Anticonvulsant

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Anticonvulsant
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  1. used interchangeably in the literature to
    describe a diverse group of medications used clinically to provide seizure
    control in patients with epilepsies.
    anticonvulsant and antiepileptic drug (AED)
  2. is the most prevalent neurological disorder
    affecting more than 0.5% of the world’s population
    Epilepsy
  3. characterized by recurrent seizures,
    unprovoked by any identifiable causes
    Epilepsy
  4. are
    symptoms of disturbed electrical activity in the brain characterized by
    episodes of abnormal, excessive, and synchronous discharge of a group of
    neurons within the brain that cause involuntary movement, sensation, or
    thought.
    Seizures
  5. may
    result from primary or acquired neurological disturbances of brain function as
    a result of an imbalance between excitatory and inhibitory processes in the
    brain.
    seizures
  6. commonly used AEDs 
    to prevent recurrence of seizure activity.
    • valproic acid (VPA),
    • carbamazepine (CBZ),
    • ethosuximide,
    • and
    • phenytoin
  7. reason for this refractory to an AED may be a result of
    coexistence of factors related to the epileptogenesis of the disease state or

    to the development of pharmacodynamic or pharmacokinetic tolerances
  8. Seizures are classified, based on their initial
    signs and symptoms and the pattern seen on the electroencephalogram (EEG), ), into two broad categories
    generalized seizures or as partial seizures.
  9. Two major types of generalized seizures are
    • generalized tonic–clonic seizures (grand mal) and
    • the absence (petit mal) seizures.
  10. preceded by a series of bilateral muscular
    jerks followed by loss of consciousness
    typical primarily generalized tonic–clonic seizure
  11. consists of a sudden brief loss of consciousness (10 seconds), some- times with no
    motor activity, although often some minor clonic motor activity exists.
    typical absence seizure (classic petit mal)
  12. recommended initial monotherapy for patients with generalized seizures are:
    • Carbamazapine (CBZ),
    • oxcarbazepine (OXC),
    • lamotrigine,
    • VPA,
    • phenytoin, and
    • topiramate (TPM),
  13. children with absence seizures are best treated
    with
    • lamotrigine,
    • VPA, or
    • ethosuximide.
  14. Major types of partial seizure are
    • simple partial seizures (focal) and
    • complex partial seizures (temporal lobe or psychomotor)
  15. most common seizure types experienced by
    approximately 60% to 70% of the adult patients.
    Partial seizures
  16. A prototypic simple partial seizure
    Jacksonian motor epilepsy
  17. first-line treatment for patients with newly
    diagnosed or untreated simple partial seizures are
    • CBZ or phenytoin for adults
    • lamotrigine or gabapentin for elderly adults,
    • and OXC for children.
  18. is represented by the psychomotor or temporal
    lobe seizure. There is an aura, then a confused or bizarre but seemingly purposeful behavior lasting 2 to 3 minutes, often with no memory of the event.
    The complex partial seizure
  19. is characterized by a neuronal hyper-
    excitability in damaged areas of the nerves
    ; is quite similar to that of epilepsy
    Neuropathic pain
  20. Mechanisms of Action of Anticonvulsants
    (a)modulation of voltage-gated ion channels (Na, Ca2, and K)

    (b)enhancement of y-aminobutyric acid (GABA)-mediated inhibitory neurotransmission

    (c)attenuation of excitatory (particularly glutamate-mediated) neurotransmission in the brain
  21. as Targets for Anticonvulsants
    Voltage-Gated Ion Channels
  22. in the presynaptic nerve terminal of the
    excitatory glutamate receptors are the molecular target for phenytoin, CBZ, and
    lamotrigine as well as some of the newer AEDs, such as OXC, felbamate (FBM),
    and zonisamide
    Voltage-gated sodium channels (VGSCs)
  23. These aromatic AEDs inhibit excessive neuronal
    firing by
    • binding to a site near the inactivation gate,
    • thereby prolonging inactivation of VGSCs.
  24. are essential in regulating Ca2 signaling,
    which is associated with many important cellular events such as the release of
    excitatory glutamate neurotransmitters, the plasticity changes of long-term potentiation in learning and memory, and the maintenance of homeostasis of
    nerve cells.
    The voltage-gated calcium channels (VGCCs)
  25. plays a critical role in the induction and
    progression of epileptic seizures
    excessive influx of Ca2
  26. require strong depolarization for activation and
    are the primary molecular targets of gabapentin and pregabalin, both of which
    are effective in refractory partial seizures
    • high-threshold L-type Ca2 channels in the presynaptic
    • glutaminergic receptors
  27. channels require only weak depolarization for activation and are the molecular targets
    of AEDs such as ethosuximide and zonisamide.
    low-threshold T-type Ca2 channels
  28. is another attractive target for designing of
    newer AEDs, because they are intimately associated with the membrane
    repolarization processes
    Potentiation of the voltage-gated K channels
  29. a novel AED recently marketed for the adjunctive therapy of refractory partial
    seizures in adults, has been suggested to work by reducing the voltage-operated
    A-type potassium currents as one of its mechanism of actions.
    Levetiracetam (LEV)
  30. It is now well recognized that cellular
    excitability leading to convulsive seizures can be attenuated by
    GABAergic stimulation in the brain.
  31. the major inhibitory neurotransmitter in the
    brain
    is one of two ligand-gated ion channels responsible for mediating the effects of GABA
    GABAA receptor
  32. increased chloride conductance, thereby
    preventing the spread of neuronal excitations.
    Activation of the GABAA/benzodiazepine (BZD) receptors/chloride channel complex
  33. The potential targets for AED’s action on the GABAergic inhibitory synapses
    include:
    (a) drugs that enhance the biosynthesis of GABA (gabapentin, pregabalin, and VPA

    (b) drugs that inhibit GABA degradation (vigabatrin)

    (c) drugs that inhibit the reuptake of GABA (tiagabine)

    (d) drugs that bind to an allosteric site on the postsynaptic GABAA receptor complex that increase chloride conduc- tance (barbiturates, BZDs,neurosteroids, FBM, TPM).
  34. GABA, is biosynthesized at the GABAergic neurons by
    the decarboxylation of the amino acid, L-glutamic acid (itself an excitatory amino acid neurotransmitter in the brain).
  35. The rate-limiting enzyme that catalyzes this
    conversion (BIOSYNTHESIS OF GABA )
    L-glutamic acid decarboxylase (GAD).
  36. The essential cofactor for this enzymatic
    reaction (biosynthesis of gaba) is
    pyridoxal phosphate (vitamin B6
  37. GABA, after its release from the synaptic nerve
    terminal, is degraded by another pyridoxal-dependent enzyme,
    the GABA transaminase (GABA-T),
  38. transaminase (GABA-T), which transfers an amino group from GABA to ketoglutarate producing
    • L-glutamic acid and succinic acid semialdehyde
    • (SSA).
  39. a 3-substituted GABA, may have the ability to activate GAD, in addition to their major anticonvulsant action at the high-thresh- old L-type Ca2 channels in the presynaptic glutaminergic receptors
    gabapentin and especially pregabalin
  40. of these drugs are weak activators of GAD, was
    able to elevate brain GABA levels (75%–100%) in patients with epilepsy within
    hour after the first dosing.
    gabapentin and pregabalin
  41. Similar to gabapentin and pregabalin, also elevates brain levels of GABA in patients
    with epilepsy.
    VPA
  42. DRUGS THAT INHIBIT GABA DEGRADATION
    Vigabatrin (y-vinyl-GABA)
  43. is an irreversible inhibitor of GABA-T,
    rationally designed based on the biochemical mechanism of transamination
    reaction
    Vigabatrin (y-vinyl-GABA)
  44. competes with GABA for binding to GABA-T and forms a Schiff base intermediate with the
    cofactor, pyridoxal phosphate similar to GABA.
    Vigabatrin (y-vinyl-GABA)
  45. DRUGS THAT INHIBIT REUPTAKE OF GABA
    Tiagabine
  46. structurally related to nipecotic acid, is a selective inhibitor of the neuronal and glial
    GAT1 at the GABAergic neurons and an effective drug for the treatment of
    patients with refractory epilepsy.
    Tiagabine
  47. enhances GABA- mediated inhibitory
    neurotransmission by increasing the frequency of chloride channel openings
    that binding of BZD agonists such as clonazepam to its receptor
  48. a broad-spectrum AED, also binds and increases the frequency of chloride channel
    opening but at a different site than the BZDs.
    TPM
  49. modulate sodium and calcium influx and
    are involved in mediating excitatory synaptic transmission including the initiation and spread of seizure activity.
    • N-methyl-D-aspartic acid (NMDA)/
    • a-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptors
  50. Excitatory Glutamate-Mediated Receptors as
    Target for Anticonvulsants; ligand-gated glutamate receptors
    • NMDA
    • AMPA
  51. Activation of these receptors is responsible for important functions in the brain including long-term potentiation in memory acquisition, learning, and some neurodegenerative disorders. These receptors are potential therapeutic targets for epilepsy.
    • NMDA
    • AMPA
  52. is an established AED with a simple chemical structure but an unusually broad spectrum of
    action.
    Limited use due to significant toxic side effect.
    CYP450
    inhibitor (2C9)
    Valproic Acid (VPA)
  53. Brand names of VPA
    • Depakote
    • Depakene
    • Depacon
  54. Very effective against all seizure types except absence.
    Aromatic hydroxylation
    Phenytoin
  55. BNs of Phenytoin
    (Dilantin, Kapseals, Phenytek)
  56. a prodrug of phenytoin, was developed and marketed to avoid complications such
    as vein irritation, tissue damage, and muscle necrosis associated with parenteral phenytoin administration.
    Fosphenytoin
  57. CBZ is useful in generalized tonic–clonic and partial seizures.
    • Carbamazepine
    • Oxcarbazepine
  58. BNs of Carbamazepine and Oxcarbazepine
    • (Tegretol)
    • (Trileptal)
  59. Broad-spectrum anticonvulsants
    with multiple mechanisms of action.
    • Gabapentin
    • Pregabalin, (S)-3-isobutyl-GABA.
  60. BNs of Gabapentin and Pregabalin
    • (Neurontin)
    • (Lyrica)
  61. a broad spectrumof action, is a carbamate ester of 2-phenyl-1, 3-propanediol, structurally similar to the anxiolytic drug meprobamate.
    -was found to be associated with rare but
    severe side effects such as aplastic anemia, idiosyncratic reactions and hepatic failures.
    • FELBAMATE
    • FLUROFELBAMATE
  62. BN of Felbamate
    Felbatol
  63. AED of the phenyltriazine class, has been found effective against refractory
    partial seizures.
    LAMOTRIGINE (what is the Brand Name)
  64. MOA of Lamotrigine
    • Blockage of sodium channels that is both voltage- and use dependent.
    • Inhibits the high-threshold calcium channel, possibly through inhibition of presynaptic N-type calcium channels and also blocks glutamate release
  65. A sulphamate-substituted monosaccharide, a derivative of the naturally occurring sugar D-fructose that exhibits broad and potent AED actions at both glutamate and GABA receptors.
    TOPIRAMATE (Brand name?)
  66. appears to block glutamate release,
    antagonize glutamate kainic acid/AMPA receptors, and increase GABAergic transmission by binding to a site distinct from BZDs or barbiturates on the GABAA receptor complex
    TPM
  67. Sulfonamide-type anticonvulsant approved for adjunctive therapy in the treatment
    of partial seizures in adults with epilepsy.
    ZONISAMIDE
  68. Zonisamid BNs
    ZONEGRAN, EXCEGRAN
  69. is an analog of the nootropic agent, piracetam.
    -does not have any affinity for the AMPA receptor thereby has no nootropic activity for
    the treatment of Alzheimer disease.
    modulating kainite/AMPA-induced
    excitatory synaptic currents, thus decreasing membrane conductance.
    LEVETIRACETAM  (BN?)
  70. Blocks GABA reuptake as a major mode of its anticonvulsant
    activity.
    TIAGABINE (BN?)
  71. considered the prototypical anticonvulsant needed for treating patients with absence seizures
    • ETHOSUXIMIDE
    • METHSUXIMIDE
  72. BN of ETHOSUXIMIDE and METHSUXIMIDE
    Zarontin and Celontin
  73. 4-vinyl analog of GABA, produces its pharmacological action by irreversibly blocking GABA catabolism catalyzed by GABA-T.
    -Caused a  reversible visual field defect associated with retinal function in the eyes
    VIGABATRIN
  74. BN of VIGABATRIN
    Sabril
  75. Useful in absence
    seizures and in myoclonic
    seizures.Tolerance to the anticonvulsant effect of the clonazepam often developed rather quickly, and it is a
    common problem with the BZDs
    Clonazepam
  76. BN of Clonazepam
    Klonopin

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