Pharmacology of Antiepileptic Drugs Melanie K. Tallent, Ph.D. tallent@drexel.edu

Basic Mechanisms Underlying Seizures and Epilepsy  Seizure: the clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons  Epilepsy: a disease characterized by spontaneous recurrent seizures  Epileptogenesis: sequence of events that converts a normal neuronal network into an epileptic network

Partial Seizures  Simple  Complex  Secondary generalized localized onset can be determined  Simple  Complex  Secondary generalized

Simple Partial Seizure Focal with minimal spread of abnormal discharge normal consciousness and awareness are maintained

Complex Partial Seizures Local onset, then spreads Impaired consciousness Clinical manifestations vary with site of origin and degree of spread Presence and nature of aura Automatisms Other motor activity Temporal lobe epilepsy most common

Secondarily Generalized Seizures  Begins focally, with or without focal neurological symptoms  Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases  Typical duration up to 1-2 minutes  Postictal confusion and somnolence

Generalized Seizures In generalized seizures, both hemispheres are widely involved from the outset. Manifestations of the seizure are determined by the cortical site at which the seizure arises. Present in 40% of all epileptic Syndromes.

Generalized seizures Absence seizures (Petit mal): sudden onset and abrupt cessation; brief duration, consciousness is altered; attack may be associated with mild clonic jerking of the eyelids or extremities, postural tone changes, autonomic phenomena and automatisms (difficult diagnosis from partial); characteristic 2.5-3.5 Hz spike-and wave pattern Myoclonic seizures: myoclonic jerking is seen in a wide variety of seizures but when this is the major seizure type it is treated differently to some extent from partial leading to generalized

Generalized Seizures (cont) Atonic seizures: sudden loss of postural tone; most often in children but may be seen in adults Tonic-clonic seizures (grand mal): major convulsions with rigidity (tonic) and jerking (clonic), this slows over 60-120 sec followed by stuporous state (post-ictal depression)

Generalized Tonic-Clonic Seizures Recruitment of neurons throughout the cortex Major convulsions, usually with two phases: 1) Tonic phase: muscles will suddenly tense up, causing the person to fall to the ground if they are standing. 2) Clonic phase: muscles will start to contract and relax rapidly, causing convulsions Convulsions: motor manifestations may or may not be present during seizures excessive neuronal discharge Convulsions appear in Simple Partial and Complex Partial Seizures if the focal neuronal discharge includes motor centers; they occur in all Generalized Tonic-Clonic Seizures regardless of the site of origin. Atonic and absence Seizures are non-convulsive

Video http://www.youtube.com/watch?v=frWcJJkXQFM

Status Epilepticus More than 30 minutes of continuous seizure activity Two or more sequential seizures spanning this period without full recovery between seizures Medical emergency

Antiepileptic Drug  A drug which decreases the frequency and/or severity of seizures in people with epilepsy  Treats the symptom of seizures, not the underlying epileptic condition Goal—maximize quality of life by minimizing seizures and adverse drug effects Currently no “anti-epileptogenic” drugs available

Therapy Has Improved Significantly “Give the sick person some blood from a pregnant donkey to drink; or steep linen in it, dry it, pour alcohol onto it and administer this”. Formey, Versuch einer medizinischen Topographie von Berlin 1796, p. 193

Current Pharmacotherapy Just under 60% of all people with epilepsy can become seizure free with drug therapy In another 20% the seizures can be drastically reduced ~ 20% epileptic patients, seizures are refractory to currently available AEDs

Choosing Antiepileptic Drugs  Seizure type  Epilepsy syndrome  Pharmacokinetic profile  Interactions/other medical conditions  Efficacy  Expected adverse effects  Cost

General Facts About AEDs Good oral absorption and bioavailability Most metabolized in liver but some excreted unchanged in kidneys Classic AEDs generally have more severe CNS sedation than newer drugs (except ethosuximide) Because of overlapping mechanisms of action, best drug can be chosen based on minimizing side effects in addition to efficacy

Classification of AEDs Classical Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproate (valproic acid) Trimethadione (not currently in use) Newer Lamotrigine Felbamate Topiramate Gabapentin/Pregabalin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin

Side effect issues Sedation - especially with barbiturates Cosmetic - phenytoin Weight gain – valproic acid, gabapentin Weight loss - topiramate Reproductive function – valproic acid Cognitive - topiramate Behavioral – felbamate, leviteracetam Allergic - many

Cellular Mechanisms of Seizure Generation emedicine.com

Targets for AEDs Increase inhibitory neurotransmitter system—GABA Decrease excitatory neurotransmitter system—glutamate Block voltage-gated inward positive currents—Na+ or Ca++ Increase outward positive current—K+ Many AEDs pleiotropic—act via multiple mechanisms

Epilepsy—Glutamate  The brain’s major excitatory neurotransmitter  Two groups of glutamate receptors Ionotropic—fast synaptic transmission NMDA, AMPA, kainate Gated Ca++ and Gated Na+ channels Metabotropic—slow synaptic transmission Regulation of second messengers (cAMP and Inositol) Modulation of synaptic activity  Modulation of glutamate receptors Glycine, polyamine sites, Zinc, redox site

Epilepsy—Glutamate

Glutamate Receptors as AED Targets NMDA receptor sites as targets Ketamine, phencyclidine, dizocilpine block channel and have anticonvulsant properties but also dissociative and/or hallucinogenic properties; open channel blockers. AMPA receptor sites as targets Since it is the “workhorse” receptor can anticipate major sedative effects

Felbamate 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, hence is restricted for use only in extreme refractory epilepsy

Topiramate Acts on AMPA receptors, blocking the glutamate binding site, but also blocks kainate receptors and Na+ channels, and enhances GABA currents (highly pleiotropic*) Used for partial seizures, as an adjunct for absence and tonic-clonic seizures (add-on or alternative to phenytoin) Very long half-life (20h)

Epilepsy—GABA  Major inhibitory neurotransmitter in the CNS  Two types of receptors GABAA—post-synaptic, specific recognition sites, CI- channel GABAB —presynaptic autoreceptors, also postsynaptic, mediated by K+ currents

GABAA Receptor

Clonazapam -Benzodiazepine used for absence seizures (and sometimes myoclonic): “fourth-line AED” -Most specific AED among benzodiazepines, appearing to be selective for GABAA activation in the reticular formation leading to inactivation of T-type Ca2+ channels, hence its useful for absence seizures -Sedating; May lose effectiveness due to development of tolerance (≤6 months)

Lorazapam and Diazepam Benzodiazepines used as first-line treatment for status epilepticus (delivered IV – fast acting) Sedating

Phenobarbital Barbiturate used for partial seizures, especially in neonates. Oldest of the currently used AEDs Very strong sedation; Cognitive impairment; Behavioral changes Very long half-life (up to ~5days); #Induces P450 Tolerance may arise; Risk of dependence Primidone, another barbiturate metabolized to Phenobarbital, and Phenobarbital are now seldom used in initial therapy, owing to side-effects

AEDs That Act Primarily on GABA Tiagabine Interferes with GABA re-uptake Vigabatrin (not currently available in US) elevates GABA levels by irreversibly inhibiting its main catabolic enzyme, GABA-transaminase

Na+ Channels as AED Targets Neurons fire at high frequencies during seizures Action potential generation is dependent on Na+ channels Use-dependent or time-dependent Na+ channel blockers reduce high frequency firing without affecting physiological firing

Anticonvulsants: Mechanisms of Action Voltage-gated sodium channel Open Inactivated Na+ Na+ X I I Carbamazepine Phenytoin Lamotrigine Valproate Na+ Na+ A = activation gate I = inactivation gate McNamara JO. Goodman & Gilman’s. 9th ed. 1996:461-486.

AEDs That Act Primarily on Na+ Channels Phenytoin, Carbamazepine Block voltage-dependent sodium channels at high firing frequencies—use dependent Oxcarbazepine Blocks voltage-dependent sodium channels at high firing frequencies Also effects K+ channels Zonisamide Blocks voltage-dependent sodium channels and T-type calcium channels

Phenytoin First-line for partial seizures; some use for tonic-clonic seizures Highly bound to plasma proteins – displaced by Valproate; #Induces P450 resulting in increase in its own metabolism, but its metabolism is also increased by alcohol, diazepam Sedating Fosphenytoin: Prodrug for Phenytoin, used for IM injection

Carbamazapine A tricyclic antidepressant used for partial seizures; some use in tonic-clonic seizures #Induces P450 resulting in increase in its own metabolism; Sedating; Agranulocytosis and Aplastic anemia (elderly); Leukopenia (10% of patients); Hyponatremia; Nausea and visual disturbances

Oxcarbazapine Newer drug, closely related to Carbamazapine, approved for monotherapy, or add-on therapy in partial seizures May also augment K+ channels* Some #induction of P450 but much less than that seen with Carbamazapine Sedating but otherwise less toxic than Carbamazapine

Zonisamide Used as add-on therapy for partial and generalized seizures -Also blocks T-type Ca2+ channels* -Very long half-life (1-3days)

Lamotrigine Add-on therapy, or monotherapy for refractory partial seizures Also inhibits glutamate release and (perhaps) Ca2+ channels (=pleiotropic*) Metabolism affected by Valproate, Carbamazapine, Phenobarbital, Phenytoin Less sedating than other AEDs; (Severe dermatitis in 1-2% of pediatric patients)

Ca2+ Channels as Targets General Ca2+ channel blockers have not proven to be effective AEDs. Absence seizures are caused by oscillations between thalamus and cortex that are generated in thalamus by T-type (transient) Ca2+ currents

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 AEDs

Gabapentin and its second generation derivative Pregabalin -Act specifically on calcium channel subunits called a2d1. It is unclear how this action leads to their 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 AEDs

What about K+ channels? K+ channels have important inhibitory control over neuronal firing in CNS—repolarizes membrane to end action potentials K+ channel agonists would decrease hyperexcitability in brain So far, the only AED with known actions on K+ channels is valproate Retiagabine is a novel AED in clinical trials that acts on a specific type of voltage-dependent K+ channel (M-channel)

Valproate (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 P450 CNS depressant; GI disturbances; hair loss; weight gain; teratogenic; (rare: hepatotoxic)

Regulation of Neurotransmitter release Several AED have actions that result in the regulation of neurotransmitter release from the presynaptic terminal, such as lamotrigine, in addition to their noted action on ion channels or receptors. Levetiracetam appears to have as its primary action the regulation of neurotransmitter release by binding to the synaptic vesicle protein SV2A:

Levetiracetam -Add-on therapy for partial seizures -Short half-life (6-8h) -CNS depression

Pleiotropic AEDs Many AEDs act on multiple targets, increasing their efficacy Felbamate, lamotrigine, topirmate, valproate

Drug Interactions 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, in other words they increase their own metabolism. Valproate inhibits cytochrome P450 enzymes.

Pharmacokinetic Considerations Most AEDs undergo complete or nearly complete absorption when given orally. Fosphenytoin (prodrug) may be administered intramuscularly if intravenous access cannot be established in cases of frequent repetitive seizures Diazepam (available as a rectal gel) has been shown to terminate repetitive seizures and can be administered by family members at home. Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproate are available as IV preparations for emergency use. Most AEDs are metabolized in the liver (P450) by hydroxylation or conjugation. These metabolites are then excreted by the kidney. Gabapentin undergoes no metabolism and is excreted unchanged by the kidney.

Treatment of Epilepsy First consideration is efficacy in stopping seizures Because many AEDs have overlapping, pleiotropic actions, the most appropriate drug can often be chosen to reduce side effects. Newer drugs tend to have less CNS depressant effects. Potential of long-term side effects, pharmokinetics, and cost are other considerations

Treatment of Epilepsy Monotherapy is preferred: better patient compliance, less adverse effects Add-on therapy is often necessary to eliminate “break-through” or refractory seizures

Primary generalized seizures AED Treatment Options Partial seizures Primary generalized seizures Tonic- Clonic Simple Complex Secondary Generalized Tonic Myoclonic Atonic Absence phenytoin, carbamazepine, phenobarbital, gabapentin, oxcarbazepine, pregabalin Ethosuximide Check notes valproic acid, lamotrigine, topiramate, (levetiracetam, zonisamide)

Status Epilepticus More than 30 minutes of continuous seizure activity Two or more sequential seizures spanning this period without full recovery between seizures Medical emergency

Status Epilepticus Treatment Diazepam, lorazapam IV (fast, short acting) Followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established

Alternative Uses for AEDs Gabapentin/pregabalin, carbamazepine—neuropathic pain Lamotrogine, carbamazepine—bipolar disorder Leviteracitam, valproate, topirimate, gabapentin—migraine

Questions?