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Anticonvulsant Information

The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. The goal of an anticonvulsant is to suppress the rapid and excessive firing of neurons that start a seizure. Failing this, an effective anticonvulsant would prevent the spread of the seizure within the brain and offer protection against possible excitotoxic effects, that may result in brain damage. Some studies have cited that anticonvulsants themselves are linked to lowered IQ in children.[1] However these adverse effects must be balanced against the significant risk epileptiform seizures pose to children and the distinct possibility of death and devastating neurological sequela secondary to seizures. Anticonvulsants are more accurately called antiepileptic drugs (abbreviated "AEDs"), and are sometimes referred to as antiseizure drugs. While the term 'anticonvulsant' is a fair description of AEDs, the use of this term tends to lead to confusion between epilepsy and non-epileptic convulsions. Convulsive seizures non-epileptic seizures are quite common, and these types of seizures do not respond to antiepileptic drugs. In epilepsy, an area of the cortex is typically hyper-irritable. This condition can often be confirmed by completing a diagnostic EEG. Antiepileptic drugs function to help reduce this area of irritability and thus prevent epileptiform seizures.

The major molecular targets of marketed anticonvulsant drugs are voltage-gated sodium channels and components of the GABA system, including GABAA receptors, the GAT-1 GABA transporter, and GABA transaminase.[2] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[3][4] The drug class was the US's 5th-best-selling in 2007.[5]

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy. That is, they either prevent the expected development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has been shown to prevent epileptogenesis (the development of epilepsy after an injury such as a head injury) in human trials.[6]

Contents

Approval

The usual method of achieving approval for a drug is to show it is effective when compared against placebo, or that it is more effective than an existing drug. In monotherapy (where only one drug is taken) it is considered unethical by most to conduct a trial with placebo on a new drug of uncertain efficacy. This is because untreated epilepsy leaves the patient at significant risk of death. Therefore, almost all new epilepsy drugs are initially approved only as adjunctive (add-on) therapies. Patients whose epilepsy is currently uncontrolled by their medication (i.e., it is refractory to treatment) are selected to see if supplementing the medication with the new drug leads to an improvement in seizure control. Any reduction in the frequency of seizures is compared against a placebo.[6]ytoin. The lack of superiority over existing treatment, combined with lacking placebo-controlled trials, means that few modern drugs have earned FDA approval as initial monotherapy. In contrast, Europe only requires equivalence to existing treatments, and has approved many more. Despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of these new drugs as initial monotherapy.[6]

Drugs

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be and removed. (October 2010)

In the following list, the dates in parentheses are the earliest approved use of the drug.

Aldehydes

Main article: Aldehyde

Aromatic allylic alcohols

Barbiturates

Main article: Barbiturate

Barbiturates are drugs that act as central nervous system (CNS) depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. The following are classified as anticonvulsants:

Phenobarbital was the main anticonvulsant from 1912 till the development of phenytoin in 1938. Today, phenobarbital is rarely used to treat epilepsy in new patients since there are other effective drugs that are less sedating. Phenobarbital sodium injection can be used to stop acute convulsions or status epilepticus, but a benzodiazepine such as lorazepam, diazepam or midazolam is usually tried first. Other barbiturates only have an anticonvulsant effect at anaesthetic doses.

Benzodiazepines

Main article: Benzodiazepine

The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties. Benzodiazepines act as a central nervous system depressant. The relative strength of each of these properties in any given benzodiazepine varies greatly and influences the indications for which it is prescribed. Long-term use can be problematic due to the development of tolerance to the anticonvulsant effects and dependency.[7][8][9][10] Of the many drugs in this class, only a few are used to treat epilepsy:

The following benzodiazepines are used to treat status epilepticus:

Nitrazepam, temazepam, and especially nimetazepam are powerful anticonvulsant agents, however their use is rare due to an increased incidence of side effects and strong sedative and motor-impairing properties.

Bromides

Main article: Bromide

Carbamates

Main article: Carbamate

Carboxamides

Carbamazepine Main article: Carboxamide

The following are carboxamides:

Fatty acids

Main article: Fatty acid

The following are fatty-acids:

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives

Main article: Fructose

GABA analogs

Hydantoins

Main article: Hydantoin

The following are hydantoins:

Oxazolidinediones

Main article: Oxazolidinedione

The following are oxazolidinediones:

Propionates

Main article: Propionate

Pyrimidinediones

Main article: Pyrimidinedione

Pyrrolidines

Main article: Pyrrolidine

Succinimides

Main article: Succinimide

The following are succinimides:

Sulfonamides

Main article: Sulfonamide (medicine)

Triazines

Main article: Triazine

Ureas

Main article: Urea

Valproylamides (amide derivatives of valproate)

Main article: Amide

Non-medical anticonvulsants

This article focuses on anticonvulsant drugs. Non-medical "anticonvulsants" are further described in Epilepsy#Other treatment

Sometimes, ketogenic diet or vagus nerve stimulation are described as "anticonvulsant" therapies as well.

Treatment guidelines

According to guidelines by the AAN and AES,[11] mainly based on a major article review in 2004,[12] patients with newly diagnosed epilepsy who require treatment can be initiated on standard anticonvulsants such as carbamazepine, phenytoin, valproic acid/valproate semisodium, phenobarbital, or on the newer anticonvulsants gabapentin, lamotrigine, oxcarbazepine or topiramate. The choice of anticonvulsants depends on individual patient characteristics.[11] Both newer and older drugs are generally equally effective in new onset epilepsy.[11] The newer drugs tend to have fewer side effects.[11] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[11] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[11]

History

The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Potassium bromide was also noted to cause impotence in men. Authorities concluded that potassium bromide would dampen sexual excitement thought to cause the seizures. In fact, bromides were effective against epilepsy, and also caused impotence; it is now known that impotence is a side effect of bromide treatment, which is not related to its anti-epileptic effects. It also suffered from the way it affected behaviour, introducing the idea of the 'epileptic personality' which was actually a result of the medication. Phenobarbital was first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the development of animal models in epilepsy research led to the development of phenytoin by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating epileptic seizures with less sedation.[13] By the 1970s, an National Institutes of Health initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a mechanism for drawing the interest and abilities of pharmaceutical companies in the development of new anticonvulsant medications.

Marketing approval history

The following table lists anticonvulsant drugs together with the date their marketing was approved in the US, UK and France. Data for the UK and France are incomplete. In recent years, the European Medicines Agency has approved drugs throughout the European Union. Some of the drugs are no longer marketed.

Drug Brand US UK France
acetazolamide Diamox 27 July 1953[14] 1988[15]
carbamazepine Tegretol 15 July 1974[16][17] 1965[15] 1963[18]
clobazam Frisium 1979[15]
clonazepam Klonopin/Rivotril 4 June 1975[19] 1974[15]
diazepam Valium 15 November 1963[20]
divalproex sodium Depakote 10 March 1983[21]
ethosuximide Zarontin 2 November 1960[22] 1955[15] 1962[18]
ethotoin Peganone 22 April 1957[23]
felbamate Felbatol 29 July 1993[24]
fosphenytoin Cerebyx 5 August 1996[25]
gabapentin Neurontin 30 December 1993[26] May 1993[15][18] October 1994[18]
lamotrigine Lamictal 27 December 1994[27] October 1991[15][18] May 1995[18]
lacosamide Vimpat
levetiracetam Keppra 30 November 1999[28] 29 September 2000[15][29] 29 September 2000[29]
mephenytoin Mesantoin 23 October 1946[30]
metharbital Gemonil 1952[31][32]
methsuximide Celontin 8 February 1957[33]
methazolamide Neptazane 26 January 1959[34]
oxcarbazepine Trileptal 14 January 2000[35] 2000[15]
phenobarbital 1912[15] 1920[18]
phenytoin Dilantin/Epanutin 1938[18][36] 1938[15] 1941[18]
phensuximide Milontin 1953[37][38]
pregabalin Lyrica 30 December 2004[39] 6 July 2004[15][40] 6 July 2004[40]
primidone Mysoline 8 March 1954[41] 1952[15] 1953[18]
sodium valproate Epilim December 1977[18] June 1967[18]
stiripentol Diacomit 5 December 2001[42] 5 December 2001[42]
tiagabine Gabitril 30 September 1997[43] 1998[15] November 1997[18]
topiramate Topamax 24 December 1996[44] 1995[15]
trimethadione Tridione 25 January 1946[45]
valproic acid Depakene/Convulex 28 February 1978[46] 1993[15]
vigabatrin Sabril 21 August 2009[47] 1989[15]
zonisamide Zonegran 27 March 2000[48] 10 March 2005[15][49] 10 March 2005[49]

Use in pregnancy

During pregnancy, the metabolism of several anticonvulsants is affected. There may be an increase in the clearance and resultant decrease in the blood concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative.[50] Therefore, these drugs should be monitored during use in pregnancy.[50] Taking valproic acid or divalproex sodium during pregnancy should be cautioned against, as this class of medications has been linked to birth defects (teratogenic).

There is inadequate evidence to determine if newborns of women with epilepsy taking anticonvulsants have a substantially increased risk of hemorrhagic disease of the newborn.[50]

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[50] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[50]

In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain. [51] [52] [53] [54] [55]

See also

References

  1. ^ Loring, David W (1 September 2005). "Cognitive Side Effects of Antiepileptic Drugs in Children". Psychiatric Times XXII (10). http://www.psychiatrictimes.com/showArticle.jhtml?articleID=171201519.
  2. ^ Rogawski MA, Löscher W (July 2004). "The neurobiology of antiepileptic drugs". Nat. Rev. Neurosci. 5 (7): 553–64. doi:10.1038/nrn1430. PMID 15208697.
  3. ^ Rogawski MA, Bazil CW (July 2008). "New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels". Curr Neurol Neurosci Rep 8 (4): 345–52. doi:10.1007/s11910-008-0053-7. PMC 2587091. PMID 18590620. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2587091.
  4. ^ Meldrum BS, Rogawski MA (January 2007). "Molecular targets for antiepileptic drug development". Neurotherapeutics 4 (1): 18–61. doi:10.1016/j.nurt.2006.11.010. PMC 1852436. PMID 17199015. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1852436.
  5. ^ http://www.joacp.org/index.php?option=com_content&view=article&id=188&catid=1 "According to the Washington Post who quoted research from IMS Health, AEDs were the fifth best selling class of drugs in the US in 2007, with sales topping 10 billion dollars. "
  6. ^ a b c Abou-Khalil BW (2007). "Comparative Monotherapy Trials and the Clinical Treatment of Epilepsy". Epilepsy currents / American Epilepsy Society 7 (5): 127–9. doi:10.1111/j.1535-7511.2007.00198.x. PMC 2043140. PMID 17998971. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2043140.
  7. ^ Browne TR (May 1976). "Clonazepam. A review of a new anticonvulsant drug". Arch Neurol 33 (5): 326–32. doi:10.1001/archneur.1976.00500050012003. PMID 817697.
  8. ^ Isojärvi, JI; Tokola RA (December 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". J Intellect Disabil Res 42 (1): 80–92. PMID 10030438.
  9. ^ Tomson T; Svanborg E, Wedlund JE (May-Jun 1986). "Nonconvulsive status epilepticus". Epilepsia 27 (3): 276–85. doi:10.1111/j.1528-1157.1986.tb03540.x. PMID 3698940.
  10. ^ Djurić, M; Marjanović B, Zamurović D (May-Jun 2001). "[West syndrome--new therapeutic approach]". Srp Arh Celok Lek 129 (1): 72–7. PMID 15637997.
  11. ^ a b c d e f AAN Guideline Summary for CLINICIANS EFFICACY AND TOLERABILITY OF THE NEW ANTIEPILEPTIC DRUGS, I: TREATMENT OF NEW ONSET EPILEPSY Retrieved on June 29, 2010
  12. ^ French JA, Kanner AM, Bautista J, et al. (May 2004). "Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society". Epilepsia 45 (5): 401–9. doi:10.1111/j.0013-9580.2004.06204.x. PMID 15101821.
  13. ^ Eadie MJ, Bladin PF (2001). A Disease Once Sacred: a History of the Medical Understanding of Epilepsy.
  14. ^ NDA 008943
  15. ^ a b c d e f g h i j k l m n o p q r Epilepsy Action: Druglist. Retrieved on 1 November 2007.
  16. ^ NDA 016608 (Initial approval on 11 March 1968 was for trigeminal neuralgia.)
  17. ^ Schain, Richard J. (1 March 1978). "Pediatrics—Epitomes of Progress: Carbamazepine (Tegretol®) in the Treatment of Epilepsy". Western Journal of Medicine 128 (3): 231–232. PMC 1238063. PMID 18748164. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1238063.
  18. ^ a b c d e f g h i j k l m Loiseau, Pierre Jean-Marie (June 1999). "Clinical Experience with New Antiepileptic Drugs: Antiepileptic Drugs in Europe" (PDF). Epilepsia 40 (Suppl 6): S3–8. doi:10.1111/j.1528-1157.1999.tb00925.x. PMID 10530675. http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1528-1157.1999.tb00925.x. Retrieved 26 March 2007.
  19. ^ NDA 017533
  20. ^ NDA 013263
  21. ^ NDA 018723
  22. ^ NDA 012380
  23. ^ NDA 010841
  24. ^ NDA 020189
  25. ^ NDA 020450
  26. ^ NDA 020235
  27. ^ NDA 020241
  28. ^ NDA 021035
  29. ^ a b EPAR: Keppra. Retrieved on 1 November 2007.
  30. ^ NDA 006008
  31. ^ NDA 008322
  32. ^ Dodson, W. Edwin; Giuliano Avanzini; Shorvon, Simon D.; Fish, David R.; Emilio Perucca (2004). The treatment of epilepsy. Oxford: Blackwell Science. xxviii. ISBN 0-632-06046-8.
  33. ^ NDA 010596
  34. ^ NDA 011721
  35. ^ NDA 021014
  36. ^ NDA 008762 (Marketed in 1938, approved 1953)
  37. ^ NDA 008855
  38. ^ Kutt, Henn; Resor, Stanley R. (1992). The Medical treatment of epilepsy. New York: Dekker. pp. 385. ISBN 0-8247-8549-5. (first usage)
  39. ^ NDA 021446
  40. ^ a b EPAR: Lyrica Retrieved on 1 November 2007.
  41. ^ NDA 009170
  42. ^ a b EPAR: Diacomit. Orphan designation: 5 December 2001, full authorisation: 4 January 2007 Retrieved on 1 November 2007.
  43. ^ NDA 020646
  44. ^ NDA 020505
  45. ^ NDA 005856
  46. ^ NDA 018081
  47. ^ Lundbeck Press Release
  48. ^ NDA 020789
  49. ^ a b EPAR: Zonegran. Retrieved on 1 November 2007
  50. ^ a b c d e Harden CL, Pennell PB, Koppel BS, et al. (May 2009). "Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society". Epilepsia 50 (5): 1247–55. PMID 19507305.
  51. ^ Bittigau P, Sifringer M, Genz K,et al. (May 2002). "Antiepileptic drugs and apoptotic neurodegenereation in the developing brain". Proc Natl Acad SCI USA 99 (23): 15089–94. doi:10.1073/pnas.222550499. PMC 137548. PMID 12417760. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC137548.
  52. ^ Manthey D, Asimiadou S, et al. (Jun 2005). "Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain.". Exp Neurol 193 (2): 497-503. doi:10.1016/j.expneurol.2005.01.006. PMID 15869952.
  53. ^ Katz I, Kim J, et al. (Aug 2007). "Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain.". J Pharmacol Exp Ther 322 (2): 494-500. doi:10.1124/jpet.107.123133. PMID 17483293.
  54. ^ Kim J, Kondratyev A, and Gale K (Oct 2007). "Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy.". J Pharmacol Exp Ther 323 (1): 165-73. doi:10.1124/jpet.107.126250. PMC 2789311. PMID 17636003. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2789311.
  55. ^ Forcelli PA, Kim J "et al." (Dec 2011). "Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain". Epilepsia 52 (12): e207-11. doi:10.1111/j.1528-1167.2011.03297.x. PMID 22050285.

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Anticonvulsants (N03)
GABAA receptor agonist
Barbiturates
Benzodiazepines
Other GABA agents
Aromatic allylic alcohols
Carbonic anhydrase inhibitor
Sulfa drugs
Channel blockers
Primarily sodium
Hydantoins
Carboxamides
Primarily calcium
Succinimides
AMPA receptor
Unknown/ungrouped
Channel openers
Potassium
Indirect GABA agents
Carboxylic acids/ Fatty acid derivatives GABA reuptake inhibitor: Tiagabine
GABA analogs
Unknown/multiple/ unsorted
Carbamates
Pyrrolidines
Propionates
Aldehydes
Bromides

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