Anticonvulsant or antiepileptic drugs

1. Anticonvulsant or antiepileptic drugs Epilepsy: Sudden and excessive electrical activity in brain (excessive firing of neurons).

3. Anticonvulsant or Antiepileptic drugs Antiepileptic agent An agent used medically to control epilepsies, not all of which are convulsive, in humans. • Drugs used to control (prevent) seizures (convulsions) or stop an ongoing series of seizures.

4. Epilepsy: Classification • Partial(local, focal) seizures • Simple (consciousness not impaired) • Complex partial seizures (psychomotor seizures) • Beginning as simple partial seizures, progressing to complex seizures • With impairment of consciousness at onset • Partial seizures evolving to secondarily generalized tonic- clonic convulsions

5. Movements such as turning the head, eye movements, smacking the lips, mouth movements, drooling, rhythmic muscle contractions in a part of the body, abnormal numbness, tingling, and a crawling sensation over the skin Complex partial seizure is represented by the psychomotor or temporal lobe seizure.

6. Classification Epilepsy: Sudden and excessive electrical activity in brain (excessive firing of neurons). • Generalized seizures (convulsive or nonconvulsive) • Absence seizures • Typical (petit mal) • Atypical • Myoclonic • Clonic • Tonic • Tonic- clonic (grand mal) • Atonic • Unclassified epileptic seizures (includes some neonatal seizures)

8. Physiology & Pharmacology

9. Physiology & Pharmacology • GABAA Receptors • drugs that enhance the • biosynthesis of GABA • (gabapentin, pregabalin, and VPA) • (b) drugs that inhibit GABA • degradation (vigabatrin) • (c)drugs that inhibit the reuptake of • GABA (tiagabine) • (d)drugs that bind to an allosteric site • (barbiturates, BZDs, neurosteroids, • FBM, TPM) Targets of AED • VOLTAGE-GATED SODIUM CHANNELS phenytoin, CBZ, and lamotrigine newer AEDs, such as OXC, felbamate, and zonisamide • VOLTAGE-GATED CALCIUM CHANNELS Gabapentin, pregabalin, ethosuximide and zonisamide • VOLTAGE-GATED POTASSIUM CHANNELS • Levetiracetam • Excitatory Glutamate-Mediated • Receptors The ligand-gated glutamate receptors such as N-methyl-D-aspartic acid (NMDA) amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) -Topiramate

10. Classification of Antiepileptic agents • Barbiturates: Phenobarbital • Benzodiazepines: Clonazepam • Hydantoins: Phenytoin • Oxazolidinediones: • Succinimides: Phensuximide Trimethadone paramethadione

11. Ureas and Monoacylureas: Carbamazepine • Miscellaneous agents: Primidone progabide

12. Antiepiletic agents: SAR Structure common to anticonvulsant drugs. Barbiturates Hydantoins Oxazolidinediones Succinimides Phenacemide

13. Antiepileptic agents: SAR • R and R’ should both be hydrocarbon radicals. Phenytoin • R and R’ are lower alkyls, the agent is active against absence seizures(petit mal) and not active against generalized tonic-clonic(grand mal) or partial seizures . Trimethadione

14. Antiepileptic agents: SAR • If one of the hydrocarbon substituent is an aryl group, activity tends to be directed towards generalized tonic-clonic and partial seizures, and not towards antiabsence activity. Mephenytoin Phensuximide • The conformational arrangement of hydrophobic group is important for antigeneralized tonic-clonic activity.

15. Antiepileptic agents: Mechanism of Action Basic action: To decrease electrical excitability at the site or at adjacent or recruited neurons. • Ion channels • Voltage-dependent sodium channels • After each depolarization , it adopts an inactive state and remain refractory to re-opening for a period of time. • While the channels are unable to open, rapid repetitive firing is diminished, and spread of electrical seizure activity to adjacent brain regions is suppressed. • Stabilization and prolongation of this inactive state appears to be the primary MOA of phenytoin, carbamazepine and valproic acid against generalized tonic-clonic seizures. • Synaptic inhibition and excitation • Enhancement of GABAergic transmission: • Benzodiazepines and valproic acid against absence seizures.

16. Mechanisms of antiseizure drugs. (A) Drugs for partial seizures: 1) Seizure activity spreads due to loss of surround inhibition; 2) drugs act in the surrounding region to 3) enhance –GABA activity or prolong Na+ channel inactivation.

17. (B) Drugs for absence seizures: 1) The seizure activity results from cyclic activity between the thalamus and the cortex; 2) drugs prevent synchronization

18. A summary of the sites of action for the antiepileptic drugs

19. Hydantoins Phenytoin Mephenytoin • 5,5-Diphenylhydantoin • First anticonvulsant • acts through its action at the VGSC • Use : all seizure types except absence • Metabolism: p-Hydroxylation of aromatic ring • N-dealkylated to 5-Ethyl-5-phenylhydantoin • Use: similar to phenytoin • Toxicity: Serious skin and blood disorders • Metabolism: p-Hydroxylation of aromatic ring 5,5-diphenylimidazolidine-2,4-dione

20. Oxazolidinediones Trimethadione Paramethadione • 3,5,5-trimethyl-1,3-oxazolidine-2,4-dione • Use: first drug against absence seizures. • acts by decreasing T-type calcium currents • Toxicity: dermatologic and hematologic, malformations or fetal death in up to87% of pregnancies • Metabolism:N-Demethylation to give active dimethadione, water soluble and excreted without further metabolism. • half-life of dimethadione is 6 to 13 days • 5-ethyl-3,5-dimethyl-1,3-oxazolidine-2,4-dione • Similar action, uses and side effects of trimethadione • Metabolism: N-Demethylation

21. Succinimides Phensuximide Ethosuximide • 1-methyl-3-phenylpyrrolidine-2,5-dione • Use: Primary, absence seizures some activity against generalized tonic- clonic seizures. • decrease in T-type calcium channel activity • N-Demethylation gives active metabolite • Metabolism: p-Hydroxylation of aromatic group • can cause morphologic changes to kidneys and liver • 3-ethyl-3-methylpyrrolidine-2,5-dione • Use: drug of choice for typical absence seizures. • More active and less toxic than trimethadione • Toxicity: skin and blood • Metabolism: some drug released intact. major metabolism by oxidation of ethyl group.

22. Ureas and Monoacylureas Phenacemide Carbamazepine • Phenylacetylurea • Use: psychomotor epilepsy • Side effects: personality changes, blood, renal and skin disorders • Metabolism: p-hydroxylation • 5H-Dibenz[ b, f]azepine-5-carboxamide Use: complex partial,tonic-clonic, and mixed-type seizures. • acts through its action at the VGSCto prevent the spread of seizures. • Toxicity: Serious hematologic • Metabolism: Epoxide at cis-stilbene double bond, get converted to 10S,11Strans-diol in humans. benzo[b][1]benzazepine-11-carboxamide

23. Miscellaneous Agents Primidone Valproic acid • 5-Ethyldihydro-5-phenyl-4,6(1H,5H)-pyrimidinedione • 5-ethyl-5-phenyl-1,3-diazinane-4,6-dione • Use: simple partial,complex partial, and tonic-clonic seizures.. • Converted to phenobarbital and phenylethylmalonyldiamide • Sometimes also called as 2-deoxybarbiturate • 2-Propylpentanoic acid • Use: good potency - absence seizures. • Metabolism: conjugation of the carboxylic acid group and oxidation of one hydrocarbon chain.

24. VIGABATRIN 4-aminohex-5-enoic acid • Vigabatrin is γ-vinyl GABA, a synthetic derivative of GABA • that was FDA approved in 2009 • monotherapy in the treatment of infantile spasms (West syndrome) in children • of 1 month to 2 years of age and as adjunctive treatment of adults with refractory complex partial seizures • exact mechanism for vigabatrin’s anticonvulsant effect is unclear, the • drug is known to be an irreversible inhibitor of GABA transaminase, • the enzyme responsible for GABA degradation

25. 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine

26. N-Bromosuccinimide Phosgene

27. 2-Amino-2'-chloro benzophenone 2-(Bromoacetamido)-2'-chloro benzophenone KNO3 in H2SO4

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