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Drugs for epilepsy
- 1. Drugs for Epilepsy Lippincott, chapter 12
- 2. Definitions
- 6. Drug selection Therapeutic strategies for managing newly diagnosed epilepsy
- 8. Mechanism of anti-seizure drugs Drugs reduce seizures through such mechanisms as: • blocking voltage-gated channels (Na+ or Ca2+), • enhancing inhibitory γ-aminobutyric acid (GABA)-ergic impulses • interfering with excitatory glutamate transmission. • Antiepilepsy medications suppress seizures but do not “cure” or “prevent” epilepsy.
- 9. Mechanism of anti-seizure drugs
- 10. Older Drugs • Barbiturates • Hydantoins • Oxazolidinediones • Succinimides • Acetylureas
- 11. New Drugs • Eslicarbazepine • Felbamat • Gabapentin • Lacosamide • Lamotrigin • Levetiracetam • Oxcarbazepine • Perampanel • Pregabalin • Retigabine • Rufinamide • Stiripentol • Tiagabine • Topiramate • Vigabatrin • Zonisamide
- 13. Pharmacokinetics • Orally active • Enter the CNS • Phenytoin, tiagabine, and valproic acid – highly bound to plasma proteins • Cleared chiefly by hepatic mechanisms • Half-life – medium or long • Older antiseizure drugs are potent inducers of hepatic microsomal enzyme activity
- 14. Adverse affects
- 15. Drugs Used in Partial and Generalized Tonic-Clonic Seizures • Older drus – phenytoin (and congeners), carbamazepine, valproate, and the barbiturates • Newer drugs – eslicarbazepine, lamotrigine, levetiracetam, gabapentin, oxcarbazepine, pregabalin, retigabine, topiramate, vigabatrin, lacosamide, and zonisamide
- 16. Phenytoin • Mechanism of Action: – It alters Na+, K+, and Ca²⁺conductance – neurotransmitters: NE, Ach, and GABA • Decreases the synaptic release of glutamate and enhances the release of GABA • Block Na⁺ channels and inhibit the generation of rapidly repetitive action potentials
- 17. Clinical Uses of Phenytoin Is effective against: – partial seizures and – generalized tonic-clonic seizures - either primary or secondary to another seizure type
- 18. Pharmacokinetics of Phenytoin (Dilantin) • Fosphenytoin, is available for parenteral use – a more soluble phosphate prodrug of phenytoin, is well absorbed after I/M • 90% bound to plasma proteins • Metabolism follows – first-order kinetics at very low doses – zero order kinetics at therapeutic doses • accumulates in brain, liver, muscle, and fat • Half-life - average 24 hrs • It takes 5–7 days to reach steady-state • Slow-release extended-action formulation can be given in a single daily dosage
- 19. Pharmacokinetics of phenytoin (continued) • Drug interactions: Phenylbutazone and sulfonamides can displace phenytoin from plasma protein binding site • Phenytoin induces microsomal enzymes increases metabolism of carbamazepin • Autostimulation of its own metabolism - insignificant • Phenytoin related drugs: Ethotoin, Mephenytoin (active metabolite – nirvanol)
- 20. Adverse Effects of Phenytoin • Nystagmus • Peripheral neuropathy • Diplopia, ataxia – dose-dependent • Sedation –at very high levels • Gingival hyperplasia and hirsutism • Coarsening of facial features • Abnormalities of vitamin D metabolism - osteomalacia • osteoporosis • Idiosyncratic reactions – rare, • Hypersensitivity reactions, skin exfoliative lesions
- 21. Carbamazepine • Drug of choice for both partial seizures and generalized tonic- clonic seizures • Other clinical uses of carbamazepin: – bipolar depression – trigeminal neuralgia • Drug of choice for treatment of epilepcy in pregnant women • Related drugs: – oxcarbazepine – Eslicarbazepine
- 22. Pharmacokinetics of Carbamazepine • Peak levels are usually achieved 6–8 hours after administration • 70% bound to plasma proteins • Volume of distribution is roughly 1 L/kg • Extended-release preparations permit twice-daily dosing for most patients • Half-life of 36 hrs, 8– 12 hours in subjects receiving continuous therapy • Induces microsomal enzymes, needs dose adjustment • Increases rate of metabolism of other drugs: primidone, phenytoin, ethosuximide, valproic acid, and clonazepam
- 23. Carbamazepine Toxicity • Dose-dependent – Diplopia and ataxia – Mild gastrointestinal upsets, unsteadiness, and, at much higher doses - drowsiness • Idiosyncratic – blood dyscrasias including fatal cases of aplastic anemia and agranulocytosis – Mild and persistent leukopenia – Erythematous skin rash
- 24. Phenobarbital (Barbiturate) • Suppresses Na+ conductance • Block some Ca2+ currents (L-type and N-type) • Enhances the GABA receptor-mediated current • Decrease release of glutamate • Blocks of AMPA responses Clinical use: • partial seizures and generalized tonic-clonic seizures • Absence, atonic attacks and infantile spasms may worsen due to phenobarbital treatment • Related drug – primidone, is metabolized to phenobarbital
- 25. Newer Drugs
- 26. Vigabatrin • Mechanism: – inhibitor of GABA aminotransferase (GABA-T) • Clinical use: – partial seizures and infantile spasms – refractory to other treatments • Typical toxicities: – drowsiness, dizziness, and weight gain • Prolonged use: – in 30–50% of patients – irreversible damage to retina – visual field defects
- 27. Lamotrigine • Mechanism: – blockade of Na+ channels, voltage- gated Ca2+ channels, particularly the N- and P/Q-type – decreases the synaptic release of glutamate • Clinical uses: – partial seizures, absence and myoclonic seizures in children, Lennox-Gastaut syndrome • Adverse effects – dizziness, headache, diplopia, nausea, somnolence, and skin rash (hypersensitivity reaction) – life-threatening dermatitis will develop in 1–2% of pediatric patients
- 28. Felbamate • Mechanism – block NMDA receptor, potentiate GABA receptor • Drug interaction – increases plasma phenytoin and valproic acid levels but decreases levels of carbamazepine • Clinical use: – partial seizures, Lennox-Gastaut syndrome – Third-line drug for refractory cases • Adverse effects: – Aplastic anemia, severe hepatitis
- 29. Levetiracetam • Mechanism – modifies the synaptic release of glutamate and GABA – inhibits N-type Ca²⁺channels • Clinical uses – primary generalized tonic-clonic seizures – myoclonic seizures of juvenile myoclonic epilepsy • Adverse effects – somnolence, asthenia, ataxia, and dizziness • No drug interactions
- 30. Gabapentin and Pregabalin Mechanism: Analogs of GABA, do not act directly on GABA receptors, block voltage-gated N-type Ca2+ channels decrease in the synaptic release of glutamate Adverse effects: somnolence, dizziness, ataxia, headache, and tremor Clinical uses of Gabapentin partial seizures and generalized tonic-clonic seizures neuropathic pain postherpetic neuralgia Clinical uses of Pregabalin neuropathic pain(painful diabetic peripheral neuropathy, postherpetic neuralgia) Fibromyalgia generalized anxiety disorder
- 31. Tiagabine • Mechanism: – inhibition of GABA uptake • Clinical use: – partial seizures • Pharmacikinetics: – highly protein bound, food decreases the peak plasma concentration, oxidized in the liver by CYP3A. – Elimination - feces (60–65%) • Adverse events: – nervousness, dizziness, tremor, difficulty in concentrating, and depression. Psychosis occurs rare. – Excessive confusion, somnolence, or ataxia may require discontinuation
- 32. Topiramate • Mechanism: – blocking of voltage-gated Na+ channels , (L-type) Ca2+ channels, – potentiates the inhibitory effect of GABA • Clinical use: – partial and generalized tonic-clonic seizures, Lennox-Gastaut syndrome, infantile spasms, absence seizures – migraine headaches • Adverse effects: – somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion – Acute myopia and glaucoma may require prompt drug withdrawal – Urolithiasis • Drug interactions: – affect topiramate level – Birth control pills may be less effective
- 33. Zonisamide • Mechanism – blocks Na+ channel, T-type voltage-gated Ca²⁺ channels • Clinical use – partial and generalized tonic- clonic seizures, infantile spasms, myoclonias • Adverse effects – drowsiness, cognitive impairment and potentially serious skin rashes • Zonisamide does not interact with other antiseizure drugs
- 34. Ethosuccimide (Zarotonin) • Ethosuximide and valproate are – the drugs of choice for absence seizures • In thalamic neurons reduces Ca²⁺currents - the low-threshold (T-type) current • Promotes inwardly rectifying K+ channels • not protein-bound • half-life of approximately 40 hours • twice-a-day dosage is common
- 35. Ethosuccimide Toxicity • Drug interactions – valproic acid decreases ethosuximide clearance • Dose-related adverse effects of ethosuximide: – gastric distress, including pain, nausea, and vomiting – transient lethargy or fatigue much less commonly: – headache, dizziness, hiccup, and euphoria • Idiosyncratic effects – extremely rare
- 36. Valproic Acid & Sodium Valproate Mechanism of action: Valproate blocks: Na⁺current, NMDA receptors, increases levels of GABA Pharmacokinetics: Bioavailability > 80%. 90% bound to plasma proteins Half-life - 9 to 18 hrs 20% of the drug is excreted as a direct conjugate of valproate
- 37. Valproate -Drug Interactions • Drug Interactions – displaces phenytoin from plasma proteins – Inhibits liver ezymes – inhibition of phenobarbital metabolism; levels of the barbiturate rises steeply, causing stupor or coma – Valproate can dramatically decrease the clearance of lamotrigine
- 38. Valproate - Toxicity • Toxicity – very popular drug, severe adverse effects are rare • Dose-related toxicity: – nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and heartburn • Sedation is uncommon with valproate alone but – may be striking when valproate is added to phenobarbital • Idiosyncratic toxicity – fatal hepatotoxicity – Careful monitoring of liver function is recommended when starting the drug – thrombocytopenia
- 39. Valproate - Clinical Uses • Broad-spectrum • Very effective against absence seizures • Effective in – tonic-clonic seizures – myoclonic seizures – atonic attacks • I/V valproate - status epilepticus • Other uses: – bipolar disorder and – migraine prophylaxis
- 42. Partial Seizures • Simple partial seizure – 60-90 sec – patient is completely aware of the attack • Secondarily generalized attack – immediately precedes a generalized tonic-clonic (grand mal) seizures • Complex partial seizures – widespread – bilateral – involves limbic system – starts from temporal lobes – automatism – motor behaviour – alteration of consciousness – lasts 30-120 seconds – feel tired
- 43. Generalized Seizures • Generalized tonic-clonic (grand mal) • Absence (petit mal) seizure • Myoclonic jerking • Atonic seizures • Infantile spasms
- 44. Treatment Strategy • Most newer drugs have – a broader spectrum of activity – well tolerated • The drugs used for generalized tonic-clonic seizures are the same as for partial seizures
- 45. Treatment Strategy Three drugs are effective against absence seizures Ethosuximide Valproate Clonazepam
- 46. Treatment Strategy • Specific myoclonic syndromes are usually treated with valproate • Others: – clonazepam, nitrazepam – Zonisamide and levetiracetam • Juvenile myoclonic epilepsy – valproate is the drug of choice • Alternative: – lamotrigine and topiramate
- 47. Treatment Strategy • Infantaile spasms – intramuscular corticotropin – repository corticotropin for injection – clonazepam or nitrazepam – Vigabatrin
- 48. Corticotropin
- 49. Treatment Strategy Status Epilepticus I/V drugs: – diazepam or lorazepam – phenytoin – phenobarbital – intubation and ventilation – general anesthesia
- 50. Other Uses of Antiepileptic Drugs • Valproate: – Migrane prophylaxis – bipolar disorder • Carbamazepin: – bipolar depression – trigeminal neuralgia • Gabapentin – neuropathic pain – postherpetic neuralgia • Pregabalin – neuropathic pain(painful diabetic peripheral neuropathy, postherpetic neuralgia) – fibromyalgia – generalized anxiety disorder
- 51. Adverse Effects • Hepatotoxicity – felbamat, valproate • Anemias – Carbamazepin, felbamat • Weight gain – Valproate • Weight loss – Topiramat, zonisamide • Steven-Jonson syndrome – Lamotrigine, – carbamazepin, – zonisamide
- 52. Teratogenicity • Phenytoin – Fetal hydantoin syndrome (dilantin syndrome) • Valproate (antifolate drug) – Spina bifida – Fetal valproate syndrome
- 53. Fetal hydantoin (Dilantin) syndrome