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What are the mechanisms of seizures?
- Alterations in ion channels in neuronal membranes
- Modification of receptors
- Modifications of gene expression
- Change in ion concentratrions (Na, K, Ca)
- Altered neurotransmitter uptake (GABA, glutamate)
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What are the MOA for medications to treat seizures?
- Blockade of Na channels
- Blockade of Ca channels
- Inhibition of glutamate (NMDA)
- GABA enhancement
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Define seizures
excess excitation or disordered inhibitioin of cortical neuron transmissions
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Which generation of antiepileptics require drug level monitoring?
1st generation
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What are the first generation antiepileptics?
- Phenytoin/Fosphenytoin
- Phenobarbital
- Carbamazepine
- Valproic Acid/Valproate
- Ethosuximide
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What are the 2nd generation antiepileptics?
- Topiramate (Topamax)
- Levetiracetam (Keppra)
- Lamotrigine (Lamictal)
- Oxcarbamazepine (Trileptal)
- Zonisamide (Zonegran)
- Gabapentin (Neurontin)
- Pregabalin (Lyrica)
- Ezobabine (Potiga)
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What is the reason to monitor blood levels of antiepileptics?
to assess efficacy and prevent toxicity
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What are narrow therapeutic index medications?
- Toxic level and therapeutic level are very close together
- Small changes in dose equal large changes in level and hence toxicity
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Which antiepileptics are NTI medications?
- Carbamazepine
- Ethosuximide
- Phenytoin
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What are the FDA approved indications for Phenytoin?
- Seizures during and following neurosurgery
- Generalized tonic-clonic seizures
- Complex partial seizures
- Status epilepticus
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What are the non-FDA approved indications for Phenytoin?
- Neuropathic pain (diabetic and non-diabetic)
- Migraine prophylaxis
- Tachycardia (ventricular and paroxysmal atrial)
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What is the MOA of Phenytoin?
Inhibits the spread of seizure activity in motor cortex by promoting sodium efflux from neurons
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What is the oral bioavailability of Phenytoin sodium?
F = 1
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What are the Phenytoin suspension limitions?
- 1. Precipitates so need to shake well
- 2. Unit dose cups = have to rinse out cup to get full dose
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What is the maximum administration rate of parenteral phenytoin?
50 mg/min
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Why is parenteral phenytoin administration limited?
- Due to IV solution containing 40% propylene glycol
- Rapid administration would cause CV collapse and CNS adverse effects
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Can phenytoin be administered IM?
No, IM may precipitate and cause tissue necrosis and severe pain
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What would you have to do first to treat the patient when administering a loading dose of phenytoin if the patient is in status epilepticus?
Must give another IV agent (benzodiazepine) since it takes time for phenytoin to be administered (cannot be given rapidly due to possible CV collapse).
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What is Fosphenytoin?
A prodrug of phenytoin that is transformed to phenytoin by acid and alkaline phosphatases
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How is dosing of Fosphenytoin expressed?
PE = phenytoin equivalents
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What is the PE conversion to Phenytoin?
Fosphenytoin 1.5mg = Phenytoin 1.0mg = PE 1.0mg
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How can Fosphenytoin be administered?
IV or IM
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What is the maximum administration rate of Fosphenytoin?
150 mg PE/min
- contains no propylene glycol
- can give with dextrose or NS solution
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What are the limitations of using Fosphenytoin?
- Takes 15 minutes to be converted to phenytoin for activity - still need to give IV lorazepam to break acute seizures
- Higher cost
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Describe the distribution of Phenytoin.
- Highly lipophilic drug
- Vd = 0.7 L/kg (higher in obese patients)
- Bound to plasma protein and tissue
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Which fraction of phenytoin is active, bound or unbound?
Only UNBOUND fraction (free phenytoin) is active
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What is the equation for the unbound fraction of Phenytoin?
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How is Phenytoin metabolized?
- CYP 450 enzymes (2C9, 2C19)
- Michaelis-Menten = saturable = non-linear (capacity limited)
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What is the (Km) plasma concentration of Phenytoin at which the rate of metabolism is one-half the maximum?
~ 4 mg/L (adult range 1-15 mg/L)
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What is the maximum rate of Phenytoin metabolim?
~ 500 mg/day (adult range 100-1000 mg/day)
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Discuss the excretion of Phenytoin?
- Average half-life of 24 hours, 7-42 hours
- Only 5% unchanged in urine
- Primarly eliminated as several inactive metabolites (glucoronides)
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What is the therapeutic level of total plasma phenytoin?
10-20 mcg/ml
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What is the therapeutic level of free plasma phenytoin (unbound)?
1-2 mcg/mL
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How does hypoalbuminemia and severe renal insufficiency (CrCl <10 ml/min or dialysis) affect the free fraction of phenytoin?
Free fraction of phenytoin is INCREASED
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What are the indications for a loading dose of phenytoin?
- initiation for acute seizures
- status epilepticus
- reload for low levels
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What is the maximum loading dose for phenytoin?
2000 mg
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