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Anti-epileptic Drugs

Anti-epileptic Drugs. Prepared by: Dr. bassim Abu Rahmeh Moderator: Dr. Afaf Al-Arini. Carpamazepine. MOA : 1-mainly inhibit Na channel so inhibit the generation of repeatative action potentials. CLINCAL USES : 1- partial seizures .1 st line .

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Anti-epileptic Drugs

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  1. Anti-epileptic Drugs Prepared by: Dr. bassim Abu Rahmeh Moderator: Dr. Afaf Al-Arini

  2. 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 .

  3. 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 .

  4. 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 .

  5. 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,warfarin .

  6. 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 .

  7. 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 .

  8. 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

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

  10. 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 .

  11. 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 .

  12. 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 .

  13. 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,confution,irritability, hyperphagia leading to WT gain .

  14. 2- metabolic effects:increase 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 <2years .

  15. 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.

  16. 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 .

  17. 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 .

  18. Side effect : 1- major side effect is sedation . 2- ataxia, irritability , CVS*Respiratory 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 .

  19. 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 .

  20. 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 .

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

  22. 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.

  23. 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 .

  24. 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 .

  25. 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: N&V, drowsiness, agitation anxiety, headache and idiosynchratic reactions like steven jhonson syndrome.

  26. 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 .

  27. 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 .

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

  29. 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

  30. 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

  31. 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

  32. 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.

  33. 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

  34. 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.

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

  36. 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

  37. THANK YOU

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