Anti-epileptic drugs. Dr.Ashok Kumar Batham, M.D.,

ANTI-EPILEPTIC DRUGS
Dr Ashok Kumar Batham, M.D.,
Chief Consultant
Dr Batham Pharma Consultants

BROAD CATEGORIES OF AEDS
I. Inhibitors of Excitation (Excitatory Post-Synaptic Potential-EPSP) –
• Sodium Channel Inhibitors – Used in Partial Epilepsy
• Calcium Channel Inhibitors – Used in Generalized Epilepsy
(Absence seizures)
II. Facilitators of Inhibition (inhibitory Post-Synaptic Potential-EPSP) –
• Chloride influx and Potassium efflux
• Mostly used in Partial Epilepsy
12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 3

ANTI-EPILEPTIC DRUGS (AEDs)
• Sodium channel blockers,
• Calcium current inhibitors,
• Gamma-aminobutyric acid (GABA) enhancers,
• Glutamate blockers,
• Carbonic anhydrase inhibitors,
• 𝑰𝒏𝒉𝒊𝒃𝒊𝒕𝒐𝒓𝒔 𝒐𝒇 𝜶2delta Ligands,
• GABA reuptake inhibitors,
• GABA transaminase inhibitors,

ANTI-EPILEPTIC DRUGS (AEDs)
• Glutamate NMDA receptor antagonists,
• Glutamate - AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-
4-propionic acid)/kainate receptor antagonists,
• Enhancers of HCN Channel activity
• Inhibitors of Synaptic Vesicle Protein 2 (SVP2)
• Hormones, and
• Drugs with unknown mechanisms of action.

SODIUM CHANNEL MODULATORS
Drugs - Phenytoin, Carbamazepine, Oxcarbazepine, Valproate, Lamotrigine,
Lacosamide, Topiramate, Felbamate
Effects:
• Block the Sodium Channel through Inactivation-Gate
• Prolong or Delay the recovery of sodium channels from refractoriness
• Control focal firing and spread of rapid repetitive action potentials
• Stabilization of neuronal membrane
• Reduced neurotransmitter release

CALCIUM CHANNEL BLOCKERS
Drugs – Ethosuximide, Valproate, Lamotrigine
Effects:
• Reduced Calcium entry through T-type Calcium Channel
• Reduced pace-maker current (slow depolarization)
underlying thalamic rhythm of spike and wave seen in
Absence Seizures

𝜶2DELTA LIGANDS
Drugs – Gabapentin, Pregabalin
Effects –
Modulation of neurotransmitter release

INHIBITORS OF GABA UPTAKE
Drug - Tiagabine
Effects:
• Increased synaptic GABA levels
• Membrane hyperpolarization
• Reduced focal firing
• Aggravated spike-wave discharges

GABA
GABA REUPTAKE
TIAGABINEGABA TRANSPORTER (GAT-1)
INHIBITORS OF GABA UPTAKE

GLUTAMIC ACID DECARBOXYLASE (GAD)
MODULATORS
Drugs: Gabapentin, Valproic acid
Effects:

GABAA RECEPTOR ALLOSTERIC MODULATORS
Drugs - Benzodiazepines, Phenobarbital, Felbamate, Topiramate,
Carbamazepine, Oxcarbazepine, Ganaloxone, Progesterone
Effects –
• Opening of Chloride-Channel
• Influx of Chloride-Ion (Cl-)
• Increased membrane hyperpolarization
• Inhibition of Neuronal Excitation
• Increased seizure threshold
• Reduced firing

GABA
GABA binding to GABAA
Opening of Chloride-Channel causing
Influx of Chloride leading to
membrane hyperpolarization
Benzodiazepines & Barbiturates
GABAA RECEPTOR ALLOSTERIC MODULATORS

INHIBITORS OF GABA TRANSAMINASE
Drug – Vigabatrin
Effects:

GABA PRODRUG
• Progabide

GABA
SUCCINIC SEMIALDEHYDE
METABOLITES
VALPROATE & VIGABATRINGABA TRANSAMINASE (GABA-T)
VALPROATESUCCINIC SEMIALDEHYDE
DEHYDROGENASE (SSD)

GLUTAMATE NMDA RECEPTOR ANTAGONISTS
Drug – Felbamate
Effects:
• Reduced slow excitatory neurotransmission
• Reduced excitotoxicity caused by Glutamate
• Delayed epileptogenesis

GLUTAMATE - AMPA (ALPHA-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-
4-PROPIONIC ACID)/KAINATE RECEPTOR ANTAGONISTS
Drugs – Phenobarbitone, Topiramate
Effects:
• Reduced fast excitatory neurotransmission

ENHANCERS OF HCN CHANNEL ACTIVITY
Drug – Lamotrigine
Effects:
• Buffers large hyperpolarizing and depolarizing inputs
• Suppresses action potential initiation by dendritic inputs

SYNAPTIC VESICLE PROTEIN 2A (SV2A)
LIGAND MODULATORS
Drug – Levetiracetam
• SV2A important for the availability of calcium-dependent neurotransmitter
vesicles ready to release their content.
• Binding of SV2A by Levetiracetam results in decreased action potential-dependent
neurotransmission, while action potential–independent neurotransmission
remains normal.
Effects:
• Unknown
• Probable decrease of neurotransmitter release 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 20

INHIBITORS OF BRAIN CARBONIC ANHYDRASE
Drugs – Acetazolamide, Topiramate, Zonisamide
Effects:
• Increased HCN mediated currents
• Decreased NMDA-mediated currents
• Increased GABA-mediated inhibition

EXPERIMENTAL MODELS OF SEIZURES
• Maximum Electroshock Seizures
• Minimum Electroshock Seizures (seizure threshold)
• Chemically induced seizures (Pentylenetetrazole, Biccuculine,
Picrotoxin)
• Audiogenic seizures
• Photic seizures

CHEMICAL CLASSIFICATION OF AEDs
• Hydantoins
• Phenytoin sodium
• Fosphenytoin
• Barbiturates (anti-seizure)
• Phenobarbitone
• Iminostilbenes
• Carbamazepine
• Oxcarbazepine
• Eslicarbazepine

Succinimides
• Ethosuximide
• Methosuximide
Valproic acid
• Valproic acid - weak organic
acid
• Sodium valproate – Sodium salt
• Divalproex Sodium - stable
coordination compound of
sodium valproate and valproic
acid

Benzodiazepines
• Clonazepam
• Clobazam
• Diazepam

GABA analogues -
• Gabapentin,
• Pregabalin,
• Vigabatrine,
Nipecotic acid derivative –
• Tiagabine

Pyrollidone -
• Levetiracetam
• Brivaracetam

D-fructose derivative –
• Topiramate
Functionalized amino acid –
• Lacosamide
Dicarbamate –
• Felbamate

Sulfonamides –
• Zonisamide
• Acetazolamide
Triazine –
• Lamotrigine
Triazole –
• Rufinamide

Substituted aniline derivative –
• Ezogabine/Retigabine
Cannabinoid -
• Cannabidiol

Bipyridine –
• Perampanel
Aromatic allylic alcohols –
• Stiripentol

PROBLEMS ASSOCIATED WITH AEDs
Efficacy: Lack of 100% efficacy, Restricted range of effectiveness in different epilepsies, Orphan
epilepsies (Lennox-Gastaut Syndrome, Dravit Syndrome)
Tolerance development: Auto-induction of drug metabolizing enzymes and other mechanisms
ADRs: Drowsiness, Dizziness, Somnolence, Ataxia, Nystagmus, Cognitive disturbances, Behavioral
problems
Long term safety: Hepatotoxicity, Megaloblastic anemia, Osteoporosis, Gingival hypertrophy, Bone
marrow depression, Steven-Johnson Syndrome, Nephrotoxicity, Oculotoxicity
Drug dependence: Withdrawal reactions,
Addiction liability: Benzodiazepines
Drug-Interactions: Due to microsomal enzyme induction as well inhibition
Poor bioavailability: Poor solubility and stability

PHENOBARBITAL (PHENOBARBITONE)
• Most popular AED of the 20th century, used since 1910.
• Potent anticonvulsant with a broad spectrum of action.
• Sparingly used currently, because of its adverse effects and drug interactions.
• Directly acts on GABA-A receptors by binding to barbiturate-binding site that prolongs the
duration of chloride channel opening.
Reduces sodium and potassium conductance and calcium influx and depresses glutamate
excitability.
• PHB is a powerful inducer of the hepatic microsomal enzymes, causes many drug interactions.
• Available as tablets of 15,30,60 and 100 mg, elixir 5 mg/ml and 200 mg/mL solution for
parenteral administration.

PHENOBARBITAL (PHENOBARBITONE)
• Still is a first-line drug for treatment of status epilepticus
• Second-line agent for partial onset and secondarily generalized tonic-clonic seizures.
• Sedation, cognitive slowing and behavior alterations (paradoxical hyperkinesis). are the most
undesirable ADRs.
• Causes psychomotor slowing, poor concentration, depression, irritability, ataxia, and decreased
libido.
• Long-term use of PHB may be associated with coarsening of facial features, osteomalacia, and
Dupuytren contractures.
• Folate deficiency, megaloblastic anemia, and idiosyncratic skin reaction are also reported.
• Hepatitis has been reported secondary to an immune-mediated process.

PRIMIDONE
• Prodrug of phenobarbitone. Introduced in UK in 1950 and in the US in 1954.
• Primidone is absorbed orally. Bioavailability is close to 100%,
• Used for partial onset and secondarily generalized seizures.
• ADRs: Similar to phenobarbitone. Intense sedation, dizziness, and nausea at the
onset of treatment, most likely secondary to administration of the parental
drug. These effects usually clear after 1 week of treatment. A very low dose is
recommended at the onset of treatment.
• Available as 250 mg Tablets.

PHENYTOIN
• Used since 1938.
• Major first-line AED for partial and secondary generalized seizures, Lennox-Gastaut
syndrome, status epilepticus, and childhood epilepsies.
• Not indicated for myoclonus and absence seizures.
• Blocks Sodium Channels and delays recovery of inactivated sodium-channels (keeps
them in latent period for longer time)
• Blocks and prevents post-tetanic potentiation (PTP).
• Limits development of maximal seizure activity, and reduces the spread of seizures.
• Inhibits calcium channels thereby inhibiting voltage-dependent neurotransmission.

PHENYTOIN -ADR
• Drowsiness, ataxia, nystagmus,
• Nausea and vomiting, rash, blood dyscrasias, headaches, vitamin K deficiency,
loss of libido, hormonal dysfunction, and bone marrow hypoplasia
• Gingival hyperplasia and coarsening of the facial features in women
• Osteoporosis
• Megaloblastic anaemia due to folate deficiency
• Teratogenic effects ; cleft palate, cleft lip, congenital heart disease, slowed
growth rate, and mental deficiency

PHENYTOIN – DRUG INTERACTIONS
• Most problematic drug interaction profiles because of (i) Highly protein-bound (>90%)
nature and (ii) Effects on P-450 enzymes.
• PHT levels increased by enzyme inhibitors - isoniazid, cimetidine, chloramphenicol,
dicumarol, and sulfonamides.
• PHT levels lowered by enzyme inducers - vigabatrin (VGB) and amiodarone.
• PHT induces hepatic enzymes and decreases levels of CBZ, ethosuximide, felbamate,
furosemide, cyclosporin A, folate, praziquantel, primidone, tiagabine (TGB), and PHB.
• PHT inhibits metabolism of dicumarol, warfarin, corticosteroids, chloramphenicol, and
quinidine.
• CBZ and PHB have variable and unpredictable effects (ie, increase or decrease) on PHT
levels.
• Valproate (VPA) raises levels of PHT by displacement from PPB site and inhibiting its
metabolism.

PHENYTOIN - STATUS
• Avoided by epileptologists because of ADRs, Drug Interactions and Availability of better
drugs.
• Still prescribed by primary care physicians because of good efficacy, once-a-day dosing,
availability of blood level monitoring facility, availability in injectable form, and
extensive cumulative experience, despite the difficult pharmacokinetics and ADRs.
• Available as capsules (25 mg, 50 mg, 100 mg, 200 mg), chewable tablets (50 mg),
suspension (30 mg/5 mL, 125 mg/5 mL), and injection (250 mg/5 mL).
• Dosing frequency is 1-2 times a day.

FOSPHENYTOIN
• Prodrug of Phenytoin intended for IM and IV administration, approved by the US
FDA in August 1996 as Injection 50 mg/ml x 10 mL (500 mg).
• Converted into active metabolite phenytoin by phosphatases.
• Safer and better tolerated (injection-site and systemic) than PHT and can be infused
3 times faster than IV PHT.
• Indicated for status epilepticus and for short-term parenteral administration when
other routes are not available or inappropriate.
• Cardiovascular depression and hypotension may occur with fosphenytoin.
• Severe burning, itching, and/or paresthesia, mainly in the groin area, have been
associated with rapid infusion. 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 40

CARBAMAZEPINE
• Tricyclic compound (iminostilbene).
• Used in Switzerland since 1963 for trigeminal neuralgia and epilepsy, approved in
in the UK in 1965 and in the US in 1974 for epilepsy.
• First-line AED for partial seizures and generalized tonic-clonic seizures.
• Acts by blocking neuronal sodium channels (i) delay the recovery of sodium
channels to active state, (II) prevent the repetitive firing of the axons, (iii) causes
stabilization of the neuronal membranes, (iv) blocks and prevents post-tetanic
potentiation, (v) limits the development of maximal seizure activity, and (vi)
reduces the spread of seizures.

CARBAMAZEPINE
ADRs:
• Dizziness, diplopia, nausea, ataxia, and blurred vision.
• Rare idiosyncratic adverse effects include aplastic anaemia,
agranulocytosis, thrombocytopenia, and Stevens-Johnson syndrome.
• Asymptomatic elevation of liver enzymes is observed commonly during
the course of therapy in 5-10% of patients.
• Rarely, severe hepatotoxic effects can occur.

CARBAMAZEPINE
Drug Interactions:
• Liver enzyme cytochrome P-4503A4 (CYP3A4) inhibitors - Macrolide antibiotics
(eg, erythromycin and clarithromycin), isoniazid, chloramphenicol, calcium
channel blockers, cimetidine, and propoxyphene, raise blood levels of CBZ.
• Liver enzyme cytochrome P-4503A4 (CYP3A4) inducers - Phenobarbital (PHB),
phenytoin (PHT), felbamate, and primidone, lower CBZ levels.
• CBZ induces its own n metabolism as well as that of TCAs, OCs, Cyclosporin A,
and Warfarin, thus reducing effectiveness.
Formulations:
• Available as tablets (100 mg, 200 mg, 400 mg), chewable tablets (100 mg, 200
mg), extended-release capsules (100 mg, 200 mg, 400 mg), suspension, syrup,
and rectal suppositories.

OXCARBAZEPINE
• Licensed in over 50 countries, first introduced in Denmark in 1993 followed by the
entire EU in 1999 and the USA in 2000.
• Keto analogue of CBZ - 10,11-dihydro-oxocarbamazepine (has a ketone in place of
C-C atoms in dibenzazepine ring).
• Converted into Licarbazepine (prodrug).
• Developed to maintain the benefits and obviating shortcomings of
Carbamazepine.
• Almost completely absorbed on oral administration; can be taken with food.
• Doesn’t cause liver enzyme induction & drug interactions.
• Does not produce the epoxide metabolite (responsible for ADRs of CBZ).12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 44

OXCARBAZEPINE
• Considered a first-line therapy for (i) partial and (II) partial seizures secondarily
generalized) in some countries.
• May aggravate absence seizures, infantile myoclonic epilepsy and juvenile idiopathic
generalized epilepsy.
• Acts by blocking neuronal sodium channels (i) delay the recovery of sodium channels to
active state, (II) prevent the repetitive firing of the axons, (iii) causes stabilization of the
neuronal membranes, (iv) blocks and prevents post-tetanic potentiation, (v) limits the
development of maximal seizure activity, and (vi) reduces the spread of seizures.
• ADRs: Somnolence, headache, dizziness, rash, hyponatremia (2.5% of adults and 7.5%
elderly), weight gain, gastrointestinal (GI) disturbances, and alopecia.
• Available as tablets (150 mg, 300 mg, 600 mg); and frequency of administration is twice
a day.

ESLICARBAZEPINE ACETATE
• Eslicarbazepine acetate is activated to eslicarbazepine (S-licarbazepine)
• Eslicarbazepine is the S-isomer of Licarbazepine, which is the major active
metabolite of Oxcarbazepine.
• Introduced in EU in 2009 and in the USA in 2013 (in 2017 UD FDA extended its
indication for use in children and adolescents 4 to 17 years of age)
• Indicated for partial-onset seizures in adults and children 4 years and older.
• ADRs: Dizziness, somnolence, nausea, headache, and diplopia.
• Available as 400 and 800 mg tablets.

ETHOSUXIMIDE
• Used since 1958.
• Inhibits T-type calcium currents in thalamic neurons.
• T-type calcium currents in thalamic neurons are said to be
responsible for generation of 3-Hz spike - and - wave rhythms
typically seen in absence seizures in thalamic neurons.
• Effective in Absence Seizures (not effective in tonic-clonic
seizures).
• Available as Capsules of 250 mg.

VALPROIC ACID
• VPA is a simple molecule, similar to endogenous fatty acids, used as a solvent, that
was serendipitously found to have anti-epileptic properties in 1882.
• Most commonly used AEDs world over.
• Licensed in Europe in the early 1960s, where it is used extensively.
• Was initially approved for Trigeminal Neuralgia.
• Used in different forms (divalproex sodium, magnesium or calcium salt, and
valpromide), which do not differ significantly.
• Valproate is available 125 mg, 250 mg, and 500 mg delayed-release tablets; 125 mg
and 250 mg sprinkle capsules; 500 mg extended-release tablets; 250 mg/5 mL
syrup; and parenteral preparation for IV injection.

VALPROIC ACID
• Mechanisms of Action:
• Causes selective modulation of voltage-gated sodium currents during
sustained, rapid, repetitive neuronal firing (delays the recovery of
inactivated sodium channels-like phenytoin and carbamazepine).
• Facilitates synthesis of GABA by stimulating Glutamic Acid Decarboxylase
(GAD).
• Blocks GABA degradation by inhibiting GABA Transaminase as well as
Succinic Semialdehyde Dehydrogenase (SSD).

VALPROIC ACID
Effective against a wide range of seizure types.
• Idiopathic generalized tonic-clonic epilepsy-drug of choice.
• Complex partial seizures secondarily generalized.
• Typical absence seizure-drug of choice.
• Juvenile myoclonic epilepsy-drug of choice (can also be use in other types of myoclonus).
• Photosensitive epilepsy-first-line drug
• Lennox-Gastaut syndrome-first-line drug.
• Infantile spasms-second choice.
• Focal epilepsy-as effective as other first-line agents.

VALPROIC ACID
• In utero exposure associated with a lower IQ in children (impaired cognitive function).
Therefore, should not be used as a first-line agent in women of childbearing
potential.
• Metabolic effects- hypocarnitinemia, hyperglycinemia, and hyperammonemia.
• Hepatic failure from VPA is extremely rare in adulthood.
• Most serious idiosyncratic adverse effect is hepatotoxicity- observed mainly in
patients younger than 2 years and with polytherapy.
• Severe sedation or even coma may result from hyperammonemia, typically with
normal liver function tests.
• An underlying urea cycle enzyme defect predisposes to encephalopathy due to acute
hyperammonemia, which may prove fatal.

VALPROIC ACID
• Hair loss or curling of hair may occur.
• Adverse endocrine effects - insulin resistance and change in sex hormone levels
causing anovulatory cycles, amenorrhea, and polycystic ovary syndrome.
• Bone marrow suppression with neutropenia and allergic rashes are rare.
• Acute pancreatitis is rare but potentially fatal and usually reversible.
• VPA is being replaced by newer AEDs because of ADRs.

LAMOTRIGINE
• A triazine compound, chemically unrelated other AEDs.
• Developed as an antifolate agent on the basis of a wrong theory (has weak antifolate
activity unrelated to anti-seizure action).
• Approved in the US in 1994. Recommended for conversion to monotherapy.
• Approved in the US for (i) partial onset and secondarily generalized tonic-clonic
seizures, and (ii) Lennox-Gastaut syndrome.Acts by:
• blocking voltage-dependent sodium-channel conductance delaying recovery of
inactivated sodium channels, and
• inhibiting glutamate release by inhibiting depolarization of the glutaminergic
presynaptic membrane.

LAMOTRIGINE
• Broader range of antiepileptic activities as compared to phenytoin and carbamazepine.
• Effective in
• partial onset and secondarily generalized tonic-clonic seizures,
• primary generalized seizures (ie, absence seizures and primary generalized tonic-clonic seizures),
• atypical absence seizures,
• tonic/atonic seizures, and
• Lennox-Gastaut syndrome.
• Sometimes effective for myoclonic seizures but can cause worsening of myoclonic seizures in some
patients with juvenile myoclonic epilepsy or myoclonic epilepsy of infancy.
• Available as tablets (25 mg, 50 mg, 100 mg, 150 mg, and 200 mg) and chewable tablets (5 mg, 25 mg,
and 100 mg); for administered twice a day.

LAMOTRIGINE
• Produces few CNS side effects.
• Rash (5%) is the main concern with its use.
• Other reported adverse reactions are headache, blood dyscrasias, ataxia, diplopia,
GI disturbance, psychosis, tremor, hypersensitivity reactions, somnolence, and
insomnia.
• Only AED with more than 500 documented pregnancy exposures.
• The International Lamotrigine Pregnancy Registry Update reported 414
monotherapy exposures, giving a risk of 2.9%.
• The North American AED Pregnancy Registry found no overall risk of major
malformations in 684 infants exposed to LTG monotherapy but noted an increased
risk of orofacial clefts.
• The EUROCAT congenital anomaly registers did not find an increased risk of orofacial
clefts for 40 children exposed to LTG monotherapy.

ZONISAMIDE
• Benzisoxazole derivative structurally related to sulphonamides.
• Introduced in Japan in 1989 and the US in 2000 as capsules of 25, 50 and 100
mg.
• Acts on Calcium and Sodium channels.
• Prevents calcium influx in T-type calcium channels (may be effective in
absence seizures and juvenile myoclonic epilepsy).
• Reduces sustained repetitive neuronal firing by delaying the recovery of
sodium channels from inactivated state blocking sodium channels.
• Exerts neuroprotective effects through free radical scavenging.
• Quickly and completely absorbed following oral administration.
• Has a long half-life of 60 hours.

ZONISAMIDE
• Approved by the US FDA for partial seizures in patients 12 years or older. Very
effective treatment for myoclonus, especially in juvenile myoclonic epilepsy.
• Spontaneous abortions and congenital abnormalities in human foetuses in 7% Vs 2-3%
in general population.
• ADRs: Somnolence, fatigue, dizziness, anorexia, headache, ataxia, confusion, speech
abnormalities, mental slowing, irritability, tremor, and weight gain.
• Renal stones in 1.5% of patients.
• Oligohidrosis has been reported in children, mainly as a result of the effect on carbonic
anhydrase.
• Clinically preferred because of effectiveness, and overall good tolerability, once-a-day
dosage due to long half-life, and lack of major drug interactions with other AEDs.12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 57

LACOSAMIDE
• Functionalized amino acid.
• Approved by the US FDA in 2008 as adjunctive therapy of partial-onset epilepsy.
• (R)-enantiomer lacosamide has about twice the potency of the racemic mixture.
• Showed efficacy against hippocampal kindled seizures (similar to phenytoin,
carbamazepine, and valproate).
• Modulates voltage-gated sodium channels by
• selective enhancement of slow inactivation, and
• inhibition of sustained repetitive firing.
• Lacosamide has no effect on AMPA, kainate, NMDA, GABAA, GABAB, or various
dopaminergic, serotoninergic, adrenergic, muscarinic, or cannabinoid receptors
and does not block potassium or calcium currents.

LACOSAMIDE
• ADRs: Dizziness, headache, nausea, and diplopia.
• Excellent pharmacokinetic profile and relative good tolerability make
this drug, easy to use, as an add-on therapy of refractory partial
epilepsy.
• Available as 50 mg, 100 mg, 150 mg and 200 mg film-coated tablets
and 200 mg/20 mL single-use vial for intravenous use

CLONAZEPAM
• Benzodiazepine, approved for treatment of typical and atypical
absences, infantile myoclonic, myoclonic and akinetic seizures.
• Available as 0.5 mg, 1 mg, and 2 mg tablets and as an IV solution.
• Used in the management of status epilepticus.
• Good for patients with concomitant anxiety disorder.
• Has high affinity for GABA-A receptor site than diazepam.
• May have some action on sodium-channel conductance.

CLONAZEPAM
• Withdrawal from clonazepam may induce status epilepticus or
exacerbation of seizures. Psychiatric withdrawal also may occur, manifested
as insomnia, anxiety, psychosis, and tremor.
• ADRs: Sedation, ataxia, hyperactivity, restlessness, irritability, depression,
cardiovascular or respiratory depression. Children and infants may have
hypersalivation.

CLOBAZAM
• Benzodiazepine with 1,5 substitution instead of the usual 1,4-diazepine.
• Compared to other benzodiazepines, its anxiolytic activity is reduced by 80% and sedative
activity reduced by 10-folds.
• Licensed in Europe since 1975 but not available in the US.
• Exhibits agonist action at the GABA-A receptor.
• May affect voltage-sensitive conductance of calcium ions and the function of sodium channels
(delay the recovery from inactivation).
• Used in partial epilepsy.
• ADRs: Sedation, dizziness, ataxia, blurred vision, diplopia, irritability, depression, muscle
fatigue, and weakness.
• Available as 10 and 20 mg tablets and 2.5 mg/mL oral suspension,
• 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 62

GABAPENTIN
• Anti-epileptic and analgesic (for neuropathic pain).
• Approved in the UK in 1993 and in the US in 1994.
• Structural analogue of GABA; however, it does not act on GABA receptor.
• Binds with the alpha2 delta subunit of calcium channels in the cerebral neocortex,
hippocampus, and spinal cord – may be responsible for analgesic property.
• Reduces brain glutamate (excitatory neurotransmitter) levels by:
• Stimulation of Glutamic Acid Decarboxylase (GAD) which converts Glutamic acid into GABA.
• Competitive inhibition of branched chain amino acid transferase, which metabolizes leucine,
isoleucine, and valine to glutamate.
• Increases brain levels of GABA and its metabolites homocarnosine and pyrrolidinone.
• May reduce monoamines and affect serotonin release. 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 63

GABAPENTIN
• Used in partial epilepsy and chronic painful states.
• Relatively well tolerated.
• No significant serious idiosyncratic or systemic adverse effects have been
reported. The incidence of rash is 0.5% and of neutropenia, 0.2%.
Electroencephalographic (EEG) changes and/or angina were found in 0.05%.
No cases of hepatotoxicity have been recorded.
• Available as capsules of 100 mg, 300 mg, 400 mg, and 600 mg and tablets of
800 mg.

PREGABALIN
• GABA analogue with an attached isobutane chain.
• Possesses analgesic, anticonvulsant, and anxiolytic properties.
• Approved in the US by FDA in 2005 for partial onset epilepsy, diabetic
neuropathic pain, post-herpetic neuralgia, neuropathic pain
associatred with spinal cord injury, and fibromyalgia.
• Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and
300 mg; and Oral Solution: 20 mg/mL.

PREGABALIN
• Pregabalin has been used in Europe since 2004 and was approved in the
United States in 2005 as adjunctive therapy for partial seizures in patients
older than 18 years. Efficacy as add-on therapy for partial epilepsy has been
demonstrated in 4 major trials.
• Pregabalin’s lack of drug interactions, lack of plasma protein binding, and
renal excretion make it particularly useful in patients with renal or hepatic
disease and in patients on complex drug regimens.
• Relatively well tolerated. Dizziness and drowsiness are the common side
effects, that are dose dependent, allthough it does have some adverse
effects, particularly in high doses.

PREGABALIN
• Inactive at GABA receptors, including GABA-A, benzodiazepine, t-
butylbicyclophosphorothionate (TBPS), and GABA-B radioligand binding
sites.
• Pregabalin binds with high affinity to both the alpha2 delta-1 and
alpha2 delta-2 subtypes.
• Binding to the alpha2 delta protein are proposed to mediate the
functional effects on calcium currents in activated neurons and on
stimulated neurotransmitter release.
• Consequently reduces release of excitatory neurotransmitters and
peptide neuromodulators under membrane hyperexcitability, which is
postulated to mediate the analgesic, anxiolytic, and anticonvulsant
effect.

TIAGABINE
• Derivative of the GABA uptake inhibitor nipecotic acid.
• Blocks reuptake of GABA from synaptic cleft by inhibition of the GABA transporter-1 (GAT-
1). Causes demonstrable increase in extracellular GABA concentrations.
• Approved in 1998 by the US FDA for use an an adjunct in partial seizures in patients 12
years and above.
• Used in partial and secondarily generalized tonic-clonic seizures as an adjunct to first-line
drugs.
• ADRs: Dizziness, asthenia, nervousness, tremor, depressed mood, and emotional lability.
• Available as tablets of 2, 4, 12 and 16 mg.

VIGABATRIN
• Close structural analogue of GABA.
• Inhibits GABA-Transaminase leading to accumulation of GABA in the brain.
• Approved by the US FDA in 2009 for adjunctive therapy of refractory partial complex
seizures in adults.
• Designated as an “orphan drug’ for infantile spasms. Useful in infantile spasms
particularly in patients with tuberous sclerosis.
• Available in the US under SHARE special distribution program of REMS (Risk
evaluation & Mitigation Strategy), because it causes progressive bilateral
permanent vision loss.
• Does not work in other epilepsies, including myoclonus, Lennox-Gastaut epilepsy.
• May worsen or produce absence seizures. 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 69

VIGABATRIN
• Causes widespread intramyelinic vacuolization throughout the brains of rats and dogs;
not demonstrated in humans.
• Affects the retina in some rodent species.
• Human studies show visual field changes, characterized by loss of peripheral vision
and preservation of central vision in more than 50% of cases.
• Clinical use is restricted because of ADRs.
• Available as 500 mg tablets and 500 mg powder for solution.

FELBAMATE
• Dicarbamate approved by US FDA in 1993.
• Potent anticonvulsant, very effective against partial seizures (including secondarily
generalized) & Lennox-Gastaut Syndrome.
• Reported to cause aplastic anaemia and hepatic failure leading to withdrawal of
approval for general use.
• Blocks the NMDA receptors and voltage-gated calcium channels and sodium-channel
conductance.
• Common adverse effects include insomnia, weight loss, nausea, decreased appetite,
dizziness, fatigue, ataxia, and lethargy.
• Available as 400 and 600 mg tablets and 600 mg/mL suspension.

TOPIRAMATE
• Very potent D-fructose derivative, used in epilepsy since 1996.
• Was initially developed as an antidiabetic
• Mechanisms of action
• Exerts an inhibitory effect on sodium conductance,
• Decreases the duration of spontaneous bursts and frequency of generated action
potentials,
• Enhances GABA by unknown mechanisms,
• Inhibits the AMPA subtype glutamate receptor, and
• Causes weak inhibition of carbonic anhydrase. 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 72

TOPIRAMATE
Currently approved for
(1) partial onset and secondarily generalized tonic-clonic seizures,
(2) primary generalized tonic-clonic seizures, and
(3) Lennox Gastaut syndrome.
• Common adverse effects : ataxia, impairment of concentration, confusion,
dizziness, fatigue, paresthesia in the extremities, somnolence, disturbance of
memory, depression, agitation, and slowness of speech. Many of these subside on
continuation of treatment.
• Adverse effects in children: are somnolence, anorexia, fatigue, and nervousness.

TOPIRAMATE
ADRS:
• Weight loss (>10 Kg) reported by many patients. May be useful in obesity.
• Propensity to cause renal calculi due to inhibition of carbonic anhydrase inhibition. .
• No idiosyncratic severe reactions or allergic rashes have been reported.
• No hepatotoxicity, hematologic toxicity, serious gastrointestinal (GI) toxicity, or
cardiotoxicity have been documented.
• Recently, acute myopia with angle-closure glaucoma has been reported as a rare
adverse event.
AVAILABILITY:
Tablets of 25 mg, 50 mg, 100 mg, and 200 mg, and as Sprinkle Formulations od 15
mg and 25 mg. 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 74

PERAMPANEL
• Glutamate inhibitor.
• Noncompetitively antagonises AMPA (alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid) receptor subtype of glutamate receptors.
• Approved by US FDA for adjunctive treatment for partial-onset seizures (with or
without secondary generalized seizures) in October 2012, and
• Approved for primary generalized tonic-clonic seizures in adults or children aged
12 years or older in June 2015.

PERAMPANEL
• Boxed warning describes serious or life-threatening psychiatric and behavioural
adverse reactions, including aggression, hostility, irritability, anger, and homicidal
ideation and threats.
• Common adverse effects include dizziness (up to 43%), somnolence, headache,
fatigue, and irritability.
• Available as tablets of 2mg,4mg,6mg,8mg,10mg,and12mg; and oral solution 0.5
mg/mL.

LEVETIRACETAM
• Levetiracetam is a piracetam (S-enantiomer pyrrolidone) derivative.
• Developed in the 1980s to enhance cognitive functions and anxiolysis.
• LEV is a unique antiepileptic drug (AED) found effective in several models of
seizures, including
• tonic and clonic audiogenic seizures in mice,
• tonic seizures in the maximum electroshock-seizure test in mice, and
• tonic seizures induced in rodents by chemoconvulsants.
• reduces bicuculline-induced hyperexcitability in rat hippocampal CA3 neurons,
suggesting a mechanism that does not involve release of gamma-aminobutyric
acid (GABA). 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 77

LEVETIRACETAM
• The mechanism of action is possibly related to a brain-specific stereo-
selective binding to synaptic vesicle protein 2A (SV2A).
• SV2A appears to be involved in making calcium-dependent
neurotransmitter vesicles ready to release their content.
• The lack of SV2A results in decreased action potential-dependent
neurotransmission, while action potential-independent neurotransmission
remains normal.

LEVETIRACETAM
Drug Interactions:
• No significant drug interactions have been identified.
• LEV does not inhibit cytochrome P-450 (CYP450) isoenzymes, epoxide hydrolase, or
uridine diphosphate (UDP)-glucuronidation.
ADRs:
• Significant adverse effects are somnolence, asthenia, and dizziness.
• Infection, usually related to upper respiratory tract, has been reported; it was not
associated with changes in WBC count and discontinuation of treatment.
• No serious acute idiosyncratic reactions have been reported, and no evidence of visual
field disturbance has been reported.

LEVETIRACETAM
Status:
• Good overall efficacy, especially in elderly patients.
• Excellent safety profile.
• Useful in patients with hepatic or renal insufficiency.
• No risk of adverse drug interactions in patients on concomitant
medications.
• Available as tablets of 250 mg, 500 mg, 750 mg, and 1000 mg.; and also as
Intravenous (IV) and oral solutions.

BRIVARACETAM
• Selective high affinity for synaptic vesicle protein 2A (SV2A) in the brain
responsible for anticonvulsant effect.
• It is indicated as monotherapy or adjunctive therapy for partial-onset
seizures in adults and children aged 16 y or older (approved by US FDA in
September 2017)
• Available as tablets: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg, Oral
solution: 10 mg/mL, and Injection: 50 mg/5 mL single-dose vial.

RUFINAMIDE
• Triazole derivative structurally unrelated to other AEDs.
• Acts by modulation of the activity of sodium channels and, in particular,
prolongation of the inactive state of the channel.
• Indicated as an adjunctive treatment for seizures associated with Lennox-
Gastaut syndrome in adults and children aged 1 y or older by the US FDA in
November 2008.
• Available as film-coated tablets of 200 and 400 mg, and oral solution 40
mg/mL.

EZOGABINE [RETIGABINE]
• Ezogabine, also known as retigabine internationally, works as a potassium channel
opener.
• Ezogabine was approved by the US FDA in June 2011, as adjunctive therapy in
partial-onset seizures uncontrolled by current medications.
• Both in terms of efficacy and tolerability, ezogabine appears comparable to prior
second-generation AEDs including lacosamide.
• Reported to cause bluish discoloration of skin, pigmentary changes in retina,
dizziness, psychiatric disturbances, including suicidality, difficulty in urination, QT-
prolongation. Being further investigated for safety.
• Available as tablets of 50, 200, 300 and 400 mg.

CANNABIDIOL
• A purified formulation of Cannabidiol (Epidiolex) has been approved by the US
FDA in June 2018 for seizures associated with Lennox-Gastaut syndrome (LGS) or
Dravet syndrome (DS) in patients aged 2 years or older.
• Cannabidiol is a structurally novel anticonvulsant.
• Cannabidiol does not appear to exert its anticonvulsant effects through CB1
receptors, nor through voltage-gated sodium channels.
• Approval was based on results from several clinical trials that compared the
benefits (change in the incidence of drop seizures from baseline) of adding
cannabidiol or placebo to conventional AEDs.
• Available as oral solution 100 mg/mL. 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 84

STIRIPENTOL
• Stiripentol is an aromatic allylic alcohols.
• The drug has been approved by the US FDA approved in August 2018 for treatment of
seizures associated with Dravet syndrome in patients aged 2 years or older who are taking
clobazam.
• Available as capsule: 250 mg or 500 mg, and powder for Oral Suspension: 250 mg or 500
mg.
• No clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.
• Possible mechanisms of action include direct effects mediated through the GABA-A
receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting
increase in blood levels of clobazam and its active metabolite.
• Approval was based on 2 multicentre placebo-controlled double-blind randomized
studies, conducted in 64 patients according to similar protocols. wherein the drug was
found to have a sizeably very high effectiveness as compared to placebo. 12-10-2019Antiepileptic Drugs. Dr.Ashok Kumar Batham, M.D., 85

IMPORTANT PHARMACOKINETIC FEATURES OF AED

AED WITH 80-90% BIOAVAILABILITY
• Phenobarbitone
• Clonazepam
• Clobazam
• Pregabalin

AED WITH BIOAVAILABILITY PROBLEMS
• Carbamazepine
• Gabapentin

AED HAVING ACTIVE METABOLITES
• Primidone Phenobarbitone

• Carbamazepine 10-11Epoxide

• Oxcarbazepine 10-Monohydroxy

• Clobazam N-Desmethylclobazam

ENZYME INDUCING AED
• Phenobarbitone
• Phenytoin
• Carbamazepine
• Oxcarbazepine
• Topiramate

AED WITH MAJOR RENAL ELIMINATION
• Gabapentin
• Levetiracetam
• Topiramate (leser extent)

AED WITH HIGH PLASMA PROTEIN BINDING
• Valproic acid - 85-95%
• Phenytoin - 70-90%
• Tiagabine - 96%
• Carbamazepine - 75%
• Clonazepam/Clobazam – 83-86%

THANK YOU

Anti-epileptic drugs. Dr.Ashok Kumar Batham, M.D.,

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