Anti-Epileptic Drugs
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Antiepileptic drugs are medications used to treat epilepsy by decreasing the frequency and severity of seizures, with the goal of maximizing quality of life by minimizing seizures and side effects from the medications. The most commonly used antiepileptic drugs include valproic acid, carbamazepine, lamotrigine, levetiracetam, phenytoin, and phenobarbital, with the choice depending on the seizure type, epilepsy syndrome, potential drug interactions and side effects. While drug therapy can control seizures in around 60% of epilepsy patients, about 20% have seizures that are resistant to currently available antiepileptic medications.
Anti-Epileptic Drugs
- 2. ANTI-EPILEPTIC DRUG (AED) A drug which decreases the frequency and/or severity of seizures in people with epilepsy Treats the symptom of seizures, not the underlying epileptic condition Goal: maximize quality of life by minimizing seizures and adverse drug effects Currently no “anti-epileptogenic” drugs available
- 3. Current Pharmacotherapy Just under 60% of all people with epilepsy can become seizure free with drug therapy In another 20%, the seizures can be drastically reduced In ~ 20% of epileptic patients, seizures are refractory to currently available AEDs
- 4. Choosing the right AED Seizure type Epilepsy syndrome Pharmacokinetic profile Interactions/other medical conditions Efficacy Expected adverse effects Cost
- 5. Classification of AEDs Classical Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproate (valproic acid) Trimethadione (not currently in use) Newer Lamotrigine Felbamate Topiramate Gabapentin/Preg abalin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin
- 6. General Facts About AEDs Good oral absorption and bioavailability Most metabolized in liver but some excreted unchanged in kidneys Classic AEDs generally have more severe CNS sedation than newer drugs (except ethosuximide) Because of overlapping mechanisms of action, best drug can be chosen based on minimizing side effects in addition to efficacy
- 7. Targets for AEDs Increase inhibitory neurotransmitter system— GABA Decrease excitatory neurotransmitter system —glutamate Block voltage-gated inward positive currents —Na+ or Ca++ Increase outward positive current—K+ Many AEDs pleiotropic—act via multiple mechanisms
- 8. AEDs: Mechanisms of Action Voltage-gated sodium channel Open Inactivated Na+ Na+ X I Na+ Carbamazepine Phenytoin A = activation gate I = inactivation gate McNamara JO. Goodman & Gilman’s. 9th ed. 1996:461-486. I Na+ Lamotrigine Valproate
- 9. AEDs: Mechanisms of Action Calcium channel blockade
- 11. Side effect issues Sedation - especially with barbiturates Cosmetic - phenytoin Weight gain – valproic acid, gabapentin Weight loss - topiramate Reproductive function – valproic acid Cognitive - topiramate Behavioral – felbamate, leviteracetam Allergic - many
- 12. END OF INTRO
- 14. CLINICAL USES Generalized Tonic-Clonic Seizures Partial Seizures Absence Seizures Myoclonic & Atypical Absence Syndromes Status Epilepticus Other Clinical Uses
- 15. GENERALIZE D TONICCLONIC SEIZURES PARTIAL SEIZURES ABSENCE SEIZURES MYOCLONI STATUS C& EPILEPTICUS ATYPICAL SYNDROMES Drugs of Choice Valproic Acid Carbamazepine Phenytoin Carbamazepine Lamotrigine Phenytoin Ethosuximide Valproic Valproic Acid Clonazepam Diazepam Lorazepam Alternativ e Agents Phenobarbital Felbamate Phenobarbital Topiramate Valproic Acid Clonazepam Levetiracetam Topiramate Zonisamide Phenytoin Phenobarbital Adjunctive Drugs Lamotrigine Topiramate Gabapentin Pregabalin Lamotrigine Levetiracetam Zonisamide Lamotrigine Felbamate
- 16. Other Clinical Uses Valproic acid –mania Carbamazepine, Lamotrigine –bipolar disorder Carbamazepine –trigeminal neuralgia Gabapentin –pain of neuropathic origin Topiramate –migraine Pregabalin –neuropathic pain
- 17. MAIN INDICATIONS OF ANTIEPILEPTIC DRUGS
- 19. Teratogenicity Valproic acid –neural tube defects Carbamazepine –craniofacial anomalies, spina bifida Phenytoin –fetal hydantoin syndrome
- 20. Overdosage Toxicity Respiratory depression Management: supportive Airway management Mechanical ventilation
- 21. Life-Threatening Toxicity Valproic acid –fatal hepatoxicity Lamotrigine –Stevens-Johnson syndrome Zonisamide –severe skin reactions Felbamate –aplastic anemia, acute hepatic failure
- 23. Drug Name Indication Mechanism Pharmacoki Therapeutic Drug of Action netics Levels and Interaction Dosage Carbamazepine Indicated It blocks for complex sodium partial channels at seizures, therapeutic generalized concentrations tonic-clonic and inhibits seizures, high frequency mixed repetitive firing seizure in neurons patterns or other Acts partial or presynaptically generalized to decrease seizures. synaptic Not transmission indicated for Absence seizures. Absorptionvaries widely among patients Maintenance dose range: 800-1200 mg/day PO in divided doses Interactions are related to the drug’s enzymeinducing properties Side effects/ ContraAdverse indications Reactions Common: Diplopia and ataxia (most common), gastrointestinal Peak levels: disturbances; 6-8 hours after Therapeutic Propoxyphene, sedation at high administration range: 4-12 troleandomycin, doses mg/L (16.9valproic acid – Distribution50.8 inhibit Occasional: slow micromoles/L) carbamazepine Retention of Volume clearance and water and distribution: Maximum dose increase hyponatremia; 1L/kg of 1600 steady-state rash, agitation mg/day carbamazepine in children Systemic recommended blood levels clearance(rarely, some Rare: 1L/kg/d patients have Phenytoin, Idiosyncratic required 1.6- phenobarbital – blood 70% bound to 2.4 g/day) decrease dyscrasias and plasma steady state severe rashes proteins concentration of carbamazepine Half-life – 36hrs •Hypersensitivity • Kidney disease • Cardiovascular disease • Seizure disorder, myasthenia gravis • Dehydration • hypothyroidism
- 24. Drug Name Indication Mechanis Pharmacokinet Therapeutic m of ics Levels and Action Dosage Phenytoin Control of Blocks grand mal & sodium complex channels partial seizure, Prevents prevention nerve & treatment conduction of seizure during or following neurosurger y, migraine, trigeminal neuralgia, certain psychoses, cardiac arrhythmias, digitalis intoxication, post-event treatment of MI. Absorption after oral ingestion may be slow, variable and occasionally incomplete Adult Initially 100 mg tid. Maintenance: 300-400 mg daily in equally divided doses. Childn ≥6 yr T1/2 = 20-30 hrs Initially 100 mg tid, subsequent Rapidly dosage should distributed to all be adjusted tissues according to therapeutic Metabolized response. primarily by liver Pedia Initially 5 P450 mg/kg/day in 2-3 Highly bound to equally divided plasma proteins doses. Max: 300 mg daily. Maintenance: 48 mg/kg/day. Susp Initially 125 mg/5 mL tid, subsequent dosage adjusted according to therapeutic response. Drug Interaction induces P450s in liver Side effects/ Adverse Reactions Hirsutism & coarsening of facial features Acne increases metabolism of Gingival hyperplasia many drugs (20-40%) Decreased reduces action serum of other drugs concentrations of folic acid, Generally, this thyroxine, and will increase vitamin K with action of other long-term use. “Fetal drugs hydantoin The combination of syndrome”: metabolism and includes protein binding growth retardation, means that microencephal phenytoin can y, and both increase craniofacial and decrease abnormalities drug action, even of the same drug Contraindications History of hypersensitivity to phenytoin or other hydantoins. Sinus bradycardia, SA block, 2nd& 3rd-degree AV block. Patients w/ Adams-Stokes syndrome. Lactation.
- 26. Drug Name Indicatio n Valproic Indicated for partial acid Mechanism Pharmacokinetic Therapeuti Drug of Action s c Levels Interaction and Dosage Valporic acid produces seizures, effect on generalize isolated d tonicneurones. clonic Therapeuticall seizures, y relevant myoclonic concentration seizure , . absence Valporic seizure . inhibits sustain repetitive firing induce by depolarization cortic and spinal cord neurones. Prolonged recovery of old age activated sodium Na+ channels from inactivation. Absorption- Raidly and compeletly after oral administration Peak levels: 14hours . Volume of distribution: 0.2L/kg t-1/2 =15 hours Metabolism-Hepatic metabolism 95% with less than 5% excreted unchanged. Initially 15mg/kg/d Childrens : 1530mg/kg/d Adult:start with 200mg TDS. Maximum daily dose 60mg/kg/d Valporate increases plasma level of phenobarbitone by inhibiting its metabolism. Volporic acid and cabamazepine induce each other metabolism. Concurrent administration of colonazapam and valporate is contraindicated. Side effects/ Adverse Reactions Contraindications Anorexia, nausea, vomiting, heart burn, drowsiness, atxia, and tremers – dose side effects.Alopa sia , rashes , thrombocytop henia Used during pregnancy it has produced spinabifida and other neural tube defect in the off spring.
- 27. DRUG NAME INDICATION MOA PHARMOKINE TICS THERAPEUTIC LEVELS AND DOSAGE DRUG INTERACTION SIDE EFFECTS SPECIAL PRECAUTIONS LEVETIRACETA M Used in combination with other antiseizure medications to treat myoclonic, partial onset, or tonic clonic seizures in children and adults Binds to synaptic vesicle protein SV2A which is involved in synaptic vesicle exocytosis Absolute oral bioavailability is nearly 100%. peak plasma concentration achieved in about an hour and steady state concentration achieved in 48 hours. It is not significantly bound to plasma. It exhibits linear, dose proportional,kineti cs, with low intrasubject and intersubject variability and a half life of 6-8 hrs. It does not undergo hepatic metabolism nor induce or inhibit cytochrome P450 enzymes. It is excreted through the kindneys unchanged as inactive metabolites. Recommended daily dose: Adults: 3000 mg Initiated with 1000mg daily (500 mg twice daily) and increased by 1000 mg/day every 2 weeks up to the maximum recommended dose of 3000mg/day Children: 60 mg/kg .initiated with 20 mg/kg (10mg/kg twice daily) and increased by 20mg/kg every 2 weeks until the recommended daily dose is reached. PROBENECID reduces the elimination of levetiracetam by the kidneys, potentially doubling the concentration of levetiracetam in the body • • • • • PREPARATIONS : tablets (immediate release) 250, 500,750 and 1000mg. Tablets (extended release) 500 and 750 mg. Oral solution: 100mg/ml Injection solution: 100mg/ml STORAGE: It should be stored at 25 C. Brief storage at 15-30 C is acceptable. • • Headache sleepiness Weakness Dizziness Difficulty walking Mood swings Anxiety It should not be discontinued suddenly because of increased seizure activity It has been associated with increased risk of suicidal thinking and behavior The medication will make you feel dizzy or drowsy. Do not drive a car or operate machinery. Nursing mothers: breastfeeding mothers should not consider breastfeeding while taking lebvetiracetam .
- 28. DRUG NAME INDICATION MOA PHARMOKINE TICS THERAPEUTI C LEVELS AND DOSAGE DRUG INTERACTION SIDE EFFECTS SPECIAL PRECAUTIONS LAMOTRIGIN E Adjunctive Therapy: indicate d as adjunctive therapy for the following seizure types in patients ≥ 2 years of age: partial seizures primary generalized tonicclonic seizures generalized seizures of Lennox-Gastaut syndrome Monotherapy:indi cated for conversion to monotherapy in adults ( ≥ 16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). Bipolar Disorder LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder Prolongation of Na chanel inactivation nd suppression of high frequency firing. In adddition it may directly block voltage sensitive Na cahnnels thus stabilizing the presynaptic memnbrane and preventing the release of excitatory neurotransmitters mainly glutamate and aspartae. WELL ABSORBED orally. It is metabolized completely in the liver . Half life is 24 hr. reduced to 16 hr in patients receiving phenytoin, carbazepine and valproate inhibits glucorinidation of lamotrigine and doubles the blood level. Recommended daily dose: Adults: 50 mg/daily initially, increase up to 300 mg/day. Levels increaed by valproate, decreased by carbamazepine,PB , phenytoin. Get emergency medical help if you have any of these signs of an allergic reaction: hives; fever; swollen glands; painful sores in or around your eyes or mouth; difficulty breathing; swelling of your face, lips, tongue, or throat. Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, or if you feel agitated, hostile, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself. Before taking lamotrigine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your doctor or pharmacist your medical history, especially of: kidney disease, liver disease. This drug may make you dizzy or drowsy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Limit alcoholic beverages. PREPARATIO NS: Tablets: Tablets are supplied for oral administration as 25 mg (white), 100 mg (peach), 150 mg (cream), and 200 mg (blue) tablets. STORAGE: Store lamotrigine at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom.
Editor's Notes
- #14: 3 main categories of therapeutics: Inhibition of voltage-gated Na+ channels to slow neuron firing. Enhancement of the inhibitory effects of the neurotransmitter GABA. Inhibition of calcium channels.
- #15: Diagnosis of a specific seizure type is important for prescribing the most appropriate antiseizure drug. Drug choice is usually made on the basis of established efficacy in the specific seizure state that has been diagnosed, the prior responsiveness of the patient, and the anticipated toxicity of the drug. Treatment may involve combinations of drugs, following the principle of adding known effective agents if the preceding drugs are not sufficient.
- #19: Chronic therapy with antiseizure drugs is associated with specific toxic effects
- #20: Children born of mothers taking anticonvulsant drugs have an increased risk of congenital malformations. Neural tube defects (spina bifida) are associated with the use of valproic acid. Carbamazepine has been implicated as a cause of craniofacial anomalies and spina bifida Fetal hydantoin syndrome has been described after phenytoin use by pregnant women
- #21: Most of the commonly used anticonvulsants are CNS depressants, and respiratory depression may occur with overdose Management is primarily supportive
- #22: Fatal hepatotoxicity has occurred with Valproic acid, with the greatest risk to children younger than 2 yrs and patients taking multiple anticonvulsant drugs. Lamotrigine has caused skin rashes and life-threatening Stevens-Johnson syndrome or toxic epidermal necrolysis. Children are at higher risk, esp if they are taking Valproic acid Zonisamide may also cause severe skin reactions Felbamate has been limited to use because of reports of aplastic anemia and acute hepatic failure
- #24: Tablet (immediate-release) Initial: 200 mg PO q12hr Increase qWeek by 200 mg/day divided PO q6-8hr <6 Years Initial (oral suspension): 10-20 mg/kg/day PO q6hr Initial (tablet): 10-20 mg/kg/day PO q8-12hr Maintenance: For tablets or suspension may divide frequency into 3-4 times daily not to exceed 35 mg/kg/day 6-12 Years Initial (oral suspension): 50 mg PO q6hr Initial (tablet, immediate- or extended-release): 100 mg PO q12hr; may increase qWeek by 100 mg/day Maintenance: 400-800 mg/day PO q6-8hr (immediate-release); q12hr (extended-release) Not to exceed 1000 mg/day >12 Years Initial (oral suspension): 10 mL (200 mg) PO q6hr Initial (tablet, immediate- or extended-release): 200 mg PO q12hr May increase by up to 200 mg/day qWeek; q12hr (extended-release tablet); q6-8hr (other formulations) 12-15 years: Dose not to exceed 1000 mg/day >15 years: Dose not to exceed 1200 mg/day
- #25: Injection: Control of status epilepticus of the grand mal type, prevention & treatment of seizures during or post neurosurgery/severe head injury. reduces action of other drugs Because it is so highly protein bound, it is one of the few drugs where protein binding matters The combination of metabolism and protein binding means that phenytoin can both increase and decrease drug action, even of the same drug LEVELS INCREASED BY Carbamazepine Phenobarbital Valproate Topiramate LEVELS DECREASED BY Carbamazepine Phenobarbital Valproate ACTION INCREASED BY Carbamazepine Phenobarbital Valproate Primidone ACTION DECREASED BY Carbamazepine Phenobarbital Valproate Primidone Topiramate