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Pharmacology .. Treatment of Epilepsy
1. 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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2. 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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3. 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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4. 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
Phenobarbiton Clobazam
Tiagabine
Complex partial Phenobarbitone Felbamate
SEIZUREs
SIMPLE
Partial with secondarily valporate Topiramate
generalised Lamotrigine Tiagabine
ne
Phenytoin Gabapentine
Ethosuximide
Clonazepam
Clonazepam
Lamotrigine
DRUG OF
CHOICE
Primidone
Phenytoin
Valporate
Valporate
Valporate
Valporate
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ne
e
N ote
Type Absence Atonic Myoclonic Grand mal/tonic/clonic
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