P H R M A C O L O G Y - NOTE 14 - Treatment of Epilepsy

ANTI-EPILEPTIC DRUGS

Partial seizures & Generalized seizures Others

gneralized tonic-clonic

Old Drugs Newer Drugs Ethosuximide Phensuximide Acetazolamide Benzodiazepines

Phenytoin Lamotrigine Trimethadone Oxazolidinediones Diazepam

Carbamazepine Gabapentine Lorazepam

• motor area (convulsion)
• hypothalamus (autonomic discharge)
Involvement of • reticular formation (unconsciousness)
Valporate Topiramate • Repeated seizure activity leads to Clonazepam
neurodegeneration due to excitotoxicity

Barbiturates Vigabatrine
Focal Seizures •remains localized
Nitrazepam

Generalized •primary (involve all cortical neurons) Clorazepate

Levetriacetam
Seizures •secondary (spread afterward) Dipotassium

• inhibitory NT.
• excitatory Nt
Felbamate TREATMENT •alter the permability of membrane
Clobazam
to ions (Na, K or Ca)

Zonisamide
Tiagabine
PARTIAL SEIZURES

GENERALISED
SEIZURES
•simple(consciousness) •Generalized tonic-clonic (grand mal)
•complex (unconsciousness) •Absence (petit mal) 35
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•PS secondarily generalized •Tonic , Atonic , Clonic & Myoclonic
seizures
•Infantile spasm

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P H R M A C O L O G Y - NOTE 14 - Treatment of Epilepsy
 Partial seizures & generalized tonic-clonic
DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT
Phenytoin  It is metabolized in the liver.  Block or alter Na-voltage channels. 1) Partial seizures DOSE DEPENDENT
 plasma conc. <10 mg/L .  At high concentration: 2) Generalized tonic-clonic seizures.  Acute effect
st
 1 order kinetics.  Inhibit release of NE & 5-TH. 3) Status epilepticus.  Nystagmus.
 plasma conc. = 10-20 mg/L .  Inhibit MAO activity. 4) Trigeminal neuralgia (2nd choice).  Diplopia.
 zero order kinetics.  Promote uptake of 5) Cardiac arrhythmia.  Ataxia.
 The metabolism is inhibited by: Dopamine  Lethargy.
o Na valporate.  Sedation.
 Chronic effect:
o Cimetidine.
 Gingival hyperplasia, Hirsutism , Acne
o Isoniazide.
 Nausea ,vomiting ,epigastric pain, anorexia.
o Chloramphenicol.
 Megaloblastic anemia.
o Co-trimoxazole.
 Mild peripheral neuropathy
 It is a inducer of HME.  Osteomalacia.
 So, it enhances metabolism of:  Hemorrhagic diseases of new born.
 Carbamazepine  Fetal Hydantoin syndrome.
 Warfarin,Steroids. HYPERSENSITIVITY
 TCA & OC  Agranulocytosis with fever, rash , SLE & fetal hepatic
necrosis.
Carbamazepine  Block Na-voltage channels. 1) Partial seizures DOSE DEPENDENT
 Act pre-synaptically: 2) Generalized tonic-clonic seizures  CNS: Diplopia, Ataxia ,drowsiness, unsteadiness.
 to  synaptic 3) Trigeminal neuralgia.  GIT: Vomiting , Diarrhoea.
transmission. 4) Mania.  H2O retention & hyponatremia.
Old Drugs

 Inhibit uptake & release of NE. 5) Diabetes Insipidus (DI). IDIOSYNACRATIC BLOOD DYSCRASIS
 Aplastic anemia
 Agranulocytosis.
 Leucopenia.
 Hepatic dysfunction.
TERATOGENECITY
 Fetal malformation ( neural tube defects).
 valporate doubles teratogenicity.
Na Valporate  NOT used during PREGNANCY .  Inhibite GABA aminotransferase 1) Partial seizures. DOSE DEPENDENT
 to  GABA conc. 2) Generalized seizures:  Nausea, vomiting, abdominal pain.
 Block Na-voltage channels. a. tonic-clonic.  Weight gain, ↑ appetite.
b. absence.  hair loss, fine tremor.
c. myoclonic. IDIOSYNATRIC REACTION
3) Bipolar disorder(mania).  Hepatotoxicity.
4) Migrine prophylaxis.  Thrombocytopenia.
 Pancreatitis.
TERATOGENECITY
 Spina bifida,Cardiovascular abnormality.
 Orofacial & digital abnormalities.
Penobarbital  It is well tolerated, with single dose  Enahancement of GABAergic 1) Partial seizures  Drowsiness , lethargy , depression
Barbiturates

Mephbarbital  Contraindication. pathway. 2) Generalized tonic-clonic seizures.  Nystagmus, ataxia. 36

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Metabarbital
o Porphyria (acute attack may occur)  Reduction of Glutamate action. 3) Status epilepticus.  Memory loss, irritability & mental confusion.
 Primidone is used in treatment of  Block Na & Ca(L,N) channels.  Teratogenic & hemorrhagic disease of new born.
Primidone 4) Febrile convulsion
Essential Tremor resistant to  Megaloblastic anemia & osteomalacia.
PROPRANOLOL.  Tolerated with single dose.

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P H R M A C O L O G Y - NOTE 14 - Treatment of Epilepsy
 Partial seizures & generalized tonic-clonic (cont…)
DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT
Lamotrigine  Block Na-voltage channels,  adjunctive therapy for refractory:  Dizziness, nausea & headache.
 to stabilize pre-synaptic o Partial seizures.  Diplopia.
o o
neuronal membranes. o 1 & 2 generalized tonic-clonic  Somnolence.
 reduces the release of excitatory seizures.  Skin rash.
amino acids (Glutamate & Aspertate)  Flu like symptoms.
Gabapentine  It is an analogue of GABA .   GABA synthesis & release. 1) Resistant partial seizures.  Somnolence.
 It crosses blood brain barrier.  block L type Ca channels. 2) Resistant generalized tonic-clonic.  Dizziness & headache.
 Agonize GABAB receptor. 3) Bipolar disorders.  Ataxia & tremors.
4) Migraine and neuropathic pain.
Vigabatrine   GABA conc. by 1) Partial seizures. NOT AT TOXIC DOSE
o
 irreversible inhibition of 2) 2 generalized responsible by  Dizziness, drowsiness.
GABA aminotransferase. seizures. other drugs  Weight gain.
3) Infantile spasms.  Agitation, confusion & psychosis.
LONG USE
 Irreversible Visual field defects.
Topiramate  NOT used during PREGNANCY .  Enahancement of GABAergic pathway.  adjunctive therapy for refractory:  Somnolence, fatigue & Dizziness.
Newer Drugs

 Block Na-voltage channels. o Partial seizures.  Nervousness & confusion.

 Block or antagonize Glutamate o Generalized tonic-clonic  Acute myopia ,glaucoma & urolithiasis.
receptors (weak). seizures.  Teratogenic abnormalities.
Tiagabine  Treatment by discontinuous doses  prolongs the inhibitory action of  adjunctive therapy for partial  Nervousness, confusion.
prevent : synaptically released GABA. seizures.  Difficulty in concentration & depression.
 Excessive confusion.  Tremor & ataxia.
 Somnolence.  somnolence & dizziness.
 Ataxia.
Zonisamide   Block Na channels. 1) Partial seizures.  Drowsiness.
 Block Ca-voltage channels. 2) Generalised tonic-clonic seizures.  cognitive impairment.
3) Infantile spasms & myoclonas.  Serious skin rashes.
Levetriacetam   At brain-specific binding site, it affects:  adjunctive therapy for partial  Asthenia.
 GABA receptors ( sensitivity) seizures  Dizziness.
 Ca-voltage channels (block).  with or without  Drowsiness.
 K-channels. generalization.
Felbamate   block NMDA receptor via GLYCINE  Refractory partial & generalized  Insomnia.
rd
binding site. seizures(3 line).  Dizziness.
 resistant seizures as in Lennox-  Ataxia.
Gastaur syndrome.  Aplastic anemia.
 Sever hepatitis.

LENNOX-GASTAURE SYNDROM
It consiste of:
 multiple seizure types.
 mental retardation.
 refractoriness to anti-seizure drugs. 37
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P H R M A C O L O G Y - NOTE 14 - Treatment of Epilepsy
 Generalized tonic-clonic
DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT
Ethosuximide  Therapeutic levels & Dosage– 60-100  Inhibits:  Absence seizures  GIT:
mg/ml achieved with 750-1500mg/day.  T type Ca-channels in thalamas.  Pain, nausea & vomiting.
 It depresses the cerebral MR.  Na/K ATPase.  CNS:
 The clearance is reduced by Valporic  GABA aminotransferase enzymes  Headache, dizziness, euphoria
Acid.  It depresses the cerebral MR.  Blood:
 Eosinophilia.
 Pancytopenia (Thrombocytopenia, leucopenia)
 Transient lethargy or fatigue.
 Skin rash.
 Steven Johnson syndrome.
 SLE.
Trimethadone  NOT used during pregnancy.  Petit mal epilepsy ( drug of choice).  Sedation.
 Act actively against Pentyleneterazole  HEMERALOPIA(reversible impaired visual
that induce seizures. adaptation)
 Others
DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT
Diazepam  used I.V. or rectally  They act as anti-epileptic by:  Generalized tonic-clonic (grand-mal).  Sedation. 
  GABAergic activity.  Status epilacticus  Tolerance.
Lorazepam  longer acting than diazepam.  CLORAZEPATE  More effective in status epilepticus.  paradoxical hyperactivity(in 
Benzodiazepines

DIPOTASSIUM---Used as an. children).

Clonazepam  Absence (petit mal) siezures. 
are common adverse effects.
  Ataxia, hypotonia , dysarthria.
Nitrazepam  Less potent than Clonazepam. Myoclonic seizures. 
 CLOBAZAM—  Salivation.
 infantile spasms.
 ADVERSE effects of  ↑respiratory secretions.
Clorazepate  adjunct to treatment of complex  Drowsiness.
Benzodiazepins ------
Dipotassium partial seizures.  Lethargy.
 . WITHDRAWAL SYMPTOMS
Clobazam  Commonly not used due to quick & high  less sedative.
 Exacerbation of seizures if
tolerance
the drug is stopped suddenly.  High TOLERANCE
Acetazolamide  It is a carbonic anhydrase inhibitor  Exerts its anti- seizure activity by:  Epilepsy during menses (as it  Tolerance (quick develop).
 Mild acidosis in the brain. discontinuously administrated, NO
rolerance)
Sulthium  It is a carbonic anhydrase inhibitor

TYPE DRUG OF CHOICE ALTERNATIVE DRUG

ALTERNATIVE

Lamotrigine

Phenobarbito

Ethosuximide
Phenobarbiton

Gabapentine
Clonazepam
Clonazepam
Simple partial Phenytoin Gabapentine

Lamotrigine
Lamotrigine

Topiramate

Carbamazepi Vigabatrine

Topiramate
Felbamate
DRUG

Phenytoin
GENERALIZED SEIZURES

Clobazam

Tiagabine
Complex partial Phenobarbitone Felbamate
SEIZUREs
SIMPLE

Partial with secondarily valporate Topiramate

generalised Lamotrigine Tiagabine

ne
Phenytoin Gabapentine

Phenobarbiton
Ethosuximide

Clonazepam
Clonazepam

Lamotrigine
DRUG OF
CHOICE

Primidone
ePhenytoin
Valporate

Valporate

Valporate

Valporate
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ne
N ote
Type Absence Atonic Myoclonic Grand mal/tonic/clonic

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