antiepileptic drugs

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

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

4
DEFINITIONS

• SEIZURE
• limited periods of abnormal discharge of
  cerebral neurons
• EPILEPSY (To Seize Upon / Taking Hold Of)
• Recurrent seizures due to a chronic underlying
  process
• CONVULSION
• Paroxysms of involuntary muscular contractions
  relaxations

5
Causes of Seizures

• Epileptogenic factors
• Precipitating factors (provocative factor)
• Sleep deprivation
• Systemic disease
• Metabolic derangements
• Acute infection
• Drugs

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

7
Diagnosis

• Laboratory studies
• Electrophysiological studies
  MRI
• Brain imaging
• 
  CT Scan

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
  
  
  

9

• Generalized
  seizures
• Absence Tonic clonic Tonic
  Clonic Atonic Myoclonic
• Typical Atypical

10

• Some other type of epilepsy
• Epilepsy syndrome
• Juvenile myoclonic epilepsy
• Lennox-Gastaut syndrome
• Mesial temporal lobe epilepsy syndrome

11

• Classification of anti epileptic drugs

12
Classification of drugs

• Barbiturates deoxybarbiturate
• Phenobarbitone
• Primidone
• 
  intermediate

13

• Hydantoin
• Phenytoin
• Fosphenytoin
• Iminostilbene
• Carbamazepine
• Oxcarbamazepine

14

• Succinimide
• Ethosuximide
• Aliphatic carboxylic acid
• Valproic acid
• Divalproex

15

• Benzodiazepines
• Clonazepam
• Diazepam
• Lorazepam
• Clobazam
• Phenyltriazine
• Lamotrigine
• Cyclic GABA analogues
• Gabapentin
• Pregabalin

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

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

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

19
Pharmacokinetics adverse effect of individual
drugs
20
Drugs Pharmacokinetics Interactions ADR
Phenobarbitone 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
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 glucose
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
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
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 gt35hr
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.
25
MECHANISMS OF ACTION1. Prolongation of
channel inactivation Phenytoin
Carbamazepine ValproateLamotrigine
Na
h
26
Ethosuximide Valproate lamotrigine
2. Inhibition of T type channel
Ca
Ca
27
3. Facilitation of GABA mediated chloride channel
opening
Gaba
Gabp.
GABA-T
SSA
Valpr.
Benzodiazepine
Barbiturate

• Barbiturates
• Benzodiazepine
• Valproic acid
• Gabapentin

cl
28
THERAPY OF SEIZURES EPILEPSY

• 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

29

• 3. Antiepileptic drug therapy
• 
  Recurrent seizure
• When to initiate
  
• 
  Single seizure
• Selection of drugs
• Older drugs Newer drug

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


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

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)

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

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)

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

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,

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

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

39

• Status epilepticus
• Generalized convulsive
  Non convulsive
• status epilepticus (GCSE)
  status epileptics
• Both types are treated by same approach

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

41
(No Transcript)
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

43

• Pregnancy
• Seizure frequency
• Unchanged in ?50 of women
• Fetal abnormality
• Mother with epilepsy 5-6

30 20
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

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 12 risk of having a child with spina
  bifida
• Topiramate has shown some teratogenicity in
  animal testing

46

• Contraception
• Enzyme inducing drugs oral contraceptives
• Alternative contraceptives

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

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.
49
References

• Tripathi KD. Essentials of medical
  pharmacology,7th ed. New Delhi, London,
  Philadelphia, Panama Jaypee brothers medical
  publishers (p) LTD 2013 .P.411-424
• Katzung Bertaam G., Trevor Anthony J. Basic
  clinical pharmacology, 13th ed. New Delhi McGraw
  Hill Education (india) private limited 2015.
  p.396-420

50

• 3. Kasper D.L., Fauci A. S., Hauser S.L., Longo
  D.L., Jameson J.L., Loscalzo J. HARISONSTM
  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 Gisvolds 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

51

THANK YOU!!