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drug discovery > lecture 6 > Flashcards

lecture 6 Flashcards

1
Q

i’m vivo pharmacology uses

A

animal models

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2
Q

what research is in vivo pharmacology

A

ADME research

activity
adsorption
metabolism
excretion

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3
Q

list the 10 in vivo pharmacology toxicology tests

A
  • acute toxicity
  • synchronic toxicity
  • chronic toxicity
  • reproductive toxicity
  • immunotoxicity
  • pharmacokinetics
  • in vitro permeation studies
  • in vivo adsorption studies
  • pharmacology
  • irritation + sensitisation
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4
Q

what is pharmacokinetics

A

where u determine concentration profiles + the drugs fate in the body

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5
Q

what is pharmacodynamics

A

examining the effect of the drug on the body

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6
Q

what must be done in order to accelerate the drug discovery program

A

u must identify the most appropriate in vivo pharmacology solution

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7
Q

the reason ppl study the in vivo PK-PD relationship is to:

A

-make quantitative analysis of the dose response relationship
- describe + predict the time course effects resulting from drug doses
- observe how much the target must be modulated in order to observe statistically significant efficacy
- identify a efficacious dosing regime with an acceptable therapeutic index

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8
Q

in vivo PK studies are extremely

A

interdisciplinary

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9
Q

interdisciplinary meaning

A

the info from PK studies are related to a bunch of different branches

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10
Q

properly executed PK-PD studies require a team of experts in what fields

A
  • establishing the most appropriate animal model
  • animal dosing and handling
  • measuring efficacy in different models
  • identifying the most appropriate PD readout for the drug + model tested
  • design quantitative PD assays
  • measure drug conc in different tissue matrices.
  • evaluate and analyse and the PK data
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11
Q

PD is the

A

drugs affect on the body

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12
Q

PK is the

A

fate of the drug in the body
+ conc profiles

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13
Q

PD memory

A

D == what the drug is doing to the body + it’s effects

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14
Q

PK memory

A

Killed = it’s fate

the fate of the drug in the body

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15
Q

what percentage of the animal models are rats or rodents

A

90%

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16
Q

why are rodents used as majority of the animal models

A
  • short lifecycle and lifespan
  • low cost + time saving + reproduce faster
  • small size so smaller dose
  • genesfor diseases with human origin have counterparts in rodents
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17
Q

why are rodents sometimes not used

A
  • larger animals are used for longitudinal studies as they live longer
  • more similar in size to humans allowing us to address issues relating to scaling up to human therapy.
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18
Q

what larger animals are usually used in animal models

A

dogs

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19
Q

what influences the selection of certain species+ what effect does this have

A

their maintenance
harder to maintain = less likely to be used

this limits the accuracy of results (hard to scale up to human therapy when small animals are used)

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20
Q

animal models must have what in relation to the human disease

A

they must recapitulate all aspects of it
must have the genes and the genotype
- they must be able to replicate the human symptoms

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21
Q

what is the new animal model

A

zebra fish

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22
Q

why are zebra fish being used as new animal modes

A
  • see through bodies; we can follow the drug
  • similar metabolic characteristics to humans
  • make many embryos allowing us to have optical clarity over the developing embryo
  • used for genetic mutant + therapeutic screening
  • CRISPR : using zebra fish is accelerating our understanding of the molecular mechanisms of human genetic diseases
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23
Q

is the body an in vivo or in vitro system

A

in vivo

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24
Q

the body in vivo system consists of what

A

inflow (absorption)
outflow (clearance)
of drugs

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25
Q

what do prospective drugs require

A

a minimal set of physiochemical properties

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26
Q

do we know the conc of a drug in in vitro

A

yesss
bc the drug is confined to a known volume

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27
Q

when are measurements taken in in vitro

A

after a steady state / equilibrium has been attained

amount plotted against time ( rises then plateaus)

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28
Q

is in vitro an open or closed system

A

closed

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29
Q

why is in vitro conc measurement critical

A

bc we know the conc of the drug

critical bc all measurements of drug activity is based on its concentration when an effect is observed ( potency, efficacy + affinity)

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30
Q

is in vivo a closed or open system

A

open

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31
Q

i’m in vivo: days describing potency is associated with what

A

it’s associated with time
as we do not know the amount of drug in a certain volume, we dk it’s concentration

32
Q

graph for in vivo

A

amount against time
rises, reaches a peak then falls once again.

33
Q

what is the C max

A

max peak concentration of a drug in the bloodstream after a dosing regime

34
Q

C min

A

the min concentration of a drug observed in the central compartment during repeated doses

35
Q

what is the extraction ratio

A

ratio of the drug quantity entering the body and the drug quantity flowing into a removal organ (liver)

36
Q

MRSD

A

maximum recomm need starting dose at the beginning of clinical trials

37
Q

NOAEL

A

no observed adverse effect level for a drug

38
Q

NOEL

A

no observed effect level for a drug

39
Q

T

A

dosage interval
period between doses on a repeating doses study

40
Q

volume of distribution meaning

A

movementof drug from intravascular compartment (blood plasma) to extravascular (intercellular + extracellular) compartments in the body

41
Q

what can the volume of distribution be used to see

A

detects small portions of the drug in different areas of the body

42
Q

what is the central compartment

A

the blood stream

43
Q

is the body an equilibrium or a non equilibrium system

A

non equilibrium

44
Q

how is the body a non equilibrium system

A

there is no time for an equilibrium to occur

drugs enter and are removed at a certain rate

45
Q

what is meant by drug clearance

A

the removal of a drug from the body

46
Q

what organs can clear drugs from a body

A

liver
kidney
brain
sweat glands
lungs 🔺🔺

47
Q

the organs that can clear drugs from the body, excluding the lungs are seen as

A

processes connected in parallel

48
Q

drugs administered orally undergo ebay metabolism

A

FIRST PASS METABOLISM

49
Q

what is first pass metabolism

A

process that happens to orally administered drugs

  • absorption from the gastrointestinal tract + then being moved to the liver via the portal vein
50
Q

first pass metabolism memory

A

1st = mouth bc most preferred
absorption
gastrointestinal tract , portal vein, liver

51
Q

why are drugs being administered orally a problem for pharmacokinetics

A
  • the drugs fate

bc they bioavailability is not 100

52
Q

what is bioavailability

A

the % of the administered drug that reaches the systemic circulation

53
Q

what bioavailability score is the best

A

100!!

high values are better
means they’re more available
more drug available to reach the target

54
Q

what administration leads to a bioavailability of 100

A

INTRA VENOUSLY administered drugs

these are not oral

55
Q

why do orally administered drugs have a lower bioavailability compared to intra venously administered drugs

A
  • intestinal epithelium absorption
  • first pass metabolism: wich reduces the conc of the active drug before it gets to the target or the systemic circulation.
56
Q

what organ is the main site of the first pass effect

A

the liver

it can still occur in the lungs or any other metabolically active tissue

57
Q

what is the bioavailability value and how is it reported

A

its an avergage value
it varies between the human polulation

its reported using a range of deviations +-

58
Q

what is F

A

oral bioavailability

total fraction of a drug that enters the central compartment when administered orally

59
Q

whats is Fabs

A

the fraction of the drug thats absorbed

60
Q

what is Fesc

A

fraction of drug that escapes// isnt metabolised by the passage in the liver

61
Q

equation to find F

A

F = Fabs x Fesc

total % entering the central compartment after being taken orally = % absorbed x % that escaped metabolism

62
Q

high F value eg

A

50% or more

63
Q

medium F value

A

25 - 50

64
Q

low F value

A

25%

65
Q

how else can we determine F

A

assessing area under the conc-time curve for intravenous drugs vs oral drugs

F = AUC oral / AUC iv

66
Q

where does first pass metabolism occur

A

gut wall or liver

prevents oral drugs from reaching the systemic circulation along with incomplete absorption

67
Q

which drugs usually have very low oral availability

A

common drugs like insulin which would be broken down by gastric acid.

68
Q

what happens when a common drug has very low oral abailability

A

it must be administered using other routes

69
Q

how are drugs that arent administered orally cleared??

A

cleared by the heptatic or renal system

70
Q

which organ clears non polar drugs

A

liver

71
Q

the efficiency of the liver being a removal organ can be expressed using what ratio

A

the EH ratio
extraction ratio

72
Q

what is the EH ratio

A

way of expressing how good the liver is at clearing

73
Q

EH ratio

A

extraction ratio

EH = 1- [out] / [in]

answer = amount of drug metabolised by the liver

74
Q

what is clearence

A

the rate of complete cleansing of a given volume of body water per unit time

time it takes to clean xxx units of water

75
Q
A

drug discovery (18 decks)

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