4. Pharmacokinetics Flashcards
what is pharmacokinetics
study of concentration time profile of a drug in the body
what principles does pharmacokinetics encompass and quantitate
absorption
distribution
metabolism
excretion
what does the absorption and elimination look like on the plasma conc over time graph
sharp increase in plasma conc = absorption
elimination so experiences decreases
why do we use plasma conc to measure drug conc
blood moves drug around the body so can assume there is a relationship between the conc of drug in plasma and that in the target receptor
at what state does the plasma conc gives relatively good index of conc at the receptor
steady state
is there more variation between conc and effect or betw dose and effect
more betw dose and effect
what is the conc time curve after oral dosing area signify
extent of absorption of drug
once what limit is reached does the pharmacological response begin
minimum effective conc
what is the difference in the plasma conc time graph for IV and oral delivered drugs
same drug and same dose but give by diff routes
what is the diff is if any with IV and oral for rate of elimination and dose level
oral = initial increase for absorption and decrease as eliminated
IV = all drug enters plasma so no absorption phase and then eliminated from body
oral dose rate of elimination is the same once reached systemic circulation as its the same drug so will be distributed to same compartment and eliminated the same way
not all dose reaches systemic circulation so plasma conc for oral dose is less than that of IV dose
what is the oral bioavailability
not all drug reaches the systemic circulation after oral dosing due to partial absorption and first pass metabolism
what does bioavailibilty reflect
fraction of dose that reaches the systemic circulation
what is the equation for bioavailibility
F = (AUCpo/AUCiv) x (doseiv/dosepo)
ideally F should be what percentage to be given orally
more than 20%
if F is too low what does that indicate
that the drug is ineffective way of delivering drugs
what is AUC po or AUC iv
area under curve
what is the unit for dose
mg
what is the unit for F
%
if you want drug exp to be same for oral and iV, what happens to the bioavailb equation
areas under curve for oral and IV should be equal and therefore =1 so can take that away from equation just to give F=IV dose/oral dose
what parameter is drug distribution defined by
volume of distribution
what is the equation for volume of distribution
VD = amount of drug in body/plasma drug conc
what is the volume of distribution determined by
6 things
body mass and composition tissue blood flow tissue blinding plasma protein binding physico-chem properties of drug natural barriers
how does the tissue binding affect the volume of distribution
tissue binding increases volume of distribution
how does the plasma protein binding affect the volume of distribution
plasma binding limits drug distribution to tissue so has an opposing effect to drug distribution
what is the bathtub model for the volume of distribution
non sponge example
drug fully dissolved and take sample of water and measure drug conc in sample
calculate the volume of distribution using equation
volume of distribution calculated corresponds with the actual volume of water in bathtub
what is the bathtub model for the volume of distribution
sponge example
dissolve drug in same bathtub but this time you take another sample of water and measure conc but this time conc is lower than non sponge example and after the VD equation the volume in bathtub is calculated to be way larger than expected volume
must be something that binds drug and allows drug to hide so isnt measured with recorded (eg 90% bound to sponge so only leaves 10% of dose to be freely measured in water)
large hydrophilic drugs will stay in what volume of fluid in the body
what does that say in terms of volume of distribution
in plasma
expect volume of distribution to be close to value of plasma volume
what does it mean when the volume of distribution is too big
drug is hiding in body where its not recorded and is stored in fat as lipophilic so not circulating in plasma
is the volume of distribution a actual volume
no its a hypothetical
drugs with high molecular weight is restricted to what body fluid compartment
why
bind extensively to plasma proteins and volume of distribution is close to volume of plasma as it is bound to it and cant move out of it
drugs with low molecular weight and hydrophilic is restricted to what body fluid compartment
why
can move out of plasma as capillary are porous but hydrophilic so cant cross cell membrane and limited to extracellular compartment
smaller and larger volume of distribution is more likely to be bound to what compartments
Smaller volume of distribution more likely drug is bound to plasma compartment, larger the volume of distrib means more likely drug us bound to tissues or fat
what is the loading dose
administered to achieve a target conc rapidly
what is the loading dose dependent on
volume of distribution
what does loading dose do to help reach target conc
helps fill volume of distribution faster to rapidly achieve the target conc
the bigger the volume of distribution what happens to the dose req to reach target conc
higher dose
what is the equation for loading dose
loading dose (mg) = VD (L) x target conc (mg/L)
if no loading dose is used, what happens to the VD and time taken to reach target conc
volume takes time to fill up so the larger the VD the longer the time to reach target conc
what is the loading dose usually given as and what effect does this have on target conc
usually given as a IV bolus so that target conc is reached quickly
how is the target conc maintained
by IV infusion but oral loading doses can also be used
what is drug elimination defined by - ie which parameter
clearance
what is clearance
describes relationship between drug conc and rate of elimination of drug from body
what is the clearance equation
clearance (L/h) = elimination rate (mg/h)/conc (mg/L)
clearance = dose/AUC
what is clearance plasma
sum of clearance from individual organ
CLplasma = CLrenal + CLhepatic + CLothers
why is clearance and rate of elimination arent the same
clearance is a unit of flow and elimination describes rate of loss
in the bathtub model what is the equivalent of the clearance and conc of drug in plasma
plughole = clearance
height = conc of drug in plasma
what is the first order process of clearance relationship between rate of elimination and drug conc
what is the assumption
amount of drug eliminated or rate of elimination is proportional to drug conc so there is a linear relationship between rate of elimination and drug conc
in the first order process what happens with higher conc
the higher the conc the more drug is presented to tissues for elimination
is the clearance independent of conc and what does this mean for proportionality
independent
so is proportionality constant = constant value of ratio betw 2 proprtional quantities (rate of elimination and conc)
what is the maintenance dose rate
what does this mean for dose rate and rate of elimination
dose rate to achieve and maintain a target conc = steady state conc
dose rate = rate of elimination
steady state conc can be achieved by what 2 methods
IV infusion or repeated oral dosing
what is the equation for maintenance dose
maintenance dose (mg/h) = clearance (L/h) x target conc (mg/L)
a rapidly cleared drug will need a large/small maintenance dose to keep drug conc at target levels
larger
what is the steady stat conc
when dose rate in equals rate of elimination so no net change in conc
what is the half life of a drug
time required for drug concentration to fall by half
what does the half life of a drug depend on
volume of distribution and clearance
what is the equation for drugs half life
T1/2 = 0.7 x VD/CL
if the half life is known what 2 things can be estimated
how much drug is left in the body
how long it will take to reach steady state
what causes the accumulation of drug
repeated dosing or infusion, drug accumulates in body until input rate = elimination rate
when does steady state occurin terms of accumulation
when drug accumulation is complete and conc have plateaued
the time required to reach steady state is related to what parameter
half life
accumulation >90% is complete after how many half lives
4 half lives
steady state is reached after how many half lives generally
4-5 half lives
if the wait is more than 5 half lives before re administration what happens to drug
drug will not accumulate as most will have been eliminated already
what is needed for the drug conc to increase until it reaches the plateau
continue to administer same dose at every half life time interval
what will happen to the drug in drug accumulation
increase by half
what is the time to reach steady state
can it be be reduced by increasing dose
drug with a long half life will take a long time to reach steady state
cannot be reduced by increasing dose
increasing the dose does what to the steady state and is half life affected
increases steady state conc
half life not affected by dose
what can shorten the time to reach steady state
loading dose
using several loading dose can reach steady state quicker and maintain it by giving continuous infusion following loading doses
time taken to reach steady state is the sum of what
elimination of loading bolus and maintenance infusion
what are the 2 models of pharmacokinetics
1 and 2 compartment models
what are compartment models and why do we use them
time course of drug in body and dictated by processes of ADME
what is the 1 compartment model and what are the assumptions
assume well stirred compartment with instantaneous mixing
linear pharmacokinetics where elimination is a first order process
does the 1 compartment model predict drug conc in tissues of the body, what does it assume and what is the curve shape of it on a graph
Does not predict actual drug conc in various tissues of body but assumes drug conc is proportional that what is measured in plasma
Log linear curve for log conc over time
what is the 2 compartment theory
distribution and elimination
first stage is fast due to instant mixing in central compartments incl tissues that are well perfused followed by slower distribution to other tissue such as muscle/fat
assumes elimination is from drug returned to plasma compartment and delivered to organs that eliminates drugs so this 2nd process is a bit slower
what does the graph look like for the 2 compartment theory
biexponential curve on log scale
