Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.

1. Presented By:
Mr Vijay Salvekar
Associate Professor
Dept. of Pharmacology
GRY Institute of Pharmacy,Borawan

4. Seizure:- paroxysmal event due to abnormal
excessive or synchronous neuronal activity in the
brain
A Seizure Latin word meaning "To take
possession of”)
Epilepsy is a disorders of brain function
characterized by paroxysmal cerebral
dysrhythmia.
In this condition a person has recurrent seizures
due to a chronic{old}, underlying process.
Patients who have two or more seizures (within
6-12 month) are considered to have epilepsy

5. History:-
 Hippocrates called “Epilepsy” as ‘Sacred disease’
Christian middle age
(14th century)-epilepsy came
from “demons”
& it was thought to be contagious.

6. Seizures
Focal Generalized
Simple Partial
Complex Partial
Secondarily
Generalized
Absence
Myoclonic
clonic
Tonic
Tonic-Clonic/GTCS
ILAE – International League AgainstEpilepsy
ILAE Classification of Seizures
Classification based on history ,clinical finding ,EEG recording & imaging studies by ILAE

25. distributed across both cerebral hemispheres.
They may result from cellular, biochemical or structural
abnormalities that have a more widespread distribution.
Several types of generalized seizures have features that place
them in distinctive categories
1.GTCS:- Generalised tonic-Clonic seizures
also called Grand mal
Main seizure type in 10% of all persons
Initial phase of the seizure is usually tonic
contraction of muscles throughout the body

26. Other feature include- Tonic
phase- Stiff, crying out, tongue bite,
Apnea- contraction of laryngeal muscle
↑ HR,↓BP, Salivation,
Clonic Phase-
 Intermittent clonic movement of muscle
 Brief relaxation involves all limbs
 Repetitive bilateral muscle jerking
Recovery:- coma last for 30 min
Post ictal Phase:-
Drowsiness, confusion, headache ,deep sleep

28. Absence seizures
(Petitmal):- No
aura{spirit}, No loss of
consciousness Sudden onset
of staring,
Bilateral motor symptoms-rapid blinking of
eyelide Children-more experience
Myoclonic seizures:-
Single or multiple sudden brief shock like
contractions of skeletal muscles.
sudden jerking movement observed while
falling asleep

29. SIMPLE PARTIAL
limited to one cerebral hemisphere (80% pt)
Usually associated with structural abnormalities of the
brain
Accompanied by transient impairment of the patient's
ability to maintain normal contact with the environment
Simple Focal seizures (SFS)/cortical focal epilepsy :-
The manifestations depend on the region of the cortex
involved:-
- no loss of consciousness
- focal motor symptoms (convulsions)
- sensory symptoms ( variety of subjective symptoms)-
symptom Not observe by other person

30. Complex Focal seizures:-
(CFS, Temporal lobe Ep. Psychomotor Ep.)
 Usually originate in the temporal lobe & are accompanied
by partial loss of consciousness
Aura –Amnesia –Abnormal behavior – Automatism

31.  Infancy and childhood
– Prenatal or birth injury
– Inborn error of metabolism
– Congenital malformation
 Childhood and adolescence
– Idiopathic/genetic syndrome
– CNS infection
 Adolescence and young
adult
– Head trauma
– Drug intoxication and withdrawal
– Trauma
 Older adult
– Stroke
– Brain tumor
– Acute metabolic disturbances
– Neurodegenerative
Etiology of Seizures and Epilepsy

32. Seizure Precipitants:-
Stimulants/Other Pro-convulsant Intoxication
 I.v. drug use
 Cocaine
 Ephedrine
 Other herbal remedies
 Alcohol withdrawal

33.  Antidepressants:-
Bupropion
Tricyclics
 Neuroleptics:-
Phenothiazines
Clozapine
 Theophylline
 Antimalarials:- chloroquine,mefloquine
 Cardiac anti arrythmics:- lidocaine,disopyramide
 Isoniazid
 Penicillins, fluoroquinolones,metronidazole
 Cyclosporin
 Radiographic contrast
Seizure Precipitants (cont.)

34.  Excitation (too much) :-
– Ionic—inward Na+, Ca++ currents
– Neurotransmitter—glutamate, aspartate
 Inhibition (too little):-
– Ionic—inward CI-, outward K+ currents
– Neurotransmitter—GABA
Cellular Mechanisms of Seizure Generation

35. Antiepileptic Drug
 Drug
 Treats
↓ frequency/severity of seizures
symptom of seizures,
underlying epileptic condition
 Goal—maximize quality of life by minimizing seizures and
adverse drug effects
 Currently no “anti-epileptogenic” drugs available

36. Clinical Classification of Antiepileptic Drugs
Seizure type Preferred drugs Alternative
drugs
GTCS Carbamazepine
Sodium valproate
Phenytoin
Phenobarbitone
Lamotrigine
Topiramate
Primidone
Simple focal
seizure
Carbamazepine
Phenytoin
Sod.valproate
Gabapentin,Lamotrigine,T
opiramate,Tiagabine
Zonisamide
Complex focal seizure Carbamazepine
Phenytoin
Sod.valproate
Gabapentin,Lamotrigine,Topi
ramate,Tiagabine
Zonisamide
Absence seizure Sod.valproate
Ethosuximide
Clonazepam
Lamotrigine
Myoclonic seizure Sodium valproate Clonazepam
Lamotrigine
Topiramate

37. Chemical Classification:-
1. Hydantoins: Phenytoin,fosphenytoin
2.Barbiturates: Phenobarbitone, Mephobarbitone
3. Iminostilbenes: Carbamazepine,oxcarbazepine
4. Succinimides: Ethosuximide
5. BZDs: Clonazepam,Diazepam,lorazepam,Clobazam,
6. Aliphatic carboxylic acid derivative: Valproic acid
7. Deoxybarbiturates: Primidone
8. Phenyltriazine:- Lamotrigine, Gabapentin, Vigabatrin
9.Cyclic GABA analogue:- Gabapentin, pregabalin
Newer drugs:-
Topiramate,Zonisamide,Levetiracetam,Tiagabine,Lacosami
de

38. Mechanism of action of different anti-epileptics
Prolongation of
Na+ channel
inactivation
Phenytoin
Carbamazepine
Valproate
Lamotrigine
Topiramate
Zonisamide
Lacosamide
Rufinamide
Cl- channel
Opening
Barbiturate
Benzodiazepine
Vigabatin
Gabapentin
Tigabine
Facilitation of Inhibition of T-
GABAmediated type Ca++
channel
Ethosuximide
Trimethadione
Valproate
Decrease of
Excitatory
Neurotransmitt
er
Lamotrigine
Felbamate
Topiramate
Hormone
ACTH
Others
oLevetiracetam
oPregabalin
oMgS04
oAcetazolamide
oKetogenic diet
oVagal nerve
stimulation

39. 1840 1860 1880 1900 1920 1940 1960 1980 2000
5
10
15
20
Bromide
0
Phenytoin
Phenobarbital Primidone
Ethosuximide
Carbamazepine
Benzodiazepines
Vigabatrin
Zonisamide
Sodium valproate
Lamotrigine
Gabapentin
Felbamate
Fosphenytoin
Oxcarbazepine
Tiagabine
Topiramate
Levetiracetam
More
Year
AEDs
Antiepileptic drug development

40. • Hydantoin derivative
• One of the most commonly used drug
• Does not produce significant Drowsiness
• Effective against all types of Partial and Tonic clonic
seizures but not absence seizures
Mechanism:-
Phenytoin
Phenytoin
Bind to voltage dependent Na+ channels
(Prolongs the inactivated state) and prevent
further entry of Na+ ions into the neuron.
(Stabilize neuronal membrane )
Inhibit the generation of repetitive action potentials
Therefore, prevent /reduce the
spread of seizure discharges

41. Other mechanism :-
• At high conc. Phenytoin
- reduce Ca2+ influx(during depolarization) into the neurons
Suppresses repetitive firing of neurons & NT
- Reduces glutamate levels
- increases GABA responses
• Pharmacokinetics:-
• Absorption- slowly after oral administration
• Highly bound to plasma proteins
• Metabolism- by Hydroxylation(CYP2C9,CYP2C19)
and glucuronide conjugation, Repeated doses cause
enzyme induction

42. • Exhibits dose dependent elimination through saliva
Phenytoin
At low doses, follow first order kinetics
As the plasma conc. increases
Elimination processes get saturated
• Plasma conc. Should be monitored in neonates and in pt
suffering with uremia, liver disease ,hypoprotenaemia
• On I.M. administration-get ppt in muscle cause pain
• Upon I.V. administration-thrombophlebitis

43. Therapeutic Uses
Epileptic uses:-
Effective drugs for all focal seizures(simple & complex)
First choice of seizure prophylaxis in head injury
First choice for Tonic-clonic seizure
Status epilepticus
May even worsen absence & myoclonic seizures
Non-Epileptics:-
Trigeminal neuralgia
To treat ventricular arrhythmias due to digitalis toxicity
To enhance wound healing
↑platelet derived growth factors-B & its mRNAfrom
enhance wound healing, promote local
Phenytoin
macrophages
angiogenesis

44. Fosphenytoin
 Water soluble Prodrug of phenytoin (Diphosphate -ester)
Active metabolite is phenytoin
 It is available for IM & IV administration
 Antiepileptic effect=phenytoin
Advantages:-
 Less irritating to vein
 Less cardiotoxic
 Safer & better tolerated-infuse 3 times faster than I.V.
phenytoin
Disadvantage:- Expensive

45. • Chemically related to tri carboxylic acid
• MOA:- Same as phenytoin but claim to cause less cognitive
impairment
Pharmacokinetics:-
 Unstable substance (protect from hot/humid condition)
 High lipid solubility-enters brain rapidly
 Therapeutic blood level:-4-12µg/ml
 Induces its own hepatic metabolism(auto induction)
USES:- 1.All focal seizures
2.Tonic-clonic seizures(not effective for absence & myoclonic
seizures)
3. trigeminal neuralgia
4. Occasionally used in manic depressive pt.
Carbamazepine

46. Benzodiazepines Barbiturate
Safest & all most free from
Severe side effects of all
Antiepileptic
Chronic treatment:-
Clonazepam,
Clobazam,
Clorazepate
In status epilepticus:-
Diazepam ,Lorazepam
Very potent anticonvulsant
SignificantADR
Chronic treatment:-
Used as 2nd line drugs
Phenobarbitone :-
•In Pregnancy
•Recurrent febrile
seizures in children

47. Tiagabine:-
 Reversibly inhibits GABA reuptake Transporter-1 (GAT-
1)
Second line adjunctive
therapy in refractory
partial or secondarily
generalized seizures
Can worsen absence
epilepsy

48. Vigabatrin:-
Uses:-
 Infantile spasms
Refractory Complex
Partial seizure
Adverse Effects:-
Visual toxicity due to
retinal atrophy and
Neuropsychiatric
Symptoms
3-6 days Resynthesize

49. -:Valproate:-
Broad spectrum anti-epileptics
Mechanism:-
 Blockade of sodium channel
 ↑GABA activity by inhibiting GABA transminases
 Inhibition of T-type Ca++ channel
 ↓ release of glutamate in brain
Therapeutic Uses:- Epileptic uses:-
 All types of Generalized & focal seizures
 DOC in idiopathic generalized epilepsy
 DOC myoclonic seizures
 DOC in absence seizures in (adult)-children ethosuximide is DOC
because of hepatotoxic potential of valproate
 DOC in tonic-clonic seizure

50.  First line drug in photosensitive epilepsy
Non-Epileptic uses:-
 DOC in bipolar disorder with rapid cyclers
 Prophylaxis of migraine
Pharmacokinetics:-
 Absorption:- Orally rapid
 Plasma protein binding:- Highly (conc. Dependent & nonlinear)
 Metabolism:- liver
 Therapeutic blood levels- 50-150mg/ml
Adverse Effects:-
Idiosyncratic,genetically determined hepatic toxicity
Nausea & vomiting

51. • ↑ appetite leading to weight gain
• Rash
• Alopecia
• Thrombocytopenia
• Endocrine effect- insulin resistance, anovulatory cycles,
amenorrhea, polycystic ovary syndrome
• Bone marrow suppression- rare
• Fatal acute pancreatitis
• Teratogenic effects especially neural tube defects
Gabapentin:- ↑GABA level(brain) ↓Glutamate level (brain)
Only modest efficacy in partial & secondary generalized
tonic-clonic seizures
 Has analgesic properties

52. Ethosuximide
 Block T-type Ca++ channels
 First choice in Absence seizure –children (below 3yr.)
 Not use in other seizures
 T1/2-60 hrs
 No drug interaction
 Sedation common side effects
 Characterized side effects- hemeralopia (Photophobia)
 Therapeutic Blood level-40-100 µg/ml

53. Very effective ,broad spectrum & well tolerated
DOC-focal seizure in elderly
Less incidence of congenital malformation(preferred
during pregnancy)
Use in manic depressive psychosis
Side effect-rash (rarely cause SJ-syndrome)
Zonisamide
• T-type Ca++ channel blocked also process weak CA-inhibiting
property
• Neuroprotective action
• Juveniles myoclonic epilepsy
• Main side effects- sedation, metabolic acidosis, renal stone
Lamotrigine

54. Glutamate Receptor blockers
Felbamate:-
o potent ,very effective against all seizures
o Blocks NMDA receptors & voltage gated Ca++ channels
o No effects on GABA receptors
oHas neuroprotective effect on hypoxic-ischemic injuries
uses:- secondary generalized seizure
Topiramate
Very potent, chemical relatives of fructose has several
action
Blocked of glutamate receptors
Blocked of voltage gated Na+ channels
↑ GABA activity at GABAA receptors

55. • Therapeutic uses:-
 Partial onset & secondarily generalized tonic clonic
seizures
 Primary GTCS
SE:- nausea, appetite subpression –weight loss
Renal stone-due to CA-Inhibition.
RX- drink plenty of fluids
Others:-
 ACTH:- acts by modulating GABA receptors (open Cl-
channels )
 Levetiracetam- inhibit Ca++ release
 Pregabalin- GABA analogue.(anticonvulsant+ analgesic
+anxiolytics)

56.  Acetazolamide:- CA-I (use:- epileptic women who
experience seizures exacerbation at the time of menses)
 MgS04- DOC in controlling Seizure in eclampsia
 Newer drugs:-
Retigabine:- (K+ channel facilitator )
Partial onset seizures in adult

57. I.V.-Lorazepam (0.1-0.15mg/Kg ) over 1-2 min(repeat if no
Fosphenytoin 20mg/kg I.V. at 150 mg/min
Or Phenytoin 20mg/Kg IV.slow
Status Epilepticus
response after 5 min)
Seizure Continue If Seizure Stop
Rx-
No further treatment
Seizure Continue
Repeat at low dose Phenytoin 7-10mg/Kg I.V. 50mg/min
No further
treatment
No further
treatment
Admit to ICU
IV anesthesia with propofol /midazolam/Phenobarbital
Phenobarbital 20mg/Kg IV.60mg/min
Seizure continue
Phenobabital 10mg/kg IV 60mg/min
Seizure Continue
Sodium valproate 25mg/kg IV
No immediate access to ICU