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Medsci 204 > 20 & 21: Toxicity and Adverse Drug Reactions > Flashcards

20 & 21: Toxicity and Adverse Drug Reactions Flashcards

1
Q

Toxicology is…

A

The study of adverse effects that are detrimental to either the survival or normal functioning of the individual

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2
Q

What is the top reason for failure in preclinical trials?

A

Toxicology (44.1%)

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3
Q

What is the top reason for failure in phase 1 trials?

A

Clinical Safety (27.9%)

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4
Q

What is the top reason for failure in phase 2 trials?

A

Efficacy (52%)

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5
Q

What is the top reason for failure in phase 3 trials?

A

Efficacy (72.5%)

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6
Q

What is the top reason for failure in registration trials?

A

Clinical Safety and Market Potential (both 30%)

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7
Q

What is Haber’s Rule?

A

C x t = k

  • developed to make ammonia from hydrogen and nitrogen
  • low conc for long time has similar effect to high conc for short time
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8
Q

What is one way that they predict toxicity?

A

in silico testing - which is cheap and very fast

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9
Q

What has to be tested for toxicity?

A

In most industrialised countries…

anything from drugs to additives that humans and other living organisms may be exposed to

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10
Q

What type of toxicology tests is there currently a lot of work into developing?

A
  • ones that explain the toxicity of compounds that isn’t seen in preclinical trials
  • ones that predict the toxicity of novel analogues
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11
Q

What should toxicology studies address? (6)

A
  • The injury produced - structural, functional, biochemical
  • The dose-response relationship
  • Mechanism/s of toxicity
  • Factors affecting the toxic response - route of exposure, species/sex, formulation etc.
  • Development of approaches for recognition of toxic responses
  • Reversibility of response - spontaneous (healing), antidotal (treatment)
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12
Q

Which toxic endpoints must be evaluated? (6)

A
  • cytotoxicity
  • systemic toxicity
  • sub-chronic toxicity
  • genotoxicity
  • irritation/intracutaneous reactivity
  • sensitisation
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13
Q

What are the 5 levels of selection in toxicology tests?

A
  • Test species
  • End point
  • Dose
  • Route
  • Duration of test
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14
Q

Wha are some considerations in choosing a test species?

A
  • If they contain the relevant target
  • If they’re subject to diurnal variation
  • Environmental factors
  • The effects of species, strain, gender, age and nutritional status on ADME
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15
Q

What are some possible types of end points?

A
  • Pharmacological
  • Direct toxicity
  • Genotoxicity
  • Immunotoxicity
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16
Q

What are some points that should be investigated to ensure effective, safe dosage?

A
  • dose required to produce pharmacological effect
  • dose required for sub-lethal toxicity
  • lethal dose
17
Q

What are some factors that could influence the shape of dosage curves?

A
  • endogenous factors (genetic polymorphisms)
  • exogenous factors (drug interactions)
  • saturation of biochemical processes that produe toxicant (via metabolism) may result in toxicity plateau
18
Q

What are Acute Toxicity Tests for?

A
  • determine the effects that occur within a short period after dosing
  • usually only use a singular dose, possibly by different routes
    => in the past were used for dose-response relationships and LD50 determination
19
Q

What is the therapeutic index?

A

TI = LD50 / ED50

Ratio of doses required to produce a toxic and a desired response

Larger the number, safer the compound - over 10 safe

No longer used

20
Q

What do Sub Acute Toxicity Tests involve?

A
  • involve animal exposure for 28-90 days
  • frequent exposure (daily)
  • information on target organs and major toxic effects
  • effects with slow onset detected
  • may indicate development of pathological lesions
  • survivors undergo complete necroscopy
  • blood chemistry, urinalysis and haematology on all ill animals
  • aids in design of chronic toxicity tests
21
Q

What do Chronic Toxicity Tests involve?

A
  • involve lifetime exposure of animals to compound
  • changes in weight and food/water intake and clincal measurements made
  • choise of dose, species, strain, route (usually in food) are all influenced by type of chemical and regulations
  • often rats and dogs
  • Rats - about 50 male and female in a group, 100 control
  • Dogs - about 10 male and female in a group
22
Q

Why are mechanistic studies important?

A
  • they can identify moieties in the pructure that may be toxic
  • elucidation of toxic mechanisms may help characterise pathways or help in deisgn of new classes of drugs - e.g. stropine from deadly nightshade can be exploited therapeutically in the right doses
23
Q

Why can human insulin not be studied in animals?

A
  • there is no effect because it is metabolised too quickly
24
Q

Why can peptides not be tested in animals?

A
  • they are designed to target human DNA, so animal testing wouled be irrelevant
25
Q

What is the chance that a patient will get an adverse drug reaction in hospital and what effects this chance?

A
  • 1-44%
  • type of hospital
  • classification of ADR
  • reporting method
  • condition of the patient
  • hospital has newer drugs than GP, and uses multiple
26
Q

How many ADR are due to pharmacological responses?

A

80%

27
Q

What are some non-pharmalogical targets that drugs or their metabolites interact with to cause ADR?

A
  • proteins - inhibition etc. - reversible
  • lipids - may dissolve in, can disrupt ion channels
  • DNA - may have mutagenic/carcinogenic properties - irreversible
28
Q

Aspirin toxicity is…

A
  • dose dependent
  • predictable
  • relatively common
29
Q

Why can NSAIDs cause GI toxicity?

A
  • chronic COX inhibition (although not completely due to this) which only occurs through oral administration - can be avoided by bypassing the GI tract
  • inhibition of COX serious as some prostaglandins are cytoprotective and initial lesion results in overt damage
  • interaction with phsophotidyl choline, reducing ability of gastric mucosa to protect from HCl etc
30
Q

What can the formation of toxic metabolites influenced by?

A
  • dose

- inter-individual variability in enzyme expression/pharmacokinetic interactions

31
Q

Paracetamol

A
  • toxic due to saturation of detoxification pathways
  • some dose-dependency and predictability
  • toxic metabolite = a quinoneimine, can react with sulfhydryl groups in critical cellular proteins
  • loss of intracellular calcium regulation disrupts mitochondrial function and leads to necrotic cell death
  • risk low if taken in small doses as recommended and sparingly.

Medsci 204 (2 decks)

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