Index
This type of drug is effective in relieving pain associated with nerve damage, either from disease or injury.
The term anticonvulsant or ‘ anticonvulsant ‘ is applied to a drug used to treat seizures, hence the synonym ‘antiepileptic’.
Anticonvulsants are also used in the treatment of neuropathic pain and as mood stabilizers in the treatment of psychiatric disorders, such as bipolar.
Anti-seizure medications include many agents that have been incriminated and cause idiosyncratic drug-induced liver disease.
In fact, several commonly used anticonvulsants (phenytoin, valproate, carbamazepine) are consistently ranked among the leading causes of drug-induced clinically apparent liver injury and are frequently listed under the causes of drug-induced acute liver failure.
Due to the importance of pharmacotherapy of epilepsy, the potential hepatotoxicity of these agents has been considered acceptable. However, attempts to develop safer agents of equivalent or superior efficacy continue.
Major anticonvulsants include hydantoin derivatives, barbiturates, benzodiazepines, succinimides, valproic acid, gamma amino butyric acid (GABA) precursors and analogs, DMDA receptor inhibitors, and a multitude of various recently introduced agents.
At least two dozen agents are licensed and approved for use as anticonvulsants in the United States.
Phenobarbital is the oldest antiepileptic drug still in use, it was introduced into clinical medicine in 1916.
Phenobarbital is an aromatic anticonvulsant and, like phenytoin and carbamazepine, can cause the anticonvulsant aromatic hypersensitivity syndrome, a form of drug reaction with eosinophilia and systemic symptoms. Questions remain about the anticonvulsant efficacy of phenobarbital and it is now rarely used for this indication.
Phenytoin, formerly known as phenytoin, was introduced to use as an anticonvulsant in 1938 and remains one of the most commonly used medications for epilepsy.
Fosphenytoin is an intravenous formulation of phenytoin that has been available since 1995 and is used for status epilepticus and as a substitute for oral phenytoin during surgery.
Phenytoin is a well-known cause of acute liver injury, which is generally part of the anticonvulsant hypersensitivity syndrome and can be severe and lead to acute liver failure and death.
Carbamazepine was introduced into use in 1963 for the treatment of generalized seizures and with other carbamazepines (oxcarbazepine, eliscarbazepine) it is still widely used.
Carbamazepine can also cause anticonvulsant hypersensitivity syndrome and is a well-known cause of drug-induced acute liver injury, as well as serious skin reactions such as Stevens Johnson syndrome and toxic epidermal necrolysis.
Lamotrigine is a more recently developed anticonvulsant that has broad anticonvulsant activity.
Lamotrigine can also cause anticonvulsant hypersensitivity syndrome and has become one of the most common causes of drug-induced clinically apparent liver injury.
Benzodiazepines are anxiolytic and antiepileptic, and several, including diazepam, clonazepam, and clorazepate, are used in the therapy of epilepsy. Benzodiazepines are also discussed under antianxiolytic drugs.
They appear to work by enhancing the activity of the gamma aminobutyric acid (GABA) receptor.
While many benzodiazepines have anticonvulsant activity, only clonazepam and cloazepate are commonly used in the long-term treatment of epilepsy. Diazepam and other parenterally administered benzodiazepams are also used for the treatment of status epilepticus.
Benzodiazepines have only been rarely associated with causing drug-induced liver damage and have not been associated with anticonvulsant hypersensitivity syndrome.
Succinimides are active against clonic motor seizures and absence seizures (petit mal) in humans. This class includes ethosuximide (1960) and methsuximide (1957).
Valproic acid or valproate is a branched-chain carboxylic acid that was found to have anticonvulsant activity somewhat accidentally.
Valproate was introduced in 1978 and quickly became a commonly used agent for partial seizures and for poorly controlled generalized seizures.
Valproic acid is also used in the treatment of mood and bipolar disorders.
Valproate can cause several distinctive forms of liver injury, ranging from asymptomatic serum aminotransferase elevations or acute hepatitis that can be severe and even fatal, to Reye’s syndrome such as liver dysfunction syndrome and microvesicular fatty liver.
High doses of valproic acid can also cause stupor and coma due to hyperammonemia without accompanying severe liver injury.
Topiramate is a sulphamate substituted monosaccharide and a unique and widely active anticonvulsant introduced in 1996 that is still widely used.
Topiramate is also used for the prevention of migraine headaches, as a weight loss agent, and (off-label) for mood disorders and bipolar illness.
Levetiracetam is a derivative of pyrrolidine and a unique anticonvulsant introduced in 1999 that has been used increasingly due to its safety and excellent tolerability.
Levetiracetam binds to glycoprotein SV2A in the synaptic vesicle and appears to work by inhibiting calcium channels involved in neurotransmitter release.
Levetiracetam has been associated with rare cases of drug-induced liver disease, but not with anticonvulsant hypersensitivity syndrome. Brivaracetam is an anticonvulsant of similar structure and activity that was approved in 2016.
Mechanism of action
Anticonvulsants vary in their effectiveness against experimental seizures in animals and against seizures in humans. The mechanical basis for this variability in the action of anticonvulsant drugs remains unclear, but numerous mechanisms of action have been proposed.
We have used mouse neurons in dissociated primary cell cultures to study the action of these anticonvulsant drugs on various aspects of membrane excitability and synaptic transmission.
We have proposed that anticonvulsant drugs can be classified according to their actions on the sustained repetitive high frequency firing (SRF) of action potentials and on the responses to postsynaptic gamma-aminobutyric acid (GABA).
Phenytoin and carbamazepine were effective against SRF but did not modify postsynaptic GABA responses at therapeutically relevant concentrations.
Phenobarbital, benzodiazepines, and valproic acid modified GABA postsynaptic and SRF responses. Ethosuximide had no effect on SRF or GABAergic mechanisms.
On the basis of these results, we have proposed that SRF blockade may underlie the action of phenytoin, carbamazepine, phenobarbital, valproic acid, and benzodiazepines against generalized tonic-clonic seizures in humans and maximal seizures due to electroshock in animals.
Increased GABAergic synaptic transmission may underlie the efficacy of benzodiazepines and valproic acid drugs against generalized absence seizures in humans and pentylenetetrazole-induced seizures in experimental animals.
The mechanism of action of ethosuximide against generalized absence seizures in humans and pentylenetetrazole-induced seizures in experimental animals may be by a third mechanism, as yet unknown.
Historical note and terminology
The term ‘anticonvulsant’ is applied to a drug used for the treatment of seizures, hence the synonym ‘antiepileptic’, which is often denoted by the abbreviation AED.
This term applies to other agents such as the ketogenic diet and procedures such as vagus nerve stimulation when used to control seizures.
Some drugs in other drug categories have an anticonvulsant effect, for example, acetazolamide, which is a carbonic anhydrase inhibitor.
Anticonvulsants are also used in the treatment of neuropathic pain and as mood stabilizers in the treatment of psychiatric disorders such as bipolar disorder.
The era of anticonvulsant drugs began with the introduction of bromides in 1857 and was followed by the discovery of the anticonvulsant effect of barbiturates in 1912 (Hauptman 1912).
Phenytoin (phenytoin), synthesized in 1908, was not introduced for the treatment of epilepsy until 1938 (Merritt and Putnam 1938). Although carbamazepine was shown to have antiepileptic properties in 1954, it was first approved in 1968 for the treatment of trigeminal neuralgia and approved in 1974 for the treatment of epilepsy.
Anticonvulsant properties of valproic acid, which is structurally unrelated to other antiepileptic drugs, was discovered by chance in 1963; however, it did not become a major anticonvulsant drug until the 1970s.
Older anti-seizure drugs with new variations are still widely used and remain the mainstay of epilepsy treatment in developing countries.
During the past 2 decades, several new anti-seizure drugs have been approved worldwide, and the use of anti-seizure drugs in indications other than epilepsy has increased. Several new drugs are in development.
Currently approved anticonvulsants include the following:
- Brivaracetam.
- Carbamazepine.
- Clobazam.
- Diazepam.
- Eslicarbazepine acetate.
- Etosuximida.
- Ezogabine (retigabina).
- Felbamato.
- Phosphophenite.
- Gabapentina.
- Lacosamida.
- Lamotrigine.
- Levetiracetam.
- Oxcarbazepina.
- Perampanel.
- Phenobarbital.
- Phenytoin
- Pregabalin.
- Primidona.
- Rufinamida.
- Stiripentol (approved in the European Union for Dravet syndrome).
- Sulthiame.
- Tiagabina.
- Topiramato.
- Valproic acid.
- Vigabatrin.
- Zonisamida.
Adverse effects of anticonvulsants
Since antiepileptic or anticonvulsant drugs have a narrow therapeutic index and their adverse effects can affect any organ and apparatus, their widespread use has important safety implications.
In general, 10-30% of people with epilepsy discontinue their initially prescribed antiepileptic medication due to intolerance.
Among patients chronically treated with antiepileptic drugs, the prevalence of adverse effects ranges from 10% to 40% when tolerability is assessed through spontaneous reports or unstructured interviews, and from 60% to 95% when adverse effects are assessed using a checklist.
For people with drug-resistant epilepsy, several studies have shown that adverse effects are the main determinants of poor quality of life and have a more important impact on quality of life than seizure frequency.
Understanding the manifestations of drug toxicity, the risk factors involved, and effective prevention measures is therefore essential for optimal clinical management.
Neurological adverse effects
Since antiepileptic drugs work by modulating the activity of brain neurons, it is not surprising that most of their adverse effects affect the central nervous system.
Those most commonly seen include:
- Sedation.
- Fatigue.
- Dizziness
- Coordination disorders (ataxia, dysarthria, diplopia).
- Temblor.
- Cognitive deficits.
- Mood disturbances
- Behavioral changes and sexual disorders (loss of libido, erectile dysfunction).
These effects are often dose dependent, tend to appear in the early stages of treatment, can sometimes be minimized by gradual dose titration, and some may regress spontaneously during continuation of therapy.
Its frequency varies in relation to the type of drug and its dose (for example, sedation and cognitive effects are more frequent with barbiturates, benzodiazepines and topiramate), the characteristics of the patients.
For example, elderly patients are more susceptible to cognitive effects and motor coordination disorders, while children more often develop behavioral effects and comedication with specific agents.
For example, the co-administration of two or more antiepileptic drugs that work by blocking sodium channels, such as carbamazepine, oxcarbazepine, lamotrigine and lacosamide, increases the risk of side effects secondary to this mechanism of action.
Among the effects on the central nervous system, the possibility of a paradoxical worsening of seizures has been reported. This phenomenon can be caused by the use of excessive doses or by the prescription of an inappropriate antiepileptic drug for the specific type of epilepsy.
For example, carbamazepine and oxcarbazepine can worsen seizures and even precipitate status epilepticus when given to patients with juvenile myoclonic epilepsy.
Idiosyncratic effects
Antiepileptic drugs, particularly lamotrigine, carbamazepine, oxcarbazepine, phenytoin, barbiturates, and felbamate, are among the drugs most frequently associated with skin reactions.
Manifestations can range from simple morbilliform eruptions to life-threatening reactions such as Stevens-Johnson syndrome, epidemic Johnson syndrome, and epidemic epidermiolysis (drug eruption with eosinophilia and systemic symptoms).
In general, these reactions appear within a few days or weeks of initiation of therapy and return after withdrawal of the offending agent. Its appearance, especially in the case of lamotrigine, can be minimized by starting treatment at low doses and increasing the dose gradually.
Due to the significant cross-reactivity, particularly among aromatic antiepileptic drugs, it is preferable for patients with these manifestations to switch to an alternative drug with an unrelated chemical structure.
The propensity to develop skin reactions is genetically controlled.
In particular, the risk of developing Stevens-Johnson syndrome and toxic epidermolysis induced by carbamazepine, oxcarbazepine, phenytoin, and probably lamotrigine, is much higher among patients of Chinese or Southeast Asian descent who are positive for the HLA-B * 1502 allele.
In these ethnic groups, HLA-B * 1502 genotyping is recommended before starting treatment with one of these drugs.
Phenytoin, and probably lamotrigine, is highly increased among patients of Chinese or Southeast Asian descent who are positive for the HLA-B * 1502 allele. In these ethnic groups, HLA-B * 1502 genotyping is recommended before start treatment with one of these drugs.
Phenytoin, and probably lamotrigine, is highly increased among patients of Chinese or Southeast Asian descent who are positive for the HLA-B * 1502 allele. In these ethnic groups, HLA-B * 1502 genotyping is recommended before start treatment with one of these drugs.
Life-threatening idiosyncratic reactions can affect other organs and tissues. Examples include felbamate-induced aplastic anemia, valproate or felbamate-induced hepatotoxicity, and valproate-caused pancreatitis.
For some of these effects, important risk factors are known: for example, valproate hepatotoxicity is more common in pediatric patients (especially under two years of age) and in the presence of certain congenital metabolic defects or concomitant therapy with enzyme-inducing antiepileptic drugs. .
Chronic effects
Some adverse effects of antiepileptic drugs develop insidiously and may manifest only after months or even years of therapy.
Examples include:
- Hirsutism and phenytoin-induced gingival hyperplasia.
- Hand-shoulder syndrome and barbiturate-induced Dupuytren’s contraction.
- Valproate, gabapentin, pregabalin, perampanel, and vigabatrin-induced weight gain.
- Topiramate, Zonisamide, and Felbamate-Induced Weight Loss.
- Metabolic disorders secondary to enzyme induction (vitamin D deficiency.
- Endocrine disorders.
- Blood lipid abnormalities) in patients chronically treated with carbamazine, phenytoin, and barbiturates.
Some serious chronic effects have resulted in a drastic reduction in the prescription of certain antiepileptic drugs, such as in the case of irreversible visual field defects induced by vigabatrin and abnormal pigmentation of the skin, lips, nails and retina induced by retigabine.
Effects on offspring
The risk of congenital malformations in newborns of mothers treated with antiepileptic drugs during pregnancy is approximately 2 to 6%, compared to 1-2% for the general population.
The risk varies in relation to the type of medicine, the dose and the number of medicines administered (the risks are higher with combination therapy than with mono therapy).
Valproate is associated with the highest risk: in a recent study, malformation rates among newborns exposed to valproate during pregnancy was 5.6% with maternal doses of approximately 700 mg / day, 10.4% with doses between 700 and 1,500 mg / day and 24.2% with Dose ≥1,500 mg / day.
Prenatal exposure to high doses of valproate also increases the risk of postnatal cognitive deficits.
The best strategy to minimize these adverse effects is to optimize antiepileptic therapy before pregnancy. Drastic treatment modifications during pregnancy are not indicated and could pose serious risks to both mother and fetus.
Concluding remarks
The list of adverse effects discussed in the previous sections is not exhaustive and more detailed information can be found in recent reviews and in the fact sheets for each medicine.
The goal of antiepileptic therapy is to achieve complete seizure control in the absence of adverse effects that have a negative impact on quality of life.
There are currently more than 25 drugs on the market for the treatment of epilepsy, many of which have similar efficacy but differ in their tolerability profile.
Optimal therapy is to tailor the choice of drug and its dosage to the characteristics of the individual patient.
Regular and careful evaluation of clinical response, monitoring of plasma drug levels when appropriate, and use of standardized instruments to identify adverse effects are important components of a rational approach to early identification of drug toxicity.
Also for the implementation of appropriate corrective interventions.
