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Pharmacology: Pharmacodynamics: Phenytoin is an anticonvulsant drug which may be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at the synaptic levels. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.
Pharmacokinetics: Phenytoin is a weak acid and has limited hydrosolubility, even in the intestine. The compound undergoes a slow and somewhat variable absorption after oral administration. After intramuscular administration, the absorption of phenytoin is slower than after oral administration, due to poor hydrosolubility of the compound and the possibility of its precipitation at the site of injection.
The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours. Phenytoin has an apparent volume of distribution of 0.6L/Kg and is highly bound (90%) plasma proteins, mainly albumin. Free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Phenytoin is distributed into cerebrospinal fluid (CSF), saliva, semen, gastrointestinal fluids, bile, and breast milk. The concentration of phenytoin in CSF, brain, and saliva approximates the level of free phenytoin in plasma.
Phenytoin is biotransformed in the liver by oxidative metabolism. The major pathway involves 4-hydroxylation, which accounts for 80% of all metabolites. CYP2C9 plays the major role in the metabolism of phenytoin (90% of net intrinsic clearance), while CYP2C19 has a minor involvement in this process (10% of net intrinsic clearance). This relative contribution of CYP2C19 to phenytoin metabolism may however increase at higher phenytoin concentrations.
Because the cytochrome systems involved in phenytoin hydroxylation in the liver are saturable at high serum concentrations, small incremental doses of phenytoin may increase the half-life and produce very substantial increases in serum levels when these are in or above the upper therapeutic range. The clearance of phenytoin has been shown to be impaired by CYP2C9 inhibitors such as phenylbutazone and sulphaphenazole. Impaired clearance has also been shown to occur in patients administered CYP2C19 inhibitors such as ticlopidine. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and eliminated in the urine partly through glomerular filtration but, more importantly via tubular secretion. Less than 5% of phenytoin is excreted as the parent compound.
A fall in phenytoin serum levels may occur when patients are switched from oral to intramuscular (IM) administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor hydrosolubility of phenytoin and the possibility of its precipitation at the site of injection. Intravenous administration is the preferred route for producing rapid therapeutic serum levels.
