Antiseizure Drugs-02

1. AntiseizureDrugs-02 Kaukab Azim, MBBS, PhD

2. Drug Groups

3. Valproic Acid Mechanism of action • The drug likely acts with multiple mechanisms, including: a) State-dependent blockade of inactivated Na+ channels. b) Blockade of NMDA receptor mediated excitation. c) Blockade of T type Ca++ channels in thalamic neurons. Pharmacological effects • A broad spectrum antiepileptic drug (see therapeutic uses) • The drug can inhibit CYP2C9 and glucuronosyltransferase, so inhibiting the biotransformation of many drugs. Pharmacokinetics • Oral bioavailability: 100% • Biotransformation: > 95% by the liver (some metabolites are active)

4. Valproic Acid – Adverse Effects CNS • Sedation, drowsiness (when given with other CNS depressants) • Dizziness, tremor, ataxia, nystagmus , diplopia, dysarthria • Nervousness, agitation (mainly in children). Gastrointestinal system • Nausea, vomiting, anorexia, weight gain (up to 20%). • Hyper-ammon-emia(50%), fulminant hepatitis Hematopoietic system • Thrombocytopenia, mainly-dose related (up to 30% of patients). Allergic reactions • Skin rashes, photosensitivity, erythema multiforme,. Reproductive system. • Menstrual disturbances (up to 20% of patients). • Increased risk of neural tube defect (up to 20 fold) when given during pregnancy. Spina bifida can ensue.

5. Valproate Hepatitis • The occurrence is about 1 in 37000 patients if the drug is given alone, but 1 in 6500 patients if other drugs are given concurrently. • Children below 2 years of age (or with mental retardation or congenital neurological disease) are especially at risk. • Hepatitis appears usually after two months of therapy, but it may show after few days or after six months. • Pathogenesis is unknown (most likely idiosyncratic)

6. Valproic Acid – Therapeutic Uses Epilepsy • Valproicacid can be considered a first or second line therapy in all forms of epilepsyin all age groups. • It is the best drug available to control myoclonic seizures (results are good and sometimes excellent) and atonic seizures (results are sometimes rather good) • It is a first line agent (together with carbamazepine and phenytoin) for tonic-clonicseizures. • It is a first line agent (together with ethosuximide) in absence seizures (for uncomplicated absence seizures ethosuximide is preferred because of valproate hepatotoxicity) • It is the preferred drug in patients with absence seizures and concomitantgrand mal seizures. • It is considered equally effective as carbamazepine in simple and complexpartial seizures. • It is an alternative drug in infantile spasms and Lennox Gastautsyndrome.

7. Valproic Acid – Therapeutic Uses Bipolar affective disorder • It is considered a drug of choice (together with lithium) for the therapy of acute mania and the prophylactic treatment of bipolar disorder, especially in rapid cycling patients. Migraine prophylaxis • It has been approved by FDA for the prevention of migraine attack (mechanism is still uncertain). There is no evidence that it might be useful in treatment of acute migraine attack.

8. Ethosuximide Mechanism of action • Blockade of voltage-sensitive T type Ca++ channels in thalamic neurons (the T type Ca++ current is thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack). Pharmacological effects • Suppression of the oscillating discharge of the thalamic seizure focus. • Prevention of the spread of excitation through thalamocorticaland corticothalamiccircuits. • Other brain circuits are unaffected at therapeutic concentrations. Pharmacokinetics • Oral bioavailability: > 90 % • Biotransformation: 75% by the liver • Half-life: 45 hours

9. Ethosuximide Therapeutic uses • It is the preferred drug in absence seizures (it prevents the attacks in more than 60% of patients and diminishes their frequency in 20-30% of patients). • The earlier is the treatment, the greater the efficacy of the therapy (best results are obtained if therapy is started within 1-3 months since the beginning of attacks). • It is considered a second choice drug in myoclonic and atonic seizures.

10. Benzodiazepines All benzodiazepines have antiseizure properties but some appear more effective than others in specific seizure types , like clonazepam. Diazepam and clonazepam are the drugs most frequently used as anticonvulsants Mechanism of action • Enhancement of GABA-induced increased frequency of bursts of openings of chloride channels. Pharmacological effects • Prevention of the spread of excitation from seizure focus • All other effects of benzodiazepine class.

11. Carbonic Anhydrase Inhibitors Drugs • Acetazolamideis the drug most frequently used Mechanism of action • Inhibition of carbonic anhydrase increases the CO2content in the brain. • Decrease in tissue pH seems to inhibit Na+ entrance into the cells. • Anticonvulsant effects (which are similar to those of carbon dioxide) rapidly undergo tolerance. Toxicity • Paresthesias, drowsiness (10%) • Nephrolithiasis • Hyperchloremicmetabolic acidosis (with high doses) • Sulfonamide-type allergic reactions Therapeuticuses • As an alternative drug in all type of seizures (efficacy is low and tolerance limit the use). • The drug may have special role in epileptic women with seizure exacerbation at the time of menses.

12. Second Generation Antiseizure Drugs

13. All second generation drugs are effective when taken in addition to another anti-seizure drug (adjuvant therapy). • All drugs can be used as second choice in tonic-clonic seizures • Most drugs can be used as first-choice in simple partial seizures • Some drugs can be used as first choice in generalized seizures: • Tonic clonicseizures (lamotigrine, topiramate, levetiracetam) • Absence seizure (lamotigrine)

14. Lamotrigine La MOE tri jeen Mechanism of action • The drug likely acts with multiple mechanisms, including: • Voltage- and frequency-dependent blockade of Na+ channels (most likely the main mechanism). • Blockade of voltage-gated CA++ channels Pharmacokinetics • Oral bioavailability: 98% • Administration: oral Adverse effects • Most common(10%) and dose-related: drowsiness, dizziness, • fatigue, ataxia, diplopia. • Generalized skin rash (8%, incidence, higher in children) • Severe rash and Sevens-Johnson syndrome (up to 0.8%).

15. Topiramate toe PYRE a mate Mechanism of action • Likely multiple, including: • Blockade of voltage-gated Na+ and Ca++ channels • Potentiation of inhibitory effects of GABA at GABA-A receptors. • Blockade of AMPA glutamate receptors. • Inhibition of carbonic anhydrase. Pharmacokinetics • Oral bioavailability: .80%. • About 50% is eliminated unchanged by the kidney • Administration: oral Adverse effects • Most common (10%) and dose-related: drowsiness, dizziness, fatigue, ataxia, aphasia, nystagmus, paresthesias. • Occasional: ocular hypertension, angle-closureglaucoma, metabolicacidosis.

16. Topiramate Contraindications and precaution • Glaucoma, COPD, nephrolithiasis, porphyria. Antiseizure uses • First or second choice or adjunct drug for: • Simplex and complex partial seizures. • Tonic-clonicseizures. Other uses • Migraine prophylaxis.

17. Gabapentin ga ba pen tin Mechanism of action • Still uncertain. It may involve: • Decreased release of glutamate from presynaptic terminals (most likely due to blockade of presynaptic voltage-gated Ca++ channels) • Increased brain GABA concentration (possibly via nonvesicularrelease of GABA) Pharmacokinetics • Intestinal absorption by a L-amino acid carrier protein. • Most drug is eliminated unchanged by the kidney • Administration: oral

18. Gabapentin Adverse effects • Most common 10%) and dose-related: fatigue, drowsiness, dizziness, ataxia. • Abrupt discontinuation can cause a withdrawal reaction (anxiety, insomnia, sweating). Antiseizure uses Second choice or adjunct drugfor: • Partial seizures, tonic-clonicseizures • (Absence, myoclonic and akinetic seizures may worsen in patients treated with gabapentin) Other uses • Essential tremor. • Neuropathic pain (post-herpetic neuralgia).

19. Felbamate Mechanism of action • Likely multiple, including • Blockade of NMDA glutamate receptors • Potentiation of GABA responses Adverse effects • Most common (10%) and dose-related: drowsiness, dizziness, fatigue, headache. • Aplastic anemia (0.03%) and severe hepatitis (0.01%) (these serious adverse effects limit felbamate use) Therapeutic uses Second choice drug for: • Atonicseizures • Lennox Gastautsyndrome

20. Levetiracetam(Le- ve-teer-A-se-tam) Mechanism of action • Still uncertain. The drug binds selectively to a synaptic vescicularprotein. This can likely modify the synaptic release of glutamate and GABA. Adverse effects • Drowsiness, fatigue ,dizziness, ataxia. Therapeutic uses First or second choice or adjunct drug for: • Partial seizures, tonic clonic seizures • Myoclonicseizures.

21. Tiagabine tye AG a been Mechanism of action • Inhibition of GABA reuptake in both neurons and glia, so enhancing GABAergictransmission. Adverse effects • Most common (10%) and dose-related: nervousness, dizziness, fatigue, tremor. • Increased incidence of status epilepticus in patients with refractory partial epilepsy Therapeutic uses Adjunct or second choice drug for partial seizures. • (Absence, myoclonic and akinetic seizures may worsen in patients treated with tiagabine)

22. Zonisamide zoe NIS a mide) Mechanism of action • Likely multiple, including • Blockade of Na+ channels • Blockade of T type CA++ channels. • Enhancement of GABAergic transmission • Inhibition of glutamatergic transmission Adverse effects • Drowsiness, dizziness, headache, irritability. • Allergic reactions (the drug is a sulfonamide Therapeutic uses Second choice or adjunct or drug for: • Partial and tonic clonic seizures. • Myoclonicseizures • Lennox Gastautsyndrome • Infantile spasms

23. FDA Pregnancy Risk for Antiseizure Drugs