Lecture 6 to 7: Clinical PK

Question 1

3 most important pharmacokinetic parameters are

Answer 1

• Volume of distribution: a measure of the apparent space in the body available to contain the drug
• Clearance: a measure of the body’s ability to eliminate the drug
• Bioavailability: the fraction of drug absorbed into the systemic circulation.

Question 2

VOLUME OF DISTRIBUTION (Vd)

Answer 2

• volume that would be required to contain all of the drug in the body at the same concentration as it is in the blood.
• Drugs that are completely retained within the vascular compartment have a minimum Vd equal to the vascular compartment.
• Drugs that have much higher concentrations in the extravascular tissue than in the vascular compartment have a very high Vd, i.e. Higher Vd -> low in blood or very lipophilic
• volume of distribution allows us to convert concentrations to amounts.
• main use of the volume of distribution is to determine the loading dose to quickly achieve a target plasma concentration.
• DETERMINATION OF Vd
  
  • A dose of a drug is injected IV.
  • The plasma drug concentration is plotted vs time.
  • Usually, the plot shows 2 phases.
    
    • The rapid fall is the distribution phase (the α phase).
    • The slower phase is the elimination phase (the β phase).
  • Extrapolation of the elimination curve to they axis, yields the concentration that would have existed at the start if the dose had been instantly distributed.

Question 3

Clearance

Answer 3

two major sites of drug elimination are the kidneys and the liver.

Question 4

1st order elimination

Answer 4

• For most drugs, CL is constant over the plasma concentrations used clinically.
• This occurs because the mechanisms of elimination are not saturated.
• Rate of elimination = CL x C
• When a drug follows first-order kinetics, a constant fraction of the drug is eliminated per unit of time.

Question 5

Half-life

Answer 5

• Css: It can be assumed that steady state is attained after about 4 half-lives.
• It can be assumed that the drug ha sbeen effectively eliminated after about 4 half-lives.
• Half-life is a constant for drugs eliminated by first-order kinetics
• Not a constant for drugs eliminated by zero-order kinetics.
• In most clinical situations it can be assumed that the drug has been effectively eliminated after about 4 half-lives.
• Note that increasing the rate of infusion does not influence the time required to reach Css.
• Note also that the half-life does not depend on the dose.

Question 6

Factors affecting half-life

Answer 6

Note: Pathologic fluid -> Edema

Question 7

KINETICS OF DRUG ELIMINATION: SATURATION KINETICS aka Zero-order kinetics

Answer 7

• Drug metabolism and tubular secretion are saturable processes.
• When drug concentration exceeds Km, nonlinear kinetics is observed.
• The rate of elimination is maximal and independent of drug concentration.
  
  • Elimination is zero-order.
  • A constant amount of drug is eliminated per unit time.
• Recall that in first-order kinetics aconstant fraction of drug is eliminated per unit time.
• Zero order elimination is observed with a small number of drugs:
  • Aspirin at high doses
  • Ethanol
  • Phenytoin
• ​Clearance is not constant.
• Clearance varies with the concentration of drug, i.e not constant
  
  • ​CL = Dose/AUC
• Concept of 4 half-lives does not apply

Question 8

Dosing plan is based on knowledge of

Answer 8

• Minimum therapeutic and minimum toxic concentrations for a given drug
  
  • The minimum effective concentration determines the trough plasma concentration.
  • The minimum toxic concentration determines the peak plasma concentration.
• Clearance of the drug
• Vd of the drug
• Bioavailability

Question 9

MAINTENANCE DOSE

Answer 9

• In most clinical situations drugs are administered to maintain a steady state of drug in the body:
• Just enough drug is given in each dose to replace the drug eliminated since the preceding dose.
• At steady state (SS) the dosing rate (“rate in”) must equal the rate of elimination (“rate out”)
• Thus, if the desired target concentration is known, the clearance in that patient will determine the dosing rate.
• If intermittent doses are given, the maintenance dose is calculated with:

Maintenance dose = dosing rate x dosing interval

When a drug is given repeatedly at regular intervals, the drug plasma concentration oscillates about a mean. Administering the drug at longer intervals increases the amplitude of the oscillations in the drug concentration, ie, the peak plasma level increases and the trough plasma level decreases. The steady-state level, the clearance, and the Vd remain unchanged.

Question 10

DRUG ACCUMULATION

Answer 10

• Whenever drug doses are repeated, the drug will accumulate in the body until dosing stops.
• Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval.

Css = infusion rate/CL

Question 11

Peak concentrations at Css

Answer 11

peak concentrations at steady-state will be equal to the peak concentration after the first dose multiplied by the AF.

PCss = PC1 x AF

Question 12

LOADING DOSE WITH INTERMITTENT DOSING

Answer 12

• When intermittent doses are given,the loading dose calculated using the equation

LD=Vd xCss

• will only reach the steady-state plasma concentration.
• It will not match the steady-state peak concentration (PCss).
• To match the steady-state peak concentration the loading dose must be calculated using the equation:

LD = Maintenance Dose x Accumulation Factor

Question 13

TIME COURSE OF DRUG EFFECT

Answer 13

• Pharmacokinetics plus pharmacodynamics: drug effect vs time.
• called the time course of effect, i.e. PK/PD

Question 14

Time course of drug effect: IMMEDIATE EFFECTS

Answer 14

• Enalapril is an angiotensin-converting enzyme (ACE) inhibitor.
• Used for hypertension and heart failure.
• T1/2 enalapril is about 3 h.
• Enalapril is given once a day
• 24 h after the previous dose, the plasma concentration of enalapril is only 0.5 ng/mL, but ACE is still 33% inhibited.
• Because the concentrations are still so high in relation to the EC50, the effect of the drug does not decrease too much. -> key factor is a high initial concentration in relation to the EC50.

Question 15

Time course of drug effect: DELAYED EFFECTS

Answer 15

• action of warfarin occurs rapidly.
• Inhibition of the enzyme is closely related to plasma concentrations of warfarin
• therapeutic anticoagulant effect is usually apparent within 24 hours of warfarin administration.
• Peak anticoagulant effect may take 72 to 96 hours.

Question 16

Time course of drug effect: CUMULATIVE EFFECTS

Answer 16

effect of many drugs used to treat cancer reflects a cumulative action.