Anticonvulsant
An anticonvulsant (from ancient Greek ἀντί 'against' and Latin convulsio 'convulsive attack' see convulsion ; plural: anticonvulsants ) is a drug used to treat or prevent epileptic , e.g. B. tonic-clonic seizures is used.
More common is the term antiepileptic (plural antiepileptics ) because it does not reduce with the drugs seizures to be treated epileptic the convulsive element that does not occur in many types of seizures (eg. As in a Absence focal complex or a (dyskognitiven) Seizure ). Analogous to terms such as antihypertensive or antidiabetic , the symptom of an epileptic seizure is addressed without restriction . The term anti-epileptic, however, incorrectly suggests that the drug itself would affect epilepsy.
chemistry
The group of anticonvulsants is a chemically heterogeneous group of drugs . Classic representatives are:
- Barbiturates (e.g. phenobarbital and primidone ),
- Hydantoin derivatives (e.g. phenytoin )
- Suximide (e.g. mesuximide )
- the carboxamides ( carbamazepine , oxcarbazepine and eslicarbazepine acetate ) derived from tricyclic antidepressants ( dibenzazepine structure ),
- the carboxylic acid valproic acid or
- Benzodiazepines (e.g. clobazam, clonazepam , diazepam , lorazepam , midazolam, or nitrazepam ).
Some newer anticonvulsants, such as gabapentin , vigabatrin , tiagabine and pregabalin are structurally derived from γ-aminobutyric acid (GABA).
The anticonvulsants brivaracetam , felbamate , lamotrigine , levetiracetam and topiramate , which are also new , show no structural similarity to other classic anticonvulsants.
pharmacology
application areas
Permanent treatment
According to the diversity of the symptoms of epileptic seizures, anticonvulsants show different prophylactic efficacy in different forms of epilepsy. While carbamazepine is the drug of choice for partial seizures that are restricted to one focus of epilepsy, valproic acid is preferred for primary and secondary generalized seizures. The older broad-spectrum anticonvulsants phenytoin, phenobarbital and primidone as well as the newer anticonvulsants gabapentin , lamotrigine , levetiracetam , oxcarbazepine and topiramate are also available as monotherapeutic agents .
As monotherapy for epileptic diseases does not lead to satisfactory results in some of the patients, combination therapy with one or two other anticonvulsants with a different mechanism of action can be considered. The active ingredients felbamate , lacosamide , tiagabine and vigabatrin are only approved for such additional treatments.
Acute therapy, status epilepticus
In status epilepticus , a condition with rapid epileptic seizures without intermediate regaining of consciousness , the benzodiazepines (e.g. lorazepam, diazepam and clonazepam) in particular have proven themselves as emergency medication. If treatment with benzodiazepines fails, phenytoin, phenobarbital or valproic acid can be used.
Other areas of application
In addition, numerous anticonvulsants have other indications. Topiramate is approved for migraine prophylaxis , and valproic acid is also used for this purpose in off-label use . Phenytoin is also used as an antiarrhythmic . Benzodiazepines are used as sleeping pills and sedatives . Barbiturates were also used as sedatives in the past . Gabapentin, pregabalin and carbamazepine are also approved for the treatment of neuralgic pain, the latter also for the treatment of manic depression .
Mechanism of action
All anticonvulsants currently on the market suppress epileptic seizures; however, they do not cure the seizure disorder. Since excitations in the central nervous system are seen as the cause of convulsions, anticonvulsants intervene by inhibiting the excitability of neurons or by inhibiting the transmission of excitation in the central nervous system.
At the molecular level, different mechanisms of action can be observed depending on the chemical heterogeneity of the anticonvulsants. For example, carbamazepine, lacosamide, lamotrigine, oxcarbazepine, phenytoin and valproic acid lead to the inactivation of voltage-dependent Na + channels . By inhibiting these ion channels , the corresponding neurons lose the ability to transmit high-frequency stimuli that induce cramps. The suximides mesuximide and ethosuximide act in a similar way by inhibiting voltage-dependent Ca 2+ channels (T-type).
The effectiveness of benzodiazepines, barbiturates, topiramate and felbamate is explained via receptor-coupled ion channels. Felbamate blocks the glutamate binding site of the NMDA receptor and topiramate blocks the AMPA receptor to inhibit the corresponding ion channels (especially Na + ) (see also glutamate receptor ).
Benzodiazepines increase the likelihood of opening the chloride channels of the GABA A receptor, while barbiturates increase the opening time. An increased chloride conductivity as well as a decreased sodium conductivity leads to an inhibition of the conduction of excitation.
Anticonvulsants such as carbamazepine, which act as sodium channel blockers and block voltage-dependent sodium channels , have an effect on the ectopic spread of excitation and stabilize the membrane.
The anticonvulsant effects of vigabatrin, tiagabine and gabapentin are independent of an effect on ion channels. Vigabatrin (and in some cases also valproic acid) slows down the breakdown of the excitation-inhibiting neurotransmitter GABA by GABA transaminase . Tiagabin is a " reuptake inhibitor" and maintains a high GABA level in the synaptic gap . The mechanism of action of gabapentin, however, is not yet fully understood.
Side effects
Characteristic side effects that can be observed with the majority of anticonvulsants are dizziness , fatigue, and ataxia . Other side effects are considered substance-specific.
Pregnancy : Numerous anti-epileptic substances are teratogenic (e.g. valproic acid) or lead to development delays in the fetus (e.g. benzodiazepines), see Sect. a. Trimethadione embryopathy . Since epileptic seizures can themselves cause harm to the child, the use of anti-epileptic drugs during pregnancy is a risk-benefit assessment.
The North American Antiepileptic Drug Pregnancy Registry in North America and the European Antiepileptic Pregnancy Registry in Europe collect data on the safety of anticonvulsants in pregnancy .
According to a meta-analysis by the US Food and Drug Administration (FDA), the tendency to suicide is significantly increased in patients taking anticonvulsants . Eleven active ingredients (clonazepam, clorazepate, divalproex, ethosuximide, ethotoin, felbamate, gabapentin, lamotrigine, lacosamide, levetiracetam, mephenytoin, methosuximide, oxcarbazepine, phenytoin, pregabalin, trimethadiramido, tiagatabin, trimethadiramabin, and tiagatabin) were examined. According to the FDA study, the frequency of suicidal ideation or behavior increases from 0.24 percent to 0.43 percent. According to the FDA, the risk exists regardless of the area in which the active ingredients are used. Although there is currently no biological explanation for the increased suicidality, it is assumed that all anti-epileptic drugs are affected and that appropriate warnings must therefore be attached.
Influence on brain development
It has been known since 2002 that various anticonvulsants have a damaging effect on the still young brain. The influence of phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin and valproic acid was examined. At doses in the order of magnitude in which medically indicated therapies are administered to small children and infants, damage to the nerve cells in the form of apoptosis (programmed cell death) was found in experimental animals . Associated with cell death is a shift in the balance of growth factors and proteins that are necessary for the normal growth of nerve cells. Estrogens ( beta estradiol ) offer some protection.
history
The evidence-based use of anticonvulsants can be traced back to 1912, when the neurologist Alfred Hauptmann introduced phenobarbital, previously used as a sleep aid, into therapy. In 1937, phenytoin, a non-sedating drug, was brought onto the market for the first time. Phenytoin was also the inspiration for a number of other anticonvulsants of the Suximide class that are still used today. In the 1950s, Leo Sternbach (1908–2005) developed the benzodiazepines, which have enriched anticonvulsant therapy since the 1960s. During the same period of time, the anti-epileptic effectiveness of valproic acid was discovered, which is still considered to be the drug of first choice today. Numerous other anticonvulsant agents have been introduced into therapy since the 1990s, of which lamotrigine and levetiracetam in particular have proven to be the first choice.
Medicinal substances
| Non-proprietary name ( INN ) | Trade names | Remarks |
|---|---|---|
| Carbamazepine | Carbium, Neurotop, Tegretal, Timonil u. a. | |
| Chloral hydrate | Chloraldurate | mostly acutely rectiole used |
| Clobazam | Frisium | only approved for additional treatment |
| Clonazepam | Rivotril, Antelepsin (no longer available in German) | mostly used acutely as an injection |
| Clorazepate | Tranxilium | mostly used acutely as an injection |
| Diazepam | Valium, Faustan et al. a. | mostly used acutely as a rectiole or injection |
| Eslicarbazepine acetate | Zebinix | only approved for additional treatment |
| Ethosuximide | Petnidan, Suxilep, Suxinutin | only approved for petit mal epilepsy |
| Felbamate | Taloxa | only approved for Lennox-Gastaut syndrome |
| Gabapentin | Gabax, Neurontin | |
| Potassium bromide | Dibro-Be mono | only approved for severe forms of epilepsy in childhood |
| Lacosamide | Vimpat | only approved for additional treatment |
| Lamotrigine | Bipolam, Elmendos, Lamapol, Lamictal, Gerolamic, Lamotrigine Desitin Quadro (D) | |
| Levetiracetam | Keppra, Levebon | |
| Lorazepam | Tavor, Temesta | mostly used acutely as an injection |
| Mesuximide | Petinutin | second choice means only |
| Midazolam | Dormicum | mostly used acutely as an injection |
| Oxcarbazepine | Apydan Extent, Timox, Trileptal | |
| phenobarbital | Lepinal, Luminal | |
| Phenytoin | Epanutin, Phenhydan, Zentropil | |
| Pregabalin | Lyrica | only approved for additional treatment |
| Primidon | Liskantin, Mylepsinum, Resimatil, Primidon Holsten | |
| Rufinamide | Inovelon | only approved for Lennox-Gastaut syndrome |
| Stiripentol | Diacomit | only approved for additional treatment in Dravet syndrome |
| Sultiam | Ospolot | only approved for rolando epilepsy |
| Tiagabine | Gabitril | only approved for additional treatment |
| Topiramate | Topamax | |
| Trimethadione | Tridione | not available in German-speaking countries |
| Valproic acid | Convulex, Depakine, Ergenyl, Leptilan, Orfiril and the like a. | |
| Vigabatrin | Sabril | only approved for severe forms of epilepsy |
| Zonisamide | Zonegran | for monotherapy for partial seizures in adults with newly developed epilepsy |
Formerly approved drugs
| Non-proprietary name ( INN ) | Trade names | Period | Remarks |
|---|---|---|---|
| Retigabine | Tobalt | 2011-2017 | - |
Individual evidence
- ↑ Tracy Glauser, et al. a .: Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes . In: Epilepsia . tape 54 , no. 3 , March 2013, p. 551-563 , doi : 10.1111 / epi.12074 (English).
- ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 173.
- ↑ Risk of suicide when taking anti- epileptic drugs ( Memento of the original from April 11, 2009 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . Deutsches Ärzteblatt online, December 17, 2008.
- ↑ Petra Bittigau, u. a .: Antiepileptic drugs and apoptotic neurodegeneration in the developing brain . In: Proceedings of the National Academy of Science . tape 99 , p. 15089–15094 (English, pnas.org [accessed January 10, 2017]).
- ↑ A. Hauptmann: Luminal in epilepsy. In: Münch Med Wchschr . tape 59 , 1912, pp. 1907-1909 .
- ↑ ABDATA Pharma-Daten-Service: Lamotrigine drug . In: https://www.apotheken-umschau.de/Medikamente/Beipackmarke/LAMOTRIGIN-Desitin-Quadro-100-mg-Tabletten-3806301.html . 19th December 2018.
Web links
- Epi-Info (PDF file; 107 kB)
