Anticonvulsant

Anticonvulsants (also commonly known as antiepileptic drugs or as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder[1] and borderline personality disorder,[2] since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.[3] Anticonvulsants suppress the rapid and excessive firing of neurons during seizures.[4] Anticonvulsants also prevent the spread of the seizure within the brain.[5] Some investigators have observed that anticonvulsants themselves may cause reduced IQ in children.[6] 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 sequelae 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.[7] 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.[8] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[9][10] 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.[11] 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.[11] Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.[12][13][14][15][16][17][18] The drug class was the 5th-best-selling in the US in 2007.[19]

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.[20] 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).[21]

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.[21] 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.[21]

Drugs

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 until 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.[24][25][26][27] 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

Triazines

Main article: Triazine

Ureas

Main article: Urea

Valproylamides (amide derivatives of valproate)

Main article: Amide

Other

Non-medical anticonvulsants

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

According to guidelines by the AAN and AES,[31] mainly based on a major article review in 2004,[32] 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.[31] Both newer and older drugs are generally equally effective in new onset epilepsy.[31] The newer drugs tend to have fewer side effects.[31] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[31] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[31]

History

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.[33] 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

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.

DrugBrandUSUKFrance
acetazolamide Diamox 27 July 1953[34] 1988[35]
carbamazepine Tegretol 15 July 1974[36][37] 1965[35] 1963[38]
clobazam Frisium 1979[35]
clonazepam Klonopin/Rivotril 4 June 1975[39] 1974[35]
diazepam Valium 15 November 1963[40]
divalproex sodium Depakote 10 March 1983[41]
eslicarbazepine Data needed
ethosuximide Zarontin 2 November 1960[42] 1955[35] 1962[38]
ethotoin Peganone 22 April 1957[43]
felbamate Felbatol 29 July 1993[44]
fosphenytoin Cerebyx 5 August 1996[45]
gabapentin Neurontin 30 December 1993[46] May 1993[35][38] October 1994[38]
lamotrigine Lamictal 27 December 1994[47] October 1991[35][38] May 1995[38]
lacosamide Vimpat 28 October 2008[48]
levetiracetam Keppra 30 November 1999[49] 29 September 2000[35][50] 29 September 2000[50]
mephenytoin Mesantoin 23 October 1946[51]
metharbital Gemonil 1952[52][53]
methsuximide Celontin 8 February 1957[54]
methazolamide Neptazane 26 January 1959[55]
oxcarbazepine Trileptal 14 January 2000[56] 2000[35]
phenobarbital 1912[35] 1920[38]
phenytoin Dilantin/Epanutin 1938[38][57] 1938[35] 1941[38]
phensuximide Milontin 1953[58][59]
pregabalin Lyrica 30 December 2004[60] 6 July 2004[35][61] 6 July 2004[61]
primidone Mysoline 8 March 1954[62] 1952[35] 1953[38]
sodium valproate Epilim December 1977[38] June 1967[38]
stiripentol Diacomit 5 December 2001[63] 5 December 2001[63]
tiagabine Gabitril 30 September 1997[64][65] 1998[35] November 1997[38]
topiramate Topamax 24 December 1996[66] 1995[35]
trimethadione Tridione 25 January 1946[67]
valproic acid Depakene/Convulex 28 February 1978[68] 1993[35]
vigabatrin Sabril 21 August 2009[69] 1989[35]
zonisamide Zonegran 27 March 2000[70] 10 March 2005[35][71] 10 March 2005[71]

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.[72] Therefore, these drugs should be monitored during use in pregnancy.[72]

Valproic acid, and its derivatives such as sodium valproate and divalproex sodium, causes cognitive deficit in the child, with an increased dose causing decreased intelligence quotient.[73] On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure.[73] Similarly, children exposed lamotrigine or phenytoin in the womb do not seem to differ in their skills compared to those who were exposed to carbamazepine.[73]

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.[72]

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[72] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[72]

In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.[74][75][76][77][78]

See also

References

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  2. ↑ American Psychiatric Association, and American Psychiatric Association. Work Group on Borderline Personality Disorder. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Pub, 2001.
  3. ↑ Rogawski, Michael A.; Löscher, Wolfgang (2004). "The neurobiology of antiepileptic drugs". Nature Reviews Neuroscience 5 (7): 553–564. doi:10.1038/nrn1430. PMID 15208697.
  4. ↑ McLean, M J; Macdonald, R L (June 1986). "Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture.". Journal of Pharmacology and Experimental Therapeutics 237 (3): 1001–1011.
  5. ↑ Harden, C. L. (1 May 1994). "New antiepileptic drugs". Neurology 44 (5): 787–787. doi:10.1212/WNL.44.5.787.
  6. ↑ Loring, David W (1 September 2005). "Cognitive Side Effects of Antiepileptic Drugs in Children". Psychiatric Times XXII (10).
  7. ↑ https://www.neurology.wisc.edu/publications/2010%20pubs/stafstrom-4.pdf
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  9. ↑ Rogawski MA, Bazil CW; Bazil (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.
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  12. ↑ Puligheddu M, Pillolla G, Melis M, Lecca S, Marrosu F, De Montis MG; et al. (2013). Charpier, Stéphane, ed. "PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings". PLoS ONE 8 (5): e64541. doi:10.1371/journal.pone.0064541. PMC 3664607. PMID 23724059.
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  14. ↑ Porta, N., Vallée, L., Lecointe, C., Bouchaert, E., Staels, B., Bordet, R., Auvin, S. (2009). "Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, exerts anticonvulsive properties.". Epilepsia 50 (4): 943–8. doi:10.1111/j.1528-1167.2008.01901.x. PMID 19054409.
  15. ↑ Lampen A, Carlberg C, Nau H; Carlberg; Nau (2001). "Peroxisome proliferator-activated receptor delta is a specific sensor for teratogenic valproic acid derivatives". Eur J Pharmacol 431 (1): 25–33. doi:10.1016/S0014-2999(01)01423-6. PMID 11716839.
  16. ↑ Maguire JH, Murthy AR, Hall IH; Murthy; Hall (1985). "Hypolipidemic activity of antiepileptic 5-phenylhydantoins in mice". Eur J Pharmacol 117 (1): 135–8. doi:10.1016/0014-2999(85)90483-2. PMID 4085542.
  17. ↑ Hall IH, Patrick MA, Maguire JH; Patrick; Maguire (1990). "Hypolipidemic activity in rodents of phenobarbital and related derivatives". Arch Pharm (Weinheim) 323 (9): 579–86. doi:10.1002/ardp.19903230905. PMID 2288480.
  18. ↑ Frigerio F, Chaffard G, Berwaer M, Maechler P; Chaffard; Berwaer; Maechler (2006). "The antiepileptic drug topiramate preserves metabolism-secretion coupling in insulin secreting cells chronically exposed to the fatty acid oleate". Biochem Pharmacol 72 (8): 965–73. doi:10.1016/j.bcp.2006.07.013. PMID 16934763.
  19. ↑ 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. "
  20. ↑ 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.
  21. 1 2 3 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.
  22. ↑ 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.
  23. ↑ "Public summary of positive opinion for orpphan opinion for orphan designation of stiripentol for the treatment of severe myoclonic epilepsy in infancy" (PDF). European Medicines Agency. 30 July 2007. Retrieved 19 May 2013. Doc.Ref.: EMEA/COMP/269/04
  24. ↑ 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.
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  27. ↑ Djurić, M; Marjanović B; Zamurović D (May–Jun 2001). "[West syndrome--new therapeutic approach]". Srp Arh Celok Lek 129 (1): 72–7. PMID 15637997.
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  29. ↑ 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.
  30. ↑ "Felbamate". MedlinePlus : U.S. National Library of Medicine. Retrieved 19 May 2013.
  31. 1 2 3 4 5 6 AAN Guideline Summary for CLINICIANS EFFICACY AND TOLERABILITY OF THE NEW ANTIEPILEPTIC DRUGS, I: TREATMENT OF NEW ONSET EPILEPSY Retrieved on 29 June 2010
  32. ↑ 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.
  33. ↑ Eadie MJ, Bladin PF (2001). "A Disease Once Sacred: a History of the Medical Understanding of Epilepsy".
  34. ↑ NDA 008943
  35. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Epilepsy Action: Druglist. Retrieved on 1 November 2007.
  36. ↑ NDA 016608 (Initial approval on 11 March 1968 was for trigeminal neuralgia.)
  37. ↑ 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.
  38. 1 2 3 4 5 6 7 8 9 10 11 12 13 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.
  39. ↑ NDA 017533
  40. ↑ NDA 013263
  41. ↑ NDA 018723
  42. ↑ NDA 012380
  43. ↑ NDA 010841
  44. ↑ NDA 020189
  45. ↑ NDA 020450
  46. ↑ NDA 020235
  47. ↑ NDA 020241
  48. ↑ NDA 022253
  49. ↑ NDA 021035
  50. 1 2 EPAR: Keppra. Retrieved on 1 November 2007.
  51. ↑ NDA 006008
  52. ↑ NDA 008322
  53. ↑ 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.
  54. ↑ NDA 010596
  55. ↑ NDA 011721
  56. ↑ NDA 021014
  57. ↑ NDA 008762 (Marketed in 1938, approved 1953)
  58. ↑ NDA 008855
  59. ↑ Kutt, Henn; Resor, Stanley R. (1992). The Medical treatment of epilepsy. New York: Dekker. p. 385. ISBN 0-8247-8549-5. (first usage)
  60. ↑ NDA 021446
  61. 1 2 EPAR: Lyrica Retrieved on 1 November 2007.
  62. ↑ NDA 009170
  63. 1 2 EPAR: Diacomit. Orphan designation: 5 December 2001, full authorisation: 4 January 2007 Retrieved on 1 November 2007.
  64. ↑ NDA 020646
  65. ↑ "NDA: 020646". DrugPatentWatch. Retrieved 19 May 2013.
  66. ↑ NDA 020505
  67. ↑ NDA 005856
  68. ↑ NDA 018081
  69. ↑ Lundbeck Press Release
  70. ↑ NDA 020789
  71. 1 2 EPAR: Zonegran. Retrieved on 1 November 2007
  72. 1 2 3 4 5 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.
  73. 1 2 3 Bromley, Rebecca; Weston, Jennifer; Adab, Naghme; Greenhalgh, Janette; Sanniti, Anna; McKay, Andrew J; Tudur Smith, Catrin; Marson, Anthony G (2014). "Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child". doi:10.1002/14651858.CD010236.pub2.
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  75. ↑ 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.
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  77. ↑ 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.
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