Medicines Design - PK Phenytoin

Question 1

When do we see linear (first order) kinetics? and when do we see non-linear kinetics?

Answer 1

Linear –> When saturation of enzymes occurs at levels above therapeutic

Non-Linear –> When enzyme saturation occurs at therapeutic levels

Question 2

How do we recognise first order/linear kinetics?

Answer 2

Cl, V and F are always constant

AUC is proportional to the dose (double dose=double AUC)

Plasma concentration are proportional to the dose given

Question 3

Which of A/B/C are linear or non-linear?

Answer 3

Linear –> Drugs B and C

Non-Linear –> Drug A

Question 4

Why is phenytoin a problematic drug? (in reference to metabolism)

Answer 4

It has capacity limited metabolism

This means that the dose isnt proportional to the serum concentration, meaning that small changes in the dose will cause disproportionae differences in the Cp

This is bad considering it has a very narrow therapeutic window! (10-20mg/L)

Question 5

Do we use the sodium phenytoin or phenytoin acid in equations?

Answer 5

Phenytoin Acid

So x 0.92 (salt factor) if converting from phenytoin sodium

/ by 0.92 (salt factor) to convert from acid to sodium

Question 6

Why does the time to reach steady state increase as you increase the dose of phenytoin?

Answer 6

Because the enzymes are saturated, so clearance is reduced and half -life prolonged, meaning that it takes longer to reach a constant level

Question 7

In non-linear PK, is the elimination half-life of drugs constant?

Answer 7

No