The Pharmacology of ANTIEPILEPTIC DRUGS Tracy A. Womble, Ph.D. Florida A&M University College of Pharmacy and Pharmaceutical Sciences

Epilepsy A group of chronic CNS disorders characterized by recurrent seizures. Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes. The term “epilepsy” is derived from the Greek word “epilambanein”, which means “to seize upon” or “to attack”. Epilepsy is the most frequent neurodegenerative disease after stroke

Epilepsy There are 2.5 million Americans with epilepsy in the US alone. More than 40 forms of epilepsy have been identified. Therapy is symptomatic majority of drugs prevent seizures, but neither effective prophylaxis or cure is available.

Classification of Epileptic Seizures I. Partial (focal) Seizures Simple Partial Seizures Complex Partial Seizures Secondarily Generalized Attack II. Generalized Seizures Tonic-Clonic Seizures Absence Seizures Atonic Seizures Myoclonic Seizures Infantile Seizures Status Epilepticus

A. Simple Partial Seizures (Jacksonian) Caused by a group of hyperactive neurons exhibiting abnormal electrical activity Confined to a single locus, does not spread Consciousness and awareness preserved Usually confined to a single limb or muscle group, sensory distortions, hallucinations May occur at any age

B. Complex Partial Seizures (Temporal Lobe epilepsy or Psychomotor Seizures) Localized but becomes widespread Complex sensory hallucinations, mental distortion Loss of consciousness Automatisms (lip smacking, swallowing, scratching, or walking about). Motor distortions may involve chewing movements, diarrhea and urination. 80% of individuals who exp. CPS experience initial seizure prior to 20 years old Usually involves limbic system The limbic system is a set of evolutionarily primitive brain structures located on top of the brainstem and buried under the cortex. Limbic system structures are involved in many of our emotions and motivations, particularly those that are related to survival. Such emotions include fear, anger, and emotions related to sexual behavior. The limbic system is also involved in feelings of pleasure that are related to our survival, such as those experienced from eating and sex

C. Secondarily Generalized Attack Partial siezure immediately precedes a generalized tonic-clonic (grand mal) seizure

II. Generalized Seizures Begin locally but spread rapidly, produce abnormal electrical discharge thru both hemispheres Manifestations of the seizure are determined by the cortical site at which the seizure arises. May be convulsive or nonconvulsive, usually loss of consciousnesss.

A. Tonic-Clonic Seizures (grand mal) Major convulsions, most common usually with two phases: 1) Tonic phase 2) Clonic phase

A. Tonic-Clonic Seizures Tonic phase: - Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation Clonic phase: - Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements. Most dramatic of all epileptic seizures Tongue or cheek may be bitten Urinary incontinence is common Begin w/o evidence 2o generalized tonic-clonic are preceded usually by a partial seizure Tx of 1o and 2o are same as for partial seizures

B. Absence Seizures (Petite Mal) Sudden onset and abrupt cessation Brief and abrupt loss of consciousness, vacant stare w/ rapid eye blinking Minor muscular twitching restricted to eyelids (eyelid flutter) and face. short duration (5-10 sec), but may occur dozens or up to 100s x/ day Often begin during childhood 3-5 yrs old (daydreaming attitude, no participation, lack of concentration).

C. Atonic Seizures Sudden loss of postural tone If seated head may drop forward Not usually seen in adults Usually wear helmets to prevent injury

D. Myoclonic Seizures Short episodes of muscle contractions Rare, occur at any age Often the result of permanent neurological damage (hypoxia, uremia, encephalitis, drug poisoning)

E. Infantile Seizures Young children (3 months – 5 yrs.) Usually accompanied with illness and high fever Frightening to observe, but do not cause death, neurologic damage, or damage Characterized by brief recurrent myoclonic jerks of the body with sudden flexion or extension of the body and limbs.

F. Status Epilepticus when seizures recur within a short period of time , such that baseline consciousness is not regained between the seizures. lasts for at least 30 minutes. May lead to systemic hypoxia, acidemia, hyperpyrexia, cardiovascular collapse, and renal shutdown.

Causes for Acute Seizures Trauma Encephalitis Drugs Birth trauma Withdrawal from depressants Tumor High fever Hypoglycemia Extreme acidosis Extreme alkalosis Hyponatremia Hypocalcemia Idiopathic

Minimize side effects with the simplest drug regimen. Treatment of Seizures Goals: Block repetitive neuronal firing. Block synchronization of neuronal discharges Block propagation of seizure. Strategies: Modification of ion conductances Na+, Ca2+, K+, Cl- Increase inhibitory (GABAergic) activity. Decrease excitatory (Glutamatergic) activity. Minimize side effects with the simplest drug regimen.

Antiepileptic Drugs (mechanism of action) MOA block the initiation of the electrical discharge from the focal area. Prevent the spread of the abnormal electrical discharge to adjacent brain areas Initial drug tx is based on the specific type of seizure tonic-clonic tx differently than absence

Antiepileptic Classification Sodium Channel Blocking agents block sodium channels - Inhibition of rapidly repetitive action potentials, prolongation of Na+ channel inactivation Phenytoin, Carbamazepine, Lamotrigine, Topiramate, Zonisamide Enhance action of GABA Enhancement of GABA mediated inhibition Barbituates (Phenobarbital), Benzodiazepines (Clonazapam, Lorazapam), Vigabatrin, Gabapentin Glutamate receptor antagonism (NMDA, AMPA, or Kainic acid) Phenobarbital, Felbamate, Topiramate T-Calcium channel blockers Inhibition of T type Ca++ current - reduces influx of calcium ions Ethosuximide, Valporate Acid Idiopathic agents Felbamate, Gabapentin, Levetiracetam

Antiepileptic Drugs Sodium Channel Blocking agents Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Topiramate, Zonisamide, Valproic Acid Enhance action of GABA Benzodiazepines, Tiagabine, Vigabatrin, Phenobarbital, Primidone T-Calcium channel blockers Ethosuximide Glutamate Receptor Topiramate, Felbamate

Sodium Channel Blocking agents Block sodium channels, Inhibit the generation of rapidly repetitive action potentials slows rate of voltage activated sodium channels, and reduces influx of calcium ions during depoarization. Carbamazepmine, Phenytoin, Lamotrigine Oxcarbazepine, Zonisamide, Valproic Acid, Sodium Valproate, Pregabalin, Lacosamide

Membrane Potential of a Neuron The normal resting potential of a typical neuron is about –70 mv. An excitatory transmitter substance slightly reduces that polarization – that is, makes the inner surface of the membrane less strongly negative – thereby creating an excitatory postsynaptic potential (EPSP). If the EPSP reaches the threshold level (usually about –50 mv), an impulse (action potential) is triggered. If the transmitter substance had been inhibitory, the membrane could have become hyperpolarized (to perhaps –75 mv), a condition called an inhibitory postsynaptic potential (IPSP) (dashed curve), and no action potential would have resulted; the neuron would slowly have returned to its resting potential after release of the transmitter had ceased

PHENYTOIN Oldest non-sedative antiseizure drug MOA – alters NA+, K+, and Ca2+ conductance, decreases release of glutamate and enhances release of GABA Therapeutic uses – all partial seizures (simple and complex), tonic-cloinc, status epilepticus caused recurrent tonic-clonic. Not effective for absence seizures (may worsen) Adverse effects – CNS depresssion, n/v, CNS depression, gingival hyperplasia, osteomalacia, megaloblastic anemia, Hirsutism, inhibition of ADH, hyperglycemia, nystagmus, ataxia, vertigo Drug interactions Inhibit phenytoin metab. – cimetidine, sulfonamides, isoniazid, dicumarol Increase metab of other drugs by phenytoin – induces P450 system, increase metab of other antiepileptics, anticoagulants, oral contraceptives, doxycycline, cyclosporine, methadona and levodopa

Carbamazepine Action – blocks sodium channels – inhibits generation of repetitive action potentials Therapeutic uses – effective for all partial seizures (simple and complex) often drug of choice. Effective for tonic-clonic seizures, trigeminal neuralgia, exacerbates absence seizures Adverse effects – chronic admin. cause stupor, coma, resp. depression, drowsiness, vertigo, ataxia and blurred vision. Irritating to stomach, n/v, aplastic anemia, agranulocytosis, thrombocytopenia, rash, photosensitivity Drug interactions – hepatic metab is inhibited by cimetidine, diltiazem, erythromycin, isoniazid, propoxyphene

Antiepileptic Drugs Sodium Channel Blocking agents Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Topiramate, Zonisamide, Valproic Acid Enhance action of GABA Benzodiazepines, Tiagabine, Vigabatrin, Phenobarbital, Primidone T-Calcium channel blockers Ethosuximide Glutamate Receptor Topiramate, Felbamate

Enhancement of the action of GABA Benzodiazepines – enhance inhibition of GABA, status epilepticus. Lorazepam, Diazapam, Clonazapam) Topiramate , Phenobarbital and Primidone Tiagabine – blocks reuptake of GABA into neurons , used for partial complex seizures. Side effects include dizziness, somnolence, nervousness nausea and confusion. Gabapentin and Pregabalin - analogue of GABA (no activity) tx of partial seizures in adults Vigabatrin – inhibitor of GABA-transaminase (GABA-T). Inc. GABA in brain. Tx of partial seizures, not used in absence or myoclonic seizures.

Phenobarbital MOA – limits spread of seizures by elevating the seizure threshold, decrease excitability by inducing chloride influx into neurons without inhibiting the sodium influx. Decrease glutamate excitatory response / release, block AMPA, enhance GABA Therapeutic uses - Drug of choice for tx recurrent seizures in children. Effective tx recurrent tonic-cloinic seizures (pts. Who do not respond to diazepam plus phenytoin). Also used as mild sedative to relieve anxiety, nervous tension and insomnia (BZP are superior) Pharmacokinetics – well absorbed orally, penetrates BBB, induces P450 system when admin. p.o. Adverse effects – sedation, ataxia, nystagmus, vertigo, and acute psychotic rxns may occur with chronic use. n/v, morbilliform rash in sensitive individuals. Agitation and confusion at high doses, rebound seizures may occur on discontinuance of Phenobarbital.

Antiepileptic Drugs Sodium Channel Blocking agents Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Topiramate, Zonisamide, Valproic Acid Enhance action of GABA Benzodiazepines, Tiagabine, Vigabatrin, Phenobarbital, Primidone T-Calcium channel blockers Ethosuximide, Valproic Acid Glutamate Receptor Topiramate, Felbamate

Agents that block T-calcium channels Ethosuximide – used for absence epilepsy Inhibits Na+/K+ ATPase , potentiates GABA activity Reduce the low-threshold calcium current (LTCC) or T-(transient) current, relatively safe, nausea, GI irritation, drowsiness, and anorexia. Valproic Acid – effective in partial and absence Na+ channel inactivation Ca++ mediated “T” current attenuation Inhibition of GABA transaminase Agents whose mechanism of action is unknown Felbamate – low toxicity, high incidence of aplastic anemia, inhibitor of voltage dependent sodium channels Gabapentin- analogue of GABA (no activity) tx of partial seizures in adults Levetiracetam – tx of partial onset seizures

Antiepileptic Drugs Sodium Channel Blocking agents Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Topiramate, Zonisamide, Valproic Acid Enhance action of GABA Benzodiazepines, Tiagabine, Vigabatrin, Phenobarbital, Primidone T-Calcium channel blockers Ethosuximide Glutamate Receptor Topiramate, Felbamate

Glutamate Receptor