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.
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Anti-Epileptic drugs
1. Presented By:
Mr Vijay Salvekar
Associate Professor
Dept. of Pharmacology
GRY Institute of Pharmacy,Borawan
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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
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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
27.
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
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
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
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
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