Introduction and drugs used to treat epilepsy

Introduction to Epilepsy and its type and Drugs used in management of Epilepsy.

1. Saddam Ansari Achiever’s Academy Introduction and Drugs used to Treat Epilepsy

2. Epilepsy? Second most common neurological disorder. Family of different recurrent seizures disorders that have in common the sudden, excessive and synchronous discharge of cerebral neurons. Abnormal movements or perceptions that are of short duration but tend to recur.

3. Types of Epilepsy Primary or Idiopathic Epilepsy: No specific anatomic cause for the seizure Inherited abnormality Treated often for lifetime with antiepileptic drugs

4. Continued… Secondary Epilepsy: Reversible disturbances such as tumors, head injury , hypoglycemia , meningeal infection or withdrawal Antiepileptic are given until primary cause is corrected Seizures secondary to stroke or trauma may cause irreversible CNS damage.

5. Classification of Seizures Partial Seizure Simple partial Complex partial

6. Continued… Generalized Seizure Tonic- clonic (grand mal) Absence (petit mal) Myoclonic Febrile seizure Status epilepticus

7. Mechanism of action of antiepileptic drugs Block the initiation of the electric discharge from the focal area Prevent the spread of the abnormal electrical discharge to adjacent brain areas Blockade of voltage gated channels Enhancement of GABAergic impulses Interference with glutamate transmission

8. Primary Antiepileptic Drugs Phenytoin Carbamazepine Oxcarbazepine Phenobarbital Primidone Valproic acid Ethosuximide Benzodiazepines

9. Adjunct Drugs Felbamate Gabapentin Lamotrigine Levetiracetam Tiagabine Topiramate Zonisamide

10. Phenytoin Formerly called as diphenylhydantoin Effective in suppressing tonic- clonic and partial seizures Choice for initial therapy , particularly in adults

11. Continued… Mechanism of action: Blocks voltage – gated sodium channels Selectively binds to the channels in inactive state and recovery rate slows down At higher concentration – block voltage dependent calcium channels and interfere with the release of monoaminergic neurotransmitters

12. Continued… Actions: Reduces the propagation of abnormal impulses in the brain Is not a generalized CNS depressant like the barbiturates But produces some degree of drowsiness and lethargy without progression to hypnosis

13. Continued… Therapeutic uses: Highly effective for all partial seizures , tonic – clonic seizures and in the status epilepticus caused by recurrent tonic- clonic seizures Not effective in absence seizures , may worsen if treated with this drug

14. Continued… Absorption and fate: Oral absorption is slow but distribution is rapid and brain concentration are high Chronic administration of phenytoin is always oral Largely bound to plasma albumin Metabolized by hepatic cytochrome P450 system to an inactive metabolite

15. Continued… Absorption and fate : At low doses, half life is 24 hours Hydroxylation system becomes saturated as dose increases Increase in plasma concentration results in drug induced toxicity In status epilepticus – IV in form of fosphenytoin

16. Continued… Adverse effects: Depression of CNS particularly in cerebellum and vestibular system – nystagmus and ataxia GIT problems – nausea and vomiting Gingival hyperplasia particularly in children Coarsening of facial features occurs in children

17. Continued… Adverse effects: Megaloblastic anemia – B12 reactions Confusion, hallucination and drowsiness Inhibition of antidiuretic hormone Insulin secretion Should not be stopped abruptly

18. Continued… Teratogenic effects: “Fetal H ydantoin Syndrome” includes cleft lip, cleft palate and congenital heart disease Stunted growth Mental deficiency Congenital birth defects in untreated mothers Drugs are given at the lowest possible dose in pregnant women

19. Continued… Drug Interactions Drugs that affect phenytoin metabolism: Chloramphenicol, dicumarol , cimetidine, sulfonamides and isoniazid Microsomal metabolism is inhibited by these drugs in the liver Phenytoin metabolism is enhanced by carbamzepine

20. Continued… Drug Interactions Increased metabolism of other drugs caused by phenytoin : Induces the cytochrome P450 system Results in increased metabolism of other antiepileptics , anticoagulants, oral contraceptives, quinidine, doxycycline, cyclosporine, mexiletine , methadone, and levodopa.

21. Carbamazepine Actions: Reduces the propagation of abnormal impulses in the brain by blocking sodium channels Inhibits the generation of repetitive action potentials in the epileptic focus and preventing their spread

22. Continued… Therapeutic uses : Highly effective for all partial seizures , first choice drug Effective in tonic- clonic seizures Used in treatment of trigeminal neuralgia Used in manic-depressive patients to ameliorate the symptoms

23. Continued… Absorption and Fate: Absorbed slowly through oral administration Highly lipid solubility Half life – 5 to 7 days Half life decreases with chronic administration Induces cytochrome P450 system, cytochrome P450 isozyme , CYP3A4

24. Continued… Adverse effects: Chronic administration can cause stupor, coma and respiratory depression along with drowsiness, vertigo, ataxia, blurred vision and rash. GIT – nausea and vomiting Liver toxicity Blood dyscrasias ( 10,11- epoxide metabolite of drug) Leukopenia and aplastic anemia Hyponatremia in elderly people

25. Continued… Drug interaction: Hepatic metabolism of carbamazepine is inhibited by Cimetidine Diltiazem Erythromycin Isoniazid Propoxyphene Toxic symptoms may arise if dose is not adjusted

26. Oxcarbazepine 10-keto derivative of carbamazepine Reduces to 10-monohydroxy metabolite and blocks sodium channels preventing the spread of the abnormal discharge Anticonvulsant spectrum and toxicities are similar to that of carbamazepine Less potent inducer of drug-metabolizing enzyme Reduced effectiveness of oral contraceptives

27. Phenobarbital Actions: Limiting the spread of seizure discharges in the brain and elevating the seizures threshold Exact mechanism is unknown Believed that potentiation of GABA neurons

28. Continued… Therapeutic uses: 50% favorable response rate for simple partial seizures Not very effective for complex partial seizures First choice of drug for recurrent seizures in children including febrile seizure ,diazepam is also effective

29. Continued… Actions: Used to treat recurrent tonic- clonic seizures (if diazepam and phenytoin is nonresponsive ) Mild sedative to relieve anxiety , nervous tension, insomnia but benzodiazepines are superior

30. Continued… Absorption and Fate: Well absorbed orally Freely penetrates the brain Approximately 75 % drug is inactivated by the hepatic microsomal system Remaining drug is excreted unchanged by the kidney Potent inducer of cytochrome P450 system

31. Continued… Adverse effects: Sedation Ataxia Nystagmus Vertigo Acute psychotic reaction with chronic use

32. Continued… Adverse effects: Nausea and vomiting with morbilliform rash Agitation and confusion at high doses Rebound seizures can occur on discontinuance of phenobarbital

33. Primidone Related to phenobarbital Alternate choice in partial and tonic- clonic seizures Often used with carbamazepine and phenytoin Ineffective in absence seizures Well absorbed orally but poor protein binding Adverse effects is same as phenobarbital

34. Valproic Acid Blocks sodium channel Enhancement of GABAergic transmission Broad-spectrum anticonvulsant Most effective in myoclonic seizures

35. Continued… Its second choice of drug due its hepatotoxicity Reduces the incidence and severity of tonic- clonic seizures Effective orally and rapidly absorbed About 90% bound to plasma proteins

36. Continued… 3% excreted unchanged Metabolized by CYP

37. Continued… Adverse effects Nausea and vomiting Sedation, ataxia and tremor are common Rare hepatic toxicity Rash and alopecia Thrombocytopenia Inhibits the metabolism of other antiepileptic drugs

38. Ethosuximide I ntroduced in 1960 in the USA. Ethosuximide has very little activity against maximal electroshock C onsiderable efficacy against pentylenetetrazol seizures; it was introduced as a "pure petit mal" drug.

39. Continued… Mechanism of Action Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current. This effect is seen at therapeutically relevant concentrations in thalamic neurons. The T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for absence seizures. (INHIBITION of thalamic neurons)

40. Continued… Therapeutic uses: Particularly effective against absence seizures V ery narrow spectrum of clinical activity Documentation of its effectiveness in human absence seizures was achieved with long-term electroencephalographic recording techniques

41. Continued… Pharmacokinetics Absorption is complete following administration of the oral dosage forms. Peak levels are observed 3–7 hours after oral administration Ethosuximide is not protein-bound. Ethosuximide is completely metabolized, principally by hydroxylation, to inactive metabolites.

42. Continued… The drug has a very low total body clearance (0.25 L/kg/d) This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.

43. Continued… Therapeutic Levels & Dosage Therapeutic levels of 60–100 mcg/mL can be achieved in adults with dosages of 750–1500 mg/d A lthough lower or higher dosages and blood levels (up to 125 mcg/mL) may be necessary and tolerated in some patients.

44. Continued… Drug Interactions Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations. No other important drug interactions have been reported for the succinimides .

45. Continued… Adverse effects and Toxicity G astric distress, including pain, nausea, and vomiting. When an adverse effect occur, temporary dosage reductions may allow adaptation. Other dose-related adverse effects are transient lethargy or fatigue and much less commonly, headache, dizziness, hiccup, and euphoria . Behavioral changes are usually in the direction of improvement.

46. Continued… Phensuximide & Methsuximide Phensuximide and Methsuximide are Phenylsuccinimides that were developed and marketed before Ethosuximide They are used primarily as anti-absence drugs Methsuximide is generally considered more toxic, and Phensuximide less effective, than Ethosuximide

47. continued… Unlike Ethosuximide , these two compounds have some activity against maximal electroshock seizures M ethsuximide has been used for partial seizures by some investigators

48. Benzodiazepines Diazepam Potentiates GABA A responses Well absorbed orally , rectal administration gives peak concentration in ~1 h with 90% bioavailability IV for status epilepticus , highly protein-bound , extensively metabolized to several active metabolites ,t1/2 ~2 d Status epilepticus , seizure clusters

49. Continued… Clonazepam Action : As for diazepam > 80% bioavailability extensively metabolized but no active metabolites , t1/2 20–50 h Therapeutic uses: Absence seizures, myoclonic seizures, infantile spasms Toxicity : Similar to diazepam

50. Felbamate B locking voltage-dependent sodium channels C ompeting with the glycine- coagonist binding site on the N-methyl-D-aspartate (NMDA) glutamate receptor B locking calcium channels

51. Continued… P otentiating the action of GABA. It is an inhibitor of drugs metabolized by CYP2C19 and â-oxidation, and induces drugs metabolized by CYP3A4. It is reserved for use in refractory epilepsies (particularly Lennox- Gastaut syndrome ) because of the risk of aplastic anemia (about 1:4000) Hepatic failure.

52. Gabapentin Decreases excitatory transmission by acting on Voltage-Gated Ca2+ channels presynaptically Bioavailability 50%, decreasing with increasing doses not bound to plasma proteins Not metabolized , excreted through kidney

53. Continued… t1/2 6–8 h Generalized tonic- clonic seizures, partial seizures, Adverse effects: Somnolence, dizziness, ataxia

54. Lamotrigine Prolongs inactivation of VG-Na+ channels A cts presynaptically on VG-Ca2+ channels Decreases glutamate release Well absorbed orally No significant protein binding

55. Continued… Metabolized primarily to the N-2 glucuronide through the UGT pathway t1/2 25–35 h Generalized tonic- clonic seizures, generalized seizures, partial seizures, generalized seizures, absence seizures Adverse effects: Dizziness, headache, diplopia, rash Interactions : Valproate, carbamazepine, oxcarbazepine

56. Levetiracetam Action on synaptic protein SV2A Well absorbed orally N ot bound to plasma proteins , t1/2 6–11 h Generalized tonic- clonic seizures, partial seizures, generalized seizures Adverse effects: Nervousness, dizziness, depression, seizures Interactions : Phenobarbital, phenytoin, carbamazepine, primidone

57. Tiagabine Blocks GABA reuptake in forebrain by selective blockade of GAT-1 Well absorbed highly bound to plasma proteins Metabolism is mainly completed by the CYP3A family of enzymes t1/2 4–8 h Partial seizures Adverse effects: Nervousness, dizziness, depression, seizures

58. Topiramate B road spectrum antiseizure activity. Blocks voltage-dependent sodium channels Increase the frequency of chloride channel opening by binding to the GABA A receptor High-voltage calcium currents (L type) are reduced

59. Continued… It is a carbonic anhydrase inhibitor and may act at glutamate (NMDA) sites Effective and approved for use in partial and primary generalized epilepsy It is also approved for treatment of migraine Topiramate is eliminated renally t1/2 20 h

60. Continued… It inhibits CYP2C19 and is induced by phenytoin and carbamazepine Lamotrigine is reported to cause an increase in topiramate concentration Coadministration of topiramate reduces ethinyl estradiol

61. Continued… Adverse effects include somnolence, weight loss, and paresthesias Renal stones are reported to occur at a higher incidence than in a non-treated population Glaucoma , oligohidrosis , and hyperthermia have also been reported

62. Zonisamide sulfonamide derivative that has a broad spectrum of action. The compound has multiple effects on neuronal systems thought to be involved in seizure generation. These include blockade of both voltage-gated sodium channels T-type calcium currents Its use should be monitored in patients with reported allergies.

63. Continued… A pproved for use in patients with partial epilepsy It is metabolized by the CYP3A4 isozyme and may, to a lesser extent, be affected by CYP3A5 and CYP2C19 t1/2 50–70 h In addition to typical CNS adverse effects, it may cause kidney stones Oligohidrosis has been reported