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  1. 1. ANTIEPILEPTIC DRUGS Dr. Hiwa K. Saaed Department of Pharmacology & Toxicology College of Pharmacy University of Sulaimani 2014-15
  2. 2. 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
  3. 3. Epilepsy: Epilepsy: is a disorder of cerebral cortex characterized by recurrent (periodic and unpredictable) seizures. often accompanied by episodes of unconsciousness and/or amnesia. Globally, epilepsy is the third most common neurologic disorder after cerebrovascular and Alzheimer’s disease. Epilepsy is not a single entity but an assortment of different seizure types and syndromes originating from several mechanisms that have in common the sudden, excessive, and synchronous discharge of cerebral neurons.
  4. 4. 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. • The site of origin of the abnormal neuronal firing determines the symptoms that are produced. For example,  if the motor cortex is involved, the patient may experience abnormal movements or a generalized convulsion.  Seizures originating in the parietal or occipital lobe may include visual, auditory, and olfactory hallucinations. Seizures may  Remain localised (focal epilepsy)  Spread (generalised epilepsy)
  5. 5. ETIOLOGY OF SEIZURES • Idiopathic: In most cases, epilepsy has no identifiable cause. • changes in physiologic factors, such as an alteration in  blood gases, pH (extreme acidosis or alkalosis), electrolytes (hyponatrmia, hypocalcemia), and blood glucose (hypglycemia) • changes in environmental factors, such as  sleep deprivation, alcohol intake (rapid withdrawal from depressants), and stress. • Epilepsy can be due to an underlying  Genetic (heredity),  Structural; CNS infection i) meningeal infection ii) tumors  or metabolic defects  High Fever  or an unknown cause.
  6. 6. Classification of Epileptic Seizures
  7. 7. 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. Jacksonian motor epilepsy: convulsion in single group of muscles or limb. 2. Jacksonian sensory epilepsy or paraesthesia in some localized region. 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).  80% of individuals experience their initial seizures before 20 years of age
  8. 8. II. Generalized Seizures begin locally, rapidly spread, affect the whole brain, both hemispheres may be convulsive or non convulsive, immediate loss of consciousness. It is divided into: 1. Tonic-clonic (grand-mal) 2. Absence (petit-mal) 3. Myoclonic 4. Febrile seizures 5. Status epilepticus
  9. 9. 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. 4) Absence: Loss of consciousness without involving motor area. Most common in children ( 4-12 yrs ).
  10. 10. II. Generalized Seizures 5) Myoclonic: rare, occur at any age Sudden, brief shock like contraction which may involve the entire body or be confined to the face, trunk or extremities. May reoccur for several minutes 6) Febrile Seizures: young children (3M-5 years) with illness accompanied by high fever. Consist of generalized tonic-clonic convulsion with short duration. 7) Status epilepticus (reoccurring seizure): Continuous (a series of rapid recurrent seizures) tonic-clonic without intervening return of consciousness. It is life-threatening emergency.
  11. 11. First aid for seizures Do • Remove harmful objects nearby • Cushion their head • aid breathing by gently placing them 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
  12. 12. 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. maximize the seizure control 2. minimize drug side effects In general, seizures can be controlled with one medication in approximately 75% of patients. Patients may require more than one medication in order to optimize seizure control, and some patients may never obtain total seizure control.
  13. 13. 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. Classification of seizures. 2. Patient’s age & health state 3. Data on efficacy, tolerability, safety and pharmacokinetics
  14. 14. Starting Treatment start low, go slow • 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
  15. 15. 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 , became the drug of choice for many years. • A number of medications similar to Phenobarbital 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.
  16. 16. 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.
  17. 17. Classification of Anticonvulsants Classical before 1990 Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Benzodiazepines Newer after 1990 Felbatol (felbamate) 1993 Neurontin (gabapentin) 1994 Lamictal (lamotrigine) 1995 Topamax (topiramate) 1996 Gabitril (tiagabine) 1998 Keppra (levetiracetam) 1999 Trileptal (oxcarbazepine) 2000 Zonegran (zonisamide) 2000 Lyrica (pregabalin) 2005 Potiga (Ezogabine) Aptiom (Eslicarbazepine) Banzel (Rufinamide), VIMPAT (Lacosamide), other
  18. 18. 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.
  19. 19. 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
  20. 20. Effects of three antiepileptic drugs on high frequency discharge of cultured neurons . Block of sustained high frequency repetitive firing of action potentials. 10-Nov-14 20
  21. 21. 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)
  22. 22. Mechanism of action of AEDs
  23. 23. Ion Channels# Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid # For general tonic-clonic and partial seizures Ca++ #: Ethosuximide Valproic acid Zonisamide # For Absence seizures Enhance Inhibitory aa # Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate # Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence Inhibit Excitatory aa Felbamate Topiramate Classification of AEDs
  24. 24. TREATMENT OF SEIZURES Seizure disorder Drugs Carbamazepine or Valproate or Phenytoin or Phenobarbital Tonic-clonic (Grand mal) Drug of Choice Topiramte Lamotrigine (as adjunct or alone) Gabapentin (as adjunct) Alternatives: Carbamazepine or Topiramte or Phenytoin or Valproate Partial (simple or complex) Drug of choice Phenobarbital Lamotringine (as adjunct or alone) Gabapentin (as adjunct ) Alternatives:
  25. 25. Treatment contd TREATMENT OF SEIZURES cont,d Absence ( petit mal) DOC* Ethosuximide or Valproate Clonazepam Lamotrigine Alternatives: Myoclonic, Atonic DOC Valproate Alternatives: Clonazepam Diazepam, i.v. or Phenytoin, i.v. or Vaproate Status Epilepticus DOC Alternatives: Phenobarbital, i.v Diazepam, rectal**, I.V Valproate Corticotropin (IM) or prednisolone Febrile Seizures * DOC = Drug of choice ** Preferred
  26. 26. AEDs pharmacokinetics Most classical antiepileptic drugs exhibit similar pharmacokinetic properties. • Good absorption (although most are sparingly soluble). • Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine). • Conversion to active metabolites (carbamazepine, primidone, fosphenytoin).
  27. 27. 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.
  28. 28. PHENYTOIN TERATOGENICITY Fetal hydantoin syndrome include: • cleft lip, cleft palate • congenital heart disease • slowed growth • mental deficiency
  29. 29. 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
  30. 30. 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.
  31. 31. 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. 10-Nov-14 31
  32. 32. Eslicarbazepine • Eslicarbazepine acetate is a prodrug that is converted to the active metabolite eslicarbazepine (S-licarbazepine) by hydrolysis. • S-licarbazepine is the active metabolite of oxcarbazepine • It is a voltage-gated sodium channel blocker • and is approved for partial-onset seizures in adults. • Eslicarbazepine exhibits linear pharmacokinetics and is eliminated via glucuronidation. • The side effect profile includes dizziness, somnolence, diplopia, and headache. Serious adverse reactions such as rash, psychiatric side effects, and hyponatremia occur rarely.
  33. 33. 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
  34. 34. 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 10-Nov-14 34
  35. 35. GABAPENTIN (Neurontin) Adverse effects:  Somnolence. • Dizziness. • Ataxia. • Headache. • Tremor. • Used as an adjunct in partial and generalized tonic-clonic seizures. • Does not induce liver enzymes. • 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. • Alleviate both diabetic neuropathies pain and post herpetic pain 10-Nov-14 35
  36. 36. VIGABATRIN • RX of Partial Seizures • Inhibit GABA transaminase ADVERSE EFFECTS: • Depression, • psychosis, • visual dysfunction
  37. 37. LAMOTRIGINE (Lamictal) Adverse effects: • Dizziness • Headache • Diplopia • Nausea • Somnolence • Rash • Presently use as add-on therapy with valproic acid. • Almost completely absorbed • T1/2 = 24 hrs • Low plasma protein binding • Blocks sodium channels, & high voltage Ca+2 channel • thus its effective in partial, generalized, myoclonic, absence seizures & Lennox- Gastaut syndrome (LGS). • Approved for use in bipolar disorder 10-Nov-14 37
  38. 38. 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)
  39. 39. TIAGABINE (Gabatril) Adverse effects: •Dizziness •Nervousness •Tremor •Difficulty concentrating •Depression •Asthenia •Emotional •Psychosis •Skin rash • 100% bioavailable, • highly protein bound. • T1/2 = 5 -8 hrs • Effective against partial and generalized tonic-clonic seizures. • GABA uptake inhibitor GAT-1. 10-Nov-14 39
  40. 40. EZOGABINE • Ezogabine is thought to open voltage-gated M-type potassium channels leading to stabilization of the resting membrane potential. • Ezogabine exhibits linear pharmacokinetics and no drug interactions at lower doses. • Possible unique side effects are  urinary retention,  QT interval prolongation,  blue skin discoloration,  retinal abnormalities.
  41. 41. TOPIRAMATE (Topamax) Adverse effects: • Somnolence • Fatigue • Dizziness • Cognitive slowing • Paresthesias • Nervousness • Confusion • Urolithiasis • Weight loss • Broad spectrum antiseizure activity, also used in migraine • Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 hrs • blocking of voltage-dependent sodium channels • Additionally ↑ the frequency of Cl- channel opening by binding to GABA receptor. • High-voltage calcium currents (L-type) are reduced • Depresses excitatory action of kainate on AMPA receptors. • Carbonic anhydrase inhibiter effect • Teratogenic in animal models. 10-Nov-14 41
  42. 42. PERAMPANEL • is a selective α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid antagonist resulting in reduced excitatory activity. • Perampanel has a long half-life enabling once-daily dosing. • It is approved for adjunctive treatment of partial-onset seizures in patients 12 years or older.
  43. 43. RUFINAMIDE acts at sodium channels. It is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children over age 4 years and in adults. Adverse effects include the potential for shortened QT intervals. Patients with familial short QT syndrome should not be treated with rufinamide.
  44. 44. 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,  Oligohidrosis has been reported, and patients should be monitored for increased body temperature and decreased sweating. hyperthermia (children)  Kidney stone
  45. 45. STATUS EPILEPTICUS Status epilepticus is life threatening and requires emergency treatment usually consisting of administration of a fast-acting medication such as a benzodiazepine, followed by a slower-acting medication such as phenytoin.
  46. 46. Special Cases: Pregnancy • Seizure very harmful for pregnant women. • Antiepileptic drugs associated with increased (2-3 fold) incidence of birth defects (cleft lip/palate and cardiac defects) • 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.
  47. 47. Special Cases: Pregnancy • Monotherapy usually better than drugs combination. • Experience with new anticonvulsants still not reliable • Newborns of mothers receiving phenobarbitone, or phenytoin may develop hypoprothrominemia, heamorrhage prevented by Vit. K • Drugs are secreted in small quantities into breast milk but not usually sufficient to prevent breast feeding (phenobarbitone significantly)
  48. 48. 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.
  49. 49. 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.
  50. 50. 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.