Pharmacologic Therapy

Special Considerations

Use of AEDs present some unique challenges, some of which relate to their pharma-cokinetic properties, which need to be clearly understood.26

Michaelis-Menten Metabolism

Phenytoin metabolism is capacity limited. Michaelis-Menten metabolism or Michaelis-Menten pharmacokinetics is when the maximum capacity of hepatic enzymes to metabolize the drug is reached within the normal dosage range. The clinical significance is that small changes in doses result in disproportionate and large changes in serum concentrations. The patient is at risk of sudden toxicity if too large a dose increase is made, or a breakthrough seizure may occur if too large a reduction in dose is made. Due to individual differences in metabolism, each patient follows a different curve in the relationship between dose and serum concentrations. These differences can only be defined by careful use of serum concentration and dosing data. There are numerous schemes for determining appropriate dosage adjustments of phenytoin, and these are discussed in pharmacokinetic textbooks. For routine clinical practice, dosage adjustments for adults with normal protein binding of phenytoin and a steady-state serum concentration can be made using the following plan:

• For serum concentrations less than 7 mcg/mL (28 p,mol/L), the total daily dose is increased by 100 mg.

• For serum concentrations of 7 to 12 mcg/mL (28-48 p,mol/L), the total daily dose is increased by 50 mg.

• For serum concentrations greater than 12 mcg/mL (48 p,mol/L), the total daily dose

is increased by no more than 30 mg. Protein Binding

Some AEDs, especially phenytoin and valproate, are highly bound to plasma proteins. When interpreting a reported concentration for these drugs, it is important to remember the value represents the total (i.e., bound and unbound) concentration in the blood. Because of differences in the metabolism of these drugs, the clinical effects of altered protein binding are different for these drugs.

Normally, 88% to 92% of phenytoin is bound to plasma protein, leaving 8% to 12% as unbound. The unbound component is able to leave the blood to produce the clinical effect in the CNS, produce dose-related side effects in the CNS and at other sites, distribute to other peripheral sites, and be metabolized. Certain patient groups are known to have decreased protein binding, resulting in an increased percentage of drug that is unbound. These patient groups include

• Those with kidney failure

• Those with hypoalbuminemia

• Pregnant women

• Those taking multiple highly protein bound drugs

• Patients in critical care

Due to the Michaelis-Menten metabolism of phenytoin, alterations in its protein binding will result in increased severity of dose-related adverse effects. In patients with suspected changes in protein binding, it is useful to measure unbound phenytoin concentrations.

When valproate protein binding is altered, the risk for severe dose-related adverse effects is much less compared to phenytoin. Michaelis-Menten metabolism is not a factor with valproate, so hepatic enzymes are able to efficiently metabolize the additional unbound portion.


Carbamazepine is a potent inducer of hepatic microsomal enzymes. Not only does it increase the rate of metabolism for many other drugs, it increases the rate of its own metabolism. Hepatic enzymes become maximally induced over several weeks, necessitating a small initial dose of carbamazepine that is increased over time to compensate for the enzyme induction (Fig. 30-3). Most dosage regimens for carbamazepine call for a starting dose that is 25% to 30% of the typical maintenance dose of 15 mg/kg/ day. The dosage is increased weekly until the target maintenance dose is achieved within 3 to 4 weeks. Titration of the carbamazepine dose lessens the risk for severe dose-related adverse effects when carbamazepine is first started.

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