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abnormalities can also lead to epilepsy. Cortical dysplasia, in which layering of the cortex isdisrupted, is one such condition. In many cases with developmental abnormalities, problems incognition are also apparent. In Fragile X, for example, the leading cause of mental retardation,epilepsy is common. This is a single gene mutation that leads to malformed circuitry andneurons.Antiepileptic drugs (AEDs)An antiepileptic drug decreases the occurrence or severity of seizures in patients withepilepsy. They are also known as anti-convulsants, however, not all seizures are “convulsive”(absence). Currently available AEDs treat the seizures (symptoms) and not the underlyingcondition. However, sometimes patients can be taken off AEDs and remain seizure free. Thegoal with AED treatment is to maximize the quality of life by balancing effectiveness vs. adverseeffects. About 60% of patients become seizure-free on AEDs. Another 20% respond with a largedecrease in seizure frequency/severity. In another 20% seizures are resistant to drug therapy.In choosing an AED, the first consideration is the type of epilepsy, which is defined bythe seizure type. Other considerations are the pharmacokinetic profile, interactions with othermedical conditions or drugs, and of course efficacy and adverse effects. Cost is anotherconsideration, with the newer drugs being more expensive than the older drugs.In general, AEDs have good oral bioavailability, most are metabolized in the liveralthough a few are excreted unchanged via the kidneys. The advantage of the newer drugs isgenerally less CNS sedative effects; the exception is ethosuximide, a classic AED with littlesedating action. Because of overlapping mechanisms of action for many of the drugs, the bestdrug is often the one with the minimal side effects in a given patient. When a single drug doesnot completely control the seizures, add-on therapy can be used. Thus many patients are onmultiple AEDs.The classic AEDs include:PhenytoinPhenobarbitalPrimidoneCarbamazepineBenzodiazapinesEthosuximideValproate (valproic acid)Newer AEDs that have been approved since 1990 include:LamotrigineTopiramateGabapentin/PregabalinTiagabineOxycarbazepineLevetiracetamFosphenytoinFelbamate--“black boxed” due to rare but seriousassociation with aplastic anemia.Vigabatrin (not approved in US)Mechanisms of action of AEDsEffective seizure treatment generally augments inhibitory processes or opposes excitatoryprocesses. As the normal resting neuronal membrane potential is intracellularly negative,inhibitory processes make the neuron more electrically negative, hyperpolarizing the membrane,while excitatory processes make the intracellular potential less negative or more positive,depolarizing the cell. On an ionic level, inhibition is typically mediated by inward chloride oroutward potassium currents, and excitation by inward sodium or calcium currents. Drugs candirectly affect specific ion channels or indirectly influence synthesis, metabolism, or function ofneurotransmitters or receptors that control channel opening and closing (figure below right). Themost important central nervous system inhibitory neurotransmitter is gamma-amino-butyric acid
Felbamate (“Black-boxed”)-Antagonizes the glycine site on the NMDA receptor and blocks Na + channels*-Very potent AED lacking sedative effect (unlike nearly all other AEDs)-Associated with rare but fatal aplastic anemia and hence is restricted for use only in extremerefractory epilepsyTopirimate-Acts on AMPA receptors, blocking the glutamate binding site, but also blocks kainate receptorsand Na + channels, and enhances GABA currents (=highly pleiotropic*)- Used for partial seizures, as an adjunct for absence and tonic-clonic seizures (add-on oralternative to phenytoin)-Very long half-life (20h)GABA receptors as targets. There are also two major classes of GABA receptors,GABAA (ionotropic) and GABAB (metabotropic). GABAA is a chloride channel and mediatesfast inhibitory transmission. GABAB is a G-protein coupled receptor that mediates slow synaptictransmission by activating K + channels; it can also be located presynaptically where it reducesneurotransmitter release. GABAA receptors have several modulatory sites. The benzodiazepines(BZs) and barbiturates bind directly to this receptor. BZs such as clonazapam, lorazapam, anddiazepam increase the frequency of channel openings. Barbiturates such as phenobarbital andprimidone prolong the time of each channel opening.Other AEDs increase GABAergic transmission not by acting on its receptor but by acting onGABA transport or metabolism.Clonazapam-Benzodiazepine used for absence seizures (and sometimes myoclonic): “fourth-line AED”-Most specific AED among benzodiazepines, appearing to be selective for GABA A activation inthe reticular formation leading to inactivation of T-type Ca 2+ channels, hence its useful forabsence seizures-Sedating; May lose effectiveness due to development of tolerance (≤6 months)
Phenytoin-First-line for partial seizures; some use for tonic-clonic seizures-Highly bound to plasma proteins – displaced by Valproate; # Induces P 450 resulting in increase inits own metabolism, but its metabolism is also increased by alcohol, diazepam, methylphenidate-SedatingFosphenytoin-Prodrug for Phenytoin, used for IM injectionCarbamazapine-A tricyclic antidepressant used for partial seizures; some use in tonic-clonic seizures- # Induces P 450 resulting in increase in its own metabolism;-Sedating; Agranulocytosis and Aplastic anemia (elderly); Leukopenia (10% of patients);Hyponatremia; Nausea and visual disturbancesOxcarbazapine-Newer drug, closely related to Carbamazapine, approved for monotherapy, or add-on therapy inpartial seizures-May also augment K + channels*-Some # induction of P 450 but much less than that seen with Carbamazapine-Sedating but otherwise less toxic than CarbamazapineZonisamide-Used as add-on therapy for partial and generalized seizures-Also blocks T-type Ca 2+ channels*-Very long half-life (1-3days)Lamotrigine-Add-on therapy, or monotherapy for refractory partial seizures-Also inhibits glutamate release and (perhaps) Ca 2+ channels (=pleiotropic*)-Metabolism affected by Valproate, Carbamazapine, Phenobarbital, Phenytoin-Less sedating than other AEDs; (Severe dermatitis in 1-2% of pediatric patients)Specific Ca 2+ channel as target. General Ca 2+ channel blockers have not proven to beeffective AEDs. However, a specific type of Ca 2+ channel, called T-type (for transient) channels,are critical in generating the thalamocortical rhythms that underlie absence seizures.Ethosuximide-Acts specifically on T-type channels in thalamus, and is very effective against absence seizures.-Long half-life (~40h)-Causes GI disturbances; Less sedating than other AEDsGabapentin and its second generation derivative Pregabalin-Act specifically on calcium channel subunits called α2δ1. It is unclear how this action leads totheir antiepileptic effects, but inhibition of neurotransmitter release may be one mechanism-Used in add-on therapy for partial seizures and tonic-clonic seizures-Less sedating than classic AEDsK + channels are important in controlling neuronal excitability. They are critical inrepolarization of neuronal membranes during the action potential. Drugs that activate or augmentK + channels should have profound effects on neuronal excitability and the response of theneuron to synaptic input. However, so far, these channels are underutilized when it comes totargets for AEDs.
Valproate (also Valproic Acid)-First-line for generalized seizures, also used for partial seizures-Also blocks Na + channels and enhances GABAergic transmission (=highly pleiotropic*)-Highly bound to plasma proteins; # Inhibits P 450-CNS depressant; GI disturbances; hair loss; weight gain; teratogenic; (rare: hepatotoxic)[Retigabine is a drug currently in clinical trials that works well in “pharmacoresistant” animalseizure models. Retigabine acts on a specific class of K + channel called M-channels, M standingfor muscarinic. This channel is inhibited by muscarinic agonists]Regulation of Neurotransmitter release. Several AED have actions that result in theregulation of neurotransmitter release from the presynaptic terminal, such as lamotrigine, inaddition to their noted action on ion channels or receptors. One AED appears to have as itsprimary action the regulation of neurotransmitter release by binding to the synaptic vesicleprotein SV2A:Levetiracetam-Add-on therapy for partial seizures-Short half-life (6-8h)-CNS depression*AEDs with multiple targets. Many of the aforementioned AEDs are pleiotropic*, that is, theyact via multiple mechanisms. This can obviously increase their efficacy.#Drug Interactions. Many AEDs are notable inducers of cytochrome P450 enzymes and a feware inhibitors. Of the classic AEDs, phenytoin, carbamazipine, phenobarbital, and primidone areall strong inducers of cytochrome P450 enzymes. They are autoinducers, in other words theyincrease their own metabolism. Valproate inhibits cytochrome P450 enzymes.Pharmacokinetic Considerations. Most AEDs undergo complete or nearly complete absorptionwhen given orally. Fosphenytoin (prodrug) may be administered intramuscularly if intravenousaccess cannot be established in cases of frequent repetitive seizures. Diazepam (available as arectal gel) has been shown to terminate repetitive seizures and can be administered by familymembers at home. Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproateare available as IV preparations for emergency use. Most AEDs are metabolized in the liver(P 450 ) by hydroxylation or conjugation. These metabolites are then excreted by the kidney.Gabapentin undergoes no metabolism and is excreted unchanged by the kidney.Summary of Treatments for Different Types of EpilepsyGeneral considerations: monotherapy is always better than polytherapy, because it simplifiestherapy, increasing patient compliance, and also reduces adverse effects. However, add-ontherapy can be necessary to eliminate “breakthrough” or refractory seizures.
Antiepileptic Drugs (AEDs)Partial SeizuresDISORDER PRIMARY AGENT(S) ADJUNCTIVEAGENT(S)Simple, complex, partialWith secondarily generalizedGeneralized SeizuresAbsence seizuresMyoclonic seizurescarbamazepine, phenytoin,oxcarbazepine, phenobarbital,valproate, topiramatelamotrigineEthosuximide, valproate,lamotrigine, clonazepamValproate, clonazepamgabapentin/pregabalin,tiagabine,levetiracetam,zonisamide, felbamate(restricted)topiramate,zonisamide,levetiracetamAtonic seizures Valproate Felbamate (restricted,these and otherseizures associatedwith Lennox-Gastaut);lamotrigineTonic-clonic seizures (notpreceded by partial seizure)Status Epilepticusvalproate, carbamazepine,phenytoin, phenobarbital,primidone,Diazepam, lorazepamfollowed by phenytoin,fosphenytoin, orphenobarbital whencontrol establishedGabapentin,lamotrigine,topiramate, zonisamideTreatment of status epilepticus (SE)SE is a state of continuous seizures. It is defined as at least 30 min of continuous seizureactivity or multiple seizures during this time without full recovery between. It is considered amedical emergency and there is significant risk of age-dependent mortality, if not controlled.Hypoxia, hypotension, acidosis, and hyperthermia can occur. The immediate goal is to stop theseizures as quickly as possible. IV benzodiazapines are the initial drugs of choice (diazepam,lorazepam). These are fast but short-acting, so they should be followed up with longer lastingdrugs, such as fosphenytoin (can be injected IM), phenytoin, or phenobarbital once control isestablished. A rectal formulation of diazepam is available that can be used by non-medicalpersonnel (i.e., parents).