ANTI EPILEPTIC DRUGS

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This is my first seminar ppt,i have presented in kmc manipal pharmacology department

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Conventional ANTIEPILEPTIC DRUGS:

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

PROTOCOL:

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 10/26/2015 Department Of Pharmacology, KMC, Manipal 2

INTRODUCTION :

INTRODUCTION Epilepsy is the 3 rd 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 10/26/2015 Department Of Pharmacology, KMC, Manipal 3

DEFINITIONS:

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 10/26/2015 Department Of Pharmacology, KMC, Manipal 4

Causes of Seizures:

Causes of Seizures Epileptogenic factors Precipitating factors (provocative factor) Sleep deprivation Systemic disease Metabolic derangements Acute infection Drugs 10/26/2015 Department Of Pharmacology, KMC, Manipal 5

Pathophysiology :

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 C onversely, 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 10/26/2015 Department Of Pharmacology, KMC, Manipal 6

Diagnosis:

Diagnosis Laboratory studies Electrophysiological studies MRI Brain imaging CT Scan 10/26/2015 Department Of Pharmacology, KMC, Manipal 7

International League against Epilepsy (ILAE) Commission on Classification and Terminology, 2005-2009 :

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 10/26/2015 Department Of Pharmacology, KMC, Manipal 8

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Generalized seizures Absence Tonic clonic Tonic Clonic Atonic Myoclonic Typical Atypical 10/26/2015 Department Of Pharmacology, KMC, Manipal 9

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Some other type of epilepsy : Epilepsy syndrome Juvenile myoclonic epilepsy Lennox- Gastaut syndrome Mesial temporal lobe epilepsy syndrome 10/26/2015 Department Of Pharmacology, KMC, Manipal 10

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Classification of anti epileptic drugs 10/26/2015 Department Of Pharmacology, KMC, Manipal 11

Classification of drugs :

Classification of drugs Barbiturates & deoxybarbiturate Phenobarbitone Primidone intermediate 10/26/2015 Department Of Pharmacology, KMC, Manipal 12

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Hydantoin Phenytoin Fosphenytoin Iminostilbene Carbamazepine Oxcarbamazepine 10/26/2015 Department Of Pharmacology, KMC, Manipal 13

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Succinimide Ethosuximide Aliphatic carboxylic acid Valproic acid Divalproex 10/26/2015 Department Of Pharmacology, KMC, Manipal 14

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Benzodiazepines Clonazepam Diazepam Lorazepam C lobazam Phenyltriazine Lamotrigine Cyclic GABA analogues Gabapentin Pregabalin 10/26/2015 Department Of Pharmacology, KMC, Manipal 15

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General pharmacokinetics of antiepileptic drugs Absorption is usually good, 80% to 100% Phenytoin, v alproic acid highly bound to plasma proteins but not other conventional drugs All must enter the CNS 10/26/2015 Department Of Pharmacology, KMC, Manipal 16

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 17

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 18

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Pharmacokinetics & adverse effect of individual drugs 10/26/2015 Department Of Pharmacology, KMC, Manipal 19

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 20

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 21

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 22

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 23

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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. 10/26/2015 Department Of Pharmacology, KMC, Manipal 24

MECHANISMS OF ACTION 1. Prolongation of channel inactivation Phenytoin Carbamazepine Valproate Lamotrigine:

MECHANISMS OF ACTION 1. Prolongation of channel inactivation Phenytoin Carbamazepine Valproate L amotrigine h Na + 10/26/2015 Department Of Pharmacology, KMC, Manipal 25

Ethosuximide Valproate lamotrigine :

Ethosuximide Valproate lamotrigine 2. Inhibition of T type channel Ca ++ Ca ++ 10/26/2015 Department Of Pharmacology, KMC, Manipal 26

3. Facilitation of GABA mediated chloride channel opening:

3 . Facilitation of GABA mediated chloride channel opening Barbiturate Benzodiazepine Gaba SSA GABA-T Gabp . Valpr. Barbiturates Benzodiazepine Valproic acid Gabapentin 10/26/2015 Department Of Pharmacology, KMC, Manipal 27 cl

THERAPY OF SEIZURES & EPILEPSY:

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 10/26/2015 Department Of Pharmacology, KMC, Manipal 28

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3. Antiepileptic drug therapy R ecurrent seizure When to initiate Single seizure Selection of drugs Older drugs Newer drug 10/26/2015 Department Of Pharmacology, KMC, Manipal 29

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 30

Initiation & monitoring of drugs :

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 10/26/2015 Department Of Pharmacology, KMC, Manipal 31

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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) 10/26/2015 Department Of Pharmacology, KMC, Manipal 32

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 33

When & how to discontinue :

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 ) 10/26/2015 Department Of Pharmacology, KMC, Manipal 34

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 35

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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, 10/26/2015 Department Of Pharmacology, KMC, Manipal 36

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 37

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 38

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Status epilepticus Generalized convulsive Non convulsive status epilepticus (GCSE ) status epileptics Both types are treated by same approach 10/26/2015 Department Of Pharmacology, KMC, Manipal 39

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 40

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EPILEPSY IN WOMEN :

EPILEPSY IN WOMEN Catamenial epilepsy Increase in seizure frequency around the time of menses Increase in antiepileptic drug dosages Natural progestin or intramuscular medroxyprogesterone 10/26/2015 Department Of Pharmacology, KMC, Manipal 42

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Pregnancy Seizure frequency U nchanged in ̴50% of women Fetal abnormality Mother with epilepsy : 5-6% 30% 20% 10/26/2015 Department Of Pharmacology, KMC, Manipal 43

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 44

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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 . P regnant 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 10/26/2015 Department Of Pharmacology, KMC, Manipal 45

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Contraception Enzyme inducing drugs & oral contraceptives Alternative contraceptives 10/26/2015 Department Of Pharmacology, KMC, Manipal 46

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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 10/26/2015 Department Of Pharmacology, KMC, Manipal 47

To conclude….:

To conclude…. This is an old saying, “ O ld 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. 10/26/2015 Department Of Pharmacology, KMC, Manipal 48

References:

References Tripathi KD. Essentials of medical pharmacology,7 th ed. New Delhi, London, Philadelphia, Panama : Jaypee brothers medical publishers (p) LTD; 2013 .P.411-424 Katzung Bertaam G., Trevor Anthony J. B asic & clinical pharmacology, 13 th ed. New Delhi: McGraw Hill Education ( india ) private limited; 2015. p.396-420 10/26/2015 Department Of Pharmacology, KMC, Manipal 49

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3. Kasper D.L., Fauci A. S., Hauser S.L., Longo D.L., Jameson J.L., Loscalzo J. HARISON’S TM principles of internal medicine,19 th 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, 12 th ed. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong kong , Sydney, Tokyo: Lippincott Williams & Wilkins, a Wolters Kluwer business; 2011. P. 491-503 10/26/2015 Department Of Pharmacology, KMC, Manipal 50

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THANK YOU…!! 10/26/2015 Department Of Pharmacology, KMC, Manipal 51

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