1. Pharmacology of Antiepileptic Drugs
Melanie K. Tallent, Ph.D.

2. 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

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

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

5. 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

6. 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

7. 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.

8. 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 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

9. 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 sec followed by stuporous state (post-ictal depression)

10. 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

11. Video

12. 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

13. 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

14. 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

15. 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

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

17. 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

18. 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

19. 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

20. Cellular Mechanisms of Seizure Generation
emedicine.com

21. 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

22. 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

23. Epilepsy—Glutamate

24. 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

25. 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

26. 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)

27. 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

28. GABAA Receptor

29. 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)

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

31. 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

32. 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

33. 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

34. 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:

35. 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

36. 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

37. 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

38. 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

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

40. 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)

41. 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

42. 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

43. 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

44. 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)

45. 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)

46. 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:

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

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

49. 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.

50. 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.

51. 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

52. 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

53. 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)

54. 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

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

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

57. Questions?