lecture 6 Flashcards
i’m vivo pharmacology uses
animal models
what research is in vivo pharmacology
ADME research
activity
adsorption
metabolism
excretion
list the 10 in vivo pharmacology toxicology tests
- acute toxicity
- synchronic toxicity
- chronic toxicity
- reproductive toxicity
- immunotoxicity
- pharmacokinetics
- in vitro permeation studies
- in vivo adsorption studies
- pharmacology
- irritation + sensitisation
what is pharmacokinetics
where u determine concentration profiles + the drugs fate in the body
what is pharmacodynamics
examining the effect of the drug on the body
what must be done in order to accelerate the drug discovery program
u must identify the most appropriate in vivo pharmacology solution
the reason ppl study the in vivo PK-PD relationship is to:
-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
in vivo PK studies are extremely
interdisciplinary
interdisciplinary meaning
the info from PK studies are related to a bunch of different branches
properly executed PK-PD studies require a team of experts in what fields
- 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
PD is the
drugs affect on the body
PK is the
fate of the drug in the body
+ conc profiles
PD memory
D == what the drug is doing to the body + it’s effects
PK memory
Killed = it’s fate
the fate of the drug in the body
what percentage of the animal models are rats or rodents
90%
why are rodents used as majority of the animal models
- short lifecycle and lifespan
- low cost + time saving + reproduce faster
- small size so smaller dose
- genesfor diseases with human origin have counterparts in rodents
why are rodents sometimes not used
- 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.
what larger animals are usually used in animal models
dogs
what influences the selection of certain species+ what effect does this have
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)
animal models must have what in relation to the human disease
they must recapitulate all aspects of it
must have the genes and the genotype
- they must be able to replicate the human symptoms
what is the new animal model
zebra fish
why are zebra fish being used as new animal modes
- 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
is the body an in vivo or in vitro system
in vivo
the body in vivo system consists of what
inflow (absorption)
outflow (clearance)
of drugs
what do prospective drugs require
a minimal set of physiochemical properties
do we know the conc of a drug in in vitro
yesss
bc the drug is confined to a known volume
when are measurements taken in in vitro
after a steady state / equilibrium has been attained
amount plotted against time ( rises then plateaus)
is in vitro an open or closed system
closed
why is in vitro conc measurement critical
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)
is in vivo a closed or open system
open
i’m in vivo: days describing potency is associated with what
it’s associated with time
as we do not know the amount of drug in a certain volume, we dk it’s concentration
graph for in vivo
amount against time
rises, reaches a peak then falls once again.
what is the C max
max peak concentration of a drug in the bloodstream after a dosing regime
C min
the min concentration of a drug observed in the central compartment during repeated doses
what is the extraction ratio
ratio of the drug quantity entering the body and the drug quantity flowing into a removal organ (liver)
MRSD
maximum recomm need starting dose at the beginning of clinical trials
NOAEL
no observed adverse effect level for a drug
NOEL
no observed effect level for a drug
T
dosage interval
period between doses on a repeating doses study
volume of distribution meaning
movementof drug from intravascular compartment (blood plasma) to extravascular (intercellular + extracellular) compartments in the body
what can the volume of distribution be used to see
detects small portions of the drug in different areas of the body
what is the central compartment
the blood stream
is the body an equilibrium or a non equilibrium system
non equilibrium
how is the body a non equilibrium system
there is no time for an equilibrium to occur
drugs enter and are removed at a certain rate
what is meant by drug clearance
the removal of a drug from the body
what organs can clear drugs from a body
liver
kidney
brain
sweat glands
lungs 🔺🔺
the organs that can clear drugs from the body, excluding the lungs are seen as
processes connected in parallel
drugs administered orally undergo ebay metabolism
FIRST PASS METABOLISM
what is first pass metabolism
process that happens to orally administered drugs
- absorption from the gastrointestinal tract + then being moved to the liver via the portal vein
first pass metabolism memory
1st = mouth bc most preferred
absorption
gastrointestinal tract , portal vein, liver
why are drugs being administered orally a problem for pharmacokinetics
- the drugs fate
bc they bioavailability is not 100
what is bioavailability
the % of the administered drug that reaches the systemic circulation
what bioavailability score is the best
100!!
high values are better
means they’re more available
more drug available to reach the target
what administration leads to a bioavailability of 100
INTRA VENOUSLY administered drugs
these are not oral
why do orally administered drugs have a lower bioavailability compared to intra venously administered drugs
- intestinal epithelium absorption
- first pass metabolism: wich reduces the conc of the active drug before it gets to the target or the systemic circulation.
what organ is the main site of the first pass effect
the liver
it can still occur in the lungs or any other metabolically active tissue
what is the bioavailability value and how is it reported
its an avergage value
it varies between the human polulation
its reported using a range of deviations +-
what is F
oral bioavailability
total fraction of a drug that enters the central compartment when administered orally
whats is Fabs
the fraction of the drug thats absorbed
what is Fesc
fraction of drug that escapes// isnt metabolised by the passage in the liver
equation to find F
F = Fabs x Fesc
total % entering the central compartment after being taken orally = % absorbed x % that escaped metabolism
high F value eg
50% or more
medium F value
25 - 50
low F value
25%
how else can we determine F
assessing area under the conc-time curve for intravenous drugs vs oral drugs
F = AUC oral / AUC iv
where does first pass metabolism occur
gut wall or liver
prevents oral drugs from reaching the systemic circulation along with incomplete absorption
which drugs usually have very low oral availability
common drugs like insulin which would be broken down by gastric acid.
what happens when a common drug has very low oral abailability
it must be administered using other routes
how are drugs that arent administered orally cleared??
cleared by the heptatic or renal system
which organ clears non polar drugs
liver
the efficiency of the liver being a removal organ can be expressed using what ratio
the EH ratio
extraction ratio
what is the EH ratio
way of expressing how good the liver is at clearing
EH ratio
extraction ratio
EH = 1- [out] / [in]
answer = amount of drug metabolised by the liver
what is clearence
the rate of complete cleansing of a given volume of body water per unit time
time it takes to clean xxx units of water
