The Pharmacology of ANTIEPILEPTIC DRUGS

THE PHARMACOLOGY OF ANTIEPILEPTIC DRUGS

Tracy A. Womble, Ph.D.Florida A&M UniversityCollege of Pharmacy and

Pharmaceutical Sciences

EpilepsyA 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.

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) SeizuresA. Simple Partial SeizuresB. Complex Partial SeizuresC. Secondarily Generalized Attack

II. Generalized SeizuresD. Tonic-Clonic SeizuresE. Absence SeizuresF. Atonic SeizuresG. Myoclonic SeizuresH. Infantile SeizuresI. 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

C. Secondarily Generalized Attack

Partial siezure immediately precedes a generalized tonic-clonic (grand mal) seizure

II. Generalized SeizuresBegin 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

Treatment of SeizuresGoals: 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 agentsBlock 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

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







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.





Ethosuximide, Valproic Acid Glutamate Receptor


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







Glutamate Receptor

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The Pharmacology of ANTIEPILEPTIC DRUGS