Anticonvulsant

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The anticonvulsants (also commonly known as antiepileptic 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. 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 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.

Conventional antiepileptic drugs block sodium channels or enhance g-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] Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.[7][8][9][10][11][12][13] The drug class was the US's 5th-best-selling in 2007.[14]

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.[15]

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.[15] 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.[15]

Drugs[edit]

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

Aldehydes[edit]

Aromatic allylic alcohols[edit]

Barbiturates[edit]

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]

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.[18][19][20][21] 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[edit]

Carbamates[edit]

Carboxamides[edit]

Carbamazepine

The following are carboxamides:

Fatty acids[edit]

The following are fatty-acids:

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives[edit]

GABA analogs[edit]

Hydantoins[edit]

The following are hydantoins:

Oxazolidinediones[edit]

The following are oxazolidinediones:

Propionates[edit]

Pyrimidinediones[edit]

Pyrrolidines[edit]

Succinimides[edit]

The following are succinimides:

Sulfonamides[edit]

Triazines[edit]

Ureas[edit]

Valproylamides (amide derivatives of valproate)[edit]

Non-medical anticonvulsants[edit]

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,[25] mainly based on a major article review in 2004,[26] 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.[25] Both newer and older drugs are generally equally effective in new onset epilepsy.[25] The newer drugs tend to have fewer side effects.[25] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[25] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[25]

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.[27] 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[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.

DrugBrandUSUKFrance
acetazolamideDiamox1953-07-2727 July 1953[28]1988[29]
carbamazepineTegretol1974-07-1515 July 1974[30][31]1965[29]1963[32]
clobazamFrisium1979[29]
clonazepamKlonopin/Rivotril1975-06-044 June 1975[33]1974[29]
diazepamValium1963-11-1515 November 1963[34]
divalproex sodiumDepakote1983-03-1010 March 1983[35]
eslicarbazepineData needed
ethosuximideZarontin1960-11-022 November 1960[36]1955[29]1962[32]
ethotoinPeganone1957-04-2222 April 1957[37]
felbamateFelbatol1993-07-2929 July 1993[38]
fosphenytoinCerebyx1996-08-055 August 1996[39]
gabapentinNeurontin1993-12-3030 December 1993[40]1993-05May 1993[29][32]1994-10October 1994[32]
lamotrigineLamictal1994-12-2727 December 1994[41]1991-10October 1991[29][32]1995-05May 1995[32]
lacosamideVimpat2008-10-2828 October 2008[42]
levetiracetamKeppra1999-11-3030 November 1999[43]2000-09-2929 September 2000[29][44]2000-09-2929 September 2000[44]
mephenytoinMesantoin1946-10-2323 October 1946[45]
metharbitalGemonil1952[46][47]
methsuximideCelontin1957-02-088 February 1957[48]
methazolamideNeptazane1959-01-2626 January 1959[49]
oxcarbazepineTrileptal2000-01-1414 January 2000[50]2000[29]
phenobarbital1912[29]1920[32]
phenytoinDilantin/Epanutin1938[32][51]1938[29]1941[32]
phensuximideMilontin1953[52][53]
pregabalinLyrica2004-12-3030 December 2004[54]2004-07-066 July 2004[29][55]2004-07-066 July 2004[55]
primidoneMysoline1954-03-088 March 1954[56]1952[29]1953[32]
sodium valproateEpilim1977-12December 1977[32]1967-06June 1967[32]
stiripentolDiacomit2001-12-055 December 2001[57]2001-12-055 December 2001[57]
tiagabineGabitril1997-09-3030 September 1997[58][59]1998[29]1997-11November 1997[32]
topiramateTopamax1996-12-2424 December 1996[60]1995[29]
trimethadioneTridione1946-01-2525 January 1946[61]
valproic acidDepakene/Convulex1978-02-2828 February 1978[62]1993[29]
vigabatrinSabril2009-08-2121 August 2009[63]1989[29]
zonisamideZonegran2000-03-2727 March 2000[64]2005-03-1010 March 2005[29][65]2005-03-1010 March 2005[65]

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.[66] Therefore, these drugs should be monitored during use in pregnancy.[66] 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.[66]

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[66] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[66]

In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.[67][68][69][70][71]

See also[edit]

References[edit]

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  2. ^ https://www.neurology.wisc.edu/publications/2010%20pubs/stafstrom-4.pdf
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  14. ^ 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. "
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  28. ^ NDA 008943
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  30. ^ NDA 016608 (Initial approval on 11 March 1968 was for trigeminal neuralgia.)
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  33. ^ NDA 017533
  34. ^ NDA 013263
  35. ^ NDA 018723
  36. ^ NDA 012380
  37. ^ NDA 010841
  38. ^ NDA 020189
  39. ^ NDA 020450
  40. ^ NDA 020235
  41. ^ NDA 020241
  42. ^ NDA 022253
  43. ^ NDA 021035
  44. ^ a b EPAR: Keppra. Retrieved on 1 November 2007.
  45. ^ NDA 006008
  46. ^ NDA 008322
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  48. ^ NDA 010596
  49. ^ NDA 011721
  50. ^ NDA 021014
  51. ^ NDA 008762 (Marketed in 1938, approved 1953)
  52. ^ NDA 008855
  53. ^ Kutt, Henn; Resor, Stanley R. (1992). The Medical treatment of epilepsy. New York: Dekker. p. 385. ISBN 0-8247-8549-5.  (first usage)
  54. ^ NDA 021446
  55. ^ a b EPAR: Lyrica Retrieved on 1 November 2007.
  56. ^ NDA 009170
  57. ^ a b EPAR: Diacomit. Orphan designation: 5 December 2001, full authorisation: 4 January 2007 Retrieved on 1 November 2007.
  58. ^ NDA 020646
  59. ^ "NDA: 020646". DrugPatentWatch. Retrieved 19 May 2013. 
  60. ^ NDA 020505
  61. ^ NDA 005856
  62. ^ NDA 018081
  63. ^ Lundbeck Press Release
  64. ^ NDA 020789
  65. ^ a b EPAR: Zonegran. Retrieved on 1 November 2007
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