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 many patients whose seizures have been completely controlled for two or more years can be successfully withdrawn from anti-epileptic meds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
Oxcarbazepine
Newer drug, closely related to carbamazapine
- approved for first line monotherapy or add on therapy in partial seizures
- slows the rate o fNa channel recovery
- may also augment K+ channels and block Ca
- as effective and better tolerated than carbamazpine, + fewer interactions
- metabolized in liver
- some induction of P450 but much less than carbamazapine
- low side effect profile –> sedating but otherwise less toxic than carbamazpine
Eslicarbazepine acetate
Similar to carbamazepine and oxcarbazpine –> blockade of fast acting voltage gated sodium channel, but a greater affinity for the inactive state rather than the resting state (waiting to fire), meaning that it could be more selective for rapidly firing neurons
- may selectively target the area of the brain where the focal seizure occurs, causing fewer neurologic side effects overall
- a pro drug that is rapidly metabolized almost exclusively into S-licarbazepine = the biologically active drug
- favorable drug-drug interaction profile –> low protein binding and minimal effect on the p450 system
- decreases OCP availability
- well tolerated –> most common dose related side effects = dizziness, somnolence, headache, nausea/vomiting
- once daily dosing
- no autoinduction of metabolism
Lacosamide
Add on therapy for poorly controlled partial onset seizures
- well tolerated
- dizziness was the most common side effect
- mechanism of action is unclear –> appear to change shape of Na channel thus slowing rate of synaptic transmission
GABAergic transmission
Excessive neuronal firing may occur as a consequence of either decreased inhibition or increased excitation of neurons. g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the forebrain and opens ligand-gated Cl- channel hyperpolarizing neurons and rendering epileptic firing less likely. In experimental animals, increased GABA-mediated inhibition has antiepileptic activity, whereas decreased inhibition can lead to seizures. GABAA receptors contain binding sites for both the benzodiazepines and barbiturates.
- GABAa receptor opening allows an influx of Cl- –> membrane hyperpolarizes –> reduces likelihood of firing of the neuron
Enhanced GABAergic transmission
- Benzos = diazepam + lorazepam
- Barbiturates = phenobarbital
- newer agents –> target to presynapse, no real effective agent in widespread use (tiagabine, vigabatrin)
Benzodiazepenes
GABA potentiating –> enhance the effectiveness of GABA mediated inhibition –> increases the frequency of Cl- channel opening when GABA is bound to receptor
- dual effect of suppressing the seizure focus by raising the threshold of the action potential + strengthening surround inhibition
Diazepam = agent of choice for tx of status epilepticus –> IV infusion for acute treatment
- effective in the tx of partial and tonic-clonic seizures but are not first line choice (fourth line)
- prominent adverse effects = sedation, dizziness, ataxia, drosiness and tolerance (may lose effectiveness in as little as 6 months)
- typically used only to ablate seizures acutely
Barbiturates = phenobarbital
Phenobarbital binds to an allosteric site on the GABAA receptor and thereby potentiates the action of endogenous GABA by greatly increasing the duration of Cl- channel opening. This enhancement of GABA-mediated inhibition, similar to that of the benzodiazepines, may explain the effectiveness of phenobarbital in the treatment of partial seizures and tonic–clonic seizures. It is used primarily as an alternative drug in the treatment of partial seizures and tonic–clonic seizures.
- GABA-mimetic and potentiating effects –> interacts with the GABAa at a binding site adjacent to the CL- channel, separate from the benzo site
- effective in tx of partial seizures and tonic-clonic seizures –> used primarily as an alternative drug
- heavily sedating, cognitive effects, tolerance and withdrawal
- clinical use has been decreasing as more effect drugs have become available
Gabapentin + pregabalin
Act specifically on voltage gated ca channel subunit
- may reduce excitatory NTM
- synthesized as a GABAergic substance, structurally related to GABA but does not interact with GABAa or b receptors
- used in add on therapy for partial seizures and tonic-clonic seizures
- approved for kids
- advantages –> no notable interactions with other drugs low to no binding of plasma proteins,, well tolerated, limited side effects, less sedating than classic AEDs
Tonic-clonic seizures
Drugs that act on Na channels or enhance GABA transmission are useful in the tx of tonic-clonic seizures
broad spectrum agents:
Valproat, lamotrigine, topiramate, levetiracetam, zonisamide
Valproate
Acts pleiotropically
- inhibits low threshold t type ca channels
- slows the rate of NA channel recovery
- increases the availability of GABA at the synapse
Multiple uses = broad spectrum
- generalized (first line)
- partial
- absences seizures
Interactions
- valproate and carbamazepine induce each others metabolism
- inhibits phenobarbital metabolism
- displaces phenytoin from binding proteins –> contributes to toxicity of phenytoin
Valproate - side effects
- sedation
- weight gain
- tremor
- hair loss
- elevated liver enzymes
- GI disturbances
- pregnancy = teratogenic –> linked to autism disorders, sensory deprivation disorders and spina bifida
Lamotrigine
Broad spectrum of activity makes it useful as add on or monotherapy in partial and secondarily generalized tonic-clonic seizures
Mechanism –>
- slows rate of recovery of voltage gated Na channels
- inhibition of glutamate release
- potential inhibition of Ca channels
Overall very well tolerated –> rash if started too quickly
- less sedating than other AEDs
Metabolized by glucoronidation
Zonisamide
Pleiotropic mechanism
- include blockade of sodium channels
- reduction of voltage dependent T-type ca currents
- reduction of glutamate induced synaptic transmission
Broad spectrum anticonvulsant = efficacious as adjunctive tx for many seizure types
- fda approved for use only in partial onset seizures, but dramatic improvement with generalized onzet seizures, especially myoclonus
Very long half life (1-3 days) –> once daily dosing
Sulphonamide group of drugs –> use is contraindicated in patients with a known sulfonamide allergy
Inhibition of glutamate transmission
AMPA and NMDA receptors
- topiramate - highly pleiotropic
- felbmate
- synaptic transmission = levetiracetam
Topiramate
Broad spectrum agent effecting in treating
- partial
- generalized tonic-clonic
- some myoclonic seizures
- ineffective for absence
Multiple mechanisms
- glutamate receptor antagonism
- GABA potentiation
- Na and Ca channel blockage
- carbonic anhydrase inhibition
Minimal drug interactions and side effect profile
Felbamate
Extremely potent anti-epileptic –> inhibition of the NMDA and AMPA subtypes of glutamate receptors
- Lacks sedative effects, but adverse behavioral effects observed
- associated with a number of cases of fatal aplastic anemia and liver failure
- use is restricted to patients with refractory epilepsy
Levetiracetam
Braod spectrum AED with a novel mode of action
- modulates synaptic vesicles enhancing release of GABA
- suggestion that it might also prevent epileptogenesis
Demonstrate a number of the characteristics of a new ideal anti-convulsant
- effective at the initial dose = important if the patient is experiencing frequent seizures
- dose escalation can be fairly rapid
- no known interactions with any AEDs
- good safety profile and appears to be well tolerated
Absence seizures
Associated with the activation of the T type calcium channels during the awake state –> primary target in the treatment of these seizures
- ethosuximide
- valproate
- newer = zonisamide
Ethosuximide
highly specific molecular profile –> acts specifically on t type channels in the thalamus
first line tx for absence seizures –> very effective, but not effective in the tx of partial or secondary generalized seizures
- no to low plasma protein binding
- less sedating than other AEDs
- overall incidence of adverse effects is low
Drug interaction potential - hepatic enzyme induction
Enzyme inducing AEDs
Carbamazepine (Tegretol)
Phenytoin (Dilantin)
Phenobarbital
Oxcarbazepine (Trileptal)
Topiramate (Topamax)
Non-enzyme inducers
Gabapentin (Neurontin)
Levetiracetam (Keppra)
Lamotrigine (Lamictal)
Tiagabine (Gabitril)
Zonisamide (Zonegran)
Valproate(Depakote)
Pregabalin (Lyrica)
Lacosamide (Vimpat)
New generation AEDs - major systemic side effects
topiramate
- Renal stones
- Cognitive/language difficulties
- OCP interaction
oxcarbazepine
- Hyponatremia (may be asymptom)
- OCP interaction
levetiracetam
- Mood irritability/psychosis
zonisamide
- Renal stones
- Anhydrosis
Alternative uses for AEDs
Neuropathic pain
- Gabapentin/pregabalin,
- Carbamazepine/oxcarbazepine
- Lamotrogine,
- Levetiracetam
- Valproate
Bipolar disorder
- Lamotrogine,
- Carbamazepine
- Valproate
Migraine
- valproate,
- topirimate,
- gabapentin
