PHENYTOIN

 

Introduction:  Phenytoin is the oldest, non-sedative, antiseizure drug, introduced in 1938 after a systematic evaluation of compounds such as phenobarbital that altered electrically induced seizures in laboratory animals. It was known for decades as diphenylhydantoin. 

Molecular structure:  Phenytoin is a diphenyl-substituted hydantoin with the structure shown below. It has much lower sedative properties than compounds with alkyl substituents at the 5 position.  A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use; this phosphate ester compound is rapidly converted to phenytoin in the plasma.

Mechanism of Action:  Phenytoin has major effects on several physiologic systems.  It alters Na⁺, K⁺,  and Ca²⁺ conductance, membrane potentials, and the concentrations of amino acids and the neurotransmitters norepinephrine, acetylcholine, and γ-aminobutyric acid (GABA).  Phenytoin also blocks the persistent Na⁺ current, as do several other AEDs including valproate, topiramate, and ethosuximide.  In addition, phenytoin paradoxically causes excitation in some cerebral neurons.  A reduction of calcium permeability, with inhibition of calcium influx across the cell membrane, may explain the ability of phenytoin to inhibit a variety of calcium-induced secretory processes, including release of hormones and neurotransmitters.

Clinical Uses:  Phenytoin is effective against partial seizures and generalized tonic-clonic seizures. In the latter, it appears to be effective against attacks that are either primary or secondary to another seizure type. 

Pharmacokinetics:  Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption.  Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours.  Phenytoin is highly bound to plasma proteins. Drug concentration in cerebrospinal fluid is proportionate to the free plasma level. Phenytoin accumulates in brain, liver, muscle, and fat. Phenytoin is metabolized to inactive metabolites that are excreted in the urine. Only a very small proportion of the dose is excreted unchanged.  The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached.

Therapeutic Levels & Dosage:  The therapeutic plasma level of phenytoin for most patients is between 10 and 20 mcg/mL.  A loading dose can be given either orally or intravenously; the latter, using fosphenytoin, is the method of choice for convulsive status epilepticus.  When oral therapy is started, it is common to begin adults at a dosage of 300 mg/d, regardless of body weight. This may be acceptable in some patients, but it frequently yields steady-state blood levels below 10 mcg/mL, which is the minimum therapeutic level for most patients. If seizures continue, higher doses are usually necessary to achieve plasma levels in the upper therapeutic range.  Because of its dose-dependent kinetics, some toxicity may occur with only small increments in dosage. The phenytoin dosage should be increased each time by only 25–30 mg in adults, and ample time should be allowed for the new steady state to be achieved before further increasing the dosage.

RELATED;

1.  CARBAMAZEPINE

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