L13, L15- Clinical Pharmacokinetics

Question 1

clinical pharmacokinetics aims to design dosage regimens which…

Answer 1

• optimize therapeutic response of drug

- minimizes adverse reactions of drug

Question 2

what is the fundamental tenet of clinical pharmacokinetics

Answer 2

there is a relationship between effects of a drug and the [drug] in blood

Question 3

list and define the 3 important pharmacokinetic parameters

Answer 3

• 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

Question 4

define Vd (include formula)

Answer 4

• 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

Question 5

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)

Answer 5

1- low (more in blood)

2- high (more in tissue)

Question 6

quinacrine has a (high/low) Vd

Answer 6

High- 50000L in a person with body volume of 70L

used for malarial and tapeworm infections

Question 7

what is the function of Vd clinically

Answer 7

• allows conversion of concentrations of drugs to actual amounts of drugs
• i.e. Loading Dose

Question 8

define loading dose

Answer 8

amount/dose of drug needed to quickly achieve target plasma concentration

Question 9

describe method used to determine Vd (include two phases)

Answer 9

• 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

Question 10

describe clearance (and its formula)

Answer 10

• volume of blood cleared of drug per unit time

- CL = (rate of elimination) / ([drug] in plasma)

Question 11

(T/F) most drugs follow first order kinetics (in terms of CL)

Answer 11

T- rate of elimination is directly proportional to [drug], and a constant fraction is eliminated per unit time

Question 12

why do most drugs follow first order kinetics (for CL)

Answer 12

the mechanisms of elimination via enzymes/transporters are not saturated

Question 13

during continuous IV drug infusion, describe the % of Css reached in terms of half-life

Answer 13

(Css = [drug] at steady state]
1 half-life: 50% Css
2: 75%
3: 87.5%
4: 93.75%

Question 14

Once IV drug infusion has stopped, describe the % of drug lost in terms of half-life

Answer 14

1 half-life: 50% drug lost

2: 75%
3: 87.5%
4: 93.75%

Question 15

give half-life equation

Answer 15

t(1/2) = (0.693*Vd) / CL

Question 16

steady-state of a drug is reached after __ half-lives

Answer 16

4 (93.75%)

Question 17

a drug has been considered successfully eliminated after __ half-lives

Answer 17

4 (93.75%)

Question 18

how is Css affected by infusion rate

Answer 18

(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)

Question 19

list the 2 factors that effect Vd and therefore the half-life of the drug

Answer 19

1) obesity –> inc Vd –> inc 1/2 life

2) pathological fluid –> inc Vd –> inc 1/2 life

Question 20

list the 6 factors that effect CL and therefore the half-life of the drug

Answer 20

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

Question 21

zero-order kinetics is also known as….

Answer 21

saturated kinetics (rate of elimination is constant at Vmax b/c receptors/enzymes are saturated)

Question 22

list the known drugs with zero-order kinetics

Answer 22

• ASA (high doses)
• ethanol
• phenytoin

Question 23

compare 1st order and Zero order kinetics (in terms of CL)

Answer 23

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]

Question 24

to maintain [drug] in plasma within specific range (therapeutic window) over a long period of time, _________ is used

Answer 24

maintenance dose

Question 25

to achieve target [drug] in plasma rapidly, ________ is used

Answer 25

loading dose

Question 26

dosing plans are based on knowing the following….

Answer 26

• min therapeutic [drug], min toxic [drug] (therapeutic window)
• CL of drug
• Vd of drug

Question 27

define therapeutic window

Answer 27

Low- min therapeutic [drug] (troughs)

High- min toxic [drug] (peaks)

Question 28

equation for maintenance dose and its factors

Answer 28

Maintenance Dose = dosing rate * dosing interval
-Dosing Rate(ss) = (CL * C) / F ( = rate of elimination(ss))

ss- steady state [drug]

Question 29

equation for loading dose

Answer 29

Loading Dose = (Vd*TC) / F

Question 30

compare continuous IV infusion or multiple IV injections with and without loading dose

Answer 30

With loading dose reaches Css immediately, Without loading dose it takes 4 half-lives to reach Css

Question 31

define accumulation factor (AF) and what it predicts

Answer 31

• 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]

Question 32

smaller doses of drug at shorter intervals reduces…

Answer 32

amplitude of the swings of [drug] between drug doses

Question 33

how does a slow or extended release formulation of an oral drug affects its [drug] in plasma

Answer 33

• peak [drug] is delayed
• peak [drug] is lowered
• [drug] is higher at later times

Question 34

doubling the dose of a drug has what effect on duration of the drug’s effect

Answer 34

• 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