Properties |
Influence on ICU management |
Chemical properties |
- Sodium salt has decent water solubility
- The injectable solution has a pH of 12, and is 40% propylene glycol (and 10% alcohol)
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- Cannot be given IM: as a depot, the phenytoin precipotates and is absorbed slowly and erratically
- When given IV, can be very irritating, and needs to be diluted
- Can only be administered together with saline
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Chemical relatives |
- A derivative of hydantoin
- Other relatives are danrolene and fosphenytoin
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- Cross-hypersensitivity may occur
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Administration |
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- Conveniently available as an oral suspension for NG administration
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Absoption |
- Well absorbed orally
- Bioavailability is ~ 85% (but varies depending on the manufacturer)
- Food influences absorption
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- Usually no need to adjust dose when changing from IV to oral
- Need to cease feeds when administering (2hrs before, 2hrs after) - enterally fed patients should be getting IV phenytoin.
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Distribution |
- Volume of distribution: 0.5-1.0L/kg
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- Susceptible to removal by plasmapheresis and haemoperfusion
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Protein binding |
- Highly protein bound: 90%
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- Not susceptible to haemodialysis
- Higher free levels are to be expected in patients with low albumin (even though total levels may be normal or low)
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Metabolism/elimination |
- Hydroxylated in the liver by a saturable enzyme system
- Enhances its own elimination through enzyme induction
- After administration, most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestine and excreted in the urine
- Zero-order kinetics after enzymes are saturated, and first-order before.
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- Enterohepatic recirculation means there may be a theoretical benefit to multiple dose activate charcoal administration
- Small dose increases may significantly increase the half-life and levels once the enzyme system is saturated
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Half life |
- mean plasma half-life is 22 hours
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- Optimal for once daily dosing
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Mechanism of action |
- "membrane stabiliser"
- blocks voltage gated sodium channels
- Most of the antiepileptic effect takes place at the motor cortex, where it inhibits the spread of seizure activity possibly by promoting sodium efflux from neuron
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- Can also be used as a Class 1 antiarrhythmic
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Indications |
- Control of generalised tonic-clonic seizures
- Prevention of post-TBI seizures
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Contraindications |
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- Levitiracetam is an (expensive) alternative
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Adverse effects |
- Rash (5% to 10% )
- Gum hypertrophy
- Ataxia, nystagmus, slurred speech
- Confusion
- Drug-induced lupus
- Agranulocytosis
- Aplastic anemia
- Hepatitis
- Anticonvulsant hypersensitivity syndrome
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- May consider another agent in a patient with already poor bone marrow function
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Interactions |
- Phenytoin is an inducer of the hepatic cytochrome P450 microsomal isoenzymes CYP3A4, CYP2D6, CYP1A2, CYP2C9 and CYP2C19
- Phenytoin is metabolised primarily by
CYP2C9 (major) and CYP2C19 (minor), thus several drugs may inhibit or induce the
metabolism of phenytoin
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Common ICU drugs which interfere with phenytoin:
- Amiodarone (increased level)
- Erythromycin (increased level)
- Fluconazole (increased level)
- Rifampicin (decreased level)
- Folate supplements (decreased level)
- Fluoroquinolones (decreased level)
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Acute overdose |
- Nystagmus appears at 20 µg/mL
- Ataxia appears at 30 µg/mL
- Nystagmus appears at 20 µg/mL
- The lethal dose in adults is estimated to be 2 to 5g.
- In overdose settings, saturation of the hepatic hydroxylation system occurs and zero order kinetics predominate
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- Activated charcoal is recommended in life-threatening overdose
- Dialysis is of no benefit
- Haemoperfusion or plasmapheresis may have some benefit
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