Anti epilepsy

• Etiology of Seizure


  • Epilepsy has no Identifiable cause
  • Focal areas that are functionally abnormal may be triggered into activity by different factors

  
• Types of Epilepsy based on Etiology/Cause

  • IDIOPATHIC/CRYPTOGENIC (Primary) Epilepsy
  • SYMPTOMATIC (Secondary) Epilepsy
  • Genetic Epilepsy
  • Structural/Metabolic Epilepsy
• IDIOPATHIC/CRYPTOGENIC (Primary) Epilepsy


  • No Specific anatomic cause
  • Most causes of epilepsy are idiopathic
  • Therapy: Antiepileptics, Vagal Nerve Stimulation
• SYMPTOMATIC (Secondary) Epilepsy


  • May be caused by tumors, drugs use, head injury, hypoglycemia, meningeal infection, alcohol withdrawal
  • Therapy: Treat underlying disease, Antiepileptics, Vagal Nerve stimulation, Surgery
• Genetic Epilepsy


  • Seizures result from an inherited abnormality in the CNS
  • Some genetic mutations have been identified in epilepsy syndromes
  • Obtaining a detailed family history may provide important information for assessing the possibility of a genetic link to seizures
• Structural/Metabolic Epilepsy


  • Elicit drug use
  • Tumor
  • Head injury
  • Hypoglycemia
  • Meningeal infection
  • Rapid withdrawal of alcohol from an alcoholic
• Rapid withdrawal of alcohol from an alcoholic can precipitate seizure
• Unknown cause


  • No specific anatomic cause of the seizure
  • Can be treated chronically with anti-epilepsy medications or Vagal Nerve Stimulation
• Classification of Seizures


  • FOCAL SEIZURE: Simple Partial & Complex partial
  • GENERALIZED SEIZURE
• Simple Partial


  • Caused by a group of hyperactive neurons exhibiting abnormal electrical activity
  • Confined to a single locus in the Brain
  • Electrical discharge DOES NOT SPREAD
  • Patient DOES NOT LOSE CONSCIOUSNESS
  • Patients may also show sensory distortions (may be spread)
  • Occur at any age

  
• Complex partial

  • These seizures exhibit complex sensory hallucinations and mental distortion
  • Motor dysfunction: Chewing movements, Diarrhea, Urination
  • Consciousness is altered
  • Occur at any age

  
• Generalized


  • It may begin locally and then progress to include: Abnormal electrical discharges throughout both Hemisphere of the brain
  • It may be convulsive or nonconvulsive
  • During attack, patient usually has an immediate loss of consciousness
• Types of Generalized Seizures

  • Tonic-clonic
  • Absence
  • Myoclonic
  • Clonic
  • Tonic
  • Atonic
• Tonic-clonic


  • It results in loss of consciousness followed by Tonic and Clonic
  • Tonic = Continuous contraction
  • Clonic = Rapid contraction and relaxation
  • From seizure ➔ ➔ ➔ period of confusion and exhaustion due to the depletion of glucose and energy stores
• Absence


  • This involved a brief, abrupt and self-limiting loss of consciousness
  • Onset: 3-5 yrs of age until puberty or beyond
  • Patient STARES and Exhibits rapid eye-blinking (3 to 5 seconds)
  • It has a very distinct three-per-second spike and wave discharge
• Myoclonic


  • These seizures consist of short episodes of muscle contractions that may recur for several minutes
  • Occur after wakening and exhibit as brief jerks of the limbs, seizure occur at any age but usually begin around puberty or early adulthood
• Clonic


  • Seizures consist of short episodes of muscle contractions that may closely resemble myoclonic seizures
  • Consciousness is more impaired with clonic seizures as compared to myoclonic
• Tonic


  These seizures involve increase tone in the extension muscles and are generally less than 60 seconds long
• Atonic


  These seizures are also known as drop attacks and are characterized by a sudden loss of muscle tone
• Antiepilepsy Medications


  • Clonazepam
  • Clobazam
  • Diazepam
  • Carbamazepine
  • Eslicarbazepine
  • Ethosuximide
  • Ezogabine
  • Felbamate
  • Gabapentin
  • Lacosamide
  • Lamotrigine
  • Levetiracetam
  • Oxcarbazepine
  • Perampanel
  • Phenobarbital and Primidone
  • Phenytoin and Fosphenytoin

  
• Clonazepam and Clobazam


  Both drugs may be prescribed as Adjunctive therapy for particular types of Seizures
• Diazepam


  Available for Rectal Administration to Avoid or Interrupt Prolonged Generalized Tonic-Clonic seizures when Oral admin is not possible

  
• Carbamazepine


  • Effective for Treatment of Focal Seizures, Generalized tonic-clonic seizures, Trigeminal neuralgia, Bipolar Disorder
  • Absorbed slowly and erratically when given orally
  • May vary from generic to generic
  • Induces its own metabolism ➔ Lower total Carbamazepine blood conc at Higher doses
  • It is an INDUCER of CYP1A2, CYP2C, CYP3A and UDP glucuronosyltransferase ➔ Increase CLEARANCE of other drugs
  • AE: Hyponatremia, drowsiness, fatigue, dizziness, blurred vision, SJS, blood dyscrasia (neutropenia, leukopenia, thrombocytopenia, pancytopenia, anemia)
  • Should not be given to those patients with ABSENCE SEIZURES because it may cause an increase in Seizure

  
• Eslicarbazepine


  • Its acetate form is A prodrug that is converted by Hyrdolysis to Active metabolite: Eslicarbazepine
  • S-licarbazepine = active metabolite of Oxcarbazepine
  • Blocks the Na+ channel
  • Approved for patients with Partial-onset seizure (Adult)
  • Exhibits linear pharmacokinetics
  • Eliminated via Glucuronidation
  • SE: Dizziness, somnolence, diplopia, Headache
  • Serious AE: Rash, Psychiatric side effects, Hyponatremia

  
• Ethosuximide


  • Reduces propagation of Abnormal Electrical activity in the brain by Inhibiting T-type Calcium channels
  • Only effective in treating Absence Seizure
• Ezogabine


  • Opens Voltage-gated M-type Potassium channels ➔ Stabilization of the Resting Membrane Potential
  • Exhibits linear pharmacokinetics
  • No drug interactions at Lower Doses
  • SE: Urinary Retention, QT interval prolongation, blue skin discoloration and Retinal Abnormalities
• Felbamate


  • Broad spectrum of Anticonvulsant action with multiple mechanism including: Blocking of Sodium channels, Competing with Glycine coagonist binding site on NMDA glutamate receptor, Blocking of Calcium channels, Potentiate GABA action
  • Inhibitor of Drug metabolized by CYP2C19, Induces Drugs metabolized by CYP3A4
  • Reserved for use in Refractory Epilepsies (Lennox-Gastaut syndrome) because of the risk of Aplastic Anemia and Hepatic failure

  
• Gabapentin


  • An Analog of GABA but does not: act at GABA receptors, enhance GABA actions or convert to GABA
  • MOA is unknown
  • Approved as Adjunct Therapy for focal seizures and Treatment of Postherpetic neuralgia
  • Exhibits nonlinear pharmacokinetics due to its uptake by a saturable transport system from the gut
  • Does not bind to plasma proteins
  • Excreted unchanged through the kidneys
  • Reduced dosing is required in renal disease
  • It is well tolerated by the Elderly with partial seizures due to its Relatively mild AE
  • Good choice for the older patient because there are few Drug Interactions
• Lacosamide


  • In vitro affects voltage-gated Sodium channels ➔ Stabilization of Hyperexcitable neuronal membranes, Inhibition of repetitive neuronal firing
  • Binds to Collapsin response mediator protein-2 (CRMP-2) which is a phosphoprotein involved in neuronal differentiation and control of axonal outgrowth
  • It is approved for Adjunctive treatment of focal seizures
  • Available in an Injectable formulation
  • AE: Dizziness, headache, fatigue

  
• Lamotrigine


  • Blocks Sodium channels, Blocks Voltage-dependent Calcium channels
  • Effective in a wide variety of Seizure types: Focal, Generalized, Absence seizures, Lennox-Gastaut syndrome
  • Also used to treat Bipolar disorder
  • Metabolized to the 2-N-glucuronide metabolite through the UGT1A4 pathway
  • General inducers Increase Lamotrigine's clearance ➔ Lower Lamotrigine's concentration
  • Divalproex = Decreases Lamotrigine's clearance ➔ Higher Lamotrigine's conc
  • Its dose should be Reduced + Valproate
  • Slow titration is necessary with Lamotrigine due to risk of rash ➔ Life-threatening Rxn

  
• Levetiracetam


  • Approved for adjunct therapy of: Focal onset, Myoclonic, Generalized tonic-clonic seizures
  • Unknown MOA
  • High affinity for a synaptic vesicle protein (SV2A)
  • It is well absorbed orally
  • Excreted in urine mostly unchanges
  • Can cause mood alterations that requires dose reduction or a change in medication

  
• Oxcarbazepine


  • A prodrug that is rapidly reduced to 10-monohydroxy (MHD) metabolite responsible to its anticonvulsant activity
  • MHD = blocks Sodium Channels and modulates Calcium channels
  • Approved for use in adults and children with Partial-Onset Seizures
  • It is less potent inducers of CYP3A4 and UGT than carbamazepine
  • AE: Hyponatremia limits its use in the elderly

  
• Perampanel


  • A selective a-amino-3-hydroxyl-5methyl-4-isoxazolepropionic acid antagonist ➔ reduced excitatory activity
  • It has a long half-life enabling once-daily dosing
  • Approved for Adjunctive treatment if Partial-onset seizures in patients 12 years or older
  • A newer antiepileptic agent

  
• Phenobarbital and Primidone


  • Phenobarbital: Enhance Inhibitory effects of GABA-mediated neurons
  • Primidone: Metabolized to phenobarbital (maj) and Phenylethylmalonamide, both with anticonvulsant activity
  • Phenobarbital is used primarily in the treatment of Status Epilepticus when other agents fail

  
• Phenytoin and Fosphenytoin


  • Phenytoin: blocks Sodium channels by selectively binding to the channels in the inactive state and slowing its rate of recovery
  • It is effective for Focal and Generalized tonic-clonic seizures and treatment of Status Epilepticus
  • Phenytoin induces drugs metabolized by CYP2C and CYP3A families and UGT enzyme system
  • Exhibits saturable enzyme metabolism ➔ nonlinear pharmacokinetic properties
  • Depression of the CNS occurs, causes nystagmus and ataxia = Elderly are highly susceptible to this effects
  • It may cause Gingival hyperplasia
  • Long-term use may lead to development of Peripheral neuropathies and osteoporosis
  • It should not be given via IM as it causes tissue damage and necrosis
  • Fosphenytoin: A prodrug that is rapidly converted to Phenytoin in the blood within minutes, given via IM and IV, DOC and standard of care for those patients needs IV and IM administration of phenytoin

  
• Phenytoin


  Binds tightly to the channels in the inactive state and slows its rate of recovery

  
• Phenytoin


  • Effective for Focal and Generalized tonic-clonic seizures
  • Used for treatment of Status Epilepticus
• Phenytoin


  Induces drugs metabolized by CYP2C and CYP3A families and UGT enzyme system
• Phenytoin


  Exhibits saturable enzyme metabolism resulting in nonlinear pharmacokinetic properties (small increase in daily dose can produce large increase in plasma concentration resulting in drug-induced toxicity)
• Phenytoin


  • Causes depression of the CNS
  • Causes nystagmus and ataxia (Elderly are highly susceptible to this effects)
  • May cause Gingival hyperplasia (causes the gums to grow over the teeth)
  • Long-term use may lead to development of Peripheral neuropathies and osteoporosis
  • Should not be given via IM as it causes tissue damage and necrosis