L13, L15- Clinical Pharmacokinetics Flashcards
clinical pharmacokinetics aims to design dosage regimens which…
- optimize therapeutic response of drug
- minimizes adverse reactions of drug
what is the fundamental tenet of clinical pharmacokinetics
there is a relationship between effects of a drug and the [drug] in blood
list and define the 3 important pharmacokinetic parameters
- Volume of Distribution (Vd): measure of apparent space in body to contain blood (theoretical)
- Clearance (CL): ability to eliminate drug
- Bioavailability (F): fraction of drug absorbed into systemic circulation
define Vd (include formula)
- volume required to contain all of the drug in the body at the same concentration as in blood
- V at which [drug] in tissue = [drug] in blood
- not necessarily a possible value
Vd = (amt drug in body) / ([drug] in plasma) = dose / Co
if most of a drug is retained in the vascular compartment, then Vd is (high/low)
if most is in extravascular tissue, then Vd is (high/low)
1- low (more in blood)
2- high (more in tissue)
quinacrine has a (high/low) Vd
High- 50000L in a person with body volume of 70L
used for malarial and tapeworm infections
what is the function of Vd clinically
- allows conversion of concentrations of drugs to actual amounts of drugs
- i.e. Loading Dose
define loading dose
amount/dose of drug needed to quickly achieve target plasma concentration
describe method used to determine Vd (include two phases)
- IV bolus given: log[drug] in plasma plotted vs time
- Phase 1- distribution phase
- Phase 2- elimination phase
- expand line from phase 2 to the y-axis to determine Co
- Vd = dose / Co
describe clearance (and its formula)
- volume of blood cleared of drug per unit time
- CL = (rate of elimination) / ([drug] in plasma)
(T/F) most drugs follow first order kinetics (in terms of CL)
T- rate of elimination is directly proportional to [drug], and a constant fraction is eliminated per unit time
why do most drugs follow first order kinetics (for CL)
the mechanisms of elimination via enzymes/transporters are not saturated
during continuous IV drug infusion, describe the % of Css reached in terms of half-life
(Css = [drug] at steady state] 1 half-life: 50% Css 2: 75% 3: 87.5% 4: 93.75%
Once IV drug infusion has stopped, describe the % of drug lost in terms of half-life
1 half-life: 50% drug lost
2: 75%
3: 87.5%
4: 93.75%
give half-life equation
t(1/2) = (0.693*Vd) / CL
steady-state of a drug is reached after __ half-lives
4 (93.75%)
a drug has been considered successfully eliminated after __ half-lives
4 (93.75%)
how is Css affected by infusion rate
(Css = [drug] at steady state)
- directly proportional
- if infusion rate doubles, Css doubles // if infusion rate id halved, Css is halved
- no effect of time required to reach Css (4 half-lives)
list the 2 factors that effect Vd and therefore the half-life of the drug
1) obesity –> inc Vd –> inc 1/2 life
2) pathological fluid –> inc Vd –> inc 1/2 life
list the 6 factors that effect CL and therefore the half-life of the drug
1) aging –> dec CL –> inc 1/2 life
2) inhibit CYP –> dec CL –> inc 1/2 life
3) induce CYP –> inc CL –> dec 1/2 life
4, 5, 6) Cardiac, Liver, Renal failure –> dec CL –> inc 1/2 life
zero-order kinetics is also known as….
saturated kinetics (rate of elimination is constant at Vmax b/c receptors/enzymes are saturated)
list the known drugs with zero-order kinetics
- ASA (high doses)
- ethanol
- phenytoin
compare 1st order and Zero order kinetics (in terms of CL)
1st- constant fraction of drug eliminated per unit time; rate of elimination is proportional to [drug]
Zero- constant amount of drug eliminated per unit time; rate of elimination is independent from [drug]
to maintain [drug] in plasma within specific range (therapeutic window) over a long period of time, _________ is used
maintenance dose
to achieve target [drug] in plasma rapidly, ________ is used
loading dose
dosing plans are based on knowing the following….
- min therapeutic [drug], min toxic [drug] (therapeutic window)
- CL of drug
- Vd of drug
define therapeutic window
Low- min therapeutic [drug] (troughs)
High- min toxic [drug] (peaks)
equation for maintenance dose and its factors
Maintenance Dose = dosing rate * dosing interval
-Dosing Rate(ss) = (CL * C) / F ( = rate of elimination(ss))
ss- steady state [drug]
equation for loading dose
Loading Dose = (Vd*TC) / F
compare continuous IV infusion or multiple IV injections with and without loading dose
With loading dose reaches Css immediately, Without loading dose it takes 4 half-lives to reach Css
define accumulation factor (AF) and what it predicts
- drug accumulates in body until dosing stops
- AF = (1 / fraction of dose lost in one dosing interval)
- AF predicts ratio of peak [drug] at steady state to peak [drug] after first dose [i.e. AF = 2 if drug is given every half life, AF = 1/0.5]
smaller doses of drug at shorter intervals reduces…
amplitude of the swings of [drug] between drug doses
how does a slow or extended release formulation of an oral drug affects its [drug] in plasma
- peak [drug] is delayed
- peak [drug] is lowered
- [drug] is higher at later times
doubling the dose of a drug has what effect on duration of the drug’s effect
- it extends the duration of the drug by ONE half-life
- it does double the [drug] in plasma, but does not double the effect
- the actual effect is determined by %effect v [drug] curve, which follows Michaelis-Menten curve
