by: Dr. Vishal Pawar, MD Pharmacology All the recent updates regarding antiepileptics, composed into a single ppt presentation to make researching and learning easier

1. By Dr. Vishal Pawar
Jr II
Dept. of Pharmacology

2.  Epilepsies are common and frequently devastating disorders
 More than 40 distinct forms of epilepsy have been identified
 Approximately 1% of the world’s population has epilepsy
 Third most common neurologic disorder after dementia and stroke
 Epileptic seizures often cause transient impairment of consciousness,
leaving the individual at risk of bodily harm and often interfering with
education and employment

3.  Term Seizure refers to a transient alteration of behavior due to the
disordered, synchronous, and rhythmic firing of populations of brain
neurons
 Term Epilepsy refers to a disorder of brain function characterized by
periodic and unpredictable occurrence of seizures
 Seizures can be "non-epileptic" when evoked in normal brain by
treatments such as electroshock or chemical convulsants, or "epileptic"
when occurring without evident provocation
 Pharmacological agents in current clinical use inhibit seizures, and thus
are referred to as anti-seizure drugs.
 Whether any of these prevent the development of epilepsy
(epileptogenesis) is uncertain

4.  Epileptic seizures have been classified into
 Partial seizures, those beginning focally in a cortical site
 Generalized seizures, those that involve both hemispheres widely from
the outset
 The behavioral manifestations of a seizure are determined by the
functions normally served by cortical site at which it arises
 For example, a seizure involving motor cortex is associated with clonic
jerking of the body part controlled by this region of cortex

6. ILAE CLASSIFICATION

7. SEIZURE
TYPE
FEATURES CONVENTIONAL
ANTI-SEIZURE
DRUGS
Partial
Seizures
Simple
partial
Diverse manifestations determined by the
region of cortex activated by the seizure
lasting approximating 20-60 seconds. Key
feature is preservation of consciousness.
Carbamazepine,
phenytoin,
valproate
Complex
partial
Impaired consciousness lasting 30 seconds to 2
minutes, often associated with purposeless
movements such as lip smacking or hand
wringing
Carbamazepine,
phenytoin,
valproate

8. Generalized
Seizures
Absence
seizure
Abrupt onset of impaired consciousness
associated with staring and cessation of
ongoing activities typically lasting less
than 30 seconds
Ethosuximide,
valproate,
clonazepam
Myoclonic
seizure
A brief (perhaps a second), shocklike
contraction of muscles that may be
restricted to part of one extremity or may
be generalized
Valproate,
clonazepam
Tonic-clonic
seizure
As described earlier in table for partial
with secondarily generalized tonic-clonic
seizures except that it is not preceded by a
partial seizure
Carbamazepine,
phenobarbital,
phenytoin,
primidone,
valproate

9. Fall into three major categories
 To limit the sustained, repetitive firing of neurons, an effect mediated by
promoting inactivated state of voltage-activated Na+ channels
 To involve enhanced Gamma amino butyric acid (GABA)–mediated
synaptic inhibition, an effect mediated either by a presynaptic or
postsynaptic action.
Drugs effective against the most common forms of epileptic seizures,
partial and secondarily generalized tonic-clonic seizures, appear to work
by one of these two mechanisms
 Drugs effective against absence seizure, a less common form of epileptic
seizure, work by a third mechanism, inhibition of voltage-activated Ca2+
channels responsible for T-type Ca2+ currents

10.  More than a century ago, john hughlings jackson, the father of
modern concepts of epilepsy, proposed
 That seizures were caused by "occasional, sudden, excessive, rapid
and local discharges of gray matter," and that a generalized
convulsion resulted when normal brain tissue was invaded by seizure
activity initiated in abnormal focus
 The pivotal role of synapses in mediating communication among
neurons in the mammalian brain suggested that defective synaptic
function might lead to a seizure
 That is, a reduction of inhibitory synaptic activity or enhancement of
excitatory synaptic activity might be expected to trigger a seizure

11.  Neurotransmitters mediating the bulk of synaptic transmission in
the mammalian brain are amino acids, with -aminobutyric acid
(GABA) and glutamate being the principal inhibitory and excitatory
neurotransmitters
 Pharmacological agents that enhance GABA-mediated synaptic
inhibition suppress seizures
 Glutamate-receptor antagonists inhibit seizures

13.  Generalized-onset seizures arise from the firing of the thalamus and
cerebral cortex
 Absence seizures have been studied most intensively
 EEG hallmark of an absence seizure is generalized spike-and-wave
discharges at a frequency of 3 per second (3 hz)
 These bilaterally synchronous spike-and-wave discharges, represent
oscillations between the thalamus and neocortex
 This Intrinsic property of thalamic neurons has effect on particular type
of ca2+ current, T-type Ca2+

14.  Channels are activated at a much more negative membrane potential
("low threshold") than most other voltage-gated Ca2+ channels
expressed in the brain
 T-type channels amplify thalamic membrane potential oscillations, with
one oscillation being the 3-hz spike-and-wave discharge of the absence
seizure
 Importantly, the principal mechanism by which anti–absence-seizure
drugs (ethosuximide, valproic acid) are thought to act is by inhibition of
the t-type Ca2+ channels
 Thus, inhibiting voltage-gated ion channels is a common mechanism of
action among anti-seizure drugs, with anti–partial-seizure drugs
inhibiting voltage-activated Na+ channels and anti–absence-seizure
drugs inhibiting voltage-activated Ca2+ channels

17. MOLECULAR
TARGET AND
ACTIVITY
DRUG CONSEQUENCES OF ACTION
Na+ channel
modulators that
enhance fast
inactivation
PHT, CBZ,
Lamotrigine,
felbamate,
OxCBZ,
topiramate, VPA
• Block action potential propagation
• Stabilize neuronal membranes
• Decrease neurotransmitter release, focal
firing, and seizure spread
enhance slow
inactivation
Lacosamide • Increase spike frequency adaptation
• Decrease AP bursts, focal firing, and
seizure spread
• Stabilize neuronal membrane
Ca2+ channel
blockers
VPA, Lamotrigine Decrease neurotransmitter release (N- &
P-types)
Decrease slow-depolarization (T-type) and
spike-wave discharges
Alpha 2 delta
ligands
Gabapentin,
Pregabalin
modulate neurotransmitter release

18. GABAA receptor
allosteric
modulators
BZDs, PB,
Felbamate,
Topiramate, CBZ,
OxCBZ
Increase membrane hyperpolarization
and seizure threshold
Decrease focal firing
GABA uptake
inhibitors/
GABA-
transaminase
inhibitors
Tiagabine,
Vigabatrin
Increase extrasynaptic GABA levels and
membrane hyperpolarization
Decrease focal firing
NMDA receptor
antagonists
Felbamate Decrease slow excitatory
neurotransmission
Decrease excitatory amino acid
neurotoxicity
delay epileptogenesis
Inhibitors of
brain carbonic
anhydrase
Acetazolamide; ,
Topiramate,
Zonisamide
Increase GABA-mediated inhibition
Decrease NMDA-mediated currents

19.  Mainly responsible for more common forms such as juvenile myoclonic
epilepsy (JME) or childhood absence epilepsy (CAE)
 Because most patients with epilepsy are neurologically normal, finding
the mutant genes underlying familial epilepsy in otherwise normal
individuals is of particular interest
 Led to identification of 25 distinct genes implicated in distinct idiopathic
epilepsy syndromes
 Almost all of mutant genes encode for voltage- or ligand-gated ion
channels
 Mutations have been identified in Na+, K+, Ca2+, and Cl– channels, in
channels gated by GABA and acetylcholine, and most recently, in
intracellular Ca2+ release channels

20.  Major application - identification of patients from south east asia who
are HLA-B*1502 positive, putting them at high risk for Stevens–johnson
syndrome from Carbamazepine and elimination of this life-threatening
complication by pretreatment screening
 Implication of genes encoding ion channels in familial epilepsy is
particularly interesting because episodic disorders involving other
organs also result from mutations of these genes.
 For example, episodic disorders of the heart (cardiac arrhythmias),
skeletal muscle (periodic paralyses), cerebellum (episodic ataxia),
vasculature (familial hemiplegic migraine), are linked to mutations in
genes encoding components of voltage-gated ion channels
 Generalized epilepsy with febrile seizures is caused by a point mutation
in the subunit of a voltage-gated Na+ channel (SCN1B)

21.  Ideal anti-seizure drug would suppress all seizures without causing any
unwanted effects
 Unfortunately, the drugs used currently not only fail to control seizure
activity in some patients, but frequently cause unwanted effects
 In 2009, all manufacturers of anti-seizure drugs were required to update
their product labeling to include a warning about an increased risk of
suicidal thoughts or actions and to develop information targeted at
helping patients understand this risk
 As a general rule, complete control of seizures can be achieved in up to
50% of patients, while another 25% can be improved significantly
 Teratogenicity resulting from long-term drug treatment

22.  Phenytoin
Toxicity : cardiac arrhythmias , CNS depression, behavioral changes, GI
symptoms, gingival hyperplasia, osteomalacia, megaloblastic anemia,
hirsutism, fetal hydantoin syndrome
 Phenobarbital
Toxicity : sedation, the most frequent undesired effect , nystagmus and
ataxia, rash
 Carbamazepine
Toxicity : stupor or coma, hyperirritability, convulsions, respiratory
depression, drowsiness, vertigo, ataxia, diplopia, blurred vision, serious
hematological toxicity, hypersensitivity reactions

23.  Ethosuximide
Toxicity : GI complaints, CNS effects (drowsiness, lethargy, euphoria,
dizziness, headache, and hiccough), urticaria, stevens-johnson syndrome,
systemic lupus erythematosus, eosinophilia, leukopenia,
thrombocytopenia, pancytopenia, and aplastic anemia
 Valproic acid
Toxicity : transient GI symptoms, including anorexia, nausea, and
vomiting in ~16% of patients. Effects on the CNS include sedation,
ataxia, and tremor, elevation of hepatic transaminases, fulminant
hepatitis, spina bifida
 Benzodiazepines
Toxicity : drowsiness and lethargy, muscular incoordination, ataxia ,
behavioral disturbances, especially in children, cardiovascular and
respiratory depression

25. Before 1993 1993-2005 2009-2011
Carbamazepine Felbamate Vigabatrin
Clonazepam Gabapentin Rufinamide
Diazepam Lamotrigine Lacosamide
Ethosuximide Levetiracetam Clobazam
Lorazepam Oxcarbazepine Ezogabine
Phenobarbital Pregabalin
Phenytoin Tiagabine
Primidone Topiramate
Valproic acid Zonisamide

26.  Phenyltriazine derivative
 MOA: blocks sustained repetitive firing of spinal cord neurons and
delays the recovery from inactivation of Na+ channels
 Completely absorbed from the gastrointestinal tract and is
metabolized primarily by glucuronidation
 T1/2 of a single dose is 24-30 hours
 Uses: monotherapy and add-on therapy of partial and secondarily
generalized tonic-clonic seizures in adults
 Toxicity: dizziness, ataxia, blurred or double vision, nausea, vomiting,
and rash

27.  Analog of GABA
 MOA: increases release of GABA
 Binds avidly to α2δ subunit of voltage-gated Ca2+ channels,
decreasing Ca2+ entry
 Decreases synaptic release of glutamate
 Not metabolized and does not induce hepatic enzymes, not bound to
plasma proteins, t1/2 5-8 hrs
 Uses: approved by FDA as adjunct for partial seizures and generalized
tonic-clonic seizures

28.  MOA: unknown
 Rapidly and almost completely absorbed after oral administration
 Not bound to plasma proteins
 Uses: approved by FDA for adjunctive therapy for myoclonic, partial-
onset, and primary generalized tonic-clonic seizures in adults and
children
 Toxicity: well tolerated

29.  MOA: inhibits GABA transporter, GAT-1, and thereby reduces GABA
uptake into neurons and glia
 Rapidly absorbed after oral administration, extensively bound to serum
or plasma proteins
 Metabolized mainly in the liver, T1/2 of ~8 hours is shortened by 2-3
hours when co-administered with hepatic enzyme–inducing drugs such
as phenobarbital, phenytoin, or carbamazepine
 Uses: FDA approved as adjunct therapy for partial seizures in adults
 Toxicity: dizziness, somnolence, and tremor

30.  MOA: reduces voltage-gated Na+ currents in cerebellar granule cells
and may act on inactivated state of channel
 In addition, activates a hyperpolarizing K+ current, enhances
postsynaptic gabaa-receptor currents, and limits activation of the
AMPA-kainate-subtype(s) of glutamate receptor
 Rapidly absorbed after oral administration, 10-20% binding to plasma
proteins, t1/2 is ~1 day
 Uses: approved by FDA as initial monotherapy (in patients at least 10
years old) and as adjunctive therapy (for patients as young as 2 years of
age) for partial-onset or primary generalized tonic-clonic seizures
 Toxicity: well tolerated, somnolence, fatigue, weight loss, and
nervousness

31.  MOA: inhibits the T-type Ca2+ channels
 In addition, inhibits sustained, repetitive firing of spinal cord neurons,
presumably by prolonging inactivated state of voltage-gated Na+ Ch

 Completely absorbed after oral administration, has a long t1/2
(~63 hours), and is ~40% bound to plasma protein
 Uses: FDA approved as adjunctive therapy of partial seizures in adults
 Toxicity: well tolerated. The most common adverse effects include
somnolence, ataxia, anorexia, nervousness, and fatigue
 Approximately 1% of individuals develop renal calculi during treatment

32.  MOA: enhances slow inactivation of voltage-gated Na+ channels and
limits sustained repetitive firing
 An injectable formulation is available for short term use when oral
administration is not feasible
 Uses: approved by FDA as adjunctive therapy for partial-onset seizures
in patients 17 years of age and older
 Toxicity: well tolerated, dizziness (25%) and ataxia (6%)

33.  Triazole derivative structurally unrelated to other currently marketed
antiepileptics
 MOA: enhances slow inactivation of voltage gated Na+ channels and
limits sustained repetitive firing, the firing pattern characteristic of
partial seizures
 Uses: approved by the FDA for adjunctive treatment of seizures
associated with lennox-gastaut syndrome (LGS) in children 4 years and
older and adults
 Toxicity: headache, dizziness, fatigue, and gastrointestinal distress,
cardiac conduction disturbances with QT interval shortening

34.  MOA: structural analog of GABA that irreversibly inhibits major
degradative enzyme for GABA, gaba-transaminase
 Thereby leading to increased concentrations of GABA in the brain
 Uses: approved by the FDA as adjunctive therapy of refractory
partial complex seizures in adults and infantile spasms
 Toxicity: permanent, bilateral concentric visual field constriction in
30% or more of patients, fatigue, peripheral neuropathy, edema and
weight gain

35.  MOA: enhancement of potassium currents mediated by a particular
family of ion channels known as KCNQ
 By activating these specific channels on neurons, ezogabine is thought
to reduce brain excitability
 First drug to control seizures by modulation of potassium channels
 Uses: approved by FDA for use as adjunctive treatment of partial
epilepsy
 Toxicity: urinary retention, neuropsychiatric symptoms, dizziness and
somnolence, and QT-interval lengthening

36.  Benzodiazepine
 Unique because of relatively low tendency to produce sedation
 And possibly lower incidence of loss of therapeutic effect over time
 Appropriate for long-term maintenance therapy
 Uses: approved by FDA for adjunctive treatment of LGS in patients 2
years or older
 Toxicity: tiredness and sedation

37.  MOA: noncompetitive, selective (AMPA) receptor antagonist, for
glutamate that mediates fast synaptic transmission in the central
nervous system
 Absorption is rapid and the drug is fully bioavailable
 Long half-life, typically ranging from 70 to 110 hours, which permits
once-daily dosing
 Uses: approved by FDA for the adjunctive treatment of primary
generalized tonic clonic seizures (PGTC seizures) in patients 12 years
of age and above

38.  MOA: proposed - high affinity for selectively binding to synaptic
vesicle protein 2A (SV2A),
 Decreases release of excitatory neurotransmitters and controls
seizures by resetting the balance from excitation to inhibition
 Uses: approved by FDA for adjunctive treatment of partial-onset
seizures in patients 16 years and older
 Toxicity: sedation, fatigue and dizziness

39.  MOA: stabilises inactive state of voltage gated sodium channels,
allowing for less sodium to enter neural cells, which leaves them less
excitable
 Absorbed to at least 90% from the gut, t1/2 10-20 hrs
 Uses: approved by FDA as adjunctive therapy for the treatment of
partial-onset seizures
 Toxicity: tiredness and dizziness, impaired coordination, diarrhoea,
nausea and vomiting, rash

40. Drug Target Condition
Muscimol GABA receptor Epilepsy
Bumetanide Neonatal Seizures
BGG492
(Selurampanel)
AMPA/kainate receptor
antagonism
Refractory partial
Seizures
Ganaxolone GABA receptors Uncontrolled partial
Epilepsy
Buspirone 5-HT1 receptor
partial agonist
Localized Epilepsy

41. YKP3089 Sodium channel
modulation,
↑ GABA release
Resistant
partial onset
Seizures
PRX-00023 5-HT
receptors
Partial Epilepsy
GWP42003-P
(Cannabidiol)
Dravet syndrome
Lennox Gastaut
Syndrome Myoclonic
Epilepsy
VX-765 Caspase-1
inhibitor
Resistant partial
epilepsy

42.  Management of epilepsy has been transformed with numerous drugs
approved
 Issue that remains is how to best tailor drug choice to the individual
patient with epilepsy
 Much work is needed to answer vital common clinical questions, such as
(1) Which drug should be used (first-generation or a new agent)?
(2) Can a certain combination of medications yield better seizure control
than a single agent?
(3) Are trial designs used to approve new drugs clinically meaningful?
 Pharmacogenomics has begun to identify specific populations in whom
certain AEDs may cause serious adverse effects
 Comparative benefit studies among AEDs are now needed

43.  Goodman and Gilman’s, pharmacotherapy of epilepsies, the
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