmacodynamics

A
  1. the study of biochemical and physiochemical effects of drugs
  2. infomation obtained includes
    - lead optimisation: improve target specificity and selectivity
    - efficacious dose range and therapeutic window
    - specificity
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3
Q

what is pharmacokinetics

A

the determination of the fate of substances administered externally to a living organism
- ADME

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4
Q

what is absorption and how does it vary

A
  1. process by which drug proceeds from site of administration to site of measurement in body
  2. varies due to administration
    - IV drug is immediate and complete
    - oral drug is delayed and incomplete
  3. relies on passage through membranes to reach blood
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5
Q

what is distribution determined by

A
  1. partitioning across various membranes
  2. binding to tissue components
  3. binding to blood components
  4. physiological volumes
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6
Q

what is metabolism determined by

A
  1. location of metabolism enzymes
  2. 1st pass metabolism
  3. induction of drug metabolising enzymes
  4. development of prodrug
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7
Q

what is elimination and how does it occur

A
  1. either by excretion unchanged or drug metabolites excreted
  2. drug metabolism is associated with a chemical modification of the drug with the overall goal of getting rid of the drug
  3. main process by which body eliminates unwanted substances
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8
Q

what is toxicology

A

concerned with the adverse effects of chemicals on living organisms

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9
Q

what does a toxicological profile consist of

A
  1. single dose toxicity
  2. repeat dose toxicity
  3. genotoxicity
  4. carcinogenicity
  5. reproductive and developmental toxicity
  6. local tolerance
  7. environmental issues
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10
Q

outline the molecular mechanisms of toxicity

A
  1. allergic response- can lead to anaphylactic shock, deplete blood cell types
  2. receptor, ion channel and enzyme mediated- animal toxins can block ion channels
  3. biochemical pathways- inhibition of mitochondrial function
  4. organ directed toxicity- hepatotoxicity, nephrotoxicity
    - changing glomerular filtration rate
  5. mutagenesis and carcinogenesis
  6. teratogenicity- thalidomide
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11
Q

what is involved in preliminary toxicity testing

A
  1. maximum non toxic dose given for 28 days to 2 species before tissue damage assessment
  2. LD50 test- the dose of the drug which kills 50% of treated animals within a specified short amount of time
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12
Q

describe what is involved in single dose studies/acute toxicity studies

A
  1. effect of single dose
  2. carried out on 2 different animal species
  3. effects of dose observed for 14 days with any mortality recorded
  4. morphological, biochemical, pathological and histological changes are investigated
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13
Q

describe what is involved in repeated dose/ sub acute or chronic studies

A
  1. 2 mammalian species
  2. long duration of studies
  3. dose is dependent on dose escalating studies
    - high dose 10x max clinical dose
    - low dose 2x clinical dose
  4. drug administered by clinical route
  5. behavioural, physiological, biochemical and histological parameters monitored
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14
Q

what are local toxicity studies and give examples

A
  1. route of administration dependent
  2. eg. dermal toxicity studies- local signs (oedema), histological studies
  3. eg. parenteral drugs- IV, IM, SC, ID
    - sites of injection examined
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15
Q

give examples of allergenicity/hypersensitivity toxicological studies

A
  1. guinea pig maximisation test- evaluation of erythema and oedema and determination of max non irritant or minimum irritant dose
  2. local lymph node assay- drug given on mouse ear skin
    - 5 days treatment followed by auricular lymph node dissection
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16
Q

what are carcinogenicity studies

A
  1. lifetime bioassays
  2. drug used for >6 months or frequent intermittent use for chronic diseases
  3. chemical structure of drug indicates carcinogenic potential
  4. therapeutic class of drugs which have produced positive carcinogenicity
17
Q

what are the clinical signs of toxicity

A
  1. respiratory- dyspnea, abnormal breathing
  2. motor activity- ataxia, tremors
  3. reflexes- pineal, light
  4. ocular signs
  5. CV signs- bradycardia
  6. autonomic signs
  7. other signs- salivation, GIT signs
18
Q

what are the 2 categories of preliminary toxicity testing

A
  1. NOAEL- no observed adverse effects level
    - highest concentration that doesnt produce toxic response
  2. LOAEL- lowest observed adverse effects level
    - lowest concentration that produces a toxic response
19
Q

describe how NOAEL is used

A
  1. determine NOAEL
  2. convert to a human equivalent dose (HED)
    - adjust for anticipated exposure in humans
    - adjust for interspecies difference in affinity and potency
  3. apply a >10 fold safety factor
20
Q

explain how to convert NOAELs to HED

A
  1. based on body surface area
    HED (mg/kg)= NOAEL (mg/kg) x animal Km/human Km
    - Km= body weight kg/m2
21
Q

what is the therapeutic index

A

the ratio of the dose of the drug that produces an unwanted effect to that producing a therapeutic effetc

22
Q

what can be used to identify target related safety

A
  1. tissue distribution- if target is highly expressed in organs other than those intended for therapeutic modulation
  2. KO animals- phenotypes observed in genetically manipulated animals are valuable in identifying potential issues
  3. siRNA approach- silencing the target in specific organs can identify toxicities
  4. inactive enantiomers- determines that the target is the cause of toxicity
23
Q

what can be used to identify chemistry related safety

A
  1. chemical series- identify structural features associated with adverse effects
  2. metabolites- is the drug metabolised into a chemical that causes adverse effects
  3. isomers- does the drug have an isomer which shows the same toxicity
  4. impurities
24
Q

what physiological parameters can be used to identify clinical monitoring of potential adverse effects

A
  1. adverse effects in animals for specific organs
  2. tissue expression of target
  3. target itself
25
Q

describe what is involved in hazard integration and risk assessment

A
  1. regarding patient safety
    - comorbidities, medications, age
  2. risk vs benefit

PY367 Licensing a new drug (9 decks)

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