Anticonvulsant or Antiepileptic Drugs 2020. 7. 25.¢  Anticonvulsant or Antiepileptic Drugs...

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Transcript of Anticonvulsant or Antiepileptic Drugs 2020. 7. 25.¢  Anticonvulsant or Antiepileptic Drugs...

  • Anticonvulsant or Antiepileptic Drugs

    Munir Gharaibeh, MD, PhD, MHPE School of Medicine, The University of Jordan

    March, 2018

  • Anticonvulsant or Antiepileptic Drugs

    Seizure: an abnormal electrical activity, not necessarily to result in a convulsion. Convulsion (Fit): the attack itself. Epilepsy: a disease characterized by recurrent attacks of convulsions.

  • Neuronal Mechanisms involved in Seizures ÚSuppression of Inhibition---------Onset ÚPost-tetanic Potentiation-------Spread and

    Maintenance ÚReinstitution of Inhibition---Termination ÚPattern related to anatomical site of the

    focus.

    March 18 3Munir Gharaibeh, MD, PhD, MHPE

  • Pathophysiological Conditions Enhancing Convulsions

    Ú Low PO2 Ú High pH Ú Increased Intracranial Pressure Ú Low Ca++ Ú Low Glucose Ú Overhydration Ú Fatigue Ú Emotional State

    March 18 4Munir Gharaibeh, MD, PhD, MHPE

  • Causes of Convulsions ÚPoisons ÚTrauma Ú Infection Ú Space Occupying Lesions ÚFever ÚDrugs ÚEpilepsies

    March 18 5Munir Gharaibeh, MD, PhD, MHPE

  • Classification of Epilepsies ÚGrand Mal or Major Epilepsy or Tonic-

    Clonic Epilepsy: Ú Aura Ú Cry-Loss of consciousness Ú Tonic Phase: Rigid violent muscle contraction

    with limbs fixed.

    Ú Clonic Phase: Repetitive muscle jerks Ú Post-ictal depression and incotinence

    March 18 6Munir Gharaibeh, MD, PhD, MHPE

  • Classification of Epilepsies Petit Mal or Minor Epilepsy or Absence States:

    Psychomotor Epilepsy: Ú Automatic movements Ú Clouded dreamy feeling Ú Aggressiveness

    March 18 7Munir Gharaibeh, MD, PhD, MHPE

  • Classification of Epilepsies

    ÚStatus Epilepticus ÚParietal Lobe Epilepsy ÚInfantile Myospasm Úetc.......

    March 18 8Munir Gharaibeh, MD, PhD, MHPE

  • March 18 9Munir Gharaibeh, MD, PhD, MHPE

  • March 18 10Munir Gharaibeh, MD, PhD, MHPE

  • Provocative Procedures

    ÚPentylene tetrazole "Metrazole"

    ÚHyperventilation

    ÚPhotic stimulation - Flicker Fusion

    March 18 11Munir Gharaibeh, MD, PhD, MHPE

  • Principles of Epilepsy Treatment Ú Seizures are self-limiting. ÚOne drug at a time( Monotherapy):

    Lower incidence of adverse reactions. Avoidance of drug interactions. Improved patient compliance. Lower medication cost.

    Ú Start with a small dose. ÚMonitor serum level.

    March 18 12Munir Gharaibeh, MD, PhD, MHPE

  • March 18 Munir Gharaibeh, MD, PhD, MHPE 13

  • March 18 14Munir Gharaibeh, MD, PhD, MHPE

  • Barbiturates

    ÚPhenobarbital ÚMephobarbital ÚMethabarbital ÚPrimidone

    March 18 15Munir Gharaibeh, MD, PhD, MHPE

  • Barbiturates ÚOldest but still used. ÚRelatively safe, but sedating. ÚEffective in Grand mal and partial seizures. ÚMight worsen patients with other types. ÚBind to GABA receptor, to prolong opening of Cl-

    channels. ÚAlso, at high doses, block Na+ and Ca++ channels (L

    and N type). Ú Also block Glutamate receptors.

    March 18 16Munir Gharaibeh, MD, PhD, MHPE

  • Barbiturates

    Adverse Effects: Ú Sedation Ú Allergies Ú Anemia Ú Drug Interactions Ú Enzyme Induction ----- Withdrawal!! Ú Additive to CNS depressants.

    March 18 17Munir Gharaibeh, MD, PhD, MHPE

  • Phenytoin(1938)

    ÚGeneralized tonic - clonic seizures ÚPartial seizures with complex symptomatology ÚAntipsychotic ÚAntiarrhythmic ÚMany others ÚRevolutionary

    March 18 18Munir Gharaibeh, MD, PhD, MHPE

  • Phenytoin Mechanism of Action: Acts on several physiologic systems. Major action is sodium channel blockade, arising from

    preferential binding to and prolongation of the inactivated state of the Na + channel.

    Also, inhibits Ca++ influx, membrane potential, as well as, the concentrations of amino acids, NE, ACh, and GABA .

    Blocks sustained high-frequency repetitive firing of action potentials.

    March 18 19Munir Gharaibeh, MD, PhD, MHPE

  • Phenytoin ÚPharmacokinetics:

    – Slow absorption – 90% bound – Metabolized:

    Zero order in high doses used in epilepsy, so, no SSL achieved.

    – Interactions: Protein binding. Enzyme induction.

    March 18 20Munir Gharaibeh, MD, PhD, MHPE

  • Phenytoin Adverse Effects:

    Ú Skin rashes, fever Ú Blood: megaloblastic anemia, agranulocytosis,

    lymphadenopathy. Ú Gingival hyperplasia (50%) Ú Hirsutism Ú "Hydantoin Facies" Ú Peripheral neuropathy Ú Cerebellar degeneration Ú Teratogenic ------- Folate Deficiency

    March 18 21Munir Gharaibeh, MD, PhD, MHPE

  • Phenytoin Overdose: Ú Nystagmus, Ú Ataxia, Ú Vertigo, Ú Diplopia Ú Loss of consciousness.

    March 18 22Munir Gharaibeh, MD, PhD, MHPE

  • March 18 23Munir Gharaibeh, MD, PhD, MHPE

  • Carbamazepine ÚPartial seizures ÚGeneralized tonic - clonic ÚNot for petit mal Ú Initially marketed for Trigeminal Neuralgia. Ú Bipolar mood disorders, it is a tricyclic compound. Ú Peripheral Neuropathy Ú Migraine ------------ etc

    March 18 24Munir Gharaibeh, MD, PhD, MHPE

  • Carbamazepine

    Mechanism of Action: Like phenytoin, blocks Na+ channels.

    March 18 25Munir Gharaibeh, MD, PhD, MHPE

  • Carbamazepine

    ÚSlow and erratic absorption ÚT½ 12-60 hr. ÚInduces liver enzymes = Autoinduction. ÚInteractions. ÚBlood monitoring is necessary.

    March 18 26Munir Gharaibeh, MD, PhD, MHPE

  • Carbamazepine Adverse Effects: Vertigo , Ataxia , Diplopia appear early. ÚDrowsiness , nausea , headache, dizziness. ÚTolerance develops to the above effects. ÚSkin rashes , fever , hepatosplenomegaly ,

    lymphadenopathy. ÚBlood dyscrasias: leukopenia, aplastic anemia,

    and agranulocytosis.

    March 18 27Munir Gharaibeh, MD, PhD, MHPE

  • Oxacarbazepine.

    ÚLess capacity to induce enzymes. ÚT½ 1-2hr. ÚMay be safer.

    March 18 28Munir Gharaibeh, MD, PhD, MHPE

  • Vigabatrin ÚGABA-Transaminase irreversible inhibitor,

    which breaks down GABA in the brain. ÚRenal elimination. ÚPartial seizures ____ Not for absence or

    myoclonic ÚWell tolerated: drowsiness, dizziness, weight

    gain, visual field defects.

    March 18 29Munir Gharaibeh, MD, PhD, MHPE

  • Lamotrigine

    ÚPartial and generalized seizures. ÚInhibits Na+ and Ca++ channels, also decreases

    release of glutamate. ÚCompletely absorbed. ÚGlucoronidated, so will not induce or inhibit

    enzymes. ÚSide Effects:

    Similar to carbamazepine. Skin rashes Cerebellovestibular symptoms.

    March 18 30Munir Gharaibeh, MD, PhD, MHPE

  • Gabapentin and Pregabalin

    ÚPartial Seizures ÚGABA analogs, but work indirectly to increase

    GABA levels in the brain. ÚGood PK Properties. ÚEffective when combined with others. ÚSafe: somnolence, dizziness, ataxia.

    March 18 31Munir Gharaibeh, MD, PhD, MHPE

  • Benzodiazepines

    ÚGABA mechanism, and, ÚNa+ channel inhibition in doses used in

    status epilepticus.

    March 18 32Munir Gharaibeh, MD, PhD, MHPE

  • Benzodiazepines

    ÚDiazepam ----------- Status epilepticus ÚLorazepam ---------- Longer acting ÚClonazepam --------- Petit mal, but causes

    sedation and drooling ÚNitrazepam -------- Infantile Spasms

    March 18 33Munir Gharaibeh, MD, PhD, MHPE

  • Valproic Acid (1969) ÚPetit mal and myoclonic epilepsy ÚMixed seizures. ÚBipolar disorder and migraine prophylaxis.

    March 18 34Munir Gharaibeh, MD, PhD, MHPE

  • Valproic Acid ÚIncreases GABA levels by enhancing synthesis

    and inhibiting transaminase. ÚAlso, blocks NMDA receptors, Na+ channels and

    T-Ca++ channels. Ú90% bound to plasma proteins.

    March 18 35Munir Gharaibeh, MD, PhD, MHPE

  • Valproic Acid

    Toxicity: ÚHepatotoxic ÚNeural tube defects Ú Thrombocytopenia. ÚAlopecia ÚGI. ÚInhibits metabolism of many drugs.

    March 18 36Munir Gharaibeh, MD, PhD, MHPE

  • Ethosuximide (1960s)

    ÚPetit mal, still first choice. ÚBlocks transient Ca++ Currents ÚSafe.

    March 18 37Munir Gharaibeh, MD, PhD, MHPE

  • Acetazolamide ÚHelpful in all types of seizures. ÚUsed as an adjunct to others in refractory

    seizures. ÚWorks by decreasing intracellular pH . ÚTolerance develops. ÚSpecial role for seizures at the time of menses.

    March 18 38Munir Gharaibeh, MD, PhD, MHPE

  • March 18 39Munir Gharaibeh, MD, PhD, MHPE