Class anti-epileptics


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Class anti-epileptics

  2. 2.  Epilepsies are the group of disorders of CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes of loss of consciousness with or without characteristic body movements(convulsions), sensory or psychiatric phenomena.(periodic and unpredictable)  Seizure is transient alteration of behavior due to disordered synchronous rhythmic firing of population in brain neurons 2
  3. 3. 1. GTCS-generalized tonic clonic seizures- Major, grandmal  Commonest  Time -1-2 min  Sequence –Aura Cry unconsciousness tonic spasms Clonic jerking  prolonged sleep prolonged sleep depression of CNS function 3
  4. 4.  Common in children  Time -30 sec  Momentary loss of consciousness  Patient apparently freezes and stares in one direction  3hz-spikes discharge- voltage regulated Ca+ channels 4
  5. 5.  Unconsciousness with relaxation of all muscles due to excessive inhibitory discharges  Myoclonic seizures  Infantile spasms- intermittent muscle spasm and progressive mental deterioration 5
  6. 6. Occasional, sudden, excessive, rapid and local discharges of gray matter Simple partial seizures-consciousness is preserved Time 30sec Localized sensory disturbances Complex partial seizures-temporal lobe epilepsy bizarre confused behavior Todds paralysis, jacksonian seizures- simple partial or complex partial 6
  7. 7. 7
  8. 8.  Genetic  Brain lesions  Infections  Metabolic discharges  Sudden withdrawal  Television 8
  9. 9. 1. Inhibition of voltage-gated Na+ channels to slow neuron firing. 2. Enhancement of the inhibitory effects of the neurotransmitter GABA. 3. Inhibition of calcium channels-absence seizures 9
  10. 10. Mechanism of drugs used in grandmal seizures Inhibition of use-dependent Na channels Phenytoin Carbamazepine Valproate Lacosamide Lamotrigine Zonisamide 10
  11. 11. Enhancement of GABA ergic action Phenobarbital and Benzodiazepines Vigabatrin Tiagabine Valproic acid Blockade of NMDA or AMPA receptors Felbamate, Phenobarbital Topiramate Lamotrigine, Valproate 11
  12. 12. Blockade of voltage gated N-type Ca+ channels  Lamotrigine and Gabapentin Selective binding to synaptic vesicular protein (SV2A) Levetiracetam By blocking the effect of neurotropic factors Lacosamide 12
  13. 13. Inhibition of T type Ca channels  Ethosuximide  Valproic acid 13
  14. 14. blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery Finally glutamate release is inhibited 14
  15. 15.  Limited water solubility – not given i.m.  Slow, incomplete and variable absorption.  Extensive binding to plasma protein.  Metabolized by hepatic ER by hydroxylation. Chance for drug interactions.  Therapeutic plasma concentration: 10-20 µg/ml  Shift from first to zero order elimination within therapeutic concentration range. 15
  16. 16. Acute Toxicity  High i.v. rate: cardiac arrhythmias ± hypotension; CNS depression.  Acute oral overdose: cerebellar and vestibular symptoms and signs: nystagmus, ataxia, diplopia vertigo. 16
  17. 17. Chronic Toxicity Folate Deficiency - megaloblastic anemia Hypoprothrombinemia and hemorrhage in newborns Hypersensitivity Reactions – could be severe. SLE, fatal hepatic necrosis, Stevens-Johnson syndrome. Pseudo lymphoma syndrome Teratogenic hirsutism Drug Interactions: decrease (cimetidine, isoniazid) or increase (phenobarbital, other AED’s) rate of metabolism; competition for protein binding sites. 17
  18. 18.  A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body.  Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes.  Otherwise similar toxicities to phenytoin. 18
  19. 19. CARBAMAZEPINE: derivative of iminostilbene with a carbamyl group, structurally related to TCAs -GTCS, trigeminal neuralgia Manic depressive psychosis may have adrenergic mechanism as well Also for trigeminal neuralgia Serious hematological toxicity: aplastic anemia, aplastic anemia Antidiuretic effect increase ADH Teratogenicity D/I-enzyme inducer OXCARBAMAZEPINE: Mild enzyme inducer 19
  20. 20. 20
  21. 21.  is a sulfonamide derivative that has a broad spectrum of actionPartial, generalized tonic clonic and myoclonic seizures, lennox-gastaut syndrome  Other Mechanism of Action: ▪ Inhibits T-type Ca2+ currents. ▪ Binds to GABA receptors. ▪ Facilitates dopaminergic and serotonergic neurotransmission. S/E-drowsiness, amnesia, kidney stones 21
  22. 22. Other Mechanism of Action: May inhibit synaptic release of glutamate. Indications: Adjunct therapy-Simple & complex partial seizures Generalized seizures of Lennox-Gastaut Syndrome Monotherapy: Simple & complex partial seizures Bipolar disorder S/E-dizziness, diplopia, enzyme inducers 22
  23. 23. Wide spectrum antiepileptic Unpredictable toxicity Blocks voltage gated Na channels Blockade of NMDA receptors USES Drug refractory epilepsies- lennox-gastaut syndrome Atonic seizures, atypical seizures, partial seizures GTCS S/E- Aplastic anemia, hepatotoxicity 23
  24. 24.  Piracetam derivative  Binds selectively to SV2A protein of synaptic vesicles in glutamatergic and GABAergic neurons.  Partial seizures S/E-Asthenia, Dizziness LACOSAMIDE- Acts by inhibiting voltage gated Na channels CRMP-2(Collapsin Response Mediator Protein) Brain Derived Neurotropic Factor epileptogenesis Bioavailability -100% 24
  25. 25. The only barbiturate with selective anticonvulsant effect. MOA-Bind at allosteric site on GABA receptor and ↑ dura on of opening of Cl channel. ↓ Ca-dependent release of neurotransmitters at high doses. Use dependent Na+ channels blockade AMPA receptors-inhibit glutamate Febrile seizures, simple partial P/K-Plasma t1/2- 100hrs Dose 60-180mg orally HS 25
  26. 26. Toxic effects: Inducer of microsomal enzymes – drug interactions. sedation (early; tolerance develops) Gingival hyperplasia, hirsutism Nystagmus & ataxia at higher dose; Osteomalacia, folate deficiency and vit. K deficiency. In children: paradoxical irritability, hyperactivity and behavioral changes. Deoxybarbiturates: primidone: active but also converted to phenobarbital. Some serious additional ADR’s: leukopenia, SLE-like. C/I-Petitmal And Porphyria's 26
  27. 27.  Sedative - hypnotic- anxiolytic drugs.  Bind to another site on GABA receptor. Other mechanisms may contribute. ↑ frequency of opening of Cl channel.  Clonazepam and clorazepate for long term treatment of complex partial seizures.  Diazepam and lorazepam: for control of status epilepticus. Disadvantage: short acting.  Toxicities: chronic: lethargy drowsiness. in status epilepticus: iv administration respiratory and cardiovascular depression. Phenytoin and PB also used. 27
  28. 28. Vigabatrin: Irreversible inhibitor of GABA transaminase.  Simple and complex partial seizures  Drug refractory epilepsy and infantile spasm  Potential to cause psychiatric disorders (depression and psychosis). Weight gain  Vigabatrin can cause irreversible visual field defects Tiagabine: decreases GABA uptake by neuronal, extraneuronal tissues and increases the GABA content of brain 28
  29. 29. Developed as GABA analogues readily cross BBB Mechanism: Increases release of GABA Inhibit N type Ca channelsinhibit synaptic release of glutamate Absorption of gabapentin from intestine depends on the carrier system Resistant partial seizures, GTCS Chronic nerve injury α2δ subunits of L-type Ca channels, in peripheral nerves, get upregulated resulting in various types of neuropathiesgabapentin binds to α2δ subunits Post-herpetic neuralgia, trigeminal neuralgia, multiple sclerosis 29
  30. 30.  Effective in multiple seizure types.  Blocks Na and Ca channels.  Inhibits GABA transaminase. Increases GABA synthesis.  Decrease in the glutamate  Antiepileptic use- absence seizures  GTCS, myoclonic seizures  DOC- Lennox gastaut syndrome  Infantile spasms  Non-epileptic use-manic depressive psychosis,  Migraine, cluster headache, cushings syndrome,  Tardive dyskinesia, trigeminal neuralgia 30
  31. 31.  Toxicity: most serious: fulminant hepatitis. More common if antiepileptic polytherapy in children < 2 years old.  Tremors, thrombocytopenia, hair loss  Drug interactions: inhibits Phenobarbital and phenytoin metabolism. 31
  32. 32.  TOPIRAMATE  multiple mechanisms of action (Na channel, GABA enhancement like BZD, antagonist at AMPA subtype of glutamate receptors (not NMDA).  GTCS, partial and absence seizures  Lennox-gastaut syndrome  S/E- urolithiasiscarbonic anhydrase inhibition 32
  33. 33.  Broad spectrum anticonvulsant  Blockade of use dependant Na channels  Inhibition of t-type of Ca channels  Negligible protein binding and renal excretion  GTCS, myoclonic seizures  Infantile spasms  Lennox- gastaut syndrome  S/E-drowsiness, amnesia, kidney stones 33
  34. 34. Drug of choice for Absence. Blocks Ca++ currents (T-currents) in the thalamus. Pure petitmal drug Preferred in pregnancy GI complaints most common CNS effects: drowsiness lethargy Has dopamine antagonist activity ( In seizure control) but causes Parkinsonian like symptoms. Potentially fatal bone marrow toxicity and skin reactions 34
  35. 35. Premonitory stage-diazepam-10-15mg repeated once after 15 min Early status-lorazepam-0.1mg/kg repeated once after 15 min Give usual AED medications if already on treatment Established status-fosphenytoin infusion15-20mg/kg Refractory status-general anaesthesia-propofol 2- 10mg/kg/hr -midazolam-0.5mg/kg/hr -Thiopental sodium 3-5mg/kg Anaesthesia continued for12-24 hrs after last clinical or electrographic seizure 35