Pharmacokinectics: Quantitative

Question 1

What is pharmacokinetics?

Answer 1

• study of time-dependent changes of drug and metabolite concentrations in blood and body fluids

Question 2

What is the therapeutic index?

Answer 2

Therapeutic Index =

Question 3

What is the difference between pharmacokinetics and pharmacodynamics?

Answer 3

pharmacokinetics: body’s effect on drug
pharmacodynamics: drug’s effect on body

Question 4

What are zero-order kinetics?

Answer 4

the rate of absorption or elimination of drug is constant, not dependent on drug concentration between where the drug is vs. where it’s going

M =kt

[M= amount of drug absorbed/ eliminated, t = time]

Question 5

What are first-order kinetics?

Answer 5

rate of absorption or elimination is proportional to the drug concentration gradient (drug still unabsorved/ uneliminated)

M=M₀e^-kt

[M is the amount of absorbed/ eliminated drug, M₀ is initial amount at the absorption/ elimination site, k is the elimination rate constant]

Question 6

Define Volume of Distribution Vd.

Answer 6

• theoretical volume in which drug is distributed
• V_d = amount of drug in body (mg) / concentration of drug in plasma (mg/L)
  [unit: L, unless written as V_d L/body weight]
• V_d can be larger than actual body volume, meaning drug disperses to other body compartments
  
  • Blood plasma = 3.5 L, Blood volume = 5.5 L,
    ECM water = 13 L

Question 7

How can V_d be extrapolated from a concentration vs. time chart?

Answer 7

V_d = dose given at t=0/
extrapolated y-axis concentration of drug at time=0

Question 8

Define Clearance.

Answer 8

volume of plasma cleared of drug, by all routes, per unit time

CL = rate of elimination (mg/hr) / plasma concentration of drug (mg/L)

[units: L/hr]

Question 9

What is the relationship between clearance and volume of distribution?

Answer 9

CL = V_d x k_e (elimination constant)

Question 10

Define half life t_1/2.

Answer 10

time required to change amount of drug in the body by 1/2

t_1/2 = 0.693 x V_d / CL

low clearance, longer half-life

Question 11

Define bioavailability (F).

Answer 11

fraction of unchanged drug reaching the systemic circulation after oral administration; dependent upon how well drug is abosbed from gut and how much is extracted by liver

F = f (1-ER)

[f= fraction/ extent absorbed from gut, ER = extraction ratio in liver]

Question 12

Define steady state.

Answer 12

point at which adding an additional dose of a drug will result in the same peak and trough concentrations of drug as the last dose administration

Question 13

Steady State Concentration RULE OF THUMB

Answer 13

time it takes a drug to reach steady state concentration in intermittent doses (or intravenous dosing) after the first dose
= 4-5 half lives

This is true no matter what you do to concentration (even doubling or tripling it)

Question 14

Define drug accumulation & accumulation factor. What does it predict?

Answer 14

• drugs are repeatedly administered: if dosing interval is shorter than four half-lives, accumulation of drug is detectable
• accumulation factor = 1/ fraction of drug lost in one dosing interval
  
  • ex. for a drug given once every half life, AF = 2
• can predict steady state concentration: peak concentration at steady state = peak concentration after first dose x AF

Question 15

Define dosing rate.

Answer 15

Dosing Rate = CL x C_SS

[units: mg/ hr]

volume of plasma cleared of drug x concentration of drug in that volume

C_SS: concentration of drug at steady state

CL: important b/c = proportionality constant between dose rate and steady-state drug concentration in plasma

Question 16

Define maintenance dose. How is dosing interval determined? When is intermittent dosing not practical?

Answer 16

If drug is given in intermittent doses,
**Maintenance Dose = dosing rate x dosing interval
= CL x C_SS x dosing interval **

dosing interval: determined by how much fluctuation in C_P can be tolerated w/o inducing toxicity (smaller and more frequent vs. larger and less frequent doses)

half-life: if t_1/2 for drug is <4 hrs, periodic dosing is not practical and constant infusion must be adopted

Question 17

Define Loading Dose.

Answer 17

Loading Dose = V_d x TC

Question 18

What are the steps to design and optimize a dosage regimen?

Answer 18

1. Identify target concentration that will produce therapeutic effect
2. Determine V_d and CL values for patient
3. Calculate maintenance dose to keep steady state level of drug in body (amount given = amount eliminated)
4. If target concentration needs to be reached quickly, loading dose might be applied
5. Check whether the calculated maintenance and loading doses actually elicit the desired effect. If not, adjust the doses accordingly – the clearance might be different from the expected value