This document discusses various anti-epileptic drugs, their mechanisms of action, and pharmacological properties. It covers older drugs like phenytoin, carbamazepine, and valproic acid, which work by modifying ion conductance or increasing GABAergic transmission. It also discusses newer drugs like lamotrigine, topiramate, and gabapentin. Lamotrigine and carbamazepine stabilize sodium channels while topiramate has multiple mechanisms including carbonic anhydrase inhibition. The document provides details on the pharmacokinetics, uses, adverse effects and drug interactions of these anti-epileptic drugs.

1. ANTI EPILEPTIC DRUGS
DR. KAUSHIK MUKHOPADHYAY
DEPT. OF PHARMACOLOGY, ESI-PGIMSR

2. SEIZURE VS EPILEPSY
• Seizure is a paroxysmal event due to abnormal excessive or
synchronous neuronal activity in the brain.
• Epilepsy describes a condition in which a person has
recurrent seizures due to a chronic, underlying process.
this definition implies that a person with a single seizure, or
recurrent seizures due to correctable or avoidable
circumstances, does not necessarily have epilepsy.

4. ACTION POTENTIAL

5. Seizure
Focal
Seizure
Without Dyscognitive
Symptoms
With Dyscognitive
Symptoms
Generalized
Seizure
Absence
Typical
Atypical
Generalized Tonic Clonic
Seizure
Tonic
Clonic
Atonic
Myoclonic
Focal, Generalized
or Unclear
(Epileptic spasms)

6. GENERATION OF SEIZURES
Absence Seizure

7. GTCS
Tonic phase:
Sustained powerful muscle
contraction (involving all body
musculature) which arrests
ventilation
Clonic phase:
Alternating contraction and
relaxation, causing a
reciprocating movement which
could be bilaterally symmetrical

8. MECHANISMS OF ANTISEIZURE DRUGS:
• Modification of ion conductance
 Prolongation of Na+ channel inactivation
 Inhibition of `T` type Ca++ current
• Increase inhibitory (GABAergic) transmission –
Cl- Channel.
• Glutamate receptor antagonism (NMDA, AMPA, or
kainic acid)

9. SODIUM CHANNEL – 3 STATES
• PHENYTOIN
• CARBAMAZEPINE
• VALPROATE
• TOPIRAMATE
• LAMOTRIGINE
• LACOSAMIDE

10. GABA MEDIATED
• BARBITURATE
• BZD
• VALPROATE
• TIAGABINE
• VIGABATRINE

11. T-TYPE CA2+ CHANNELS @ THALAMUS

12. PHENYTOIN
(DILANTIN/EPSOLIN/EPTOIN)
Pharmacological actions:
• Not CNS depressant
• Abolish tonic phase of GTC seizure
• Prevents spread of seizure activity
• Tonic-clonic epilepsy is suppressed but no change in
EEG and aura..
• In CVS – depresses ventricular automaticity,
accelerates AV conduction

13. PHENYTOIN – CONTD.
Mechanism of action:
• Prevents repetitive detonation of normal brain cells
during `depolarization shift`
• Prolonging the inactivation of voltage gated Na+ channel
• At concentrations 5- to 10-fold higher - reduction of
spontaneous activity and enhancement of responses to
GABA
Pharmacokinetics
• Slow oral absorption, 80-90% bound to plasma protein
• Metabolized in liver by hydroxylation and glucoronide
conjugation
• Elimination varies with dose – first order to zero order
• T1/2 life is 12 to 24 hrs
• Monitoring of plasma concentration

14. PHENYTOIN – CONTD.
Adverse effects:
• Hirsutism, coarsening of facial features
• Gum hypertrophy and Gingival hyperplasia.
• Hypersensitivity – rashes, lymphadenopathy
• Megaloblastic anaemia
• Osteomalacia
• Hyperglycaemia
• Cognitive impairment
• Fetal Hydantoin Syndrome
Toxicity
• Ataxia, Vertigo, Confusion, Disorientation
• i.v – local vascular injury, arrhythmia

15. PHENYTOIN – CONTD.
DDI:
• CBZ & Phenytoin – induce each other’s metabolism
• Valproate, Cimetidine, Isoniazid – inhibits metabolism
• Acidic drug displaces from protein binding sites
Fosphenytoin
• Aqueous soluble prodrug

16. CARBAMAZEPINE (TEGRETOL/TEGRITAL)
• Chemically related to imipramine
• Trigeminal neuralgia
• Lithium like action – mood stabilizer
• Resembles phenytoin in pharmacological actions
• MOA:
• Stabilizes Na+ channel (Voltage gated) in inactivated state – less excitability
• Potentiation of GABA receptor

17. CARBAMAZEPINE – CONTD.
• Pharmacokinetics:
• Poorly water soluble and
oral absorption is low
• 75% bound to plasma
protein
• Metabolized in liver
• Substrate and inducer of
CYP3A4
• Half life – 20 to 40hrs.
Decreases afterwards due
to induction
• Adverse effects:
• Autoinduction of metabolism
• Hypersensitivity – rash,
photosensitivity, hepatitis,
• granulocyte suppression and
aplastic anemia
• ADH action enhancement –
hyponatremia and water
retention
• Teratogenicity
• Exacerbates absence seizures

18. CARBAMAZEPINE – CONTD.
• Uses:
• Complex partial seizure
• GTCS and SPS
• Trigeminal and related neuralgias
• Manic depressive illness and acute mania
• Available as tabs (100mg 200, 400 etc.) and
syr.
Oxcarbamazepine

19. VALPROIC ACID
(ENCORATE/VALPARIN)
• Broad spectrum anticonvulsant
• Effective in partial, GTCS and absence seizures
• Mechanism:
• Na+ channel inactivation
• Ca++ mediated `T` current attenuation
• Inhibition of GABA transaminase
• Pharmacokinetics:
well absorbed orally, 90% bound to plasma protein and completely
metabolized in liver and excreted in urine t1/2 is 10-15 hrs.

20. VALPROIC ACID – CONTD.
• Adverse effects:
• Elevated liver
enzymes
• Abdominal pain and
heartburn
• Tremor, hair loss,
weight gain
• hepatotoxicity
• In Girls – polycystic
ovarian disease and
menstrual
irregularities
• Teratogenicity: spina
bifida
• Drug Interactions:
• Valproate and
carbamazepine induce each
others metabolism
• Inhibits phenobarbitone
metabolism and increases
its plasma level
• Displaces phenytoin from
protein binding sites and
thereby decreases its
metabolism – phenytoin
toxicity

21. ETHOSUXIMIDE
• Drug of choice for absence seizures
• Not plasma protein or fat binding
• Mechanism of action involves reducing low threshold Ca2+
channel current (T-type channel) in thalamus
At high concentrations:
• Inhibits Na+/K+ ATPase
• Depresses cerebral metabolic rate

22. BZD
• Diazepam:
• Commonly used as anticonvulsant in a variety of convulsions
• But, not used for long term – sedation effect
• Mechanism of anticonvulsant is mediated by same mechanism of
sedation: Cl- channel
• Used in emergency control of convulsion – status epilepticus, tetanus,
febrile convulsion etc.
• Status epilepticus – Diazepam, Lorazepam may be used as alternative
• Usually given 0.2 to 0.5 mg/kg body weight IV followed by repeated
doses if required – maximum dose 100 mg/day
• Rectal diazepam

23. PHENOBARBITONE
• First effective organic antiseizure agent
• Mechanism:
• GABAA receptor mediated like other Barbiturates
• Pharmacokinetics:
• Slowly absorbed and long t1/2 (80 – 120 hrs)
• Metabolized in liver and excreted unchanged in kidney
• Uses:
• Many consider them the drugs of choice for
seizures only in infants
• GTC
• Dose:
• 60 mg 1-3 times a day
• Child: 3-6 mg/kg/day

24. PHENOBARBITONE – CONTD.
• Adverse effects:
• Sedation
• Behavioural abnormalities
• Hyperactivity in children
• Rashes, megaloblastic anaemia and osteomalacia
• Primidone:
• Deoxybarbiturate
• Converted to Phenobarbitone and PEMA Short half life
6-14 hrs

25. NEWER ANTIEPILEPTICS
1. Lamotrigine
2. Topiramate
3. Levetiracetam
4. Tiagabine
5. Vigabatrine
6. Gabapentin
7. Lacosamide

26. LAMOTRIGINE
• Phenyltriazine derivative, newer agent
• CBZ like, Broad spectrum activity
• Mechanisms:
• Delays recovery from inactivation of Na+ channels prolong Na+ channel
inactivation
• Glutamate and aspartate inhibition: By directly blocking Na+ channels -
stabilizes pre synaptic membrane and prevent release by excitatory
neurons
• Uses: Partial (simple and complex) and secondarily generalized,
absence seizure, myoclonic seizure in youngs
• Mood Stabilizer
• ADR: Rash

27. TOPIRAMATE
• Broad spectrum antiseizure drug
• Pharmacological effects and MOA:
• Carbonic anhydrase inhibitor
• Multiple actions – Na+ channel, K+ channel, AMPA-kainate subtypes of
glutamate
• Pharmacokinetics:
• Rapidly absorbed orally, 10-20% bound to plasma protein, excreted
unchanged in urine
• Metabolized by hydroxylation, glucoronidation and hydrolysis
• Reduction in estradiol level
• Uses: GTCS, SP and CPS as supplement drug in refractory cases

28. GABAPENTIN
• GABA derivative and can cross BBB
• MOA - Enhances GABA release, but not agonist of GABAA
Binds a protein in cortical membrane – similar to L type of voltage sensitive Ca++ channel, but do not alter
Ca++ currents
• Pharmacokinetics:
• Absorbed orally
• Not metabolized in humans
• Not bound to plasma proteins and excreted unchanged in urine
• ADR:
• Sedation, dizziness

31. Thank You