Antiseizure drugs pres


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Antiseizure drugs pres

  1. 1. ANTISEIZURE DRUGS OR Antiepileptic drugs
  2. 2. Epilepsy <ul><li>Chronic disorder characterized by recurrent seizures </li></ul><ul><li>Seizures is a sudden, excessive, abnormal discharge of cerebral neurons </li></ul><ul><li>Causes of seizures </li></ul><ul><li>Heredity – major contributing factor </li></ul><ul><li>may occur due to infection, neoplasm or head injury </li></ul><ul><li>Environmental causes-alteration in blood gases, pH, electrolytes, or glucose availability </li></ul>
  3. 3. Seizure classified into two broad groups <ul><ul><li>Partial: simple or complex </li></ul></ul><ul><ul><li>Generalized: absence, tonic, clonic, tonic-clonic, myoclonic, febrile </li></ul></ul>
  4. 4. PARTIAL SEIZURES <ul><li>Simple partial seizures (without loss of consciousness) </li></ul><ul><ul><li>confined to a single locus in brain </li></ul></ul><ul><ul><li>abnormal activity in one limb or muscles </li></ul></ul><ul><ul><li>With autonomic symptoms (nausea, blood pressure changes,...) </li></ul></ul><ul><li>Complex partial seizures (with loss of consciousness) </li></ul><ul><ul><li>Simple partial followed by a loss of consciousness </li></ul></ul><ul><ul><li>Impaired consciousness from the onset </li></ul></ul><ul><ul><li>Exhibits complex sensory hallucination </li></ul></ul><ul><ul><li>Motor dysfunction may involve chewing movements, diarrhea or urination </li></ul></ul>
  5. 5. Generalized seizures <ul><li>Electrical discharge spread to both hemisphere </li></ul><ul><li>May be convulsive (shaken repeatedly) or non convulsive </li></ul><ul><li>Immediate loss of consciousness occurs </li></ul><ul><li>Types </li></ul><ul><li>generalized tonic-clonic (grand mal) seizures </li></ul><ul><li>absence (petit mal) seizures </li></ul><ul><li>tonic seizures </li></ul><ul><li>atonic seizures </li></ul><ul><li>clonic and myoclonic seizures </li></ul><ul><li>febrile seizures </li></ul>
  6. 6. ======================= <ul><li>Partial Seizures localized onset of attack ascertained, either by clinical observation or by EEG – attack begins in a specific locus in brain </li></ul><ul><li>Simple Partial seizures – least complicated, characterized by minimal spread of abnormal discharge, normal consciousness and awareness are preserved – pt may have a sudden onset of clonic jerking of an extremity lasting 60-90 secs; residual weakness lasts for 15-30 mins after attack. </li></ul><ul><li>Pt completely aware of attack, can describe it in detail </li></ul><ul><li>EEG may show an abnormal discharge highly localized to the involved portion of brain </li></ul>
  7. 7. ======================= <ul><li>Complex Partial seizures – localized onset, discharge becomes more widespread (usually bilateral) and almost always involves limbic system </li></ul><ul><li>most (not all) CPS arise from one of the temporal lobes, possibly because of the susceptibility of this area to insults such as hypoxia or infection </li></ul><ul><li>Clinically, pt may have a brief warning followed by an alteration of consciousness during which some pts may stare and others may stagger or even fall </li></ul><ul><li>More, however, demonstrate fragments of integrated motor behavior called automatisms for which pt has no memory </li></ul><ul><li>after 30-120 secs, pt makes a gradual recovery to normal consciousness but may feel tired or ill for several hours after attack </li></ul>
  8. 8. Generalized Seizures Tonic-clonic seizures <ul><li>characterized by </li></ul><ul><li>tonic phase  continuous rigidity of all extremities </li></ul><ul><li>clonic phase  massive jerking of body ( rapid contraction and relaxation) </li></ul><ul><li>Tongue or cheek bitten, urinary incontinence common </li></ul><ul><li>Seizure followed by period of confusion and exhaustion due to depletion of energy </li></ul>
  9. 9. Absence seizure (petit mal) <ul><li>Typical absence seizures consists of staring for a few seconds (altered consciousness) then returning to full function, as if nothing occurred </li></ul><ul><li>Brief duration (< 10 secs) </li></ul><ul><li>ass with mild clonic jerking of eyelids, patient stares & exhibit rapid eye blinking </li></ul><ul><li>begin in childhood or adolescence and may occur up to hundreds of times a day </li></ul><ul><li>The patient has no recollection of the event. </li></ul>
  10. 10. Myoclonic seizures <ul><li>Myoclonic jerking – seen in generalized tonic-clonic seizures, partial seizure, absence seizures, and infantile spasms </li></ul><ul><li>Short episode of muscle contractions </li></ul><ul><li>Occurs due to permanent nurologic damage due to hypoxia, uremia, encephalitis or drug poisoning </li></ul>
  11. 11. Atonic seizures <ul><li>sudden loss of postural tone , if standing pt falls suddenly and may be injured, if seated, may suddenly drop forward </li></ul>
  12. 12. Infantile spasms <ul><li>characterized clinically by brief recurrent myoclonic jerks of body with sudden flexion or extension of the body and limbs </li></ul><ul><li>90% of affected pts have their 1 st attack before age of 1 yr </li></ul><ul><li>Most pts mentally retarded </li></ul><ul><li>cause  infection, kernicterus and hypoglycemia </li></ul>
  13. 13. Febrile fits <ul><li>Frequently occurs in young children (6 months- 6 yrs) during high grade fever </li></ul><ul><li>Characterized by tonic clonic convulsions of short duration (1 to 5 min), eye rolling & unresponsiveness </li></ul><ul><li>Benign, do not cause death, nurologic damage, injury, or learning disorder </li></ul><ul><li>Status epilepticus </li></ul><ul><li>Continuous, rapid, recurrent seizures </li></ul>
  14. 14. Antiepileptic drugs <ul><li>Primary drugs </li></ul><ul><li>Phenytoin </li></ul><ul><li>Carbamazepine </li></ul><ul><li>Clonazepam (BZ) </li></ul><ul><li>Clorazepate (BZ) </li></ul><ul><li>Diazepam (BZ) </li></ul><ul><li>Ethosuximide </li></ul><ul><li>Lorazepam (BZ) </li></ul><ul><li>Phenobarbital </li></ul><ul><li>Primidone </li></ul><ul><li>Valproic acid </li></ul><ul><li>Adjunct drugs </li></ul><ul><li>Fel bamate </li></ul><ul><li>Gaba pentin </li></ul><ul><li>Lamo trigine </li></ul><ul><li>Leve tira cetam </li></ul><ul><li>Tiaga bine </li></ul><ul><li>Topira mate </li></ul><ul><li>Zoni samide </li></ul><ul><li>Viga batrin </li></ul>
  15. 15. Pathophysiology of Seizures <ul><li>Increased CNS excitability </li></ul><ul><ul><li>Membrane depolarization </li></ul></ul><ul><ul><li>Increased excitatory input </li></ul></ul><ul><ul><li>Decreased inhibitory (GABA) input </li></ul></ul>
  16. 16. Strategies in Treatment <ul><li>Stabilize membrane by blockade of voltage gated channels (Na & Ca)  prevent depolarization by action on ion channels </li></ul><ul><li>Increase GABAergic transmission </li></ul><ul><li>Decrease Excitatory glutamate transmission </li></ul>
  17. 17. Classification of Anticonvulsants Felbamate Topiramate Benzodiazepines Barbiturates Valproic acid Gabapentin Vigabatrin Topiramate Felbamate Na + : Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca ++ : Ethosuximide Valproic acid Inhibit glutamate Transmission Enhance GABA Transmission Action on Ion Channels
  18. 18. Phenytoin <ul><li>Diphenylhydantoin – oldest antiseizure drug </li></ul><ul><li>Mechanism of action . </li></ul><ul><li>Blocks voltage gated Na+ channels in inactive state , slows recovery </li></ul><ul><li>blocks repetitive firing of action potentials, promotes stabilization of membrane, reduce propagation of abnormal impulse in brain </li></ul><ul><li>At higher dose blocks Ca 2+ conductance </li></ul><ul><li>Interfere with release of neurotransmitters norepinephrine, acetylcholine </li></ul><ul><li>Produces drowsiness and lethargy </li></ul>
  19. 19. Phenytoin /Clinical use <ul><li>Highly effective in </li></ul><ul><li>Partial seizures (simple and complex) </li></ul><ul><li>Tonic-clonic seizures </li></ul><ul><li>Status epilepticus </li></ul><ul><li>Arrhythmia </li></ul><ul><li>Not effective in absence seizures </li></ul>
  20. 20. Phenytoin /Adverse effects <ul><li>Depression of CNS  Sedation, Nystagmus, diplopia and ataxia, confusion & hallucination </li></ul><ul><li>Reversible Gingival hyperplasia and hirsutism </li></ul><ul><li>GIT  nausea & vomiting </li></ul><ul><li>Long term use </li></ul><ul><li>Coarsening of facial features occurs in children </li></ul><ul><li>Mild peripheral neuropathy  deep tendon reflexes in lower extremities </li></ul><ul><li>Osteomalacia due to abnormalities of vitamin D metabolism </li></ul>
  21. 21. Phenytoin /Adverse effects <ul><li>Megaloblastic anemia due to folate deficiency </li></ul><ul><li>Inhibition of antidiuretic hormone secretion </li></ul><ul><li>Hyperglycemia and glycosuria   insulin secretion </li></ul><ul><li>Teratogenic effects  fetal hydantoin syndrome  includes cleft lip, cleft palate, congenital heart disease, growth retardation and mental deficiency </li></ul>
  22. 22. Phenytoin/ Drug Interactions <ul><li>Phenytoin metabolism decrease by  Cimetidine, isoniazid, Chloramphenicol, dicumarol, sulfonamide </li></ul><ul><li>Phenytoin metabolism increase by Carbamazepine </li></ul>
  23. 23. Carbamazepine <ul><li>M.O.A </li></ul><ul><li>By blocks sodium channels  reduce the propagation of abnormal impulses </li></ul><ul><li>inhibits high-frequency repetitive firing in neurons </li></ul><ul><li>decrease synaptic transmission, inhibits uptake and release of NE from brain </li></ul><ul><li>postsynaptic action of GABA potentiated </li></ul>
  24. 24. Carbamazepine /Clinical use <ul><li>Drug of choice in all partial seizures </li></ul><ul><li>Highly effective in tonic–clonic seizures </li></ul><ul><li>Trigeminal neuralgia </li></ul><ul><li>Use in Manic depressive patient to decrease the symptoms </li></ul>
  25. 25. Carbamazepine Adverse effects <ul><li>Respiratory depression </li></ul><ul><li>Drowsiness, vertigo, diplopia, blurred vision, ataxia & coma </li></ul><ul><li>Irritating to stomach  n & v may occurs </li></ul><ul><li>Serious liver toxicity </li></ul><ul><li>hyponatremia and water intoxication </li></ul><ul><li>Idiosyncratic blood dyscrasias,including fatal cases of aplastic anemia and agranulocytosis </li></ul><ul><li>Is an enzyme inducer </li></ul>
  26. 26. Drugs inhibiting metabolism of Carbamazepine <ul><li>Cimetidine </li></ul><ul><li>Diltiazem </li></ul><ul><li>Erythromycin </li></ul><ul><li>Isoniazid </li></ul><ul><li>Propoxyphene </li></ul>
  27. 27. Phenobarbital <ul><li>clinically useful as antiseizure drugs phenobarbital, mephobarbital, metharbital, </li></ul><ul><li>Mechanism of Action </li></ul><ul><li>Elevate seizure threshold </li></ul><ul><li>Limits the spread of seizure discharge in brain </li></ul><ul><li>Binds to a regulatory site on GABA receptor, prolonging the openings of Cl- channels </li></ul><ul><li>Blocks excitatory responses induced by glutamate </li></ul>
  28. 28. Phenobarbital/ clinical uses <ul><li>Doc in children with febrile fits </li></ul><ul><li>Effective in simple partial seizures </li></ul><ul><li>Recurrent tonic clonic seizures </li></ul><ul><li>Relieve anxiety </li></ul><ul><li>insomnia </li></ul>
  29. 29. Phenobarbital adverse effects <ul><li>Sedation </li></ul><ul><li>Ataxia </li></ul><ul><li>Nystagmus </li></ul><ul><li>Vertigo </li></ul><ul><li>N &v </li></ul><ul><li>Morbilliform rash (measles like) </li></ul><ul><li>Agitation & confusion </li></ul><ul><li>Rebound seizures can occur on discontinuation of drug </li></ul>
  30. 30. Primidone <ul><li>2-deoxyphenobarbital </li></ul><ul><li>Metabolized to Phenobarbital and phenyl-ethyl-malonamide </li></ul><ul><li>All 3 are active anticonvulsants </li></ul><ul><li>M.O.A. – similar to Phenobarbital </li></ul><ul><li>Effective against partial and tonic clonic seizures </li></ul>
  31. 31. Valproic acid <ul><li>Drug of choice for myoclonic seizures </li></ul><ul><li>Effective in tonic clonic & absence seizures </li></ul><ul><li>Block sodium channels & enhance GABAergic transmission </li></ul><ul><li>Adverse effects  N, V, ataxia, sedation, tremors, rash & alopecia </li></ul>
  32. 32. Ethosuximide <ul><li>Inhibit T-type calcium channels in brain  reduce propagation of abnormal electrical activity </li></ul><ul><li>First choice in absence seizures </li></ul>
  33. 33. Benzodiazepines <ul><li>Benzodiazepines are safest antiepileptic drugs </li></ul><ul><li>Clonazepam  use for chronic treatment of absence & myoclonic seizures </li></ul><ul><li>Chlorazepate  effective in partial seizures </li></ul><ul><li>Diazepam & lorazepam  drug of choice in acute treatment of status epilepticus (interrupt repeated seizures) </li></ul><ul><li>A/E  sedation, drowsiness, fatigue, ataxia, respiratory and cardiac depression </li></ul>
  34. 34. Adjunct antiepileptic drugs <ul><li>Newer agents </li></ul><ul><li>Use as add on therapy in refractory epilepsies </li></ul><ul><li>Also effective as monotherapy </li></ul>
  35. 36. Lamotrigine <ul><li>M.O.A. –blocks sodium channels, voltage activated calcium channels & decreased synaptic release of glutamate </li></ul><ul><li>Add on therapy, monotherapy for partial seizures, absence and myoclonic seizures in children </li></ul><ul><li>Dizziness, headache, diplopia, nausea, somnolence, and skin rash – potentially life-threatening dermatitis develops in 1-2% of pediatric pts </li></ul>
  36. 37. Felbamate <ul><li>Broad spectrum </li></ul><ul><li>Use only in refractory cases (may cause aplastic anemia & hepatic failure) </li></ul><ul><li>block sodium channels & inhibits glycin & glutamate transmission </li></ul><ul><li>Effective in partial seizures </li></ul>
  37. 38. Gabapentin <ul><li>Amino acid, analog of GABA, effective against partial seizures </li></ul><ul><li>M.O.A. – in spite of its close structural relationship to GABA, it appears not to act on GABA receptors, interfere with voltage gated calcium channels </li></ul><ul><li>Used in Partial and G tonic clonic seizures, diabetic neuropathic pain, postherpetic neuroralgia in adults </li></ul>
  38. 39. To-pira-mate <ul><li>Effective in refectory partial and secondary generalized seizures </li></ul><ul><li>M.O.A. </li></ul><ul><li>Blocks voltage dependent sodium channels </li></ul><ul><li>Potentiate inhibitory effect of GABA, acting at a site different from BNZs or barbs </li></ul>
  39. 40. Ti-aga-bine <ul><li>M.O.A. – inhibitor of GABA uptake </li></ul><ul><li>Prolongs inhibitory action of synaptically released GABA </li></ul><ul><li>Indicated for adjunctive treatment of partial seizures </li></ul>
  40. 41. Zonisamide <ul><li>Primary site of action is on sodium channel </li></ul><ul><li>Also act on voltage dependent calcium channels </li></ul><ul><li>Effective against partial and G tonic clonic seizures, also against infantile spasms and certain myoclonias </li></ul><ul><li>S/E – drowsiness, cognitive impairment, serious skin rashes </li></ul>
  41. 42. Levetiracetam <ul><li>M.O.A. – unknown </li></ul><ul><li>Effective for the treatment of refectory partial seizures </li></ul><ul><li>S/E – somnolence, asthenia, dizziness </li></ul>
  42. 43. Acetazolamide <ul><li>Inhibits carbonic anhydrase </li></ul><ul><li>Mild acidosis in brain – mech by which drug exerts its antiseizure activity </li></ul><ul><li>Used for all types of seizures </li></ul><ul><li>Use severely limited by rapid development of tolerance usually within weeks </li></ul>