Anticonvulsant

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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. 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 site that anticonvulsants themselves are linked to lowered IQ in children.[1] However these studies may be moot given 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"), sometimes referred to as antiseizure drugs. While an anticonvulsant is a fair description of AEDs, it neglects to differentiate the difference between convulsions and epilepsy. Convulsive non-epileptic seizures are quite common and these types of seizures will not have any response to an antiepileptic drug. In epilepsy an area of the cortex is typically hyperirritable that can often be confirmed by completing an 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].

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.[5]

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.[5]

Once there is confidence that a drug is likely to be effective in monotherapy, trials are conducted where the drug is compared to an existing standard. For partial-onset seizures, this is typically carbamazepine. Despite the launch of over ten drugs since 1990, no new drug has been shown to be more effective than the older set, which includes carbamazepine, valproate and phenytoin. 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.[5]

Drugs

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

Aldehydes

Main article: Aldehydes

  • Paraldehyde (1882). One of the earliest anticonvulsants. Still used to treat status epilepticus, particularly where there are no resuscitation facilities.

Aromatic allylic alcohols

  • Stiripentol (2001 - limited availability). Indicated for the treatment of severe myoclonic epilepsy in infancy (SMEI).

Barbiturates

Main article: Barbiturates

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: Benzodiazepines

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.[6][7][8][9] 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

Main article: Bromides

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

Carbamates

Main article: Carbamates

  • Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.

Carboxamides

Carbamazepine

Main article: Carboxamides

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

Main article: Fatty acids

The following are fatty-acids:

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives

Main article: Fructose

Gaba analogs

Hydantoins

Main article: Hydantoins

The following are hydantoins:

Oxazolidinediones

Main article: Oxazolidinediones

The following are oxazolidinediones:

Propionates

Main article: Propionates

Pyrimidinediones

Main article: Pyrimidinediones

Pyrrolidines

Main article: Pyrrolidines

Succinimides

Main article: Succinimides

The following are succinimides:

Sulfonamides

Main article: Sulfonamides

Triazines

Main article: Triazines

Ureas

Main article: Ureas

Valproylamides (amide derivatives of valproate)

Main article: Amides

Non-medical anticonvulsants

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

Treatment guidelines

According to guidelines by the AAN and AES,[10] mainly based on a major article review in 2004,[11] 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.[10] Both newer and older drugs are generally equally effective in new onset epilepsy.[10] The newer drugs tend to have fewer side effects.[10] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[10] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[10]

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[12]. 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 1953-07-2727 July 1953[13] 1988[14]
carbamazepine Tegretol 1974-07-1515 July 1974[15][16] 1965[14] 1963[17]
clobazam Frisium 1979[14]
clonazepam Klonopin/Rivotril 1975-06-044 June 1975[18] 1974[14]
diazepam Valium 1963-11-1515 November 1963[19]
divalproex sodium Depakote 1983-03-1010 March 1983[20]
ethosuximide Zarontin 1960-11-022 November 1960[21] 1955[14] 1962[17]
ethotoin Peganone 1957-04-2222 April 1957[22]
felbamate Felbatol 1993-07-2929 July 1993[23]
fosphenytoin Cerebyx 1996-08-055 August 1996[24]
gabapentin Neurontin 1993-12-3030 December 1993[25] 1993-05May 1993[14][17] 1994-10October 1994[17]
lamotrigine Lamictal 1994-12-2727 December 1994[26] 1991-10October 1991[14][17] 1995-05May 1995[17]
levetiracetam Keppra 1999-11-3030 November 1999[27] 2000-09-2929 September 2000[14][28] 2000-09-2929 September 2000[28]
mephenytoin Mesantoin 1946-10-2323 October 1946[29]
metharbital Gemonil 1952[30][31]
methsuximide Celontin 1957-02-088 February 1957[32]
methazolamide Neptazane 1959-01-2626 January 1959[33]
oxcarbazepine Trileptal 2000-01-1414 January 2000[34] 2000[14]
phenobarbital 1912[14] 1920[17]
phenytoin Dilantin/Epanutin 1938[17][35] 1938[14] 1941[17]
phensuximide Milontin 1953[36][37]
pregabalin Lyrica 2004-12-3030 December 2004[38] 2004-07-066 July 2004[14][39] 2004-07-066 July 2004[39]
primidone Mysoline 1954-03-088 March 1954[40] 1952[14] 1953[17]
sodium valproate Epilim 1977-12December 1977[17] 1967-06June 1967[17]
stiripentol Diacomit 2001-12-055 December 2001[41] 2001-12-055 December 2001[41]
tiagabine Gabitril 1997-09-3030 September 1997[42] 1998[14] 1997-11November 1997[17]
topiramate Topamax 1996-12-2424 December 1996[43] 1995[14]
trimethadione Tridione 1946-01-2525 January 1946[44]
valproic acid Depakene/Convulex 1978-02-2828 February 1978[45] 1993[14]
vigabatrin Sabril 2009-08-2121 August 2009[46] 1989[14]
zonisamide Zonegran 2000-03-2727 March 2000[47] 2005-03-1010 March 2005[14][48] 2005-03-1010 March 2005[48]

Use in pregnancy

During pregnancy, the metabolism of several anticonvulsants is affected. There may be an increase in the clearance an 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.[49] Therefore, these drugs should be monitored during use in pregnancy.[49]

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.[49]

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[49] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[49]

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. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004 Jul;5(7):553-564. PMID 15208697
  3. ^ Rogawski MA, Bazil CW. New molecular targets for antiepileptic drugs: α2δ, SV2A, and K(v)7/KCNQ/M potassium channels. Curr Neurol Neurosci Rep. 2008 Jul;8(4):345-352. PMID 18590620
  4. ^ Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics. 2007 Jan;4(1):18-61. PMID 17199015
  5. ^ 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. PMID 17998971. 
  6. ^ Browne TR (May 1976). "Clonazepam. A review of a new anticonvulsant drug". Arch Neurol 33 (5): 326–32. PMID 817697. 
  7. ^ 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. 
  8. ^ Tomson T; Svanborg E, Wedlund JE (May-Jun 1986). "Nonconvulsive status epilepticus: high incidence of complex partial status". Epilepsia 27 (3): 276–85. doi:10.1111/j.1528-1157.1986.tb03540.x. PMID 3698940. 
  9. ^ Djurić, M; Marjanović B, Zamurović D (May-Jun 2001). "[West syndrome--new therapeutic approach]". Srp Arh Celok Lek 129 (1): 72–7. PMID 15637997. 
  10. ^ 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
  11. ^ 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. 
  12. ^ Eadie MJ, Bladin PF (2001). A Disease Once Sacred: a History of the Medical Understanding of Epilepsy. 
  13. ^ NDA 008943
  14. ^ 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.
  15. ^ NDA 016608 (Initial approval on 11 March 1968 was for trigeminal neuralgia.)
  16. ^ 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. PMID 18748164. PMC 1238063. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1238063. Retrieved 14 March 2007. 
  17. ^ 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. 
  18. ^ NDA 017533
  19. ^ NDA 013263
  20. ^ NDA 018723
  21. ^ NDA 012380
  22. ^ NDA 010841
  23. ^ NDA 020189
  24. ^ NDA 020450
  25. ^ NDA 020235
  26. ^ NDA 020241
  27. ^ NDA 021035
  28. ^ a b EPAR: Keppra. Retrieved on 1 November 2007.
  29. ^ NDA 006008
  30. ^ NDA 008322
  31. ^ 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. 
  32. ^ NDA 010596
  33. ^ NDA 011721
  34. ^ NDA 021014
  35. ^ NDA 008762 (Marketed in 1938, approved 1953)
  36. ^ NDA 008855
  37. ^ Kutt, Henn; Resor, Stanley R. (1992). The Medical treatment of epilepsy. New York: Dekker. pp. 385. ISBN 0-8247-8549-5.  (first usage)
  38. ^ NDA 021446
  39. ^ a b EPAR: Lyrica Retrieved on 1 November 2007.
  40. ^ NDA 009170
  41. ^ a b EPAR: Diacomit. Orphan designation: 5 December 2001, full authorisation: 4 January 2007 Retrieved on 1 November 2007.
  42. ^ NDA 020646
  43. ^ NDA 020505
  44. ^ NDA 005856
  45. ^ NDA 018081
  46. ^ Lundbeck Press Release
  47. ^ NDA 020789
  48. ^ a b EPAR: Zonegran. Retrieved on 1 November 2007
  49. ^ 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. 

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