Drug Distribution

Question 1

What is the definition of drug distribution?

Answer 1

It is the dispersion of a drug among fluids and tissues of the body.

Question 2

What order kinetics do most drugs follow, and how could it be described?

Answer 2

Most drugs, if used in the right concentration range, follow first-order kinetics.
There is a constant half-life (t1/2) and a constant clearance (volume of blood cleared of drug per unit time). This means that the time to remove the drug is independent of the dose given.

There is also no saturation of processes, so no enzymes, etc. needed are at saturation point. This means that your body is able to cope with a change in drug concentration (within a range) by increasing the enzyme’s rate of reaction to deal with the increased drug amounts. This is to ensure that a certain fraction (not amount) of the drug is eliminated per unit time.

That’s what makes for predictable kinetics, which is incredibly useful in the pharmaceutical industry.

Question 3

Describe when drugs follow zero-order kinetics.

Answer 3

A few drugs obey zero-order kinetics, examples being alcohol and phenytoin.
They follow ‘saturation kinetics’ in which t1/2 and clearance fluctuate with the drug’s concentration.

A constant amount (not fraction) of the drug is removed, which means that the bigger the dose, the longer it takes to remove it.

As the dose decreases and fall below saturation point, the processes return to first-order kinetics.

Question 4

What are the four pharmacokinetic parameters?

Answer 4

• half-life (t1/2)
• clearance (CL)
• volume of distribution (Vd)
• bioavailability (F)

Question 5

What is the volume of distribution?

Answer 5

It indicates the extent of distribution of a drug. It is clinically important for adjusting dosage.
It is influenced by lipid/water solubility and binding to plasma proteins.

The equation is:
total amount of drug/[plasma] = apparent volume of distribution (Vd)

Question 6

What is plasma clearance?

Answer 6

It is the volume of plasma cleared of a drug per unit time. It is a constant in first-order reactions.
As clearance increases, half-life decreases.

The equation is:
CL = rate of elimination/[drug plasma]

Question 7

What is bioavailability?

Answer 7

It is the fraction of the drug in circulation compared to the dose. It measures the extent of absorption, and is normally represented by a percentage.

Question 8

What causes low bioavailability?

Answer 8

• poor absorption
• chemical reactions at the site of delivery
• first-pass metabolism

Question 9

What is the choice of route guided by?

Answer 9

• bioavailability
• chemical properties of the drug
• convenience
• need to control specificity of action
• desired onset/ duration/ offset of action

Question 10

What happens with dosing regimens?

Answer 10

Multiple dosing leads to a ‘steady state’ where the amount of drug absorbed equates to the amount of drug eliminated. Additional doses are administered before the drug concentration reaches zero.
The drug concentration variation depends on the half-life and dose interval.

For drugs with a long half-life, the achievement of a ‘steady state’ can be accelerated by a loading dose.

Question 11

What are the general rules of achieving a ‘steady state’?

Answer 11

• repeated doses of the drug eventually produce a steady state (plateau) concentration
• the time to plateau is 4-5 times longer than the half-life
• 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