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Antiepileptics Antiepileptics Presentation Transcript

  • ANTIEPILEPTIC DRUGS Dr. Hiwa K. Saaed Department of Pharmacology & Toxicology College of Pharmacy University of Sulaimani 2013-14
  • Antiepileptic drugs (AEDs)  Definitions and Terminology  Historical overview  Classification of AEDs  Etiologies and risk factors  Classifications of seizures  Management of epilepsy  Principles of treatment  Classification of Antiepileptic  Mechanism of Antiepileptic drug  Special cases: pregnancy  Vagal nerve stimulation and deep brain stimulation
  • Epilepsy: is a disorder of cerebral cortex characterized by recurrent (periodic and unpredictable) seizures. often accompanied by episodes of unconsciousness and/or amnesia
  • Seizures Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction, resulting from abnormal electrical discharge in cerebral neuronal cells, associated with prolonged depolarisation of cerebral neurons result in motor, sensory or behavioral changes. Seizures may  Remain localised (focal epilepsy)  spread (generalised epilepsy)
  • Historical overview • Modern treatment of seizures started in 1850 with the introduction of bromides, which was based on the theory that epilepsy was caused by an excessive sex drive. • In 1910, phenobarbital (PHB), became the drug of choice for many years. • A number of medications similar to PHB were developed, including primidone. • In 1940, phenytoin has become a major first-line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures.
  • Historical overview • In 1968, carbamazepine (CBZ) was approved, initially for the treatment of trigeminal neuralgia; later, in 1974, it was approved for partial seizures. • • Ethosuximide has been used since 1958 Valproate (VPA) was licensed in Europe in 1960 and in the United States in 1978, and now is widely available throughout the world.
  • Classification of Anticonvulsants Newer Classical • • • • • • • Felbatol (felbamate) 1993 Neurontin (gabapentin) 1994 Lamictal (lamotrigine) 1995 Topamax (topiramate) 1996 Carbamazepine Gabitril (tiagabine) 1998 Ethosuximide Keppra (levetiracetam) 1999 Valproic Acid Trileptal (oxcarbazepine) 2000 Phenytoin Phenobarbital Primidone benzodiazepines Zonegran (zonisamide) 2000 Lyrica (pregabalin) 2005 Ezogabine Rufinamide, Lacosamide, other
  • Causes for Acute Seizures • • • • • • Idiopathic Trauma Encephalitis Drugs Withdrawal from depressants • • • • • • High fever Hypoglycemia Extreme acidosis Extreme alkalosis Hyponatremia Hypocalcemia Tumor TRIGGERS: Fatigue, stress, poor nutrition, alcohol and sleep deprivation.
  • Classification of Epileptic Seizures
  • I. Partial (Focal) Seizures 1. Partial (focal) seizures (60%): they start locally in a certain site, its divided into: A. Simple partial: may occur at any age, without loss of consciousness, 1. 2. Jacksonian motor epilepsy: convulsion in single group of muscles or limb. Jacksonian sensory epilepsy or paraesthesia in some localized region.
  • I. Partial (Focal) Seizures B. Complex partial (psychomotor or temporal lobe): it is associated with loss of consciousness for about 30 seconds to 2 minutes. Disturbances of cognitive, affective, and psychomotor (chewing movement, diarrhoea, urination) or sensory hallucinations (smell or taste).
  • II. Generalized Seizures  begin locally,  rapidly spread,  affect the whole brain,  may be convulsive or non convulsive,  immediate loss of consciousness.
  • II. Generalized Seizures 1) Tonic-clonic. Patient fall in convulsion & may bite his tongue & may lose control of his bladder or bowel. 2) Tonic. Some patients, after dropping unconscious experience only the tonic or clonic phase of seizure. 3) Atonic ( akinetic). Starts between the ages 2-5 yrs. The pt’s legs simply give under him & drops down.
  • II. Generalized Seizures 4) Myoclonic: Sudden, brief shock like contraction which may involve the entire body or be confined to the face, trunk or extremities. 5) Absence: Loss of consciousness without involving motor area. Most common in children ( 4-12 yrs ). 6) Status epilepticus (reoccuring seizure): Continuous seizure without intervening return of consciousness.
  • First aid for seizures Do • • • Remove harmful objects nearby Cushion their head aid breathing by gently placing in recovery position Don’t • • • Restrain the person movement Put anything in the person’s mouth Give them anything to eat and drink until they are fully recovered them
  • Management of Epilepsy Therapy is symptomatic in that the majority of drugs prevent seizures, but neither effective prophylaxis or cure is available. The goal of the therapy is to improve the patient’s quality of life through: 1. 2. maximize the seizure control minimize drug side effects
  • Management of Epilepsy Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m-1year) Drug choice is based on: 1. 2. 3. Classification of seizures. Patient’s age & health state Data on efficacy, tolerability, safety and pharmacokinetics
  • Starting Treatment • Rx should always be started with a single drug at a small dose • All common side-effects must be discussed • teratogenicity and contraception if applicable • • Importance of compliance should be stressed Careful titration is a must - start low, go slow
  • Anti-epileptic drugs (AEDs) AEDS act by: I. Block the initiation of the electrical discharge from the focal area II. Prevent the spread of abnormal electrical discharge to adjacent brain area AEDs prevent depolarisation of neurones by:  Modification of ion conductance (direct membrane stabilisation)  inhibition of excitatory (glutamergic) activity  stimulation of inhibitory (GABAergic) transmission.
  • They do their actions by: -↓ axonal conduction by preventing Na+ influx through fast Na+ channels Example: Carbamazepine, oxcarbamazepine, phenytoin, also at high doses barbiturates and valproate. Lamotrigine, felbamate, topiramate -↓ presynaptic Ca+2 influx through type T channels in thalamic neurons Example: Ethosuximide, valproic acids, lamotrigine
  • Effects of three antiepileptic drugs on high frequency discharge of cultured neurons . Block of sustained high frequency repetitive firing of action potentials.
  • They do their actions by: -↑ inhibitory tone through 1. facilitation of GABA-mediated hyperpolarization (Barbs, BZs), 2. inhibiting GABA metabolism valproic acid and vigabatrin 3. or action on the reuptake of GABA (as with tiagabine) -↓ excitatory effects of glutamic acid 1. lamotrigine, topiramate (block AMPA receptors); 2. Felbamate, Phenobarbital (blocks NMDA receptors)
  • Mechanism of action of AEDs
  • Classification of Anticonvulsants Ion Channels# Enhance Inhibitory aa # Inhibit Excitatory aa Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid # For general tonic-clonic and partial seizures Ca++ #: Ethosuximide Valproic acid Zonisamide # For Absence seizures Benzodiazepines Felbamate (diazepam, clonazepam) Barbiturates (phenobarbital) Topiramate Valproic acid Gabapentin Vigabatrin Topiramate Felbamate # Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence
  • TREATMENT OF SEIZURES Seizure disorder Drugs Tonic-clonic (Grand mal) Drug of Choice Carbamazepine or Valproate or Phenytoin or Phenobarbital Alternatives: Topiramte Lamotrigine (as adjunct or alone) Gabapentin (as adjunct) Partial (simple or complex) Drug of choice Carbamazepine or Topiramte or Phenytoin or Valproate Alternatives: Phenobarbital Lamotringine (as adjunct or alone) Gabapentin (as adjunct )
  • Treatment contd TREATMENT OF SEIZURES cont,d Absence ( petit mal) DOC* Valproate or Ethosuximide Alternatives: Clonazepam Lamotrigine Myoclonic, Atonic DOC Valproate Alternatives: Clonazepam Status Epilepticus DOC Diazepam, i.v. or Phenytoin, i.v. or Vaproate Alternatives: Phenobarbital, i.v Febrile Seizures Diazepam, rectal**, I.V Valproate Corticotropin (IM) or prednisolone * DOC = Drug of choice ** Preferred
  • AEDs pharmacokinetics Most classical antiepileptic drugs exhibit similar pharmacokinetic properties. • • Good absorption (although most are sparingly soluble). • Conversion to active metabolites (carbamazepine, primidone, fosphenytoin). Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine).
  • PHENYTOIN Adverse effects • • • • • • • • • • Ataxia and nystagmus. Cognitive impairment. Hirsutism Gingival hyperplasia, Coarsening of facial features. folate dependent megaloblastic anaemia, Osteomalacia, Inhibition of ADH, inhibition of insulin secretion→hyperglycemia and glycosuria Hypoprothrominemia—coagulopathy Exacerbates absence seizures.
  • PHENYTOIN TERATOGENICITY Fetal hydantoin syndrome include: • • • • cleft lip, cleft palate congenital heart disease slowed growth mental deficiency
  • CARBAMAZEPINE Pharmacokinetics • • Absorbed slowly, enters brain rapidly Potent inducer of hepatic drug metabolising enzymes • own half life reduces over 2-3 weeks • increases metabolism of theophylline, warfarin and various hormones • complex drug interactions with other anticonvulsant agents
  • CARBAMAZEPINE Adverse effects • • • • • • • • • • Stupor, coma, respiratory depression, drowsiness, dizziness, vertigo, ataxia, blurred vision, diplopia, bradycardia, skin rashes, GI upsets. Hyponatremia in elderly The 10,11-epoxide metabolite →blood dyscrasias (leukopenia and aplastic anaemia), and serious liver toxicity.
  • OXCARBAZEPINE (Trileptal) • • • • 10-KETO DERIVATIVE OF CARBAMAZEPINE With improved toxicity profile. Less potent than carbamazepine. Active metabolite. Mechanism of action, similar to carbamazepine Adverse effects:  Hyponatremia,  Less hypersensitivity, and induction of hepatic enzymes than with carbamazepine.
  • SODIUM VALPROATE inhibits P450 system Adverse effects:  Elevated liver enzymes including own.  Tremor, hair loss, changes in hair growth  increased appetite Weight gain.  coagulopathy (inhibition of platelet aggregation),  Idiosyncratic hepatotoxicity.  Negative interactions with other antiepileptics.  Teratogen: spina bifida
  • FELBAMATE (Felbatrol) • Effective against partial seizures but has severe side effects. • Thus, used only for refractory cases. • One of the metabolites; α,β-unsaturated aldehyde, 2- phenylpropenal is chemically reactive, like acrolein covalently linking proteins as well as DNA, it can cause liver and bone marrow toxicity
  • GABAPENTIN (Neurontin) • Used as an adjunct in partial and generalized tonic-clonic seizures. • • • • • Does not induce liver enzymes. • Alleviate both diabetic neuropathies pain and post herpetic pain not bound to plasma proteins. drug-drug interactions are negligible. Low potency. An a.a.. Analog of GABA that does not act on GABA receptors, it may however alter its metabolism, non-synaptic release and transport. Adverse effects:  Somnolence. • • • • Dizziness. Ataxia. Headache. Tremor.
  • VIGABATRIN • • RX of Partial Seizures Inhibit GABA transaminase ADVERSE EFFECTS: • • • Depression, psychosis, visual dysfunction
  • LAMOTRIGINE (Lamictal) • Presently use as add-on therapy with valproic acid. • • • • Almost completely absorbed • thus its effective in partial, generalized, myoclonic, absence seizures & LennoxGastaut syndrome (LGS). • Approved for use in bipolar disorder T1/2 = 24 hrs Low plasma protein binding Blocks sodium channels, & high voltage Ca+2 channel Adverse effects: • • • • • • Dizziness Headache Diplopia Nausea Somnolence Rash
  • LEVETIRACETAM (Keppra) • • Adjunct Rx of refractory Partial Seizure Unknown mechanism of action but binds to presynaptic vesicle protein ADVERSE EFFECT Dizziness, sleep disturbances, headache, and asthenia (LACK OF ENERGY)
  • TIAGABINE (Gabatril) • • • • 100% bioavailable, • GABA uptake inhibitor GAT-1. highly protein bound. T1/2 = 5 -8 hrs Effective against partial and generalized tonic-clonic seizures. Adverse effects: •Dizziness •Nervousness •Tremor •Difficulty concentrating •Depression •Asthenia •Emotional •Psychosis •Skin rash
  • TOPIRAMATE (Topamax) • • • • • • • • Broad spectrum antiseizure activity, also used in migraine Adverse effects: • Somnolence Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 • Fatigue hrs • Dizziness blocking of voltage-dependent sodium channels • Cognitive Additionally ↑ the frequency of Cl- channel slowing opening by binding to GABA receptor. • Paresthesias High-voltage calcium currents (L-type) are • Nervousness reduced • Confusion Depresses excitatory action of kainate on AMPA • Urolithiasis receptors. • Weight loss Carbonic anhydrase inhibiter effect Teratogenic in animal models.
  • ZONISAMIDE • • • Sulfonamide derivative Orally active half-life 50-60 hrs Both focal and generalized MECHANISM OF ACTION • • Blocks voltage-gated Na+ channels and T-type Ca+2 current, enhancement of GABA-receptor function ADVERSE EFFECTS:  somnolence,  Ataxia,  hyperthermia (children)  Kidney stone
  • Special Cases: Pregnancy • • Seizure very harmful for pregnant women. • Significant risk of neural tube defects, folic acid is recommended to be given for every pregnant women with epilepsy • Phenytoin, sodium valproate are absolutely contraindicated and oxcarbamazepine is better than carbamazepine. Antiepileptic drugs associated with increased (2-3 fold) incidence of birth defects (cleft lip/palate and cardiac defects)
  • Special Cases: Pregnancy • • • Monotherapy usually better than drugs combination. • Drugs are secreted in small quantities into breast milk but not usually sufficient to prevent breast feeding (phenobarbitone significantly) Experience with new anticonvulsants still not reliable Newborns of mothers receiving phenobarbitone, or phenytoin may develop hypoprothrominemia, heamorrhage prevented by Vit. K
  • ANTISEIZURE DRUG INTERACTIONS With other drugs: antibiotics  phenytoin, phenobarb, carb. anticoagulants phenytoin and phenobarb metabolism. cimetidine displaces pheny, v.a. and BDZs isoniazid  toxicity of phenytoin oral contraceptives antiepileptics  metabolism. salicylates displaces phenytoin and v.a. theophyline carb and phenytoin may effect.
  • VAGAL NERVE STIMULATION (VNS) VNS requires surgical implant of a small pulse generator with a battery and a lead wire for stimulus. The device is implanted and its lead wires wrapped around the patient’s vagal nerve. This treatment was approved in 1997. The device is also approved for treatment of depression. The mechanism of action is unknown. VNS has been effective in treatment of partial onset seizures and has enabled reduction of drug therapy in some cases. It is an alternative for patients whose conditions have been refractory to multiple drugs and in those who are sensitive to the many adverse effects of antiseizure drugs and those who have difficulty adhering to medication schedules. However, VNS is a costly and invasive procedure.
  • DEEP BRAIN STIMULATION (DBS) DBS therapy uses a pacemaker-like device to deliver targeted electrical stimulation to the anterior nucleus of the thalamus. The therapy is FDA approved with conditions for adjunctive treatment for partial-onset seizures in adults with medically refractory epilepsy. DBS is also FDA approved for treatment of advanced Parkinson disease and essential tremor.