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1. Central Nervous System Depressant Anticonvulsant By, Dr. Ganesh S. Andhale, Alard College of Pharmacy 2. Classification of Anticonvulsant The various structurally…
  • 1. Central Nervous System Depressant Anticonvulsant By, Dr. Ganesh S. Andhale, Alard College of Pharmacy
  • 2. Classification of Anticonvulsant The various structurally classified anticonvulsant can be classified as: 1. Barbiturates: Phenobarbitone. 2. Hydantoins : Phenytoin sodium, Ethotoin, Mephenytoin 3. Oxazolidine diones: Trimethadiones, Paramethadone 4. Succinimides: Phensuximides, Methsuximides, Ethosuximide. 5. Urea and Monoacylureas: Phenacemides, Carbamazepines. 6. Benzodiazepines: Clonazepams, Diazepam 7. Miscellaneous: Primidones, Valproic acid.
  • 3. General SAR of Anticonvulsant  Structure common to anticonvulsant drug:  R”=  Barbiturate =  Hydantoins = N O O R R' R'' NH O N NH OO R R' O NH N NH OO R R'
  • 4.  Oxazolidinediones:  R’’=  Succinimides:  R’’= N O O R R' R'' O N O OO R R' CH2 N CH2 OO R R'
  • 5.  R & R’’ Should be hydrocarbon radical.  If Both R and R’ are lower alkyls, the tendency is to be active against absence seizures (petit mal) and not active against generalized tonic-clonic (grand mal) OR partial seizures.  If one of the hydrocarbon substituent's is an aryl group, activity tends to be directed towards generalized tonic-clonic and partial seizures and not antiabsence activity.
  • 6. 1. Barbiturate  Only penobarbital and mephobarbital shows enough anticonvulsant selectivity.  The metabolism of Phenobarbital involves p-hydroxylation, followed by conjugation
  • 7. Phenobarbital  IUPAC: 5-ethyl-5-phenyl barbituric acid.  Brand Name: Luminal  Metabolized to p-hydroxy compound followed by glucuronide conjugation. Uses: 1. Sedative 2. Hypnotic 3. Anticonvulsant.  The anticonvulsant action is mainly due to the Presence of a phenyl at 5th position. 7
  • 8. 2. Hydantoins  These are structurally related to barbiturates but lacking 6-oxo group.  Hydantoins are more effective as antigeneralized tonic-clonic rather than antiabsence activity.  All the clinically useful generalized tonic- clonic compounds possess an aryl substituents on the 5th position  Hydantoins with lower alkyl substituents reportedly have antiabsence activity. N NH R" OO R R'
  • 9. 1. Phenytoin: • IUPAC: 5,5-diphenyl hydantoin. • It is the prototype drug of Hydantoin class • It is prime example of an anticonvulsant acting as a sodium channel blocker. • The drug is useful against all seizures except absence. • Metabolism proceeds by stereospecific p- hydroxylation of an aromatic ring followed by conjugation. O HN NH O phenytoin
  • 10. 2. Ethotoin: • Brand Name: Peganone • IUPAC: 3-ethyl-5-phenyl-imidazolidine-2,4- dione • Metabolism: The N-dealky metabolite, is the active compound, as well as metabolized by p-hydroxylation, & then it is conjugated. • Used against generalized seizures, on an adjunctive basis due to its low potency. O N NH O H2C H3C H
  • 11. 3. Mephenytoin: • Brand Name: Mesantoin • IUPAC: 5-ethyl-3methyl -5-phenyl- hydantoin. • Metabolism: N-dealkylated to 5-ethyl-5- phenylhydantoin assumed that active agent. • Counterpart of phenobarbital. • Introduced as a sedative-hypnotic and anticonvulsant as Nirvanol but withdrawn because of toxicity. • Activity spectrum similar to phenytoin. O N NH O H3C
  • 12. 3. Oxazolidinedione Eg: Trimethadione, Paramethadione • Replacement of the N-H group at position 1 of the hydantoin system with oxygen atoms yield the oxazolidine-2,4-dione. • It is having antiabsence activity. • Aryl substituted oxazolidinedione shown activity against generalized tonic-clonic seizures but toxicities may be the problem. O HN O O
  • 13. 1. Trimethadione: Brand Name: Tridione IUPAC: 3,5,5-trimethyl-2,4-oxazolidine Dione. Uses: 1st drug introduced specially for treating absence seizures. Toxicities: Dermatological & hematological limits its clinical use. Metabolism: by N-demethylation to the dimethadione. Is a calcium-T channel blocker. O N O O H3C H3C CH3
  • 14. 2. Paramethadione: IUPAC: 5-ethyl-3,5-dimethyloxazolidine-2,4- dione. Uses: Anticonvulsant O N O O H3C H3C H2 C CH3
  • 15. 4. Succinimide  Eg: Phensuximide, Methsuximide, Ethosuximide  Is a cyclic imide with the formula C4H5NO2  Pyrrolidine-2,5-dione N CH2 O O R R' R''
  • 16. 1. Phensuximide: Brand Name: Milontin IUPAC: 1-methyl-3-phenylpyrrolidine-2,5-dione Uses: Used primarily against absence seizures. • The phenyl substituent confers some activity against generalized tonic-clonic and partial seizures. Metabolism: N-demethylation to yield active metabolite then p-hydroxylation. N CH2 O O H H3C
  • 17. 2. Methsuximide: Brand Name: Celontin • IUPAC: 1,3-dimethyl-3-phenylpyrrolidine-2,5-dione. • Is found to be effective and potent than phensuximide. • Is used against absence and complex partial seizures. N CH2 O O H3C H3C
  • 18. 3. Ethosuximide: Brand Name: Zarontin IUPAC: 3-ethyl-3-methylpyrrolidine-2,5-dione. • It is calcium T channel blocking drug. • Major metabolite is produced by oxidation of ethyl group. • Use: Conforms very well to the general structural pattern for antiabsence activity. N CH2 O O H3C CH2 H CH3
  • 19. 5. Urea and Monoacylureas: Eg: Phenacetamide, Carbamazepine. Long History of producing compounds with anticonvulsant activity. 1. Phenacemide: IUPAC: Phenyl acetyl urea Use: • Possess good anticonvulsant activity. • Less therapeutic value in petit mal, grand mal and mixed seizures. H2 C O H N C O NH2 phenylacetyl urea
  • 20. 2. Carbamazepine: Brand Name: Tegretol • The Two Phenyls substituted on the urea nitrogen fit the pattern of antigeneralized tonic activity. • The overall shape suggest the mode of action, sodium channel block. • Use: Generalized tonic-clonic and partial seizures. • Toxicity: potential hematological toxicity. • Metabolism: Proceeds largely through the epoxide formed at the (Z)cis-stilbine double bond. Then coverts to the 10s, 11s-trans-diol. N O NH2
  • 21. • The epoxide is a suspect in the idiosyncratic reactions • thus, oxcarbazepine were developed.
  • 22. 6. Benzodiazepine Eg: Clonazepam, Diazepam, Chlorazepam. Detail study regarding Chemistry and SAR were sees in anxiolytic-sedative-hypnotic drugs. Animal models predict that it modestly effective against generalized tonic-clonic and partial seizures and very highly active against absence seizures.
  • 23. 1. Clonazepam • IUPAC: 5-(2-chlorophenyl)-3-dihydro-7-nitro-2H- 1,4-benzodiazpin-2-one • Brand Name: Klonopin • Uses: in absence seizure • Tolerance often developed • Metabolism: Hydroxtlation of the 3 position, followed by glucuronidation. • Nitro group reduction followed by acetylation. O C N H O2N C Cl N CH2
  • 24. 2. Diazepam IUPAC: 7-chloro-1,3-dihydro-1-methyl -5-phenyl-1,4-bezodiazepin-2-one. Brand Name: Valium  Was the 1st member of the benzodiazepin-2-one group. • It is very nonpolar and rapidly absorb. USES: Anxiolytics in low doses Antiepileptics Central muscle relaxant METABOLISM: By N-demethylation to nordazepam which is then covert to oxazepam then excreted by glucuronide conjugation.
  • 25. 7. Miscellanious agents  Eg: Primidone & Valproic acid. 1. Primidone: IUPAC: 5-ethyldihydro5-phenyl- 4,6-(1H,5H)-pyrimidinedione Brand Name: Mysoline. • Also Called as 2-deoxybarbiturates. Uses: Against all types of Seizures except absence. N O C H2 N CH2 H O H3C H
  • 26. 2. Valproic Acid IUPAC: 2-propylpentoic acid Brand name: Depakene SAR: 1. Activity increase with increasing chain length. 2. Introduction of double bond decreases the activity. 3. Introduction of sec. or ter. Hydroxyl group or replacement of carboxyl by hydroxyl group has no effect. MOA: Act on GABA deactivating Enzyme. COOH C H2 CH2 H2 CH3C H2 CH3C
  • 27. Metabolism: by conjugation of the carboxylic acid group and oxidation of the one of the hydrocarbon chains. USES: Active against typical and atypical absences seizures and absence seizures with generalized tonic-clonic seizures.
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