Anticonvulsant

Anticonvulsants, also known as antiepileptic or antiseizure drugs, are a class of medicines used in the treatment of epilepsy and other conditions that cause seizures.^[1][3] Some may be used to treat bipolar disorder or neuropathic pain.^[4] Which one is used depends on the type of epilepsy or type of seizure.^[5] They are available to take by mouth, injection into vein, or insertion into rectum.^[5] They may be taken one or more times a day.^[5] Sometimes more than one anticonvulsant is required.^[5]

Side effects vary between the different anticonvulsants.^[6] Interactions with other medicines may lead to toxic levels of antivulsants.^[5] Stopping them suddenly can be dangerous.^[5] Use in pregnancy may harm the baby, but if needed lamotrigine and levetiracetam may be options.^[5]

Anticonvulsants act by affecting certain molecules in the brain.^[1] They suppress the excessive rapid firing of neurons during seizures and may also prevent the spread of the seizure within the brain.^[7][8] Conventional anticonvulsants may block sodium or calcium channels, or enhance GABA function.^[4] Some anticonvulsants have multiple or uncertain mechanisms of action.^[4] Next to the voltage-gated sodium channels and components of the GABA system, their targets include GABA_A 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]

The first anticonvulsant was bromide, suggested in 1857 by the British gynecologist Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy).^[13] Phenobarbital is the least expensive at around US$5 a year in the developing world.^[14] In the United States it generally costs less than 20 USD per month as of 2021.^[15] Access, however, may be difficult as some countries label it as a controlled drug.^[14]

Types

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

Carboxamides

Carbamazepine

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).

Side effects

• 
  Skin reaction to an anticonvulsant
• 
  Skin reaction to an anticonvulsant
• 
  Skin reaction to an anticonvulsant

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.^[29] Therefore, these drugs should be monitored during use in pregnancy.^[29]

Many of the common used medications, such as valproate, phenytoin, carbamazepine, phenobarbitol, gabapentin have been reported to cause increased risk of birth defects.^[30] Among anticonvulsants, levetiracetam and lamotrigine seem to carry the lowest risk of causing birth defects.^[5] 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.^[31] On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure.^[31] 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.^[31]

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.^[29]

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.^[29] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.^[29]

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.^[32]

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.^[33]

In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.^{[34][35][36][37][38]}

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.^[39] 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).^[40]

Mechanism

They generally act by interacting with certain molecules in the brain.^[1]

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.^{[41][42][43][44][45][46][47]}

Non-medicine based

The ketogenic diet and vagus nerve stimulation are other treatments for epilepsy. However, both of them can cause severe side effects. The side effects of vagus nerve stimulation are more severe, and it's efficacy is questionable in comparison to medications or the ketogenic diet.

Guidelines

Guidelines by the American Academy of Neurology and American Epilepsy Society, recommend people with newly diagnosed epilepsy who require treatment be started on standard anticonvulsants such as carbamazepine, phenytoin, valproic acid/valproate semisodium, phenobarbital, or on the newer anticonvulsants gabapentin, lamotrigine, oxcarbazepine or topiramate.^[48][49] The choice of anticonvulsants depends on individual patient characteristics.^[48] Both newer and older drugs are generally equally effective in new onset epilepsy.^[48] The newer drugs tend to have fewer side effects.^[48] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.^[48] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.^[48]

History

The first anticonvulsant was bromide, suggested in 1857 by the British gynecologist 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.^[50] 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.

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. People 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.^[40] 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 more. Despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of new medications as initial monotherapy.^[40]

References

External links

• eMedicine: Antiepileptic Drugs: an overviewArchived 2012-02-08 at the Wayback Machine
• NINDS: Anticonvulsant Screening Program Archived 2007-03-11 at the Wayback Machine
• Use of Anticonvulsants in Pharmacotherapy of Bronchial Asthma Archived 2017-09-16 at the Wayback Machine
• MDNG: Anticonvulsants and Bone Health
• Miami Children's Brain Institute – Anticonvulsants
• Drug Reference for FDA Approved Epilepsy Drugs Archived 2021-05-07 at the Wayback Machine
• Epilepsy Action: UK Anti-Epileptic Drugs List Archived 2011-03-01 at the Wayback Machine