Anti-epileptic drugs Flashcards
What is an anti-epileptic drug?
A drug which decreases the frequency and/or severity of seizures in people with epilepsy –> treats the symptoms of seizures, but NOT the underlying epileptic condition
- currently, no “anti-epileptogenic” drugs are available
- goal = maximize quality of life by minimizing seizures and adverse drug effects
- may not be a life long treatment –> many patients whose seizures have been completely controlled for two or more years can be successfully withdrawn from anti-epileptic meds
~60% of all people with epilepsy can become seizure free with treatment
~20% of seizures can be drastically reduced
~30% of epileptic patients are refractory to currently available medications –> among these patients, a very high proportion suffer from partial seizures
General facts about anti-epileptic drugs
- most have good oral absorption and bioavailability
- most are metabolized in the liver but some are excreted unchanged in the kidneys
- older AEDs generally have more severe CNS sedation (except ethosuximide) and more side effects than newer drugs –> because of overlapping mechanisms of action, best drug can be chosen based on minimizing side effects in addition to efficacy
Anti-epileptic drug development
Prior to 1993, the choice of an anticonvulsant medication was limited to phenobarbital, primidone, phenytoin, carbamazepine, and valproate.
- Although these “traditional” anticonvulsants have the advantage of familiarity as well as proven efficacy, many patients are left with refractory seizures as well as intolerable adverse effects.
- Since 1993, 8 new medications have been approved by the US Food and Drug Administration (FDA), expanding treatment options.
- The newer antiepileptic drugs offer the potential advantages of fewer drug interactions, unique mechanisms of action, and a broader spectrum of activity.
Newer anti-epileptic drugs…
- equally effective as older durgs
- most are better tolerated
- most have fewer interactions with other meds than older drugs
Drug drug interactions of anti-epileptic drugs
- Many AEDs are notable inducers of cytochrome P450 enzymes and a few are inhibitors.
- Of the classic AEDs, phenytoin, carbamazipine, phenobarbital, and primidone are all strong inducers of cytochrome P450 enzymes –>They are autoinducers = increase their own metabolism.
- Valproate inhibits cytochrome P450 enzymes.
Older anti-epileptic drugs
Phenobarbital Phenytoin Ethosuximide Diazepam Carbamazepine Valproate
Newer anti-epileptic drugs
Felbamate Gabapentin Lamotrigine Topiramate Levetiracetam Oxcarbazepine Zonisamide Pregabalin Lacosamide Exlicarbazepine
Selection of AED therapy
AEDs are generally selected according to seizure type
- the simplest drug regimen
- monotherapy vs. polypharmacy –> If seizures continue after drug therapy begins and dose increases are inadvisable because of side effects, one should try at least one and sometimes another drug as monotherapy before considering the use of two drugs simultaneously
Minimize side effects
Cost
Patient compliance
Broad spectrum Anti-epileptics (in order of preference)
Valproate Lamotrigine Topiramate Levetiracetam Zonisamide
Anti-epileptics for generalized onset seizures
Absence - ethosuximide
Myoclonic, atonic, tonic - benzos
Anti-epileptics for tonic-clonic seizures + partial onset seizures (simple + complex)
Carbamazepine Phenytoin Phenobarbital Gabapentin Oxacarbazepine Pregabalin Lacosamide
Na channel blockers
During a partial seizure, neurons undergo depolarization and fire action potentials at high frequencies. This pattern is uncommon during physiological neuronal activity. Thus, selective inhibition of this firing would be expected to reduce seizures with minimal unwanted effects. Selective inhibition of high frequency firing is accomplished by reducing the ability of Na+ channels to recover from inactivation
- Because firing at a slow-rate permits sufficient time for Na+ channels to recover from inactivation, these drugs have little effect or no effect on low frequency firing patterns present in normal physiology
Na channel blockers
- reduces repetitive firing of neurons via use dependent blockade
- prolonged inactivation state of the Na channel leading to increased refractory period
- does not alter the first action potential but rather reduces the likelihood of repetitive action potentials
- neurons retain their ability to generate action potential at the lower frequencies common during normal brain function
Drugs that act primarily on Na channels
- Phenytoin
- Carbamazepine
- Oxcarbazepine
- Lacosamide
Phenytoin
First line for partial seizures –> acts directly on the Na channel to slow the rate of recovery
Lots of side effects and drug interactions
- More than 95% bound to plasma albumin
- inactivated by metabolism in the liver
- induces P450s –> results in increase in its own metabolism
- interactions with many other anti-epileptic drugs
- low doses –> linear relationship between dose and plasma concentration
- higher dose –> transition to a non-linear (zero order) relationship due to enzyme saturation
- small increases in dose can cause large and often unpredictable increases in plasma drug concentration
- different doses in each patients –> must start at low doses and increase them gradually; must be tailored to each patient
Given IV in status epilepticus
Phenytoin side effects
- ataxia
- nystagmus
- incoordination
- confusion
- hirsutism
- facial coarsening
- systemic skin rash
- gingival hyperplasia in 15-50% of patients –> most likely to occur in patients with gingivitis and dental plaque
***side effects at just above therapeutic range
Carbamazepine
First line for partial seizures; some use in tonic-clonic seizures –> acts directly on the Na channel to slow the rate of channel recovery
- often the drug of choice for partial seizures because of its dual action in the suppression of seizure foci and the prevention of spread of activity
- inactivated by metabolism in the liver
- active 10-11 epoxy metabolite may contribute to neurotoxicity
- induces its own metabolism –> rate of metabolism increases during the first three to six weeks of treatment
- larger doses become necessary to maintain constant serum concentrations
- reduces the efficacy of OCPs
Carbamazepine side effects
- sedation
- drowsiness
- headache
- dizziness
- blurred vision
