PHENYTOINE 250MG/5ML

Indications

• Epilepsy
• Focal seizures
• Generalized tonic-clonic seizures
• Status epilepticus
• Neurosurgery to prevent seizures

Dosage

Adults: The initial dose for adults is usually 100 mg to 300 mg daily, administered in divided doses. The dosage may be adjusted based on serum levels and

Mechanism of action

Phenytoin acts as a non-specific sodium channel blocker, targeting nearly all subtypes of voltage-gated sodium channels. It inhibits the positive feedback loop that facilitates the propagation of high-frequency action potentials in neurons. The drug stabilizes neuronal membranes by decreasing sodium and calcium ion influx and prolonging the inactivation time of sodium channels during nerve impulse generation. Additionally, phenytoin decreases synaptic transmission and post-tetanic potentiation, enhancing sodium ATPase activity in neurons and influencing second messenger systems, including calcium-calmodulin protein phosphorylation.

Pharmacodynamics

As an anticonvulsant, phenytoin exhibits a narrow therapeutic index, with a recommended serum concentration range of 10-20 mg/L. Variability in metabolism due to genetic polymorphisms, albumin levels, and comorbidities can complicate achieving optimal dosing. Phenytoin is highly protein-bound, and only the unbound fraction exerts a pharmacological effect. Therefore, changes in protein binding due to drug interactions can significantly affect therapeutic outcomes.

Pharmacokinetics

Phenytoin is absorbed from the gastrointestinal tract and is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, particularly CYP2C9. The drug exhibits nonlinear pharmacokinetics due to saturation of metabolic pathways at higher doses. Phenytoin is highly protein-bound, with approximately 90% of the drug bound to plasma proteins. Its elimination half-life can vary widely, typically ranging from 7 to 42 hours, depending on individual metabolic factors.

Contra-indications

• Hypersensitivity to phenytoin or any of its components
• History of acute hepatotoxicity due to phenytoin
• Sinus bradycardia
• Second- and third-degree atrioventricular block

Adverse effects

• Dizziness
• Nausea
• Vomiting
• Ataxia
• Confusion
• Gingival hyperplasia
• Rash
• Hepatotoxicity
• Blood dyscrasias
• Nystagmus

Interactions

• CYP2C9 and CYP2C19 inhibitors and inducers
• Other antiepileptic drugs
• Warfarin
• Oral contraceptives
• Antibiotics such as isoniazid and sulfonamides

Precautions

• Use with caution in patients with liver disease
• Monitor for signs of toxicity, especially in the elderly and those on multiple medications
• Regular monitoring of serum phenytoin levels is recommended
• Consider genetic testing for CYP2C9 polymorphisms in patients with variable drug response

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Folic acid supplementation is recommended.

Breast-feeding

Phenytoin is excreted in breast milk. Monitor infants for potential adverse effects.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral capsules
• Oral suspension
• Injectable solution

Mechanism of action

Although phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated. Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels. Phenytoin is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes. More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials. The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. In neurons, phenytoin decreases sodium and calcium ion influx by prolonging channel inactivation time during generation of nerve impulses. Phenytoin blocks the voltage-dependant sodium channels of neurons and inhibits the calcium flux across neuronal membranes, thus helping to stabilize neurons. It also decreases synaptic transmission, and decreases post-tetanic potentiation at the synapse. Phenytoin enhances the sodium ATPase activity of neurons and/or glial cells. It also influences second messenger systems by inhibiting calcium-calmodulin protein phosphorylation and possibly altering cyclic nucleotide production or metabolism. Phenytoin may act to normalize influx of sodium and calcium to cardiac Purkinje fibers. Abnormal ventricular automaticity and membrane responsiveness are decreased. Also, phenytoin shortens the refractory period, and therefore shortens the QT interval and the duration of the action potential. Exact mechanism is unknown. Phenytoin may act in the CNS to decrease synaptic transmission or to decrease summation of temporal stimulation leading to neuronal discharge (antikindling). Phenytoin raises the threshold of facial pain and shortens the duration of attacks by diminishing self-maintenance of excitation and repetitive firing. Phenytoin's mechanisms of action as a muscle relaxant is thought to be similar to its anticonvulsant action. In movement disorders, the membrane stabilizing effect reduces abnormal sustained repetitive firing and potentiation of nerve and muscle cells. A number of studies suggest that keratinocyte growth factor (KGF) plays a major part in reepithelialization after injury, via binding to the specific KGF receptor (KGFR). Several pharmacological agents, including the anti-epileptic drug phenytoin (PHT), have been widely used clinically to promote wound healing. Although the mechanism of action of PHT in this process is still not well understood, it is possible that the activity of PHT in wound healing is mediated via KGF and the KGFR. In the present study, using the enzyme-linked immunosorbant assay and flow cytometry we have shown that PHT increases KGF secretion and KGFR expression by more than 150% in gingival fibroblasts and epithelial cells, respectively. Moreover, semi-quantitative reverse transcriptase-polymerase chain reaction analysis showed that PHT also markedly increased both KGF and KGFR gene transcription by these cells.

Pharmacodynamics

Phenytoin is an anticonvulsant with a narrow therapeutic index. Although the recommended therapeutic range is cited to be between 10-20 mg/L, differences in albumin levels, genetics, comorbidities, and body composition can make achieving an ideal phenytoin dose challenging. For example, studies have confirmed that phenytoin metabolism is impacted by CYP2C9 genotype polymorphisms and possibly by CYP2C19 genotype polymorphisms (the latter has not been as extensively studied). It is worth nothing that although phenytoin is highly protein bound, only the fraction unbound is able to exert a pharmacological effect. Therefore, factors that reduce or increase the percentage of protein bound phenytoin (for example: concomitant administration of drugs that can cause displacement from protein binding sites) can have a marked impact on phenytoin therapy.