Novel Drugs for Seizure disorder, Newer Drugs for seizure disorders, Recent Advances in treatment of seizure disorder, Recent Advances in Pharmacotherapy of sizure disorders, Recent Advances in Treatment of epilepsy, Newer Antiepileptics, Newer Anticonvulsants

1. RECENT ADVANCES INTREATMENT OF
SEIZURE DISORDERS
DR MD SHAMIM
PG 3rdYEAR
DEPARTMENTOF PHARMACOLOGY
PATNA MEDICAL COLLEGE, PATNA

2. CONTENTS
• Introduction
• Current therapy and drug targets.
• Need for newer molecules.
• Newer molecules on older targets.
• Newer molecules on novel targets.
• Novel Drug Delivery systems.
• Non pharmacological advances.
• Summary.

3. INTRODUCTION
• The term Epilepsy is derived from the Greek word “Epilambanein , which
means ‘to be seized’.
• Epilepsy is one of the world’s oldest recognized conditions (around 4000 BC)
• Around 900 BC, Punarvasu Atreya described epilepsy as loss of
consciousness.
• Seizure is a transient occurrence of signs or symptoms due to abnormal
excessive or synchron0us neural activity in the brain.
• Epilepsy is a recurrent seizure due to chronic, underlying process.
• Convulsion is a condition in which muscles contracts and relax quickly and
causes uncontrollable shaking of the body.

4. Epidemiological Data
• Second most common neurological disease.
• 70 million people worldwide have epilepsy.
• 90% of epilepsy cases worldwide are found in developing countries.
• In India:
•>12 million people have epilepsy.
•Incidence rate – 2- 6 cases per 10000 population.
•Prevalence rate- 37-51 cases per 10000 population.

5. CLASSIFICATION
FOCAL GENERALISED UNKNOWN
MOTOR NON-MOTOR
TONIC-CLONIC ATONIC MYOCLONIC
ABSENCE
TYPICAL ATYPICAL
SIMPLE COMPLEX

6. 68.7
5.5
4.1
3.6
2.6 1.8
0.5
ETIOLOGY
IDIOPATHIC
DEVELOPMENTAL
HEAD TRAUMA
BRAIN TUMOR
INFECTIONS
DEGENERATIVE
OTHERS

7. NEUROTRA
NSMITTERS
ION
CHANNELS
NEURONAL
ACTIVITY IN
BRAIN
EXCITATORY
Glutamate
INHIBITORY
GABA
EXCITATORY
Na+, Ca2+
INHIBITORY
K+, Cl-
PHYSIOLOGY OF
NEURONALACTIVITY

8. Neuronal Activity In Brain In Seizure
Excitation
Inhibition

9. THERAPEUTIC
TARGETS
ACTION OF GABA
ACTION OF GLUTAMATE
EXCITATORY ION
CHANNELS
INHIBITORY ION
CHANNELS
THERAPEUTIC TARGETS IN SEIZURE DISORDERS

10. THERAPEUTIC TARGETS OF ANTISEIZURE DRUGS

11. CHOICE OF DRUGS IN SEIZURE DISORDERS
TYPES FOCAL GTCS TYPICAL
ABSENCE
ATYPICAL
ABSENCE,
MYOCLONIC,
ATONIC
FIRST LINE LAMOTRIGINE
CARBAMAZEPINE
OXCABAZEPINE
PHENYTOIN
LEVETIRACETAM
LAMOTRIGINE
VALPROICACID
VALPROICACID
ETHOSUXIMIDE
LAMOTRIGENE
VALPROICACID
LAMOTRIGINE
TOPIRAMATE
ALTERNATIVES VALPROICACID
PHENOBARBITONE
TOPIRAMATE
TIAGABINE
ZONISAMIDE
PRIMODINE
PHENYTOIN
CARBAMAZEPINE
OXCARBAZEPINE
TOPIRAMATE
ZONISAMIDE
FELBAMATE
PRIMODINE
CLONZEPAM CLONAZEPAM
CLOBAZM
FELBAMATE
RUFINAMIDE

12. Why we need newer therapies?
Because Older Drugs have:-
• More side effects.
• Troublesome drug interactions.
• Multiple daily doses leading to reduce compliance.
• Effects wane off after some time.
• Teratogenicity.

13. Novel Drugs For Seizure Disorders
Novel Drugs
Novel Drugs At
OlderTargets
Novel Drugs At
NovelTargets

14. NOVEL DRUGS AT OLDERTARGETS
1. GANAXOLONE
2. CENOBAMATE
3. STIRIPENTOL
4. BRIVARACETAM
5. ESLICABAZEPINE ACETATE
6. CLOBAZAM

15. GANAXOLONE
• FDA Approved in March 2022 for the treatment of seizures associated with Cyclin-
Dependent Kinase- like5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and
older.
• It is a neuroactive steroid.
• MOA:
• Exact mechanism in CDD is unknown.
• Positive allosteric modulators of GABAA receptors.
• Dosage:
• ≤28 Kg- Initial dose- 6 mg/Kg tid (18 mg/Kg/day).
Maxm dose- 21 mg/Kg tid (63 mg/Kg/d).
• >28 Kg- Initial dose- 150 mg tid (450 mg/d).
Maxm dose- 600 mg tid (1800 mg/d).
• A/E- Somnolence, Pyrexia, Salivary hypersecretion and Allergy.

16. CENOBAMATE
• FDA Approved in 2020 for the treatment of Partial onset seizures in adult patients.
• MOA-
• Exact mechanism is unknown.
• InhibitingVoltage gated Na+ channel.
• Positive allosteric modulator of GABAA Channel.
• Dosage-
• Initial dose – 12.5 mg OD
• Maintenance dose – 200 mg OD
• Maxm dose - 400 mg OD
• A/E- Hypersensitivity, Somnolence, Dizziness, Fatigue, Diplopia and Headache.
• Other- QT Shortening, Suicidal ideation.

17. STIRIPENTOL
• FDA Approved in 2018 for the treatment of seizures associated with Dravet
syndrome in patients 2 year of age or older.
• MOA:
• Increases GABA Release.
• Inhibits GABA reuptake.
• Extensively bound to plasma proteins.
• Potent inhibitor of CYP3A4, CYP1A2, CYP2C19.
• AdjunctiveTherapy with Sod.Valproate and clobazam.
• Dosage: Initial dose 50 mg/Kg/day PO in 2 or 3 divided doses, increasing up to 100
mg/Kg/day (maximum of 4g/day).
• A/E: Loss of appetite, Drowsiness, Ataxia, Diplopia, Cognitive impairment.

18. BRIVARACETAM
• FDA Approved in Jan 2016 for add-on treatment to other antiepileptics to treat Partial onset seizure
in patients one month of age and older.
• MOA:
• Exact mechanism of action is unknown.
• High and selective affinity for SynapticVesicle Protein 2A
(SV2A) in the brain.
• 1o-fold greater affinity to synaptic vesicle protein 2A (SV2A)
ligand than Levetiracetam.
• Dosage:
• ≥ 16 year- Initial dose- 50 mg twice daily.
Maxm dose – 200 mg twice daily.
• One month to <16 year- Initial dose- 0.5 mg/Kg twice daily.
Maxm dose- 3 mg/Kg twice daily.
• A/E: Somnolence or Sedation, Drowsiness, Dizziness, Fatigue, Nausea andVomiting.
• Reduced suicidal ideation as compare to Levetiracetam.

19. ESLICABAZEPINE ACETATE
• FDA Approved in Nov 2013 as an adjunctive treatment for Focal seizure.
• MOA: Inhibits voltage dependent Na+ channel.
• Rapidly converted to S(+)-licarbazepine (active form).
• Less neurotoxic than carbamazepine and oxcarbazepine.
• Does not undergo autoinduction.
• Dosage- 400-1200 mg/day OD
• A/E: Headache, Dizziness and Nausea, Less incidence of HYPONATREMIA.
• Minimal interaction with Cytochrome P450 liver enzymes.

20. CLOBAZAM
• FDA Approved in 2011 for adjunctive treatment of seizure associated with Lennox-Gastaut
syndrome (LGS) in patients 2 year of age or older.
• MOA- Binds to Benzodiazepine site of the GABAA
receptor to potentiate the GABAergic neurotransmission.
• Dosage-
• ≤30 Kg- Initial dose- 5 mg OD PO
Maxm dose-20 mg OD PO
• >30 Kg- Initial dose- 10 mg OD PO
Maxm dose- 40 mg OD PO
• Doses >5 mg should be divided into 2 doses.
• A/E- Somnolence, Sedation, Drooling,Constipation, UrinaryTract Infection, Dysarthria and
Fatigue.
• Monitor for suicidal thoughts or behaviours.
• Alcohol increases the blood levels of Clobazam by approximately 50%.

21. NOVEL DRUGS AT NOVELTARGETS
1. FENFLURAMINE
2. CANNABIDIOL
3. PERAMPANEL
4. RETIGABINE

22. FENFLURAMINE
• FDA Approved in Mar 2022 for the treatment of seizures associated with
Dravet syndrome and Lenoux- Gastaut syndrome in patients 2 years of age
and older.
• MOA:
• Exact mechanism as antiseizure drug is not known.
• May exhibit agonist activity at serotonin 5- HT2 receptors.
• Dosage:
• Initial dose- 0.1 mg/Kg twice daily.
• Maxm- 0.35/Kg twice daily.
• A/E: Decreased appetite, Sedation, Lethargy, Asthenia, Ataxia and salivary
hypersecretion

23. CANNABIDIOL
• FDA Approved in April 2018 for treatment of Lennox- Gastaut syndromre
and Dravet syndrome in patients 2 years of age and older.
• It is a cannabinoid that naturally occurs in the Cannabis sativa plant.
• MOA- Exact mechanism is unknown. Cannabidiol does not appear to exert
its anticonvulsant effects through interaction with cannabinoid receptors.
• Dosage-
•Initial dose- 2.5 mg/ Kg twice daily
•Maintenance dose- 5 mg/ Kg twice daily
•Maxm dose- 10 mg/ Kg twice daily
• A/E- Somnolence, decreased appetite, Diarrhea, Fatigue, Insomnia and
Asthenia.
• May cause FoetalToxicity.

24. PERAMPANEL
• FDA Approved in Nov 2012 for treatment of refractory partial onset seizures with or without
secondarily generalised seizure in patients 4 years of age and older.
• MOA:
• Exact mechanism is not known.
• Highly selective non competitive α- Amino-3-hdroxy-
5-Methyl-4-isoxazole Propionic Acid (AMPA) type
glutamate receptor antagonist.
• Dosage:
• Initial dose- 2 mg once daily.
• Maxm dose- 12 mg once daily.
• A/E: Dizziness, Somnolence, Fatigue,Vertigo,Ataxia andWeight gain..
• Boxed warning about the risk for serious neuropsychiatric events like irritability, aggression,
anger, anxiety and rarely homicidal ideation.

25. RETIGABINE
• FDA Approved in 2010 as an adjunctive treatment for Partial seizure.
• MOA:
• Opens the voltage gated K+ channels.
• Dosage:
• Initial dose- 100 mg thrice daily.
• Maxm dose- 400 mg thrice daily.
• A/E: Drowsiness, tinnitus, vertigo, confusion, tremor and slurred speech.
• Recommended use only in cases where other antiseizure drugs are not
adequate or not tolerated.
• Rarely blue skin discoloration and pigment changes in the retina.

26. DRUGS IN PIPELINE
DRUG MOA STATUS
Becampanel AMPA/ kinase receptor antagonist PreclinicalTesting
Talampanel Same PreclinicalTesting
Selurampanel Same Phase II
ICA105665 K+ Channel Opener Completed Preclinical testing
YKP3089 K+ Channel Opener Phase II
YKP3089 Na+ Channel blocker & increase
presynaptic release of GABA
Phase II
JZP4 Structural analogue of Lamotrigene PHASE I

27. NOVEL DRUG DELIVERY SYSTEM
1. INTRANASAL FORMULATIONS
• Absorption from nasal mucosa within
3-5 minutes.
• Rapid penetration into the CNS.
• Feasible to administer in children also.
• A/E- Nasal discomfort,Throat irritation
eg. Midazolam
Diazepam: Phase ITrial
2. Diazepam autoinjection.
• Autoinjector provides a minimum dose of
10 mg diazepam.

28. NON PHARMACOLOGICAL ADVANCES
1. VAGUS NERVE STIMULATOR (VNS)
• FDA Approved Device.
• Provides chronic intermittent electrical
stimulation of theVagus nerve.
• Exact mechanism is not known.
• Indicated in patients with Refractory seizure
• Partial or Generalised
• Lennox-Gastaut Syndrome.
• A/E- Cough, Hoarseness of voice, Difficulty in
swallowing,Throat discomfort.
2. DEEP BRAIN STIMULATION
• Based on stimulating widespread inhibitory pathways

29. SUMMARY
• Seizure disorder can be treated but complete cure??
• Classical Antiseizure drugs having pros and cons.
• Needs long term therapy.
• Need for new treatment with novel mechanism of action.
• Non pharmacological therapy showing promise.