Anti-epileptic Drugs

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Anti-epileptic Drugs

• Prepared by Dr. bassim Abu Rahmeh
• Directed by Dr. Afaf Al-Arini

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• For how long you should treat epilepsy?
• It depend on certain risk factors of recurrence
  which include
• Partial seizures mainly complex
• Abnormal EEG
• Abnormal neurological findings
• Family history of epilepsy

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• Indications for drug level monitoring
• At onset of anticonvulsant treatment to confirm
  that drug is within the theraputic level.
• Non-compliant patients
• At time of status epilepticus
• For patients with poly-therapy.
• For uncontrolled seizures or seizures changing in
  type
• For symptomatic drugs with appearance of signs
• For hepatic or renal disease.

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• Anti-epileptic drugs act by interfering with one
  or more of the following mechanisms
• Na channels or current.
• Ca channels or current
• GABA receptors
• Sex hormone
• Carbonic anhydrase inhibitor

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Carpamazepine

• MOA
• 1-mainly inhibit Na channel so inhibit the
  generation of repeatative action potentials.
• CLINCAL USES
• 1- partial seizures .1st line .
• 2- generalized tonic-clonic seizures .1st line .
• 3- trigeminal neuralgia .

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• Pharmacokinetics
• T peak 4-8 hrs .
• T1/2 . 24-45 hrs ----8-24 hrs .
• 75-85 bind to protein .
• It is enzyme inducer that induce cytochrome P450
  system in liver so also induce its own metabolism
  .
• Once metabolized it will produce active
  metabolite which is CBZ10-11epoxide .

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• Side effect
• 1- dose dependent like dizziness, diplopia,
  ataxia, blurred vision .
• 2- idiosyncratic Rxn aplastic anemia, steven
  johnson, agranulocytosis .
• 3- liver toxicity or increase liver enzymes in
  5-10 .
• so you have to do CBC,LFT monthly mainly during
  first few months .

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• Drug interaction
• 1- drugs that inhibit metabolsim (P450) like
  cimitidine, macrolides , isoniazide (INC).
• 2- drugs that induce metabolsim like
  Phenobarbital,phenytoin,primidone .
• 3- CBZ induce metabolism of TCA,cyclosporin,OCP,wa
  rfarin .

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Phenytoin

• MOA
• 1-inhibit Na channels .
• 2- inhibit Ca channels .
• Clinical uses
• 1- partial seizures .
• 2- generalized tonic-clonic seizures .
• 3- Lennox gaustate.
• 4- Status epilepticus .
• 5- childhood epileptic syndromes .

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• Pharmacokinetics
• T peak 4-12 hrs .
• T1/2 . 4-42 hrs .
• 90-95 bind to protein .metabolized by P450
  oxidase systems .
• It is enzyme inducer .
• No active metabolites .
• Excreted through kidneys .
• Side effect
• 1-Ataxia ,nystagmus .
• 2- N,V, hedache, blood dyscrasia, DEC folate, B.M
  hypoplasia .
• 3- Course facial appearance gengival hyperplasi
  
• 4- conginital CHD, cleft lip palate ,slow
  growth rate, mental defect .

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• Drug interaction
  drugs that inhibit metabolsim (P450) like
  cimitidine, macrolides , isoniazide (INC).
• 2- drugs that induce metabolsim like CBZ.
• 3- induce metabolism of CBZ, PHT
  TCA,cyclosporin,OCP,warfarin

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Phenobarbitone

• MOA
• 1- binding to GABA R .
• Clinical uses
• 1- Partial seizures .
• 2- 2nd generalized seizures .
• 3- Status epilepticus .

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• Pharmacokinetics
• T1/2 .,.. 50-144 hrs .
• T peak 1-4 hrs .
• 50 binding to protein .
• Powerful inducer of liver enzymes .major
  metabolite is p-OHPHB which is inactive.
• Metabolized in liver .
• 20-40 excreted in urine .
• Side effect
• 1- cognitive behavioral problem .
• 2-sedation .
• 3- poor conc. Psycohmotor slowness ,ataxia .
• 4- folate deficiency .
• 5- in long term osteomalacia .

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• 7- idiosyncratic Rxn rash ,SLE, ..
• 8- on D/C rebound seizures .
• Drug interaction
• 1-Inhibit metabolism by phenytoin,VA.
• 2-Increase metabolism by enzyme inducer drugs
  like rifambin .
• 3-Bcz enzyme inducer will interfere on
  CBX.VA,OCP, clonazepam .

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Valproic acid

• MOA
• 1-inhance GABA function .
• 2-selective modulation of voltage gated Na
  channels during neuronal firing .
• CLINCAL USES
• 1-DOC in idiopathic generalized
  epilepsy(tonic-clonic,abscense,myoclonic ) .
• 2-DOC in juvenile myoclonic seizures other
  types of myoclonus .
• 3-first line for lennox gastaute epilepsy .
• 4-partial seizures .
• 5-second line in infantile spasm .

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• Pharmacokinetics
• T peak 13 min-2hrs
• T1/2 16 hrs .
• 90 binding to protein .
• 96 metabolized in liver by P450 system 4
  excreted unchanged in urine ,so no active
  metabolites .
• It is not enzyme inducer .
• Side effect
• 1-dose dependent like N,V,tremors,sedation,confut
  ion,irritability, hyperphagia leading to WT gain
  .

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• 2- metabolic effectsincrease
  ammonia(sedation,coma W/ normal LFT, may be
  fatal in urea cycle defect),decrease carnitine
  level (hypotonia,fatigue)
• 3- hair loss .
• 4- BM suppresion neutropenia .
• 5- allergic RXN .
• 6- acute pancreatitis (reversible if stopped)
• 7-idiosyncratic RXN the most serious is
  hepatotoxicity mainly at age lt2years .

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• Drug interaction
• Inhibition of oxidatin glucorinidation so
  increase level of PH,phenobarb,CBZ,LGT .
• Drug level DEC by enzyme inducing drugs
• Drug level INC by felbamate clobazam.

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Clonazepam

• MOA
• 1- bind to GABA R .
• 2- some action on Na channels .
• Clinical uses
• 1- DOC for myoclonic seizures .
• 2-in generalized seizures (mainly abscence)
• 3-status epilepticus .
• 4- infantile spasm .
• 5- lennox gastaute .
• 6-less effect on partial seizures .

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• Pharmacokinetics
• T1/2 .,.. 2-40 hrs .
• T peak 1-4 hrs .
• 85 binding to protein .
• Acetylated in liver .
• No active metabolites .
• Plasma level antiepileptic effect not
  correlated .
• 2 excreted in kidney .

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• Side effect
• 1- major side effect is sedation .
• 2- ataxia, irritability , CVSRespiratory
  depression .
• 3- hyper salivation in pediatric .
• 4- idiosyncratic Rxn like blood dyscrasia is
  rare.
• Drug interaction
• No significant interaction but level of drug DEC
  by enzyme inducer drugs .

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Lamotrigine

• MOA
• 1- inhibit Na channels .
• 2- inhibit glutamate release .
• Clinical uses
• 1- add on Rx for generalized seizures (To-Clo ,
  absence).not good for myoclonic seizures even may
  INC it .
• 2- add on Rx for partial seizures .
• 3- lennox gastaute .
• 4- atypical abscence seizures .

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• Pharmacokinetics
• T1/2 .,.. 24-42 hrs .
• T peak 2-3 hrs .
• 55 binding to protein .
• Not liver enzyme inducer or inhibitor .
• Metabolized in liver .
• No active metabolites .
• Excreted through kidney .
• Side effect few CNS S/E as compared w/ others
• 1- idiosyncratic as skin rash (imp), SJ,TEN,
• angioedema (mainly w/ VA if developed
  stop),blood dyscrasia .
• 2- CNS headache ataxia ,diplopia, psychosis ,GI
  disturbance. Rare
• Preffered Rx for elder pregnancy .

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• Drug interaction
• 1- increase level wl VA .
• 2- decrease level wl drugs induse liver enzymes .
• 3- not affect lipid soluble drugs like OCP,
  anticoagulant .

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Topiramate

• Derived from D-fructose .
• MOA
• 1- inhibit Na channels .
• 2- inhance GABA function .
• 3- weak inhibitor of carbonic anhydrase .
• Inhibit glutamate R .
• Clinical uses
• 1- drug resistance generalized epilepsy as
  adjuvant Rx .
• 2- refractory partial seizures as adjuvant Rx .
• 3-juvenile myoclonic seizures ,lennox-gastaute.

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• Pharmacokinetics
• T1/2 .,.. 18-23 hrs .
• T peak 2-3 hrs .
• 15 binding to protein .
• 15 metabolized in liver 85 excreted unchanged
  in urine .
• Side effects
• 1- most common ataxia, impairment conc.,
• Dizziness, parasthesia in extremities .
• 2- most common side effect in children is
  somnolence ,anorexia ..Wt loss, fatigue.
• 3- increase stone formation .

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• Drug interaction
• 1- DEC level by enzyme inducer drugs like CBZ .
• 2- not affect concentration of other drugs but
  occasionally may inactivate OCP INC level of
  digoxin .

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Ethosuximide

• MOA inhibition of Ca channels
• Clinical uses first choice for absent seizures.
• Kinetics 75 metabolized in the liver to
  inactive metabolites and 25 excreted unchanged
  in urine, it is not enzyme inducer.
• Side effects NV, drowsiness, agitation anxiety,
  headache and idiosynchratic reactions like steven
  jhonson syndrome.

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Gabapentin

• MOA
• 1- analogue to GABA but little effect on GABA
  receptor .
• 2- INC level of GABA in brain .
• 3-Competitive inhibition of amino acid
  transferase so DEC glutamate level .
• CLINCAL USES
• 1-add on Rx for poorly controlled partial seizure
  .
• 2-add on Rx for poorly controlled 2 generalized
  tonic-clonic seizure .
• Not effective in most generalized seizures
  myoclnic seizures .

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• Pharmacokinetics
• T peak 5-7 hrs .
• T1/2 2-3 hrs.
• 0 binding to protein .
• Not metabolized so excreted un changed in urine .
• Not induce liver enzymes .
• Side effect well tolerated w/ low S/E
• 1-idiosyncratic RXN like rash ,neutropenia which
  not significant .
• 2-Dizziness ataxia, diplopia, N,V, somnolonece ,
  WT gain .

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• Drug interaction
  
  GBP GBPhas
  no drug interaction.However,antiacid can reduce
  the bioavailabity of GBP .

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Vigabatrin

• MOA
• 1- analogue to GABA so bind irreversibly .
• 2- INC GABA concentration by binding to GABA
  transaminase .
• Clinical uses
• 1- adjuvant in refractory partial seizures.
• 2- In infantile spasm drug of choice in many
  countries
• 3- less effective in primarily or secondary
  generalized tonic clonic seizures
• Not good for absence or myoclonic seizures

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• Side effects
• Most common drowsiness
• Neuropsychiatric symptoms like depression,
  agitation, confusion, and rarely psychosis.
• Minor side effects like fatigue headache,
  dizziness, tremor, increase weight
• Double vision with visual field problem mainly
  peripheral. Because of this side effect not FDA
  approved.
• Idiosynchratic reaction like skin rash, allopeica
  rare.
• Drug interactions can decrease phenobarbital
  level by decrease absorption.
• No other interactions known

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Tegabine

• MOA inhibit reuptake into neuronal glial cells.
• Clinical uses as second line add on therapy in
  patient with partial seizures refractory to
  treatment.
• Side effects most troublesome include dizziness,
  nervousness, depressed mood, diarrhea, abdominal
  pain, pharyngitis, and sometimes idiosynchratic
  reaction
• Not used in generalized seizures because it may
  cause status epilepticus.

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Zonisamide

• MOA unknown
• Clinical uses
• Add on therapy for partial seizures
• Can be used in myoclonic seizures
• Side effect renal stone

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Other methods of treatment

• ACTH
• It is preferred drug for infantile spasm
• Prednisolone equally effective
• Side effects hyperglycemia, lytes abnormalities,
  increase infection, increase blood pressure, GI
  disturbances
• 1/3 of patients will relapse after discontinuing
  of prednisolone or ACTH
• Surgery for epilepsy
• Vagal nerve stimulation
• Ketogenic diet

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