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Antiseizure Drugs

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  1. Antiseizure Drugs By Bohlooli S, PhD School of Medicine, Ardabil University of Medical Sciences

  2. Introduction • Approximately 1% of the world's population has epilepsy • Epilepsy is a chronic disorder characterized by recurrent seizures • Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons • The causes of seizures are many • infection to neoplasm and head injury

  3. Classification of seizure types

  4. Drug Development for Epilepsy • threshold pentylenetetrazol clonic seizures in mice • Screening of drug for absence seizures • the maximal electroshock test (MES) • for generalized tonic-clonic seizures and complex partial seizures • Limbic seizures induced in rats by the process of electrical kindling • screen for predicting efficacy in complex partial seizures

  5. Drug Development for Epilepsy • New antiseizure drugs are being sought by more rational approaches • Enhancement of GABAergic (inhibitory) transmission • Diminution of excitatory (usually glutamatergic) transmission • Modification of ionic conductances

  6. Molecular targets for antiseizure drugs at the excitatory, glutamatergic synapse

  7. Molecular targets for antiseizure drugs at the inhibitory, GABAergic synapse

  8. BASIC PHARMACOLOGY OF ANTISEIZURE DRUGS • Chemistry (five very similar chemical groups) • Barbiturates • Hydantoins • Oxazolidinediones • Succinimides • Acetylureas • carbamazepine, valproic acid, and the benzodiazepines • felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide.

  9. Chemistry Figure 24-1. Antiseizure heterocyclic ring structure. The "X" varies as follows: hydantoin derivatives, -N-; barbiturates, -C-N-; oxazolidinediones, -O-; succinimides, -C-; acetylureas, -NH2 (N connected to C2). R1, R2, and R3 vary within each subgroup.

  10. Pharmacokinetics • The antiseizure drugs exhibit many similar pharmacokinetic properties • selected for oral activity • all must enter the central nervous system • with 80-100% of the dose reaching the circulation • Most antiseizure drugs are not highly bound to plasma proteins • cleared chiefly by hepatic mechanisms • Many are converted to active metabolites that are also cleared by the liver


  12. INTRODUCTION • The classic major drugs : • Phenytoin (and congeners) • Carbamazepine • Valproate • Barbiturates • Newer drugs: • Lamotrigine, levetiracetam, gabapentin • Oxcarbazepine, pregabalin, topiramate • Vigabatrin, and zonisamide

  13. PHENYTOIN • the oldest nonsedative antiseizure drug • known for decades as diphenylhydantoin.

  14. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use PHENYTOIN: chemical

  15. PHENYTOIN; Mechanism of Action • to block sodium channels • inhibiting the generation of rapidly repetitive action potentials • A reduction of calcium permeability: • may explain the ability of phenytoin to inhibit a variety of calcium-induced secretory processes

  16. PHENYTOIN: Clinical Use • Effective against: • Partial seizures • Generalized tonic-clonic seizures

  17. PHENYTOIN:Pharmacokinetics • Absorption is highly dependent on the formulation of the dosage form • Absorption after intramuscular injection is unpredictable • highly bound to plasma proteins • Phenytoin accumulates in brain, liver, muscle, and fat. • Phenytoin is metabolized to inactive metabolites that are excreted in the urine • The elimination of phenytoin is dose-dependent • The half-life of phenytoin varies from 12 hours to 36 hours

  18. Nonlinear relationship of phenytoin dosage and plasma concentrations

  19. PHENYTOIN: Drug Interactions & Interference with Laboratory Tests • Drug interactions are primarily related to : • protein binding • metabolism • Hypoalbuminemia? • has an affinity for thyroid-binding globulin • Inducer of microsomal enzymes

  20. PHENYTOIN: Toxicity • Dose-related adverse effects are similar to other antiseizure drugs in this group • Nystagmus occurs early • Diplopia and ataxia • Sedation • Gingival hyperplasia and hirsutism • Long-term use : • coarsening of facial features • abnormalities of vitamin D metabolism • Idiosyncratic reactions are relatively rare

  21. MEPHENYTOIN, ETHOTOIN • No well-controlled clinical trials have documented their effectiveness • Mephenytoin: The incidence of severe reactions such as • Dermatitis • Agranulocytosis • hepatitis is higher than for phenytoin • Ethotoin: adverse effects and toxicity are generally less severe than those associated with phenytoin, but the drug appears to be less effective

  22. Closely related to imipramine and other antidepressants Effective in treatment of bipolar depression CARBAMAZEPINE

  23. CARBAMAZEPINE :Mechanism of Action • similar to that of phenytoin • blocks sodium channels • inhibits high-frequency repetitive firing in neurons in culture • It also acts presynaptically to decrease synaptic transmission

  24. CARBAMAZEPINE: Clinical Use • has long been considered a drug of choice for • partial seizures • generalized tonic-clonic seizures • is not sedative in its usual therapeutic range • very effective in some patients with trigeminal neuralgia • useful in some patients with mania

  25. CARBAMAZEPINE:Pharmacokinetics • The rate of absorption varies widely among patients • Distribution is slow, and the volume of distribution is roughly 1 L/kg • has a very low systemic clearance of approximately 1 L/kg/d • initial half-life of 36 hours observed, decreases to as short as 8-12 hours. • Carbamazepine is completely metabolized in humans to several derivatives

  26. CARBAMAZEPINE: Therapeutic Levels & Dosage • Carbamazepine is available only in oral form • the therapeutic level is usually 4-8 mcg/mL

  27. CARBAMAZEPINE:Drug Interactions • exclusively related to the drug's enzyme-inducing properties: • an increased rate of metabolism of other drugs • primidone, phenytoin, ethosuximide, valproic acid, and clonazepam • Other drugs such as propoxyphene, troleandomycin, and valproic acid may inhibit carbamazepine clearance • Anticonvulsants such as phenytoin and phenobarbital • decrease steady-state concentrations of carbamazepine through enzyme induction

  28. CARBAMAZEPINE: Toxicity • The most common dose-related adverse effects are • diplopia and ataxia • Mild gastrointestinal upsets • Unsteadiness • Drowsiness : at much higher doses • Hyponatremia and water intoxication • idiosyncratic blood dyscrasias • fatal cases of aplastic anemia and agranulocytosis • The most common idiosyncratic reaction is an erythematous skin rash

  29. OXCARBAZEPINE • closely related to carbamazepine • have an improved toxicity profile • Its activity resides almost exclusively in the 10-hydroxy metabolite • hyponatremia may occur more commonly with oxcarbazepine than with carbamazepine

  30. PHENOBARBITAL • Many consider the barbiturates the drugs of choice for seizures only in infants • clinically useful as antiseizure drugs are : • phenobarbital, mephobarbital, metharbital, and primidone

  31. PHENOBARBITAL : Mechanism of Action • The exact mechanism of action of phenobarbital is unknown • enhancement of inhibitory processes • diminution of excitatory transmission • selectively suppress abnormal neurons • Block sNa+ conductance • blocks some Ca2+ currents (L , N type) • enhances the GABA receptor-mediated current • blocks excitatory responses induced by glutamate (AMPA)

  32. PHENOBARBITAL : Clinical Use • useful in the treatment of • partial seizures • generalized tonic-clonic seizures • There is little evidence for its effectiveness in generalized seizures • such as absence, atonic attacks, and infantile spasms • it may worsen certain patients with these seizure types


  34. PRIMIDONE • the mechanism of action is more like that of phenytoin • effective against partial seizures and generalized tonic-clonic seizures

  35. PRIMIDONE : • is completely absorbed • Primidone is metabolized • by oxidation to phenobarbital • by scission of the heterocyclic ring to form PEMA • efficacious when plasma levels are in the range of 8-12 mcg/mL • The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital • except drowsiness occurs early

  36. VIGABATRIN • irreversible inhibitor of GABA aminotransferase (GABA-T) • useful in the treatment of partial seizures and West's syndrome • Typical toxicities include drowsiness, dizziness, and weight gain • long-term therapy with vigabatrin has been associated with development of visual field defects

  37. LAMOTRIGINE • a voltage- and use-dependent inactivation of sodium channels. • Blocking actions on voltage-activated Ca2+ channels • decreases the synaptic release of glutamate

  38. LAMOTRIGINE: Clinical Use • effective for partial seizures • As add on or monotherapy • There is evidence that the drug is also active against: • absence and myoclonic seizures in children • Adverse effects include: • dizziness, headache, diplopia, nausea, somnolence, and skin rash • a potentially life-threatening dermatitis will develop in 1-2% of pediatric patients

  39. FELBAMATE • effective in some patients with partial seizures • causes aplastic anemia and severe hepatitis at unexpectedly high rates • a third-line drug for refractory cases • a use-dependent block of the NMDA receptor • potentiates GABAA receptor responses • effective against the seizures that occur in Lennox-Gastaut syndrome


  41. GABAPENTIN & PREGABALIN • modify the synaptic or nonsynaptic release of GABA • act presynaptically to decrease the release of glutamate • as an adjunct against: • partial seizures and generalized tonic-clonic seizures • effective in the treatment of neuropathic pain • The most common adverse effects are: • somnolence, dizziness, ataxia, headache, and tremor • the drugs are excreted unchanged

  42. LEVETIRACETAM • binds selectively to a synaptic vesicular protein SV2A • modifies the synaptic release of glutamate and GABA • The drug is for the treatment of partial seizures • Two thirds of the drug is excreted unchanged in the urine

  43. TIAGABINE • was "rationally designed" as an inhibitor of GABA uptake

  44. TIAGABINE • inhibitor of GABA uptake in both neurons and glia • adjunctive treatment of partial seizures • Minor adverse events are dose-related and include: • nervousness, dizziness, tremor, difficulty in concentrating, and depression • Rash is an uncommon idiosyncratic • Food decreases the peak plasma concentration • The drug is oxidized in the liver by CYP3A

  45. TOPIRAMATE • a substituted monosaccharide

  46. TOPIRAMATE • blocking of voltage-gated sodium channels • potentiate the inhibitory effect of GABA • depresses the excitatory action of kainate on glutamate receptors • effective against partial and generalized tonic-clonic seizures • has a broader spectrum, with effectiveness against: • Lennox-Gestaut syndrome • West's syndrome • absence seizures. • approved for the treatment of migraine headaches • dose-related adverse effects include • somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion • Acute myopia and glaucoma • Urolithiasis

  47. ZONISAMIDE • a sulfonamide derivative • site of action appears to be the sodium channel • act on voltage-gated calcium channels

  48. ZONISAMIDE • effective against partial and generalized tonic-clonic seizures • useful against infantile spasms • Adverse effects include: • drowsiness, cognitive impairment, and potentially serious skin rashes


  50. ETHOSUXIMIDE • Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current