Sun28November0628PM 45

A 56-year old man with longstanding epilepsy presents to his doctor with "heartburn".

He takes 300 mg phenytoin/day in divided doses. His plasma levels of phenytoin are measured regularly and normally lie between 10 mcg/mL and 12 mcg/mL (therapeutic levels are normally 10-20 mcg/mL). He is prescribed cimetidine 200 mg b.d. for his symptoms.

One month later his phenytoin levels are rechecked and are found to be 40 mcg/mL.

Which one of the following options best describes the elimination kinetics of phenytoin at higher plasma concentrations?

(Please select 1 option)

Plasma concentration plotted against time is exponential

Plasma concentration plotted against time is linear This is the correct answer

Log of plasma concentration plotted against time is linear

Elimination rate is proportional to the plasma concentration

Change in plasma concentration is not linear Incorrect answer selected

Explanation

Phenytoin has a narrow therapeutic index and plasma concentrations need to be monitored closely.

The clearance of phenytoin is by oxidative metabolism by cytochrome P450 enzymes in the liver. These enzymes are subject to inhibition and induction.

At low plasma concentrations the elimination of phenytoin follows a profile of "first order kinetics". The rate of elimination is proportional to plasma concentration. The incorrect answer options here describe the exponential process of first-order pharmacokinetics.

Rate of elimination can be described by the following equation:

C = C0e-Kt

Where:

C = drug concentration

C0 = drug concentration at time zero (extrapolated)

k = rate constant

t = time

When phenytoin concentrations exceed the normal range, elimination of the drug becomes "zero-order" as enzyme systems become saturated. The drug is metabolised at a fixed rate and independent of plasma concentration. Other important examples of drugs that behave in this way are aspirin and ethyl alcohol.

Cytochrome P450 in this clinical scenario is likely to have been inhibited by cimetidine leading to early saturation kinetics.

Phenytoin is highly plasma protein bound (90% albumin) and the free fraction of the drug can be affected by serum albumin concentration and other highly protein bound drugs that have the potential to compete for binding sites.

Answer Statistics

1

20%

2

31%

3

13%

4

13%

5

25%

Times answered: 251