1: Clinical Pharmacokinetics 2 Flashcards
what are the three components of renal clearance?
CLrenal = filtration + secretion - reabsorption
what is a normal GFR?
120 mL/min
what types of drugs are filtered by the glomerulus?
only unbound drugs
what are two markers for GFR?
creatinine and inulin
- unbound to plasma proteins
- neither secreted nor absorbed
- about 100 mL/min
renal clearance and dosage adjustment + corrected dose equation
renal disease often changes drug clearance -> this can be used to adjust dose to maintain the Css
corrected dose= avg dose (pt CLcreatinine/ 100 ml/min)
when do you adjust dosages?
only when drug is >50% cleared by renal elimination and renal fxn is reduced to 50% or less of normal
first order elimination
- constant % of drug eliminated/time
- when drug dose increases, Css increases proportionately
- how 95% of drugs work
- accumulation + elimination change exponentially for a single dose over time
- linear Cp accumulation with increase in dose
zero order elimination
- constant amount of drug eliminated/time
- ER same regardless of [C]
- linear decrease in [C] over time
- non-linear Cp accumulation with increase in dose
Michaelis-Menton kinetics: rate of elimination
= (Vmax x C)/(Km + C)
definition of Km
[drug] at 50% of Vmax
-measure of the affinity of the substrate for the enzyme
definition of half life
time it takes to eliminate 50% of the drug from the body - only applies to first order drugs
what is the elimination rate constant?
K or Ke - fraction of Vd elimination remains constant per unit time
equation for half life
= 0.693/ Ke = (0.693 x Vd)/ CL
is half life dependent on concentration?
newp
describe the accumulation and elimination of a drug according to half-lives
95% of final accumulation plateau reached after 4.5x
95% of total dose eliminated after 4.5x
why is half life important? (3 reasons)
- determine time to reach Css
- determine duration of action
- determine proper dosing frequency to avoid large fluctuations in Cp
how will doubling the dose administered change the duration of action?
increases duration by one half life
one compartment model: Vd with elimination
- equation for Vd
- assumptions
Vd = dose/Co
Assumptions:
- FIRST ORDER
- body is ONE homogeneous compartment
- instantaneous mixing
two compartments: Vd distribution without elimination
- distribution b/w compartments slower than distribution within each compartment
- distribution phase typically
two compartments: Vd distribution with elimination
-distribution to 2nd compartment slower than distribution w/i 1st compartment
two compartment model assumptions
- FIRST ORDER
- instant mix in ‘each’ compartment
- slower mix ‘between’ compartments
designing dose regimens for i.v. vs p.o: DR
iv: DR = (CL)(Css)
po: DR = (CL x Css)/F
designing dose regimens for i.v. vs p.o: loading dose
iv: loading dose = (Vd)(target Cp)
po: loading dose = (Vd x target Cp)/F
designing dose regimens: therapeutic window at different values of half life
- if dosing interval = t1/2, Cmax/Ctrough = 2
- if dosing interval t1/2, Cmax/Ctrough > 2 (may exceed therapeutic window)
equation to adjust dosage regimen
new rate = (old rate)(desired Css/ measured Css)
what is the purpose of therapeutic drug monitoring?
use Cp to:
- individualize dose
- predict effect
- diagnose toxicoses
what kinds of drugs are monitored?
- marked PK variability
- narrow therapeutic window
- therapeutic and AE related to [drug]
- desired therapeutic effect difficult to monitor
- inter-individual variation in PK parameters
