2 ObjectivesAt the end of the lectures, students should 1- Describe types of epilepsy 2- List the antiepileptic drugs 3- Describe briefly the mechanism of action of antiepileptic drugs. 4- Enumerate the clinical uses of each drug 5- Describe the adverse effects of each antiepileptic drug 6- Describe treatment of status epilepticus
3 Prof. Mohammed Saad Al-Humayyd Azza HafizEl-MedanyProf. Mohammed Saad Al-Humayyd
4 DefinitionEpilepsy is a chronic medical condition characterized by 2 or more unprovoked seizures.It is not a disease, it is a syndrome ( what is the difference ).
7 Etiology Idiopathic Symptomatic Inherited abnormality in the C.N.S. Patients are treated chronically with antiseizure drugs or vagal nerve stimulationTumorsHead injuryHypoglycemiaMeningeal infectionsDrug withdrawalPhoto epilepsy ( by watching TV)
9 Tonic-clonic (Grand mal) Absence (Petit mal) Generalized: Both hemispheres + loss of consciousness. Tonic-clonic(Grand mal)Stiffness (15-30 sec) followed by violent contractions & relaxation (1-2 minute)Absence(Petit mal)Brief loss of consciousnesswith minor muscle twitcheseye blinkingMyoclonicRhythmic, jerking spasmsClonicSpasms of contraction & relaxationTonicMuscle stiffnessAtonicSudden loss of all muscle tone
10 PartialArise in one cerebral hemisphere Simple (consciousness is retained)Features depend on part of brain affectedMotor(Jacksonian epilepsy)Jerking, muscle rigidity, spasms, head-turningSensoryUnusual sensationsAutonomicPsychologicMemory or emotional disturbances Complex (Altered consciousness)Automatisms & behavioral changes Secondarily generalized seizureBegins as partial (simple or complex) and progress into grand mal seizure
13 Absence seizuresbrief; loss of consciousness accompanied by minimal motor manifestationscessation of an ongoing behaviorfull recovery is evidentafter 5-15 sec.
14 Partial seizures Simple Complex consciousness is often preserved. (e.g.deviation of the head& eyes to one side)Complexloss of awareness or contact with the environment, often associated with behavioral or complex motor movements for which the patient is amnesic after the attacks
15 General rules for treatment of epilepsy Antiepileptic drugs suppress but not cure seizuresAntiepileptic drugs are indicated when there is two or more seizures occurred in short interval ( 6 m-1y)An initial therapeutic aim is to use only one drug (monotherapy).
16 Drugs are usually administered orally Monitoring plasma drug level is usefulTriggering factors can affect seizure control by drugs.Sudden withdrawal of drugs should be avoided
17 Withdrawal startedAfter seizure –free period of 2-3 or more years from the last fit. Normal neurological examination , Normal EEG Relapse rate is 20-40%.
18 Pathophysiology of Epilepsy How Drugs Act?Blockade of voltage –gated channels (Na+ or Ca+)Enhancement of GABAOr interference withGlutamate transmission (citatory)(inhibitory)
20 Classification of antiepileptic drugs First-generationPhenytoinCarbamazepineValproateSecond- generationLamotrigineLevetiracetam
21 Carbamazepine Pharmacokinetics : Available only orally Well absorbed Strong enzyme inducer including its own metabolismMetabolized by the liver to active & inactive metabolitesExcreted in urine
22 Carbamazepine Therapeutic uses: Mechanism of action Drug of choice in partial seizures.Tonic-clonic seizures (1ry & 2ry generalized) but Not in absence seizures.Neuropathic painMood stabilizerMechanism of actionBlockade of Na+ channelsreduce the propagation of abnormal impulses in the braininhibit the generation of repetitive action potentialInhibit the release of glutamate
23 Side effects GIT upset. Hypersensitivity reactions Drowziness , ataxia, headache & diplopiaBlood dyscrasisHyponatremia & water intoxicationTeratogenicity ( neural tube defects ).Induction of hepatic P450
24 Phenytoin Pharmacokinetics : Well absorbed orally, it is also available as iv. (for emergency )Enzyme inducerMetabolized by the liver to inactive metabolitesExcreted in urine
25 Phenytoin Mechanism of action Blockade of Na+ channels. Interfere with the release of excitatory transmittersPotentiate the action of GABATherapeutic uses:Partial and generalized tonic-clonic seizures Not in absence seizure.In status epilepticus, IV .Cardiac arrhythmias
26 Side effects A ) dose-related : Nausea or vomiting Neurological like headache, vertigo, ataxia, diplopia , nystagmusSedation
27 B) Non –dose related Gum hyperplasia Coarsening of facial features HirsutismAcneMegaloblastic anemiaOsteomalciaTeratogenic effectEnzyme inducer
28 Sodium Valproate Broad spectrum antiepileptic Pharmacokinetics :Available as capsules, Syrup , I.VMetabolized by the liver ( inactive )Enzyme inhibitorExcreted in urine
29 Sodium valproate Therapeutic Uses Mechanism of action [I] Epilepsy: It is effective for all forms of epilepsy e.g.Generalized tonic-clonic seizures (1ry or 2ry ).Absence seizuresComplex partial seizuresMyoclonicAtonicphotosensitive epilepsyMechanism of actionBlockade of Na+ channels.Inhibits GABA -transaminaseSuppress glutamate action.Blocks T-type Ca2+ channels[II] Other uses:Bipolar disorder and maniaProphylaxis of migraineLennox-Gastaut syndrome
30 Side effects: Weight gain (appetite ). Transient hair loss, with re-growth of curly hairThrombocytopeniaHepatotoxicityTeratogenicity ( spina bifida)Enzyme inhibitor of P -450
31 Lamotrigine Mechanism of action Blockade of Na+ channels Inhibits excitatory amino acid release ( glutamate & aspartate )Therapeutic UseAs add-on therapy or as monotherapy in partial seizuresLennox-Gastaut syndrome
32 Side effects Influenza-like symptoms. Skin rashes (may progress to Steven –Johnson syndrome )SomnolenceBlurred visionDiplopiaAtaxia
33 Levetiracetam Pharmacokinetics : Taken orally ( tablets or solutions) Not metabolized & excreted unchanged in urineDoes not affect liver enzymesDrug interactions are minimal
34 Levetiracetam Mechanism of action Unknown Therapeutic Uses Adjunctive therapy in :Partial seizuresGeneralized tonic-clonic seizuresMyoclonic seizures (used alone)
35 Side effects Ataxia Dizziness Somnolence Pin & needles sensation in extremitiesBlurred vision
36 Other antiepileptics New antiepileptics for adjunctive treatment: Old: Phenobarbital and PrimidoneBenzodiazepines (e.g.Clonazepam and diazepam)New antiepileptics for adjunctive treatment:Gabapentin, vigabatrin, Felbamate, topiramate and others
37 Type of seizureChoice among drugsPartial seizures:Carbamazepine or phenytoin or valproate or lamotrigine.Generalised seizures:Tonic-clonic (grand mal)Valproate or carbamazepine or phenytoin or lamotrigineMyoclonicValproate, clonazepamAbsenceEthosuximide or valproateAtonicValproate
38 Drugs used for treatment of Status Epilepticus Most seizures stop within 5 minutes. When seizures follow one another without recovery of consciousness, it is called “status epilepticus”. It has a high mortality rate . Death is from cardiorespiratory failure.
39 Intravenous injection of : Lorazepam is the drug of choiceDiazepamPhenytoinfosphenytoinphenobarbital .
40 Vagal nerve stimulation It is an alternative for patients who have been refractory to multiple drugs .Who are sensitive to the many adverse effects of antiseizure drugsIt is an expensive procedure
42 Pregnancy & antiepileptic medications NO antiepileptic drug is safe in pregnancy.Patient has to continue therapy.If follow up of pregnancy reveals teratogenic effect, terminate this pregnancy.
43 Summary- Epilepsy is classified into partial or generalized according to the site of lesion.The main mechanism of antiepileptic action is through blocking the activated sodium channelsPhenytoin is mainly used for treatment of generalized tonic-clonic seizures .The adverse effects of phenytoin include gum hyperplasia , teratogenecity.Carbamazepine is mainly used for treatment of partial seizures
44 Summary ( con.) The main adverse effects of carbamazepine includes : Blood dyscrasis & hepatic toxicitySodium valproate is a broad spectrum antiepileptic drugThe adverse effects of sodium valproate includes hepatic toxicity , increase body weightLamotrigine & levetiracetam are used as monotherapy or adjunctive therapy in refractory casesLorazepam , diazepam , phenytoin are used intravenously for treatment of status epilepticus