This document discusses conventional antiepileptic drugs. It begins with definitions of epilepsy, seizures, and convulsions. It then covers the classification, pharmacokinetics, and therapy of antiepileptic drugs. The document classifies antiepileptic drugs and discusses their mechanisms of action, pharmacokinetics, interactions, and adverse drug reactions individually. It emphasizes the importance of treating underlying conditions, avoiding precipitating factors, and carefully initiating and monitoring antiepileptic drug therapy to prevent seizures and side effects.

1. Conventional
ANTIEPILEPTIC
DRUGS
By: Mr. Kameshwor Yadav
Mr. ysphaneendra.m
Moderator: Miss Swapna

2. PROTOCOL
 INTRODUCTION
 Definition of seizure, epilepsy, convulsion
 Causes, pathophysiology of epilepsy & diagnosis
 Types of epilepsy
 CLASSIFICATION OF ANTIEPILEPTIC DRUGS
 PHARMACOKINETICS & DYNAMICS
 THERAPY OF EPILEPSY & SEIZURE
 EPILEPSY IN WOMEN
 CONCLUSION
 REFERENCES
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3. INTRODUCTION
 Epilepsy is the 3rd most common neurologic disorder
 Affects approximately 3% of individuals
 About 10% of the population will have at least one seizure
 Highest incidence in early childhood & late adulthood
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4. DEFINITIONS
o SEIZURE
 limited periods of abnormal discharge of cerebral
neurons
o EPILEPSY (To Seize Upon / Taking Hold Of)
 Recurrent seizures due to a chronic underlying
process
o CONVULSION
 Paroxysms of involuntary muscular contractions
& relaxations
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5. Causes of Seizures
 Epileptogenic factors
 Precipitating factors (provocative factor)
 Sleep deprivation
 Systemic disease
 Metabolic derangements
 Acute infection
 Drugs
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6. Pathophysiology
 In normal circumstances, recurrent & collateral inhibitory
circuits in cerebral cortex limit synchronous discharge of
adjacent group of neurons
The inhibitory transmission GABA has important role in
this
Evidence : drugs that block GABA receptor provokes
seizures
 Conversely, excessive stimulation by excitatory
neurotransmitter such as Ach, glutamate & aspartate,
provoke seizure
Thus, it is likely that both reduction of inhibition and
excessive excitation plays part
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7. Diagnosis
• Laboratory studies
• Electrophysiological studies MRI
• Brain imaging
CT Scan
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8. International League against Epilepsy (ILAE) Commission
on Classification and Terminology, 2005-2009
CLASSIFICATION OF SEIZURES
FOCAL SEIZURES GENERALISED SEIZURES MAY BE
FOCAL,
GENERALISED,
OR UNCLEAR
Without dyscognitive With dyscognitive Evolution of focal
features features to generalized
seizures
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9. Generalized seizures
Absence Tonic clonic Tonic Clonic Atonic Myoclonic
Typical Atypical
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10. Some other type of epilepsy :
• Epilepsy syndrome
• Juvenile myoclonic epilepsy
• Lennox-Gastaut syndrome
• Mesial temporal lobe epilepsy syndrome
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11. Classification of anti epileptic drugs
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12. Classification of drugs
 Barbiturates & deoxybarbiturate
 Phenobarbitone
 Primidone
intermediate
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13.  Hydantoin
 Phenytoin
 Fosphenytoin
 Iminostilbene
 Carbamazepine
 Oxcarbamazepine
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14.  Succinimide
 Ethosuximide
 Aliphatic carboxylic acid
 Valproic acid
 Divalproex
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15.  Benzodiazepines
 Clonazepam
 Diazepam
 Lorazepam
 Clobazam
 Phenyltriazine
 Lamotrigine
 Cyclic GABA analogues
 Gabapentin
 Pregabalin10/26/2015 Department Of Pharmacology, KMC, Manipal 15

16. General pharmacokinetics of antiepileptic drugs
 Absorption is usually good, 80% to 100%
 Phenytoin, valproic acid highly bound to plasma proteins
but not other conventional drugs
 All must enter the CNS
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17.  Most conventional drugs (except gabapentin)
metabolized in liver & in some cases active
metabolite formed
 Many antiseizure drugs are medium to long acting
because slow plasma clearance
 Older antiseizure drugs are potent inducer of hepatic
microsomal enzyme ex. carbamazepine & phenytoin
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18.  Drugs that inhibit antiseizure drug metabolism or displace
anticonvulsants from plasma protein
 Drugs that induce hepatic drug metabolizing enzyme
make
antiseizure drugs inadequate for seizure control
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19. Pharmacokinetics & adverse effect
of individual drugs
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20. Drugs Pharmacokinetics Interactions & ADR
Phenobar
bitone
 Slow oral absorption
 80-120 hr. plasma half life
 Steady state reached after 2-3 weeks
 Sedative action
 Long term- behavioral
abnormalities, diminution of
intelligence, impairment learning &
memory, hyperactivity in children &
mental confusion in older people
 Rashes, megaloblastic anaemia &
osteomalacia
Primidone  2/3 metabolized to phenobarbitone &
phenyl ethylmalonate
 Half life 6-14 hr
 Anaemia, leukopenia
phenytoin  Slow oral absorption
 Bioavailability different according to
manufacturer
 80-90 % plasma protein binding
 Metabolism is capacity limited
Therapeutic levels-
 Gum hypertrophy
 Hirsutism
 Foetal hydantoin syndrome
 Inhibit insulin release-
hyperglycaemia
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21. Drugs Pharmacokinetics Interactions & ADR
High plasma level-
 Cerebellar & vestibular manifestations
 Drawsiness, behavioral alterations
 Epigastric pain & nausea, vomiting
 I .V. cause local injury
 I .V. cause Fall in B.P. & arrhythmia & ECG monitoring
Interactions
 With Phenobarbitone
 With carbamazepine
 With valproate
 Enzyme inhibitor-chloramphenicol, isoniazid, cimetidine
 Competitively Inhibits warfarin metabolism
 Phenytoin induce microsomal enzyme
 Acidic drugs displace it from protein binding sites
 Sucralfate binds phenytoin in GIT
Fosphenyt-
oin
 Water soluble
 Mixed in saline
& glucose10/26/2015 Department Of Pharmacology, KMC, Manipal 21

22. Drugs Pharmacokinetics Interactions & ADR
Carbamazepine  Oral absorption is slow & variable
 75% bound to the plasma protein
 By oxidation in liver produce 10-11
epoxy carbamazepine
 Initially half life 20-40hr then 10-20
 Sedation, dizziness, vertigo,
diplopia & ataxia
 Diarrhoea, vomiting worsening
of seizure
 Water retention &
hyponatremia
 Minor foetal malformation
 Enzyme inducer reduce efficacy
of haloperidol, oral
contraceptives
 Metabolism induced by
phenobarbitone, phenytoin &
vice versa
 Erythromycin, fluoxetine,
isoniazid inhibit metabolism
Oxcarbazepine  Active metabolite is glucuronide
conjugate
 Weak enzyme inducer
 Better tolerated
 Lower risk of hepatotoxicity
 Hyponatraemia is more
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23. Drugs Pharmacokinetics Interactions & ADR
Ethosuximide  Slowly but completely
absorbed
 Not protein bound
 Half life 48 hr. in adults,
32 hr. in children
 Gastrointestinal intolerance
Valproic acid  Good oral absorption
 90% bound to plasma
 Half life 10-15 hr.
 Anorexia, vomiting, loose motions, heart
burn
 Asymptomatic rise in serum transaminase
 Fulminant hepatitis & pancretitis
 Spinal bifida & neural tube defect
 Increases phenobarbitone & lamotrigine by
inhibiting metabolim
 Displace phenytoin
 Inhibit hydrolysis of epoxide metabolite of
carbamazepine
 With carbamazepine foetal abnormality is
more
Divalproex Slow oral absorption but
same bioavailability
Gastric tolerance better
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24. Drugs Pharmacokinetics Interactions &
ADR
Clonazepam  Good oral absorption
 Completely metabolized in liver
 Half life 24 hr.
 Sedation &
dullness
Clobazam  Good oral absorption
 Half life 18hr & metabolite has >35hr
Diazepam  Half life 30-60 hr.
 Rectal & iv route
Lamotrigine  Good oral absorption
 Completely metabolized in liver
 Half life is 24 hr. but reduced to 16hr.
 Ataxia,
diplopia,
dizziness
Gaba analogues  Lipophilic GABA derivative
 Well absorbed orally
 Excreted unchanged
 Half life 6hr.
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25. MECHANISMS OF ACTION
1. Prolongation of channel inactivation
Phenytoin
Carbamazepine
Valproate
Lamotrigine
h
Na+
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26. Ethosuximide
Valproate
lamotrigine
2. Inhibition of T type channel
Ca++
Ca++
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27. 3. Facilitation of GABA mediated chloride channel opening
Barbiturate Benzodiazepine
Gaba
SSA
GABA-T
Gabp.
Valpr.
Barbiturates
Benzodiazepine
 Valproic acid
Gabapentin
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cl

28. THERAPY OF SEIZURES & EPILEPSY
1. Treatment of underlying conditions
Sole cause of seizure is metabolic disturbance
If the apparent cause of seizure is medicine
Seizure caused by structural CNS lesion
2. Avoidance of precipitating factors
Situations that lower seizure threshold
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29. 3. Antiepileptic drug therapy
Recurrent seizure
 When to initiate
Single seizure
 Selection of drugs
Older drugs Newer drug
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30. Generalised-Onset Tonic-
Clonic
Focal Typical
Absence
Atypical
Absence,
Myoclonic,
Atonic
First line
Lamotrigine
Valproic acid
Lamotrigine
Carbamazepine
Oxcarbazepine
Phenytoin
Valproic acid
Ethosuximide
Lamotrigine
Valproic acid
Lamotrigine
Alternative
Phenytoin
Carbamazepine
Oxcarbamazepine
Phenobarbital
Primidone
Valproic acid
Gabapentin
Phenobarbital
Primidone
Lamotrigine
Clonazepam
Clonazepam
Clobazam
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31. Initiation & monitoring of drugs
 GOAL-prevents seizures & side effects of treatment
 Starting doses are usually the lowest value
 Subsequent increases should be made only after
achieving a steady state with the previous dose
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32.  Monitoring of serum antiepileptic drug levels can be
very useful for establishing the initial dosing schedule
 Concentration of free drug that reflects extracellular
levels in the brain and correlates best with efficacy
(impaired liver & renal disease)
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33. If seizures continue, despite gradual increases to the
maximum
tolerated dose
It become necessary to switch another antiepileptic drugs
usually done by maintaining the patient on the first drug while
a second drug is added
second drug should be adjusted to decrease seizure frequency
without causing toxicity
Once this is achieved the first drug can be gradually withdrawn
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34. When & how to discontinue
• Approximately one-third of patients with epilepsy do not
respond to treatment with a single antiepileptic drug
• In most cases, the initial combination therapy combines
first line drugs (i.e. carbamazepine, oxcarbazepine,
lamotrigine, valproic acid, levetiracetam and phenytoin)
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35. • These drugs are unsuccessful then the addition of
other drugs such as topiramate, zonisamide,
lacosamide, or tiagabine is indicated
• If there is no improvement, a third drug can be
added while the first two are maintained
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36.  Gradually stopped to avoid increased seizure
frequency and severity
 In general, withdrawal of anti-absence drugs is easier
than withdrawal of drugs needed for focal or
generalized tonic-clonic seizures
 Barbiturates and Benzodiazepines are the most
difficult to discontinue; weeks or months may be
required, with very gradual dosage decrements,
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37. Treatment of refractory epilepsy
 One-third of patients with epilepsy do not respond to
treatment with a single antiepileptic drug
 In most cases, the initial combination therapy combines
first-line drugs
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38.  Treatment of status epilepticus
 Status epilepticus refers to continuous
seizures or repetitive, discrete seizures with
impaired consciousness in the inter-ictal
period
 Traditional definition ( 15-30min)
 Practical definition
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39. Status epilepticus
Generalized convulsive Non convulsive
status epilepticus (GCSE) status epileptics
 Both types are treated by same approach
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40. • GCSE is an emergency and must be treated
immediate， because cardiorespiratory
dysfunction， hyperthermia， and metabolic
derangements can develop as a consequence of
prolonged seizures， and these can lead to
irreversible neuronal injury
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41. 10/26/2015 Department Of Pharmacology, KMC, Manipal 41

42. EPILEPSY IN WOMEN
 Catamenial epilepsy
 Increase in seizure frequency around the time of
menses
 Increase in antiepileptic drug dosages
 Natural progestin or intramuscular
medroxyprogesterone
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43.  Pregnancy
 Seizure frequency
Unchanged in ̴50% of women
 Fetal abnormality
Mother with epilepsy : 5-6%
30% 20%
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44.  Uncontrolled convulsive seizures on the mother and fetus
outweighs the risk of teratogenic effects of antiepileptic drugs
 Monotherapy, at the lowest effective dose
 Folate ( 1 -4 mg/d)
Antiepileptic drugs are Enzyme inducing –reversible deficiency
of vitamin K dependent factors in newborns
 Mother should be treated with oral vitamin K (20 mg/ d，
phylloquinone) in the last 2 weeks of pregnancy, and the infant
should receive intramuscular vitamin K ( 1 mg) at birth
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45. • Note:-
Phenytoin has been implicated in a specific syndrome
called fetal hydantoin syndrome, although not all
investigators are convinced of its existence and a similar
syndrome has been attributed both to phenobarbital
and to carbamazepine
 Valproate, has been also implicated in a specific
malformation, spina bifida. Pregnant woman taking
valproic acid or sodium valproate has a 1–2% risk of having
a child with spina bifida
Topiramate has shown some teratogenicity in animal
testing
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46.  Contraception
 Enzyme inducing drugs & oral contraceptives
 Alternative contraceptives
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47. Breast feeding
 Ratio of drug concentration in human breast milk relative
to serum ranges from ̴̴5% (valproic acid) to 300%
(levetiracetam)
however, NO evidence of harm but potential benefit of
breast feeding supports to continue the breast feeding
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48. To conclude….
This is an old saying, “Old is gold”, which holds true for
conventional antiepileptic drugs, and is highlighted by the fact
that older drugs are still first line drugs for the treatment of
major types of epilepsy, while only 2 newer drugs
levetiracetam (focal) and topiramate (atypical absence,
myoclonic, atonic) are being used as first line drugs in epilepsy.
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49. References
1. Tripathi KD. Essentials of medical pharmacology,7th ed.
New Delhi, London, Philadelphia, Panama : Jaypee
brothers medical publishers (p) LTD; 2013 .P.411-424
2. Katzung Bertaam G., Trevor Anthony J. Basic & clinical
pharmacology, 13th ed. New Delhi: McGraw Hill Education
(india) private limited; 2015. p.396-420
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50. 3. Kasper D.L., Fauci A. S., Hauser S.L., Longo D.L., Jameson J.L.,
Loscalzo J. HARISON’STM principles of internal medicine,19th ed. New
York, Chicago, San Francisco, Athens, London, Madrid, Mexico City,
Milan, New Delhi, Singapore, Sydney, Toronto: McGraw-Hill education;
2015.P. 2542-2558
4. Lu Matthias C. Antoconvulsants. In: Beale John M., Block John H.
Wilson & Gisvold’s Textbook of organic medicinal & pharmaceutical
chemistry, 12th ed. Philadelphia, Baltimore, New York, London, Buenos
Aires, Hong kong, Sydney, Tokyo: Lippincott Williams & Wilkins, a
Wolters Kluwer business; 2011. P. 491-503
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51. THANK YOU…!!10/26/2015 Department Of Pharmacology, KMC, Manipal 51