section name header

Info


A. Considerations in Choice of Agent navigator

  1. Drug Abbreviations
    1. cbz = carbamazepine
    2. clon = clonazepam, clonazepate
    3. esm = ethosuximide
    4. fel = felbamate
    5. fpht = fosphenytoin
    6. gab = gabapentin
    7. lam = lamotrigine
    8. lev = levatiracetam
    9. oxc = oxcarbazepine
    10. phb = phenobarbital
    11. pht = phenytoin
    12. pre = pregabalin
    13. prim = primidone
    14. tiag = tiagabine
    15. top = topiramate
    16. vpa = valproate
    17. vig = vigabatrin
    18. zon = zonisamide
  2. Use of single agent recommended whenever possible (~65% of patients)
    1. Preferences depend on type of seizure and specific patient issues, side effects
    2. Surgical evaluation may be considered if drug combinations fail
    3. Special attention to drug interactions in elderly patients
    4. Newer agents (gab, lam, tiag, top, vig, zon) showed no detectable differences in efficacy in partial epilepsy, but lam had superior time to treatment failure including to cbz [3]
  3. Broad Spectrum Anti-Epileptics
    1. Generally good choices for treatment of adults
    2. Vpa, lam, top, lev, zon
  4. Narrow Spectrum Drugs
    1. Restricted to focal epilepsy with partial and secondarily generalized seizures
    2. Cbz, oxc, pht, gab, tiag, pre
  5. Choice of Agent in Elderly
    1. Gab is probably best tolerated of all, and may be first line choice in elderly
    2. Gab or lam are better tolerated than carbamazepine in new-onset geriatric epilepsy [28]
    3. Oxc should be substituted for cbz whenever possible
    4. Gab, vig and lam are reasonable add-on choices
    5. These three agents may be used first line in partial or secondarily generilized epilepsy
    6. Phb, prim, and clobazam are best avoided
  6. Treating Symptomatic Partial Epilepsy [1,5]
    1. Traditional: cbz, prim, phb, pht, vpa
    2. Newer Agents: lam > tiag, top, gab, oxc, zon
    3. Lam likely most effective overall, with cbz second [3]
  7. Treating Idiopathic Generalized Epilepsy [5]
    1. Absence seizures (onset in childhood): esm > vpa = lam
    2. Absence seizures (onset in adulthood): vpa > esm = lam
    3. Newer Agents: lam, top, zon
    4. Vpa is superior to lam on efficacy, and better tolerated than top; overall first choice in adults with generalized and unclassifiable epilepsy [6]
  8. Hepatic Enzyme Inducing Anticonvulsants [1]
    1. Include pht, cbz, oxc, phb, top
    2. Increase clearance of certain drugs including oral contraceptive pills (OCP)
    3. If OCPs are to be used with these agents, at least 50µg ethinyl estradiol should be used
  9. Resistance to multiple anticonvulsants may be associated with high expression of the drug efflux pump ABCB1 [4]

B. Acute Therapy for Generalized Seizures navigator

  1. Phenytoin (dilantin) 1gm load IV (hypotension common side effect)
  2. Phenobarbital 30-60mg iv repeated every 5-10 minutes
  3. Benzodiazapines: mainly for alcohol-related seizures (see below)
    1. Pentobarbital: status epilepticus; induce coma

C. Benzodiazepines (bzd) navigator

  1. Benzodiazepines bind to alpha subunit of GABA-R, augment endogenous GABA actions
  2. Especially useful for alcoholic and alcohol withdrawal seizures
  3. Diazapam (Valium®): grand mal (tonic-clonic), alcoholic related seizures; 5mg IV/IM
  4. Lorazepam (Ativan®): shorter t1/2 than diazapam; easier to use for alcohol withdrawal
  5. Lorazepam 2mg IV after acute alcohol related seizure reduces second seizures 90%
  6. Diazepam (Valium®) may be slightly less effective than lorazepam (Ativan®) for out of hospital status epilepticus; both are safe [8,9]
  7. Clonazepam (Klonopin®): myoclonic seizures, also useful for anxiety
  8. Midazolam: effective for halting seizures, may be given in buccal cavity as liquid [10]
  9. Buccal (liquid) midazolam as effective as rectal diazapam in stopping seizures [10]

D. Phenytoinsnavigator

  1. Phenytoin (pht; Dilantin®)
    1. Use: Partial Epilepsy, Generalized Tonic-Clonic seizures
    2. Side Effects: cognitive changes, gum hyperplasia, hirsutism, nystagmus, ataxia
    3. Hypotension often occurs with intravenous loading (usually 50mg per minute to 1gm)
    4. Overdose: ataxia, nystagmus (especially vertical), induction of seizures, lethargy
    5. Note that phenytoin overdose usually occurs when patients on drug are given IV loading
    6. Blood level monitoring required for optimal dosing
  2. Fosphenytoin (fphyt; Cerebyx®)
    1. Metabolite of phenytoin which allows IV or IM loading
    2. Rapid IV loading is not associated with significant hypotension
    3. Blood level monitoring required for optimal dosing

E. Carbamazepinesnavigator

  1. Carbamazapine (cbz; Tegretol®)
    1. Use: Complex-partial seizures, Generalized Seizures, Second Line Myoclonic Seizures
    2. Effects likely due to blockade of voltage-sensitive sodium channels
    3. Now recommended second line for partial epilespy in adults, after lam [3]
    4. Side Effects: drowsiness, diplopia, GI upset, low WBC (5-10%), rash, allergy
    5. Severe Side Effects: Agranulocytosis, platelet decrease, aplastic anemia (1/20,000)
    6. WBC and Platelets should be monitored each week initially, then each month
    7. Metabolized by CYP3A4 and can reduce effectiveness of oral contraceptives
    8. Drug Interactions: warfarin, estrogens, theophylline, alcohol, naproxen
    9. Blood level monitoring required for optimal dosing
    10. Risk of Stevens-Johnson Syndrome (SJS) >3/10,000 in white populations
    11. Risk of SJS >30/10,000 new users in Asian populations, particularly Chinese
    12. Association of SJS and carbamazepine in Asians found with HLA-B*1502 and genetic testing for this allele is recommended for all Asian patients before initiation carbamazepine [7]
  2. Oxcarbazepine (oxc; Trileptal®) [11]
    1. Analog of cbz, pro-drug requires liver metabolism
    2. FDA approved for oral use in partial seizures
    3. May be used as monotherapy or adjunctive therapy in adults; adjunctive in children
    4. Effects likely due to blockade of voltage-sensitive sodium channels
    5. Monotherapy as effective as carbamazepine, valproate, or phenytoin in adults
    6. Side effects include somnolence, dizziness, nausea, vomiting, rash; less than cbz
    7. Hematologic and hepatic toxicity has NOT been reported
    8. Cross-reactivity of oxc in patients with hypersensitivity to cbz is 20-30%
    9. Can inhibit CYP 2C19, CYP3A4/5; not affected by CYP3A4 inhibitors
    10. Starting dose 300mg bid; increase to maximum 1200-2400mg po divided
    11. Can convert from cbz to 1.5 fold increased dose of oxcarbazepine immediately

F. Valproates navigator

  1. Valproic Acid / Valproate (vpa; Depokene®, Depokote®)
  2. Divalproex is now the preferred agent
  3. Use: All seizure types; first line for generalized and unclassifiable epilepsy in adults [6]
  4. Side Effects: gastrointestinal upset, weight and apetite increase, fatigue, tremor, hair loss (5-10%; reversible)
  5. Severe: hepatotoxic reactions (usually on other drugs); monitor liver function tests
  6. May also cause hyperandrogenism, polycystic ovaries, and oligomenorrhea
  7. Also used for mania in patients with manic-depressive disorder
  8. Useful for migraine prophylaxis
  9. Blood level monitoring required for optimal dosing

G. Ethosuximide (esm; Zarontin®)navigator

  1. Use: petit mal only (without other seizure types)
  2. Side Effects: blood dyscrasias, ataxia, dizziness, hepatitis (monitor CBC, liver function)
  3. Dose: 500mg po qd initially, increase by 250mg q4-7 days to maximum 1.5gm/d
  4. Increases valproate, phenobarbital, phenytoin levels
  5. Blood level monitoring required for optimal dosing

H. Gabapentin and Pregabalinnavigator

  1. Gabapentin (gaba; Neurontin®) [12,13]
    1. Efficacy for partial and secondary generalized seizures, alone or as add on agent
    2. Reduces incidence in secondary generalized seizures
    3. Well tolerated relative to other agents; consider first line in elderly [28]
    4. Inhibits sodium channels and affects amino acid transport in CNS
    5. Drug interactions: does not alter plasma concentrations of other agents
    6. Good for chronic pain, including postherpetic neuralgia, some neuropathic pain [14]
    7. Safer than other agents; long term effects are generally insignificant
    8. Side Effects: mild in general; somnolence, dizziness, ataxia, fatigue, nystagmus, nausea
  2. Pregabalin (pre; Lyrica®) [27]
    1. Structural analog of GABA and gabapentin; alters calcium channel function
    2. Approved for postherpetic neuralgia and diabetic peripheral neuropathic pain
    3. Also approved for epilepsy
    4. Initial dose is 150mg per day divided 2-3 times (bid or tid)
    5. May increase to maximum of 300mg per day for neuropathic pain, 600mg/d for epilepsy
    6. Adverse effects are dose related: dizziness, somnolence, blurred vision, weight gain, peripheral edema
    7. Associated with euphoria and Schedule V controlled substance by FDA

I. Lamotrigine (lamo; Lamictal®) [12,15] navigator

  1. Approved in USA for use in partial seizures in adults
  2. Blocks voltage dependent sodium channels
  3. Metabolism by glucuronidation, does not induce P450 enzymes, few drug interactions
  4. Valproate inhitibs metabolism of lamo, and lamo decreases valproate levels
  5. Generally very well tolerated when added to other drugs or used alone
  6. Reasonable first line in geriatric patients with new onset epilepsy [28]
  7. Overall clinically more effective than cbz, gab, topiramate for partial epilepsy [3]
  8. Not as effective as cbz for complex generlized seizures [6]
  9. Most patients begin at 50mg po qd x 2 weeks, increase slowly to 300-500mg/day
  10. Elderly may be started at 25mg po qd x 2 weeks, the bid, with slow increases [16]
  11. Effective and well tolerated in children with the Lennox-Gastaut Syndrome [17]

J. Topiramate (top; Topamax®) [12,18] navigator

  1. Blocks sodium channels, attenuates kainite responses, enhances GABA effects
  2. Approved for adjunctive therapy in adults with partial seizures
  3. Side effects include mental slowing, fatigue, somnolence; generally well tolerated
  4. Renal stones occurred in 1.5% of patients taking this agent
  5. Like nearly all other anti-seizure agents, showed teratogenic effects in animals
  6. May increase serum phenytoin levels up to 25%; other agents decrease topiramate levels
  7. May have utility for prevention of relapse in alcoholics [19]
  8. Dose is 200-400mg po qd as adjunctive therapy

K. Tiagabine (tiag; Gabitril®) [20] navigator

  1. Low concentrations of brain GABA have been associated with poor seizure control
  2. This agent inhibits neuronal and glial uptake of GABA
  3. Approved in USA as add-on therapy in refractory partial seizures in adults
  4. Starting dose is 4mg/day, increased weekly to 4-8mg/day
  5. Dose is 32-56mg / day, taken with food (maximum dose ~60mg/d)
  6. Main side effects are dizziness, headache, somnolence
  7. Pht, cbz and phb increase metabolism and decrease half-life of tiagabine

L. Levetiracetam (Keppra®) [11,21]navigator

  1. FDA approved for adjunctive therapy for partial seizures in adults
  2. Unclear mechanism of action
  3. Effective in refractory partial seizures (50% seizure reduction in ~35% of patients)
  4. Side effects very mild: somnolence, asthenia, psychiatric symptoms
  5. Cognitive symptoms (difficulty in speech, concentration) have not been reported
  6. No significant drug interactions, and does not require dose titration
  7. Dose is 500mg po bid, up to a total dose of 1500mg po bid
  8. Reduce dose in renal insufficiency and in elderly (250mg tablets available)

M. Zonisamide (Zonegran®) [22]navigator

  1. FDA approved for adjunctive therapy for partial seizures in adults
  2. Blocks sodium and calcium channels; blocks carbonic anhydrase weakly
  3. Dose 100mg qd initially, up to 600mg (increase q2 weeks) given as once or twice
  4. Dizziness, ataxia, weight loss, somnolence reported
  5. Nephrolithiasis reported in 4%, likely due to carbonic anhydrase inhibition
  6. Also being evaluated as a weight loss agent [23]

N. Phenobarbital (phb) navigator

  1. Classic barbiturate with good antiseizure activity below hypnotic doses
  2. Pharmacology
    1. Barbiturates bind to ß-subunit of GABA(A)-recetpro
    2. This leads to potentiation of endogenous GABA actions
    3. GABA stimulates chloride entry into neurons and is inhibitory
    4. Inhibitory neuronal activity can lead to cessation of seizures
  3. Effective in tonic-clonic and partial seizures
  4. Side Effects
    1. Sleepiness, sedation, depression, personality changes, behavioral disturbances
    2. Sedation is reduced with chronic dosing
    3. Scarlatiniform or morbiliform rash (possibly with other allergic symptoms) in 1-2%
    4. Encephalopathy and hyperammonemia can also occur in adults

O. Primidone (prim; Mysoline®)navigator

  1. Chemically highly related to phb (deoxybartiburate)
  2. Effective in partial and tonic-clonic seizures; ineffective in absence seizures
  3. Side Effects: Sleepiness, secation, dizziness, ataxia, diplopia, nystagmus
  4. Serious rash or leukopenia, thrombocytopenia, systeim lupus very uncommon
  5. Depression and personality changes have been reported
  6. Generally second, third or fourth line therapy

P. Phenyl Dicarbamates [24]navigator

  1. Meprobamate (Equanil®)
  2. Felbamate (Felbatol®): oral only; approved for partial seizures ± generalization
  3. Blocks sodium channels and some NMDA receptors, enhances g-aminobutyric acid (GABA)
  4. Felbamate has shown efficacy in highly refractory patients
  5. Less behavior and other side effects than earlier agents
  6. Side Effects: mild to moderate, HA, insomnia, fatigue, anorexia, nausea, and/or vomiting
  7. Serious side effects include aplastic anemia and drug-induced hepatitis
  8. Aplastic anemia risk with felbamate requires close monitoring

Q. Vigabatrin [25]navigator

  1. Structural analog of GABA
  2. Enzyme-activated irreversible inhibitor of GABA transaminase
  3. Increases GABA levels in CNS
  4. Used in combination with other drugs reduces seizure frequency and severity
  5. Carbamazepine is superior to, but had more side effects than, vigabatrin [25]
  6. Minimal mental effects, mild increased depression, 30% decrease in phenytoin levels
  7. Weight gain ~10% and psychiatric symptoms do occur
  8. Dose 500-3000mg po bid
  9. Approved in Canada, not in USA

R. Combination Therapy for Refractory Seizures [2]navigator

  1. Valproate and lamogrigine
  2. Valproate and carbamazepine
  3. Carbamazepine and vigabatrin
  4. Lamogrigine and topiramate

S. Drug Treatment During Pregnancy [1]navigator

  1. Seizures are generally well controlled during pregnancy
  2. Teratogenecity of Anticonvulsants [26]
    1. Overall risk of birth defects ~3X increased in women taking anticonvulsants
    2. Epilepsy itself confers no increased risk of birth defects
    3. Increase in serious fetal malformations (~3% versus 2% for average pregnancy) [1]
  3. Phenytoin levels may fall during pregnancy
  4. Women on valproate or carbamazepine should take folic acid 5mg po qd during pregnancy
  5. Slight increase in risk of Vitamin K depletion on cbz, pht, phb, and prim
  6. Recommend 20mg vitamin K during last few weeks of pregnancy if on these medications

T. Summary Of Uses Of Anti-Convulsive Agents [2]navigator
DrugGeneralizedAbsenceMyoclonicPartial
Carbamazapine (Tegretol®)++--+
Clonazepate-++++
Clonazapam (Klonopin®)++++
Diazapam (Valium®)+-++
Ethosuximide-++--
Felbamate (Felbatol®)+++-+
Gabapentin (Neurontin®)+--+
Lamotrigine (Lamictal®)+++++
Oxcarbazepine (Trileptal®)++--+
Phenobarbital++-++
Phenytoin (Dilantin®)++---
Primidone+-?+
Topiramate (Topamax®)+?++
Tiagabine (Gabitril®)+??+
Valproate (Depokote®)++++++++
Zonisamide+?++

References navigator

  1. French JA and Pedley TA. 2008. NEJM. 359(2):166 abstract
  2. Browne TR and Holmes GL. 2001. NEJM. 344(15):1145 abstract
  3. Marson AG, Al-Kharusi AM, Alwaidh M, et al. 2007. Lancet. 369(9566):1000 abstract
  4. Siddiqui A, Kerb R, Weale ME, et al. 2003. NEJM. 348(15):1442 abstract
  5. LaRoche SM and Helmers SL. 2004. JAMA. 291(5):615 abstract
  6. Marson AG, Al-Kharusi AM, Alwaidh M, et al. 2007. Lancet. 369(9566):1016 abstract
  7. Genetic Testing for Carbamazepine Induced Stevens-Johnson Syndrome. 2008. Med Let. 50(1284):32
  8. Alldredge BK, Gelb AM, Isaacs SM, et al. 2001. NEJM. 345(9):631 abstract
  9. Treiman DM, Meyers PD, Walton NY, et al. 1998. NEJM. 339(12):792 abstract
  10. Scott RC, Besag FMC, Neville BGR. 1999. Lancet. 353(9153):623 abstract
  11. Oxcarbazepine and Levetiractetam. 2000. Med Let. 42(1076):33 abstract
  12. Dichter MA and Brodie MJ. 1996. NEJM. 334(23):1583
  13. Gabapentin. 1994. Med Let. 36(921):39 abstract
  14. Gabapentin for Chronic Pain. 2004. Med Let. 46(1180):29 abstract
  15. Lamotrigine. 1995. Med Let. 37(944):21 abstract
  16. Stephen LJ and Brodie MJ. 2000. Lancet. 355(9213):1441 abstract
  17. Motte J, Trevathan E, Arvidsson JFV, et al. 1997. NEJM. 337(25):1807 abstract
  18. Topiramate. 1997. Med Let. 39(1001):51 abstract
  19. Johnson BA, Alt-Daoud N, Bowden CL, et al. 2003. Lancet. 361(9370):1677 abstract
  20. Tiagabine. 1998. Med Let. 40(1024):45 abstract
  21. Shorvon S. 2001. Lancet. 358(9296):1885 abstract
  22. Zonisamide. 2000. Med Let. 42(1089):94 abstract
  23. Gadde KM, Franciscy DM, Wagner HR II, Krishnan KRR. 2003. JAMA. 289(14):1820 abstract
  24. Felbamate. 1993. Med Let. 35(910):107 abstract
  25. Chadwick D. 1999. Lancet. 354(9172):13 abstract
  26. Holmes LB, Harvey EA, Coull BA, et al. 2001. NEJM. 344(15):1132 abstract
  27. Pregabalin. 2005. Med Let. 47(1217):75 abstract
  28. Rowan AJ, Ramsay RE, Collins JF, et al. 2005. Neurology. 64:1868 abstract