Pharmacokinetics Flashcards
Pharmacokinetics
study of time-dependence of drug metabolite concentrations in blood and body fluids (getting does to site of action)
abosorption if IV
no absorption if IV bc already in blood
main ways to excrete drug
liver (metabolism)
kidney (excretion)
course of drug
moves from site of administration -> blood -> distributes and move out of blood and equilibrate in diff tissues
dilution of drug
depending on how far it distributes, further the drug goes the larger the value
single-dose time course
- steep when absorbing in blood then maxs out at level lower than dose because starts getting eliminated once its in blood then down slope where no more ot absorb only toelimiate
- log is linear when purely elimination
time course of serum drug concentration
drug is eliminated by half lives; goal is to keep dose at therapeutic level but below toxic level
important clinical factors from concentration time courses
- Concentration required to produce response (Therapeutic level)
- Time of onset of response
- Duration of response
basic parameters of pharmacokinetsic
- apparent volume (Vd)
- half life (T1/2)
- Clearance (Cl)
apparent volume of distribution (Vd)
volume of fluid drug would occupy if evenly distributed through that volume at the concentration measured in plasma
can be recognizable volume or unreal volume
Vd formulas
C= D/Vd Vd= D/C
D- dose
C- plasma concentration
recognizable volume
- plasma volume (0.05 L/kg)
- extracellular fluid (0.2 L/kg)
- total body water (0.6 L/kg)
unreal volume
one intermediate between recognizable volumes; Vd can also exceed total body volume when preferential binding to tissues at expense of plasma (often to fat)
get drug into blood it will distribute
at least into interstitial fluid and when drug in interstitial fluid it decreases concentration in blood; can distribute into interstitial fluid, extracell space, intracell space, tissues (often lipids)
half life
time it takes for drug concentration to decline by 50% in most cases half life is same regardless of dose or plasma concentration (always true for 1st order elimination)
- t1/2 inversely related to rate constant of elimination ke
- rarely absolute constant bc affect by physiologic, pathologic, and environmental factors
clearance
- Cl
- rate of elimination relative to plasma concentration
- units: ml/ min/ kg or ml/min
- can estimate by measuring steady-state concentration fo drug during constant-rate intravenous infusion
- defined as volume of fluid cleared of the drug per unit of time to account for observed rate of elimination
Clearance formulas
Cl= rate of elimination/ C Rate of elimnation= Cl * C Cl= X/Css C= concentration X= constant-rate intravenous infusion Css= steady-state concentration
with first order elimination clearance
clearance related to rate constant of eliminated and apparent volume of distribution and can be calculated from area under curve of single-dose time course
Cl=KeVd= 0.693Vd/T1/2
Cl= D/ AUC
AUC= D/Cl
AUC= area under curve
mathematic basis pharmacokinetics is
one-compartment model
dose (not IV) -> site of administration -> absorption (Ka) -> Volume Vd (Central Compartment) -> elimination (excretion and metabolism)
Or
IV dose -> volume Vd (central compartment) -> elimination (excretion plus metabolism)
C(t)
plasma concentration as function of time
ke
rate constant of elimination
ka
rate constant of absorption
D
dose
f
bioavalibity = relationship between dose you give and dose that gets into blood
1 if given IV
<1 if given by another way
divide dose by Vd
gives C
on compartment model with no elimination
Ao= [D/Vd] Ke= 0 t1/2= infinity Ka= 6.93/hr D= 1mg/kg Vd= 0.2L/kg this is unrealistic bc body always trying to get rid of stuff curve steep slope up to plateau at top of curve
one compartment model with IV injection
Ka= infinity T1/2= .5hrs D= 1mg/kg Vd= 0.2 L/kg Ke= 1.39 hours graph starts at max plasma concentration then nice C shaped curve of decreasing concentration
time curve with absorption and elimination
d= 1mg/kg Vd= 0.2 L/Kg F=1 Ka= 6.93/hr Ke= 1.39/hr T1/2= 0.5 Curve: steep slope up hits peak around 4.00 then C shape down
Two compartment model
Iv dose -> central compartment -> Elimination
OR
Central compartment -> interstitial fluid -> intracellular space
- movement back and forth (equilibrium) between central compartment and interstitial fluid and intracellular space and interstitial fluid
- most drugs once into central compartment do rapid distribution and cross into interstitial fluid can pass through lipids go into intracellular space
Two compartment time course linear plot
steep diagonal line down at beginning than less steep diagonal line down
two compartment time course log plot
rapid phase = redistribution = steep pt at beginning than slope less steep (slow phase= elimination)
First-order elimination kinetics
- Ke units measured in min^-1
- exponential decrease in plasma concentration
- with iv administration and increasing dose: peak highest with high does; independent of dose gone almost at same time bc rate elimination is higher if higher concentration bc T1/2 so no matter what dose drug essentially gone in same time
Zero-order elimination
- linear decrease of plasma concentration bc saturation of metabolizing enzymes or eliminating transporters
- with IV administration and increasing dose
- comes about with elimination by metabolism like liver enzyme bc only have so many liver enzymes and can only eliminate certain # mg/ min not fraction/min
- anytime protein is involved only so many of them and you can fill them up rate becomes mg/ min not fraction. min
- rate becomes exponential once you have enough enzymes avalailable for all molecules you’re breaking donw
- this is how alchohol works
- some individuals have more enzymes than others which -> higher rate of break down
- graph horizontal lines slanted diagnollay go further on time axis if start higher on blood concentration axis
first-order absorption
- from site of administration
- exponential increase in plasma concentration (units of Ka are min^-1)
intravenous injection (kinetics of absorption)
- Ka-> infinity
- instantaneous increase in plasma concentration
- starts at D/Vd and drops exponentially
zero-order absorption
- intravenous infusion: CRI= constant rate infusion
- constant rate of infusion, units are mg/min
zero order absorption with no elimination
- linear increase in blood concentration
- 0 order bc mg/min= CRI= no elimination
- curve = linear increase in old concentration
- w/ constant rate infusion start w/ blood concentration increase then rate infusion balanced by rate infusion
zero order absorption with first-order elimination
- It can be shown that the time course for reaching steady state with constant infusion is a function of infusion rate (= dose rate=DR) and rate constant of elimination (ke)
increasing the dose rate
- increases steady state level but does not affect time to reach steady state
- time to reach steady state determined only by rate constant of elimination
time to reach steady state
determined only by the rate constant of elimination
- rise dependent on rate constant of elimination NOT on rate of infusion concentration determined by rate constant infusion
t1/2 getting to steady state=
t1/2 getting to elimination
decreasing rate constant of elimination
- increasing elimination half life
- increases both steady-state level and time to reach steady state
- decrease in rate constant of elimination causes a proportional increase in steady-state concentration
eliminate slower = ___ steady state
eliminated slower= greater steady state but takes longer to get there (slower elimination = longer it takes to reach steady state)
decrease in rate constant of elimination causes
a proportional increase in steady state concentration
first order elimination time to reach steady state determined by
elimination half life; t1/2 to reach steady state is equal to t1/2 of elimination
t1/2 to reach steady state is
equal to t1/2 of elimination; if you know elimination half life of drug you can estimate the time it will take to reach steady state
longer half life means ____ steady state level
longer half life means higher steady state level
try to mimic constant infusion when
trying to get steady state try to mimic constant infusion using multi dose infusions (give intermittent constant dose rate not continuous) if know t1/2 know how long you wait to reach steady state
for steady state concentration and clearance for constant infusion
steady state plasma concentration (Css) can be shown to be:
Css= Dose rate/ keVd = Dose rate/ Cl
KeVd=
clearance (cl)
since KeVd = Cl
steady state concentration is directly proportional to dose rate and inversely proportional to clearance and Ke
rate constant of elimination (ke) inversely related to
t1/2 of elimination (ke=0.693/t1/2) and therefore:
Css= dose rate * t1/2 / 0.693Vd
Css=
dose rate * t1/2 / 0.693 Vd
