Anticonvulsant

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Anticonvulsants (also commonly known as antiepileptic drugs or as antiseizure drugs) 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. Anticonvulsants suppress the rapid and excessive firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain. Some investigators have observed that anticonvulsants themselves may cause reduced IQ in children.[1] However these adverse effects must be balanced against the significant risk epileptic 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 often referred to as antiseizure drugs because they provide symptomatic treatment only and have not been demonstrated to alter the course of epilepsy.

Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid (GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action.[2] Next to the voltage-gated sodium channels and components of the GABA system, their targets include GABAA receptors, the GAT-1 GABA transporter, and GABA transaminase.[3] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[4][5] By blocking sodium or calcium channels, antiepileptic drugs reduce the release of excitatory glutamate, whose release is considered to be elevated in epilepsy, but also that of GABA.[6] This is probably a side effect or even the actual mechanism of action for some antiepileptic drugs, since GABA can itself, directly or indirectly, act proconvulsively.[6] The drug class was the US's 5th-best-selling in 2007.[7]

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.[8] That is, they either prevent the development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has been shown in human trials to prevent epileptogenesis (the development of epilepsy in an individual at risk, such as after a head injury).[9]

Approval[edit]

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.[9] 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.[9]

Drugs[edit]

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

Aldehydes[edit]

Main article: Aldehyde
  • Paraldehyde (1882). One of the earliest anticonvulsants. It is still used to treat status epilepticus, particularly where there are no resuscitation facilities.

Aromatic allylic alcohols[edit]

Barbiturates[edit]

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[edit]

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.[12][13][14][15] Of the many drugs in this class, only a few are used to treat epilepsy:

The following benzodiazepines are used to treat status epilepticus:

  • Diazepam (1963). Can be given rectally by trained care-givers.
  • Midazolam (N/A). Increasingly being used as an alternative to diazepam. This water-soluble drug is squirted into the side of the mouth but not swallowed. It is rapidly absorbed by the buccal mucosa.
  • Lorazepam (1972). Given by injection in hospital.

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[edit]

Main article: Bromide
  • Potassium bromide (1857). The earliest effective treatment for epilepsy. There would not be a better drug until phenobarbital in 1912. It is still used as an anticonvulsant for dogs and cats.

Carbamates[edit]

Main article: Carbamate
  • Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.[16][17][18]

Carboxamides[edit]

Carbamazepine
Main article: Carboxamide

The following are carboxamides:

  • Carbamazepine (1963). A popular anticonvulsant that is available in generic formulations.
  • Oxcarbazepine (1990). A derivative of carbamazepine that has similar efficacy but is better tolerated and is also available generically.
  • Eslicarbazepine acetate (2009)

Fatty acids[edit]

Main article: Fatty acid

The following are fatty-acids:

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives[edit]

Main article: Fructose

GABA analogs[edit]

Hydantoins[edit]

Main article: Hydantoin

The following are hydantoins:

Oxazolidinediones[edit]

Main article: Oxazolidinedione

The following are oxazolidinediones:

Propionates[edit]

Main article: Propionate

Pyrimidinediones[edit]

Main article: Pyrimidinedione

Pyrrolidines[edit]

Main article: Pyrrolidine

Succinimides[edit]

Main article: Succinimide

The following are succinimides:

Sulfonamides[edit]

Triazines[edit]

Main article: Triazine

Ureas[edit]

Main article: Urea

Valproylamides (amide derivatives of valproate)[edit]

Main article: Amide

Other[edit]

Non-medical anticonvulsants[edit]

This article is about anticonvulsant drugs. For non-medical "anticonvulsants", see Epilepsy#Other treatment.

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

Treatment guidelines[edit]

According to guidelines by the AAN and AES,[19] mainly based on a major article review in 2004,[20] 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.[19] Both newer and older drugs are generally equally effective in new onset epilepsy.[19] The newer drugs tend to have fewer side effects.[19] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[19] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[19]

History[edit]

The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Bromides are effective against epilepsy, and also cause impotence, which is not related to its anti-epileptic effects. Bromide also suffered from the way it affected behaviour, introducing the idea of the 'epileptic personality' which was actually a result of 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.[21] By the 1970s, a 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[edit]

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 1953-07-2727 July 1953[22] 1988[23]
carbamazepine Tegretol 1974-07-1515 July 1974[24][25] 1965[23] 1963[26]
clobazam Frisium 1979[23]
clonazepam Klonopin/Rivotril 1975-06-044 June 1975[27] 1974[23]
diazepam Valium 1963-11-1515 November 1963[28]
divalproex sodium Depakote 1983-03-1010 March 1983[29]
eslicarbazepine Data needed
ethosuximide Zarontin 1960-11-022 November 1960[30] 1955[23] 1962[26]
ethotoin Peganone 1957-04-2222 April 1957[31]
felbamate Felbatol 1993-07-2929 July 1993[32]
fosphenytoin Cerebyx 1996-08-055 August 1996[33]
gabapentin Neurontin 1993-12-3030 December 1993[34] 1993-05May 1993[23][26] 1994-10October 1994[26]
lamotrigine Lamictal 1994-12-2727 December 1994[35] 1991-10October 1991[23][26] 1995-05May 1995[26]
lacosamide Vimpat 2008-10-2828 October 2008[36]
levetiracetam Keppra 1999-11-3030 November 1999[37] 2000-09-2929 September 2000[23][38] 2000-09-2929 September 2000[38]
mephenytoin Mesantoin 1946-10-2323 October 1946[39]
metharbital Gemonil 1952[40][41]
methsuximide Celontin 1957-02-088 February 1957[42]
methazolamide Neptazane 1959-01-2626 January 1959[43]
oxcarbazepine Trileptal 2000-01-1414 January 2000[44] 2000[23]
phenobarbital 1912[23] 1920[26]
phenytoin Dilantin/Epanutin 1938[26][45] 1938[23] 1941[26]
phensuximide Milontin 1953[46][47]
pregabalin Lyrica 2004-12-3030 December 2004[48] 2004-07-066 July 2004[23][49] 2004-07-066 July 2004[49]
primidone Mysoline 1954-03-088 March 1954[50] 1952[23] 1953[26]
sodium valproate Epilim 1977-12December 1977[26] 1967-06June 1967[26]
stiripentol Diacomit 2001-12-055 December 2001[51] 2001-12-055 December 2001[51]
tiagabine Gabitril 1997-09-3030 September 1997[52][53] 1998[23] 1997-11November 1997[26]
topiramate Topamax 1996-12-2424 December 1996[54] 1995[23]
trimethadione Tridione 1946-01-2525 January 1946[55]
valproic acid Depakene/Convulex 1978-02-2828 February 1978[56] 1993[23]
vigabatrin Sabril 2009-08-2121 August 2009[57] 1989[23]
zonisamide Zonegran 2000-03-2727 March 2000[58] 2005-03-1010 March 2005[23][59] 2005-03-1010 March 2005[59]

Use in pregnancy[edit]

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.[60] Therefore, these drugs should be monitored during use in pregnancy.[60] 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.[60]

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[60] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[60]

In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.[61][62][63][64][65]

See also[edit]

References[edit]

  1. ^ Loring, David W (1 September 2005). "Cognitive Side Effects of Antiepileptic Drugs in Children". Psychiatric Times XXII (10). 
  2. ^ https://www.neurology.wisc.edu/publications/2010%20pubs/stafstrom-4.pdf
  3. ^ Rogawski MA, Löscher W (July 2004). "The neurobiology of antiepileptic drugs". Nature Reviews Neuroscience 5 (7): 553–64. doi:10.1038/nrn1430. PMID 15208697. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ a b Kammerer, M.; Rassner, M. P.; Freiman, T. M.; Feuerstein, T. J. (2 May 2011). "Effects of antiepileptic drugs on GABA release from rat and human neocortical synaptosomes". Naunyn-Schmiedeberg's Archives of Pharmacology 384 (1): 47–57. doi:10.1007/s00210-011-0636-8. 
  7. ^ 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. "
  8. ^ Kaminski, R. M.; Rogawski, M. A.; Klitgaard, H (2014). "The potential of antiseizure drugs and agents that act on novel molecular targets as antiepileptogenic treatments". Neurotherapeutics 11 (2): 385–400. doi:10.1007/s13311-014-0266-1. PMC 3996125. PMID 24671870.  edit
  9. ^ 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. 
  10. ^ Plosker, GL (November 2012). "Stiripentol : in severe myoclonic epilepsy of infancy (dravet syndrome)". CNS Drugs 26 (11): 993–1001. doi:10.1007/s40263-012-0004-3. PMID 23018548. 
  11. ^ "Public summary of positive opinion for orpphan opinion for orphan designation of stiripentol for the treatment of severe myoclonic epilepsy in infancy". European Medicines Agency. 30 July 2007. Retrieved 19 May 2013. "Doc.Ref.: EMEA/COMP/269/04" 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ Djurić, M; Marjanović B; Zamurović D (May–Jun 2001). "[West syndrome--new therapeutic approach]". Srp Arh Celok Lek 129 (1): 72–7. PMID 15637997. 
  16. ^ Sankar, editors John M. Pellock, Blaise F.D. Bourgeois, W. Edwin Dodson ; associate editors, Douglas R. Nordli, Jr., Raman (2008). Pediatric epilepsy : diagnosis and therapy (3rd ed., updated and new. ed.). New York: Demos Medical Pub. ISBN 1-933864-16-8. 
  17. ^ French, J; Smith, M; Faught, E; Brown, L (12 May 1999). "Practice advisory: The use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society". Neurology 52 (8): 1540–5. doi:10.1212/WNL.52.8.1540. PMID 10331676. 
  18. ^ "Felbamate". MedlinePlus : U.S. National Library of Medicine. Retrieved 19 May 2013. 
  19. ^ 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 29 June 2010
  20. ^ 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. 
  21. ^ Eadie MJ, Bladin PF (2001). A Disease Once Sacred: a History of the Medical Understanding of Epilepsy. 
  22. ^ NDA 008943
  23. ^ 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.
  24. ^ NDA 016608 (Initial approval on 11 March 1968 was for trigeminal neuralgia.)
  25. ^ 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. 
  26. ^ 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. Retrieved 26 March 2007. 
  27. ^ NDA 017533
  28. ^ NDA 013263
  29. ^ NDA 018723
  30. ^ NDA 012380
  31. ^ NDA 010841
  32. ^ NDA 020189
  33. ^ NDA 020450
  34. ^ NDA 020235
  35. ^ NDA 020241
  36. ^ NDA 022253
  37. ^ NDA 021035
  38. ^ a b EPAR: Keppra. Retrieved on 1 November 2007.
  39. ^ NDA 006008
  40. ^ NDA 008322
  41. ^ 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. 
  42. ^ NDA 010596
  43. ^ NDA 011721
  44. ^ NDA 021014
  45. ^ NDA 008762 (Marketed in 1938, approved 1953)
  46. ^ NDA 008855
  47. ^ Kutt, Henn; Resor, Stanley R. (1992). The Medical treatment of epilepsy. New York: Dekker. p. 385. ISBN 0-8247-8549-5.  (first usage)
  48. ^ NDA 021446
  49. ^ a b EPAR: Lyrica Retrieved on 1 November 2007.
  50. ^ NDA 009170
  51. ^ a b EPAR: Diacomit. Orphan designation: 5 December 2001, full authorisation: 4 January 2007 Retrieved on 1 November 2007.
  52. ^ NDA 020646
  53. ^ "NDA: 020646". DrugPatentWatch. Retrieved 19 May 2013. 
  54. ^ NDA 020505
  55. ^ NDA 005856
  56. ^ NDA 018081
  57. ^ Lundbeck Press Release
  58. ^ NDA 020789
  59. ^ a b EPAR: Zonegran. Retrieved on 1 November 2007
  60. ^ 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. doi:10.1111/j.1528-1167.2009.02130.x. PMID 19507305. 
  61. ^ Bittigau P, Sifringer M, Genz K,et al. (May 2002). "Antiepileptic drugs and apoptotic neurodegenereation in the developing brain". Proceedings of the National Academy of Sciences of the United States of America 99 (23): 15089–94. doi:10.1073/pnas.222550499. PMC 137548. PMID 12417760. 
  62. ^ 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. 
  63. ^ 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. 
  64. ^ 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. 
  65. ^ 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. PMC 3230752. PMID 22050285. 

External links[edit]