Drug Distribution

Question 1

Define zero- and first-order kinetics, and influence on half-life, volume of distribution and clearance of a drug

Answer 1

1st: A constant fraction of drug is removed  constant clearance
•The time to remove the drug is independent of dose (if you increase [dose] the same fraction is removed)  constant half-life

0: A constant amount of drug is removed
•The bigger the dose the longer the time to remove it

Vod; Total amount of drug / [Plasma] = Apparent volume of distribution (Vd)
•Indicates the extent of distribution for a drug
•Clinically important for adjusting dosage
•Influenced by lipid/water solubility, binding to plasma proteins

C; Describes activity of metabolising enzymes/excretion mechanisms 
Plasma clearance (CL):
•Volume of plasma cleared of drug per time (ml min-1)
•CL = Rate of elimination / [drug plasma]
•A constant for 1st order reactions

Question 2

Define bioavailability

Answer 2

Bioavailability : Fraction of drug in circulation compared to dose
Measures extent of absorption

Calculated by: Equal oral/iv doses, measure AUC oral / AUC iv
e.g. oral dose, F = 0.1 (10% bioavailability)

Question 3

Describe factors that influence choice of drug route

Answer 3

Low bioavailability is caused by
Poor absorption
Chemical reactions at site of delivery
First-pass metabolism

•Choice of route guided by
Bioavailability
Chemical properties of drug
Convenience
Need to control specificity of action
Desired onset/duration/offset of action

Question 4

Discuss reasons for using different dosage regimen

Answer 4

Multiple dosing leads to a ‘steady state’
•Additional doses administered before [drug] falls to zero
•[Drug] variation depends on half-life and dose interval
•Multiple dose therapy compromises:
- minimisation of drug level variability
- simplicity

Question 5

Describe the steady-state principle

Answer 5

-Idea of dosing regime is to balance:

Dosing rate = Rate of elimination

 Dosing rate = Clearance x Css

Dosing rate x F = CL x Target Concentration

Question 6

How to achieve steady state

Answer 6

• Repeated doses of drug eventually produce a steady state (plateau) concentration
• Time to plateau is 4-5 x drug half-life
• When dose is changed a new plateau is reached in 4-5 half-lives
• Steady state levels are not actually flat
• Fluctuation size is inversely proportional to the number of daily doses
• Fluctuations create the potential for sub-therapeutic treatment or toxicity
• For drugs with long half lives achievement of steady state can be accelerated by a loading dose