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Mohammad Shariful Alam (Shohan)


Epilepsy is the second most common neurological disorder after stroke. Epilepsy: Epilepsy is a heterogeneous symptom complex- a chronic disorder characterized by recurrent seizures. Seizure: Seizures are finite episodes of brain dysfunction resulting form abnormal discharge of cerebral neuron. Causes of seizure: Infection to neoplasm, head injury etc. History: Phenobarbitone was first used for epilepsy (1912). In 1938 Phenytoin was found to be effective. Classification of seizure: It can be classified into following two types1) Partial seizure 2) Generalized seizure. Partial seizure: In partial seizures neuronal discharge remains localized in one area of the brain. It can be again classified into two types Simple partial seizure- no loss of consciousness. Complex partial seizure- impaired consciousness. Generalized seizure: It begins locally but rapidly spread through both hemisphere of the brain. Types:


Tonic clonic (most common) Absence Myoclonic Status epilepticus.

Tonic clonic: Resulting loss of consciousness followed by tonic phase and then clonic phase. During tonic phase body becomes rigid as all the muscles go spasm. After a minute later rhythmic contraction of the limbs and trunks muscle occurs. Mohammad Shariful Alam

Absence seizure: It is characterized by sudden loss of consciousness, lasting for a few seconds. Myoclonic seizure: Here muscle contraction that may reoccur for several minutes. Status epilepticus: It is a medical emergency where there is repeatedly seizure and no recovery between seizures. Due to convulsions there is hyperpyrexia, acidosis and respiratory failure. Treatment:

Drug of choice- Diazepam 5-10 mg of drug should be administered I/V slowly at a rate of 1-2 mg/min. If necessary the dose may be repeated after 20-30 minutes until the convulsion is controlled. Diazepam + Phenytoin sodium.
[Rx of status epilepticus (a medical emergency): I. Early status epilepticus II. Established status epilepticus III. Refractory status epilepticus Lorazepam Clonazepam Diazepam Phenytoin Phenobarbital Thiopental-Na or Propofol or Midazolam with full intensive care support.

Classification of anti-epileptic drugs: According to mechanism of action/Molecular classificationA. Enhancement of GABAergic (inhibitory) transmission/GABA potentiator Phenobarbitone Primidone Vigabatrin Gabapentin. B. Diminution of excitatory (usually glutametargic) transmission Topiramate Remacemide. C. Modification of ionic conductancei) Na-channel modifier Phenytoin Mephenytoin Carbamazepine Na valproate ii) Ca++ channel modifier Ethosuximide Trimethadione Paramethadione. Another way of classification: o 1st line drugsCarbamazepine Ethosuximide Phenytoin Valproic acid.

Mohammad Shariful Alam (Shohan)

2nd line drugs Gabapentin Vigabatrin.

Drugs of choice for treatment of epilepsy:

Seizure disorders I. Partial or secondary generalized seizures Drugs of choice Carbamazepi ne Na valproate Alternative drugs Phenytoin Lamotrigine Vigabatrin Gabapentin Oxacarbazep ine Clonazepam Phenytoin Topiramate Clonazepam Lamotrigine

II. Generalized tonic-clonic seizures, GTCS III. Absence (petit mal) seizures IV. Atypical absence, myotonic, atonic

Na-valproate Lamotrigine Ethosuximide Na-valproate Na-valproate Clonazepam Lamotrigine Phenytoin Ethosuximide Phenobarbital Na-valproate Clonazepam

V. Myoclonic


Phenyt oin
Pharmacokinetics: Routes of administrationOral for chronic use Parenteral-I/V for status epilepticus. Absorption- Slow. Plasma protein binding: 80-90% Plasma half life: 80 hours. Metabolism- Liver (glucoronide conjugation) EliminationIn low dose phenytoin shows first order kinetics In high dose zero order kinetics.
(Shohan) [First-order kinetics: In normal dosage, most drugs are eliminated at a rate proportionate to the plasma concentration. This is called first-order kinetics. Mohammad Shariful Alam

Zero-order kinetics: If the plasma concentration of a drug is very high and normal metabolism is saturated, the rate of elimination may become fixed. This is called zero-order kinetics.]

Mechanism of action:

The basic principle of action of antiepileptic drugs have been found to concern voltage operated ion channels and inhibitory and excitatory synaptic function. Voltage dependent Na++ channels enter an inactive state following each action potential. Prolongation of this inactive state with a concomitant prolongation of refractoriness is thought to be the principal mechanism of action of phenytoin, carbamazepine, and lamotrizine.
[It stabilizes neuronal membrane to depolarization by decreasing the influx of Na+ in neuron resting state or during depolarization. It also reduces the influx of Ca ++ during depolarization & also reduces propagation of abnormal impulse in the brain.]

Indications: In all types of epilepsy except absence seizure and myoclonic seizure. As anti dysrrhythmic drugs. Advantage of phenytoin over other anticonvulsant drugs It is cheap and effective. Therapeutic level in serum is well defined than others. Adverse effects: a. Nausea, vomiting and anorexia. b. Dose related cerebellovestibular a/e ex- Ataxia, nystigmus, dysarthriae and vertigo. c. Chronic administration of phenytoin cause gingival hyperplasia, osteomalasia, megaloblastic anaemia, hersutism, lymhadenopathy. Q. How phenytoin produces gum hyperplasia? Excess collagen synthesis is inhibited by collagenase enzyme Phenytoin inhibit collagenase enzyme Excess synthesis of collagen Causes gingival hyperplasia or gum hyperplasia. Q. How phenytoin causes megaloblastic anaemia? Increase folate metabolism by phenytoin, induces the enzyme which is responsible for hydroxylation Folate deficiency No maturation of RBC Megaloblastic anaemia. Q. How phenytoin causes osteomalasia?
Mohammad Shariful Alam (Shohan)

3 mechanisms are responsible for this1. Phenytoin causes altered metabolism of Vit. D (i.e. metabolism of vit. D) 2. It decreases absorption of calcium along with vit. D from GIT. 3. They cause metabolism of vit. K and vit. K dependent protein which are responsible for calcium metabolism. So, concentration of vit. K, vit. D and Calcium thereby causes osteomalasia. Drug interaction:

Chloral hydrate and carbamazepine decrease the effect of phenytoin due to increase breakdown of phenytoin in liver. TCA may increase the incidence of epileptic seizure. BDZs, chloramphenicol, cimetidine, isoniazide, phenothiazines, sulphonamides, trimethoprim increase the effect of phenytoin due to decrease breakdown of phenytoin in liver. Phenytoin by induction of hepatic microsomal enzyme may increase the metabolism of OCP, corticosteroids, dicumarol, digitalis, doxycycline, haloperidol resulting decrease in P/E.

Carbamazepi ne

Closely related to TCA (Tri Cyclic Antidepressants). Drug of first choice in partial seizure. Can be given in trigeminal neuralgia. No sedation. It is the only epileptic drug that can be given in pregnancy. The drug has enzyme inducing property.

Indication: - Partial seizure - Generalized tonic clonic seizure - Trigeminal neuralgia. Q. Which drug can be given in pregnancy and why? Drug of choice in pregnancy is carbamazepine, because Phenytoin and valproate produces FHS (Foetal hydantoin syndrome). Na valproate produces spina bifida. Phenobarbitone produces - Withdrawal syndrome - Neonatal hemorrhage.

Mohammad Shariful Alam (Shohan)

Trimethadone and Para methadone produces FHS like malformation syndrome Foetal hydantoin syndrome: This is the syndrome which develops after administration of phenytoin during pregnancy.
In foetusCleft lip, cleft palate, congenital heart disease, retardation of growth and mental health occurs. In diabetic patientPhenytoin increases blood sugar level so contraindicated in untreated diabetic patients. But phenytoin can be given to the patient getting insulin for treatment. Guidelines of anticonvulsant therapy: Start with first line drug Start with low dose; gradually increase for effective control of seizure or s/e. Use minimum divided dose. First line drug if fail start with second line drug. Try 3 drugs singly before using combination to avoid drug interaction. Do not use more than two drugs in combination.

Duration of antiepileptic therapy: Withdrawal should be slow. Over 6 months, if a fit occurs, full therapy must be resumed again, for about 2-3 years.