Epilepsy treatment

pharmacology treatment of Epilepsy

1. Pharmacology of Antiepileptic DrugsPharmacology of Antiepileptic Drugs

2. Basic Mechanisms UnderlyingBasic Mechanisms Underlying
Seizures and EpilepsySeizures 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 SeizuresPartial Seizures
 Simple
 Complex
 Secondary generalized
localized onset can be determined

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

5. Complex Partial SeizuresComplex 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 SeizuresSecondarily 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 SeizuresGeneralized 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 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

9. Generalized Seizures (cont)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)

10. • 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
•
Generalized Tonic-Clonic Seizures Generalized Tonic-Clonic Seizures

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

12. Antiepileptic DrugAntiepileptic 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

13. Therapy Has Improved SignificantlyTherapy 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

14. Current PharmacotherapyCurrent 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

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

16. General Facts About AEDsGeneral 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

17. Classification of AEDsClassification 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

18. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzo-
diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira-
mate, valproate; the result is increased permeability to chloride ion,
which reduces neuronal excitability. Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.
(2) Reducing cell membrane permeability to voltage-dependent
sodium channels: carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to calcium T-channels:
valproate, ethosuximide; the result is diminishing of the generation
of action potential.
(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.

19. Carbamazepine
Lamotrigine
Oxcarbazepine
Phenytoin
Topiramate
Valproate
Ethosuximide
Levetiracetam
Pregabalin
Valproate
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin
(
Na
+
)(
Ca
2+ %
GABA

20. Side effect issuesSide effect issues
•Sedation - especially with barbiturates
•Cosmetic – phenytoin (hirsutism gingival
hyperplasia-porphyria)
•Weight gain – valproic acid, gabapentin
•Weight loss - topiramate
•Reproductive function – valproic acid
•Cognitive - topiramate
•Behavioral – felbamate, leviteracetam
•Allergic - many

21. Stevens–Johnson syndrome

22. Cellular Cellular
Mechanisms of Mechanisms of
Seizure GenerationSeizure Generation

23. Targets for AEDsTargets 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

24. Epilepsy—GlutamateEpilepsy—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

25. Epilepsy—GlutamateEpilepsy—Glutamate

26. Glutamate Receptors as AED TargetsGlutamate 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

27. FelbamateFelbamate
•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

28. TopiramateTopiramate
•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)

29. Epilepsy—GABAEpilepsy—GABA
 Major inhibitory neurotransmitter in the
CNS
 Two types of receptors
–GABA
A
—post-synaptic, specific
recognition sites, CI
-
channel
–GABA
B
—presynaptic autoreceptors,
also postsynaptic, mediated by K
+

currents

30. GABAGABA
AA Receptor Receptor

31. ClonazapamClonazapam
•-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)

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

33. PhenobarbitalPhenobarbital
–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

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

35. Na+ Channels as AED TargetsNa+ 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

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

37. 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
AEDs That Act Primarily on Na+ AEDs That Act Primarily on Na+
ChannelsChannels

38. PhenytoinPhenytoin
•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

39. CarbamazapineCarbamazapine
•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

40. OxcarbazapineOxcarbazapine
•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

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

42. LamotrigineLamotrigine
•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)

43. CaCa
2+2+
Channels as Targets 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) Ca
2+
currents

44. EthosuximideEthosuximide
•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

45. Gabapentin Gabapentin and its second generation and its second generation
derivativederivative Pregabalin 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

46. What about K+ channels?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)

47. Valproate (Valproic Acid)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)

48. Regulation of Neurotransmitter releaseRegulation 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:

49. LevetiracetamLevetiracetam
•-Add-on therapy for partial seizures
•-Short half-life (6-8h)
•-CNS depression

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

51. Drug InteractionsDrug 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.

52. Pharmacokinetic ConsiderationsPharmacokinetic 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.

53. AED Treatment OptionsAED Treatment Options
MyoclonicTonic
Primary generalized seizuresPartial seizures
Simple
Complex
Secondary
Generalized
Ethosuximidephenytoin, carbamazepine, phenobarbital,
gabapentin, oxcarbazepine, pregabalin
valproic acid, lamotrigine, topiramate,
(levetiracetam, zonisamide)
Tonic-
Clonic
AtonicAbsence
Check notes

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

55. MAIN INDICATIONS OF ANTIEPILEPTIC DRUGS

56. Alternative methods
for treatment of epilepsy:
• Neurosurgery +
laser therapy

57. Questions?Questions?