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

2. 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

3. 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.

4. 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

5. 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

6. 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

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

8. 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.

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

10. 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

11. 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).

12. 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

13. 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)

14. 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.

15. 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.

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

17. 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.

18. 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

19. 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

21. 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

22. 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

23. 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

24. 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

27. 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

28. 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

29. 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.

31. 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.

32. 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

33. 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

34. 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

35. Glutamate Receptor