Anticonvulsants
The disposition of phenytoin and valproic acid shows important changes in patients with decreased renal function and hypoalbuminemic conditions.
These changes are a manifestation of decreased protein binding with a concomitant increase in the volumes of distribution of these drugs. This phenomenon has been closely investigated with phenytoin, and it is likely that parallels can be drawn with valproic acid. Both drugs are highly protein bound; so in patients with renal dysfunction or with hypoalbuminemia, displacement from serum proteins occurs with a concomitant increase in the volume of distribution. The clinical importance of this phenomenon is that the patient with renal dysfunction manifests the same concentration of free drug in serum at a lower total blood concentration than does the subject with normal renal function. Since most clinical laboratories measure only total concentration of drug in the blood, the importance of the phenomenon is in the proper interpretation of a blood level for these drugs in such patients. In some circumstances it may be desirable to obtain a measurement of the unbound drug concentration. Fundamentally, clinicians should not misinterpret diminished concentrations of total phenytoin in such patients.
In summary, in a uremic or hypoalbuminemic subject, one should not misinterpret a low serum phenytoin concentration as subtherapeutic. The clinician must depend on clinical measures of end points of response. Phenytoin is readily assessed because patients with therapeutic concentrations often have nystagmus and increasing the dose in such patients would result in toxicity. On the other hand, the dose can be safely increased if there is a lack of efficacious effect and the patient does not have nystagmus. It is also important to note that phenytoin follows dose dependent kinetics. As a consequence, increments in dosing should be small and sufficient time should be allowed for the patient to achieve a new steady state.
These changes are a manifestation of decreased protein binding with a concomitant increase in the volumes of distribution of these drugs. This phenomenon has been closely investigated with phenytoin, and it is likely that parallels can be drawn with valproic acid. Both drugs are highly protein bound; so in patients with renal dysfunction or with hypoalbuminemia, displacement from serum proteins occurs with a concomitant increase in the volume of distribution. The clinical importance of this phenomenon is that the patient with renal dysfunction manifests the same concentration of free drug in serum at a lower total blood concentration than does the subject with normal renal function. Since most clinical laboratories measure only total concentration of drug in the blood, the importance of the phenomenon is in the proper interpretation of a blood level for these drugs in such patients. In some circumstances it may be desirable to obtain a measurement of the unbound drug concentration. Fundamentally, clinicians should not misinterpret diminished concentrations of total phenytoin in such patients.
In summary, in a uremic or hypoalbuminemic subject, one should not misinterpret a low serum phenytoin concentration as subtherapeutic. The clinician must depend on clinical measures of end points of response. Phenytoin is readily assessed because patients with therapeutic concentrations often have nystagmus and increasing the dose in such patients would result in toxicity. On the other hand, the dose can be safely increased if there is a lack of efficacious effect and the patient does not have nystagmus. It is also important to note that phenytoin follows dose dependent kinetics. As a consequence, increments in dosing should be small and sufficient time should be allowed for the patient to achieve a new steady state.
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