Mechanism Of Action of Phenytoin
Acts by various mechanisms.
Membrane stabilizing effect
Most important, as belongs to sodium channel blockers, preventing the influx of sodium during resting state and depolarization.
Activation of sodium potassium ATPase
In hyper excitable state, increase in sodium in cells leads to activation of Na K ATPase to bring back concentration to resting level. In patients of epilepsy, decrease in activity of Na K ATPase occurs, phenytoin causes increase in the enzyme so increase outflux of Na+ occurs, along with increased influx of K+ ions.
Delayed potassium Conductance
Out flux of potassium is responsible for repolarization. Phenytoin Na delays potassium conductance, there will be increase in refractory period of cells. This contributes to increased refractory period of cells.
Decrease post-tetanic potentiation
Stimulation of pre-synaptic neurons followed by activation of post-synaptic neurons is responsible for spread of impulses to other parts of brain. Increase in spread of impulses to neighboring areas leads to decrease in entry of calcium in nerve membrane.
Decrease in release of noradrenaline is very important for post tetanic potentiation.
Increase GABAergic transmission
Very small effect.
- pK value is 8.3-9.5
- Drug is basic and is ionized in acidic medium so less absorbed from stomach.
- Absorbed mainly from small intestine.
- Plasma protein binding of drug occurs after about 3-12 hours.
- After absorption, drug is distributed to all body compartments.
- Plasma protein binding is up to 90% (extensive).
- Concentration in CSF is equal to unbound fraction in plasma.
- Concentration is increased in certain conditions, especially neonates, uremia, hypoalbunemia
- When fraction of drug bound to plasma proteins is decreased, increased levels of drug in plasma leads to toxicity, so have to decrease the dose of drug.
- Mainly metabolized by liver by hydroxylation. 5% is excreted unchanged in urine.
- As has low therapeutic index, so in low doses, follows 1st order kinetics. Fixed fraction of the drug is excreted in unit time.
- Half life is about 24 hours.
- A small increase in dose may result in zero order kinetics, due to saturation of enzyme system in liver. Half life is then increased up to 60 hours. This may lead to toxicity, thus there is small difference between therapeutic and toxic dose.
- Is also enzyme inducer.
Adverse Effects of Phenytoin
- Patient may be drowsy
- Cerebellar changes
- Vestibular changes
- Behavioral changes
- Peripheral neuritis or neuropathy, characterized by decrease in reflexes.
Depression of myocardium especially on I/V administration.
- May cause anorexia
- Abdominal discomfort
Coarsening of facial features
Children may appear aged
May cause gingival hyperplasia
Increased metabolism of vitamin D
Decreased levels of calcium, may lead to osteomyelitis in adults and rickets in children.
There are two main reasons:
- Interference in vitamin B12 metabolism
- Due to decreased levels of folates, increased hydration.
After prolonged administration, may be reversible or irreversible.
Manifested by skin rashes, articaria.
May cause blood dyscrasias, eosinophilia, basophilia, thrombocytopoenia
Decrease release of insulin leading to hyperglycemia, glycosuria in patients suffering.
Flexion of ring and little finger, due to contraction of palmer aponeurosis.
Fetal Hydantoin syndrome
Due to administration during pregnancy, may cause cleft lip and palate, cardiac abnormality, mental changes, decrease in growth of fetus.
- All types of epilepsy, except Petit mal epilepsy or absence seizures.
- Treatment of neuralgias (pain in nerves)
- Treatment of digitalis induced arrhythmias.
- Can increase the metabolism of other anti-epileptics
- Can increase the metabolism of anti-coagulants, antibiotics, quinidine and levo dopa.
- Plasma concentration of phenytoin is increased if in combination with enzyme inhibitors (cimetidine, isoniazid, sulphonamides)
As the drug has narrow therapeutic index, small increase in dose leads to toxicity, thus have to monitor plasma levels.
5-6 mg/kg body weight. Start gradually then increased. Dose is adjusted where seizures are controlled or toxic effects start appearing.
As drug is taken for whole life, phenytoin plasma concentration is maintained above 10µg/ml.
Maximum plasma levels which can be maintained are up to 20-40 µg/ml.
Water soluble derivative of phenytoin, which is a prodrug, so given parenteral.
Prefer in status epilepticus –more chances of cardiac toxicity by phenytoin so preferred.