المعرفة

مضادات التشنج

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.[1] Anticonvulsants are also increasingly being used in the treatment of bipolar disorder[2][3] and borderline personality disorder,[4] since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.[5] Anticonvulsants suppress the excessive rapid firing of neurons during seizures.[6] Anticonvulsants also prevent the spread of the seizure within the brain.[7]

مضادات التشنج
صف عقاقير
مميزات الصف
المرادفاتAntiepileptic drugs, antiseizure drugs
الاستخدامEpilepsy
كود ATCN03
الهدف الحيويBrain
In Wikidata

Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid (GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action.[8] 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.[9] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[10][11] 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.[12] 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.[12] Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.[13][14][15][16][17][18][19] The drug class was the fifth-best-selling in the United States in 2007.[20]

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.[21] 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).[22]

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المصطلحات

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.


الأدوية المضادة للصرع

ومضادات الصرع هي مجموعة متنوعة من الأدوية المستخدمة في علاج نوبات الصرع. ومضادات الصرع أيضا أصبحت تستخدم بشكل متزايد في علاج الإضطراب ثنائي القطب و بينما يبدو أن الكثير من تلك العقاقير تعد بمثابة مثبتات للمزاج.فإن الهدف من مضادات الصرع هو منع الإشتعال السريع والمفرط لتيارات الخلايا العصبية التي تبدأ النوبة. وبسبب هذا ، فإن مضادات أثبتت فعاليتها في علاج أنواع كثيرة من القلق ذى الخلل الوظيفى. وإذا تعذر ذلك ، فإن وجود مضاد فعال في منع انتشار الاستيلاء داخل الدماغ ، وتوفر حماية ضد آثار excitotoxic الممكنة التي قد تؤدي إلى تلف في المخ. ومع ذلك ، مضادات أنفسهم وقد تم ربط خفض معدل الذكاء لدى الأطفال [1]. مضادات الاختلاج غالبا ما تسمى أدوية الصرع (مختصر "AEDs") ، على الرغم من إسم عقاقير antiseizure قد يكون من الأنسب نظرا لأن "AEDs" يمكن أن تحدث تغيرا في الحالة المرضية.

الأهداف الرئيسية الجزيئية من عقاقير مضادات الصرع التى يتم تسويقها هى عقاقير تستهدف فرق الجهد لبوابات قنوات الصوديوم ومكونات نظام غابا ، بما في ذلك مستقبلات GABAA ، والجات - 1 وناقلات غابا ، وغابا transaminase. 2] المزيد من الأهداف تشمل البوابات المستهدفة لفرق الجهد لقنوات الكالسيوم SV2A, and α2δ. [3][4].

بعض مضادات أظهرت آثارا antiepileptogenic في نماذج حيوانية لعلاج الصرع. وهذا هو ، لأنها إما أنها تمنع التطور المتوقع من الصرع أو يمكن أن توقف أو تعكس تطور الصرع. ومع ذلك ، لا يوجد أي دواء لمنع epileptogenesis (تنمية الصرع بعد إصابة مثل إصابة في الرأس) في التجارب على البشر [5].


ينتج الصرع Epilepsy عن اضطرابات فجائية ذات إفراغ شاذ وزائد في العصبونات الدماغية.حيث تبدأ النوبة بإفراغ شحنة شاذة محلية، ثم تنتشر في المناطق الأخرى من الدماغ، فإذا انتشرت على نصف كرة مخية واحدة يسمى بالصرع البؤري ، أما إذا انتشرت على الدماغ بأكمله فإنه يسمى بالصرع المعمم.


العقاقير المضادة للصرع

فى القائمة التالية, التواريخ بين الأقواس هى الأقدم من حيث الموافقات على إقرار الدواء .

الألديهات

المقالة الرئيسية: الألديهات

  • بارالديهايد (1882). و يعد واحدا من أقدم مضادات الصرع . و مايزال قيد الإستخدام في حالات status epilepticus , وخاصة حيث لا توجد مرافق إنعاش.

الكحول الأليلى العطرى

  • Stiripentol (2001 - توافر محدود). يوصف لعلاج آثار شديدة myoclonic الصرع لدى الأطفال (SMEI).

الباربيتيورات

''المقالة الرئيسية: الباربيتيورات

الباربيتيورات هى عقاقير والتي تكون بمثابة مثبطات الجهاز العصبي المركزي(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.[23][24][25][26] 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)


أسباب الصرع

لم يتحدد سبب واضح له حتى الآن، لكن يعتقد بأن الصرع قد يحدث للأسباب التالية:

1. أي أذية دماغية يمكن أن تعبر كعامل مؤهب لحدوث الصرع، مثل: الرضوض – النزف - الأورام الدماغية – الانتانات السحائية.

2. متلازمات عصبية.

3. تغير العوامل المحيطية (انخفاض السكر، تناذر السحب السريع للكحول، تغير PH الدم أو الغازات أو الشوارد).

أنواع الصرع

A. الجزئي أو البؤري Partial Epilepsy :

ينجم عن زيادة الفعالية الكهربائية في نصف الكرة المخية الواحدة. ويصنف إلى :

أولاً : الصرع الجزئي البسيط Simple Partial Epilepsy:

حيث تقتصر الفعالية الكهربائية على بؤرة واحدة صغيرة في المنطقة القشرية الحركية، ويبدي المريض غالباً فعالية شاذة في طرف أو عضلة منفردة، و لا يترافق بفقدان الوعي.

ثانياً : الصرع الجزئي المعقد Complex Partial Epilepsy:

و هنا تشمل النوبة هزة عنيفة متكررة لمجموعة عضلية معنية تبدأ من جهة واحدة من الجسم ، غالباً ما تكون الإبهام أو زاوية الفم، ثم تنتشر ويمكن أن تشمل معظم الجسم خلال دقيقتين.و يتميز هذا النوع من الصرع بفقدان وعي المريض و باضطرابات حركية تشمل :البلع – الإسهال – التبول.تكون النوبة في البداية موضعية، لكنها لا تلبث أن تنتشر مسببة تفريغاً كهربائياً شاذاً يشمل كامل نصفي الكرتين المخيتين.

B.الصرع المعمم Generalized Epilepsy:

يتميز هذا الصرع بفقدان المريض للوعي فجأة وبشكل فوري، حيث تكون النوبة في البداية موضعية، لكنها تصبح منتشرة مسببة تفريغ كهربائي شاذ يشمل كامل نصفي الكرتين المخيتين.

و يقسم الصرع المعمم إلى :

ا- الصرع المقوي الخلجاني (الصرع الكبير) (Tonic-Clonic (Grand mal: تبدأ النوبة بفقدان الوعي، ثم يتبعها الطور المقوي- وهو تقلص مستمر،يصبح الوجه أزرق ومنتفخ فيها خلال دقيقة.

ثم الطور الخلجاني: وهو تقلص سريع + ارتخاء سريع، ثم تخليط ذهني وإنهاك.

2- نوبات الغيبوبة (الصرع الصغير) (Absence-Seizures (Petit mal :

يبدأ من عمر 3 – 5 سنوات، ويستمر حتى البلوغ، و يتميز بفقدان وعي مفاجئ وقصير الأمد.

3- الحالة الصرعية Status Epileptics:

حيث تكون النوبات معاودة بسرعة دون أن يرجع المريض إلى وعيه.

4- الصرع العضلي الخلجاني Myo-Clonic:

يحدث هذا الصرع في جميع الأعمار ، و هو عبارة عن سلسلة من التقلصات العضلية القصيرة تشمل: الوجه – الجذع – الأطراف. تنتج غالباً عن أذية عصبية دائمة مكتسبة تالية لنقص الأكسجة، أو التهاب الدماغ، أو الانسمام الدوائي.

5- النوبات الحرورية Febrile Seizure:

تحدث عند الأطفال بعمر 3 أشهر إلى 5 سنوات، نتيجة ارتفاع الحرارة.و تتميز بنوب مقوية خلجانية معممة قصيرة الأمد،و نادراً ما تتطلب المعالجة الدوائية، إذ أنها لا تسبب الموت أو أية أذية عصبية.

6- متلازمة Lennox-Gastaut:

و هو نوع حاد جداً من الصرع. يحدث عند الأطفال، ويرتبط بالتأخر العقلي المتطور.


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تاريخ الموافقة على التسويق

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.

العقار الاسم التجاري US UK فرنسا
acetazolamide Diamox 1953-07-2727 July 1953[27] 1988[28]
brivaracetam Briviact 2016-02-1818 February 2016[29][30]
carbamazepine Tegretol 1974-07-1515 July 1974[31][32] 1965[28] 1963[33]
cenobamate Xcopri 2019-11-2121 November 2019
clobazam Onfi/Frisium 2011-10-2121 October 2011[34][35] 1979[28]
clonazepam Klonopin/Rivotril 1975-06-044 June 1975[36] 1974[28]
diazepam Valium 1963-11-1515 November 1963[37]
divalproex sodium Depakote 1983-03-1010 March 1983[38]
eslicarbazepine Aptiom 2013-08-1111 August 2013[39][40]
ethosuximide Zarontin 1960-11-022 November 1960[41] 1955[28] 1962[33]
ethotoin Peganone 1957-04-2222 April 1957[42]
everolimus Afinitor/Votubia 2009-03-3030 January 2009[43]
felbamate Felbatol 1993-07-2929 July 1993[44]
fosphenytoin Cerebyx 1996-08-055 August 1996[45]
gabapentin Neurontin 1993-12-3030 December 1993[46] 1993-05May 1993[28][33] 1994-10October 1994[33]
lacosamide Vimpat 2008-10-2828 October 2008[47]
lamotrigine Lamictal 1994-12-2727 December 1994[48] 1991-10October 1991[28][33] 1995-05May 1995[33]
levetiracetam Keppra 1999-11-3030 November 1999[49] 2000-09-2929 September 2000[28][50] 2000-09-2929 September 2000[50]
mephenytoin Mesantoin 1946-10-2323 October 1946[51]
metharbital Gemonil 1952[52][53]
methsuximide Celontin 1957-02-088 February 1957[54]
methazolamide Neptazane 1959-01-2626 January 1959[55]
oxcarbazepine Trileptal 2000-01-1414 January 2000[56] 2000[28]
phenobarbital 1912[28] 1920[33]
phenytoin Dilantin/Epanutin 1938[33][57] 1938[28] 1941[33]
piracetam Nootropil Data needed
phensuximide Milontin 1953[58][59]
pregabalin Lyrica 2004-12-3030 December 2004[60] 2004-07-066 July 2004[28][61] 2004-07-066 July 2004[61]
primidone Mysoline 1954-03-088 March 1954[62] 1952[28] 1953[33]
rufinamide Banzel/Inovelon 2008-11-1414 November 2008[63][64]
sodium valproate Epilim 1977-12December 1977[33] 1967-06June 1967[33]
stiripentol Diacomit 2018-08-2020 August 2018[65][66] 2001-12-055 December 2001[67] 2001-12-055 December 2001[67]
tiagabine Gabitril 1997-09-3030 September 1997[68][69] 1998[28] 1997-11November 1997[33]
topiramate Topamax 1996-12-2424 December 1996[70] 1995[28]
trimethadione Tridione 1946-01-2525 January 1946[71]
valproic acid Depakene/Convulex 1978-02-2828 February 1978[72] 1993[28]
vigabatrin Sabril 2009-08-2121 August 2009[73] 1989[28]
zonisamide Zonegran 2000-03-2727 March 2000[74] 2005-03-1010 March 2005[28][75] 2005-03-1010 March 2005[75]


الحمل

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.[76] Therefore, these drugs should be monitored during use in pregnancy.[76]

Many of the common used medications, such as valproate, phenytoin, carbamazepine, phenobarbitol, gabapentin have been reported to cause increased risk of birth defects.[77] Among anticonvulsants, levetiracetam and lamotrigine seem to carry the lowest risk of causing birth defects. The risk of untreated epilepsy is believed to be greater than the risk of adverse effects caused by these medications, necessitating continuation of antiepileptic treatment.

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.[78] On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure.[78] 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.[78]

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.[76]

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[76] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[76]

Data from studies conducted on women taking antiepileptic drugs for non-epileptic reasons, including depression and bipolar disorder, show that if high doses of the drugs are taken during the first trimester of pregnancy then there is the potential of an increased risk of congenital malformations.[79]

Pregnancy planning is being explored as a method that could decrease the risk of possible birth defects. Since the first trimester is the most susceptible period for fetal development, planning a routine antiepileptic drug dose that is safer for the first trimester could be beneficial to prevent pregnancy complications.[80]

In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.[81][82][83][84][85]

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للاستزادة

  • Anti epileptic activity of novel substituted fluorothiazole derivatives by Devid Chutia, RGUHS

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