Clinical pharmacokinetics

Question 1

1. What is the goal of clinical pharmacokinetics?

Answer 1

Designing a dosage regimen that will optimize the therapeutic response of a drug while minimizing the chance of adverse reactions – the theory is that there is a relationship b/t the effect of a drug and the concentration of a drug in a readily accessible area

Question 2

2. What are the 3 most important pharmacokinetic parameters?

Answer 2

1. Volume of distribution (Vd) – measure of the apparent space in the body available to contain a drug
2. Clearance (Cl) – measure of the body’s ability to eliminate drug
3. Bioavailability (F) – fraction of drug absorbed in to the systemic circulation

Question 3

3. What is the volume of distribution (Vd)?

Answer 3

Vd is the volume that would be required to contain all the drug in the body at the same concentration (ex. blood or plasma). This value is used to determine loading dose of a drug to quickly achieve a target plasma concentration.
Vd= (amount of drug in the body aka dose pt took)/(plasma drug concentration)
*A drug only in the plasma will have a minimum Vd equal to that of the plasma volume (Ex. 2.8L/70kg)
High Vd → higher [drug] in extravascular tissue compared to vascular (Vd = 50,000L for a 70kg person for Quinacrine)
Low Vd → higher [drug] in vascular compared to extravascular tissue

Question 4

4. Compare drug properties to body compartments (and volumes) they will enter in to.

Answer 4

1. Total body water (0.6 L/kg) → liposoluble molecules (ex. ethanol)
2. Extracellular water (0.2 L/kg) → hydrophilic molecules (ex. gentamicin)
3. Blood (0.08 L/kg) or plasma (0.04 L/kg) → strongly plasma protein-bound molecules and large molecules (ex. heparin)
4. Fat (0.2-0.35 L/kg) → highly liposoluble molecules (ex. DDT)
5. Bone (0.07 L/kg) → certain ions (ex. lead, fluoride)

Question 5

5. Discuss how to calculate Vd.

Answer 5

Vd= Dose/Co
Two phases on drug plasma concentration vs. time graph: rapid initial fall (DISTRIBUTION PHASE – a PHASE) and slower phase (ELIMINATION PHASE- B PHASE).
Take the logarithm of drug concentration (y-axis) which creates a straight line with 2 slops for the distribution and elimination phase.
Extrapolate the elimination curve to the y-axis and that will tell you the Co (initial concentration).
Therefore, you know initial concentration and you know the dose given allowing you to calculate Vd.

Question 6

6. What equation allows you to calculate the dose needed to achieve quickly a target plasma drug concentration (TC)?

Answer 6

Dose = Vd * TC

Question 7

7. What is clearance and how do you calculate it?

Answer 7

Clearance is the volume of blood cleared of drug per unit time. It will predict the rate of elimination of the drug in relation to the drug concentration.
CL = (rate of elimination of drug [amt/time])/ (plasma drug concentration [amt/volume])
*Clearance of a drug is usually constant over the range of concentrations b/c the rate of elimination is directly proportional to its concentration in the plasma. Elimination of drugs is not saturable.

Question 8

8. What is the equation for rate of elimination?

Answer 8

Rate of elimination = Clearance x Concentration in plasma
When CL is constant → 1st order elimination, linear kinetics, constant fraction of drug is eliminated per unit time (exponential decay with log turning it to a linear line) [CL = dose/AUC]
If drug elimination can be saturable → 0 order elimination, constant amt of drug eliminated per unit of time

Question 9

9. What are the major sites of drug elimination?

Answer 9

Kidneys and liver

Question 10

10. Define half life.

Answer 10

Time required to change the amt of drug in the body by 50% during elimination (or constant infusion). This value indicates the time required to attain 50% of the steady-state level during constant infusion (decay 50% from steady-state level during elimination).
1st order kinetics → half life is constant
0 order kinetics → not a constant
t(1/2) = (0.693*Vd)/CL [units= time]
50% of steady state concentration → reached after 1 half-life
75% of ss → 2 half lives
87.5% of ss → 3 half lives
93.75% of ss → 4 half lives [assume steady state has been attained after 4 half-lives!!!]
^These values above can also relate to the amt of drug left in the body once infusion of the drug is ceased. When 93.75% of the drug has been eliminated in the body, at least 4 half lives have past. Assume drug has been effectively eliminated after 4 half lives!

Question 11

11. What factors effect Vd effect half-life?

Answer 11

Obesity → increase half-life

Pathologic fluid → increase half-life

Question 12

12. What factors affect CL (clearance) effect half-life?

Answer 12

Aging → increases half life
CYP induction → decreases half life
CYP inhibition → increases half life
Cardiac failure → increases half life
Liver failure → increases half life
Renal failure → increases half life

Question 13

13. What is the equation for rate of elimination with saturation kinetics (when drug concentration exceeds Km)?

Answer 13

Rate of elimination = (Vmax*C)/Km+C)
Km = plasma concentration at which half of the maximal rate of elimination is reached
Vmax = max rate of elimination
**as drug concentration increases, the increment in elimination rate decreases. When drug concentration is significantly higher than the Km, the equation reduces to: Rate of elimination = (Vmax+C)/C = Vmax ← at this pt the rate of elimination is maximal and independent of drug concentration therefore 0 order elimination has been reached and elimination is a constant amt.
If dosing rate exceeds the elimination capacity, a steady state cannot be achieved and drug concentration will keep on rising as long as dosing continues. Clearance = rate of elimination/C = Vmax/(Km+C)