Pharmacology

Pharmacodynamics. The main actions of currently used anticonvulsants are:

(1) Modulation of voltage-gated sodium and calcium channels. (2) Synaptic inhibitory neurotransmission by agonist effect on the GABA system. (3) Attenuation of brain excitation by decreased glutamate transmission.

Anticonvulsants in use can be classified according to their predominant mode of action as shown in Table 1, but some drugs have more than one mechanism of action, and some of the mechanisms are not known.

Some of the newer anticonvulsant drugs do not fit into the pattern of mode of actions of older drugs. For example, retigabine primarily acts to stabilize neuronal potassium-gated ion channels (35). Currently, no other marketed anticonvulsant drug shares this mode of action. It has been approved both in Europe and in the United States for the adjunctive treatment of partial-onset seizures in adults.

Table 1. Predominant Mode of Action of Anticonvulsant Drugs

Sodium channel	Calcium channel	GABA	Glutamate	Other mechanisms
Carbamazepine Eslicarbazepine acetate Lacosamide Lamotrigine Oxcarbazepine Phenytoin Rufinamide Zonisamide	Ethosuximide Pregabalin Zonisamide	Barbiturates Benzodiazepines Gabapentin Tiagabine Valproate Vigabatrin	Felbamate Perampanel Topiramate	Brivaracetam Levetiracetam Lacosamide Retigabine (Ezogabine)

Use of anticonvulsants in epilepsy. The primary criterion for the selection of anticonvulsant drugs is the patient's seizure type; determination is largely based on drug studies that assess the drugs’ effectiveness for specific seizure types rather than the defined causes of seizures. Despite restriction to partial seizures, the response to an investigational anticonvulsant is quite variable. The reasons for this include: (1) patient-to-patient variation in the metabolism of the drug, (2) variations in the ability of drug to bind to the target, (3) variations in the amount of drug target produced by different individuals, and (4) different pathophysiological events accounting for the same seizure phenotype.

No single anticonvulsant is clearly superior to others. Causes of variability of effects of anticonvulsants include genetic differences, pathogenesis and severity of epilepsy, age, nutritional status, renal and liver function, concomitant illnesses, and drug interactions. An antiepileptic drug that is effective for one type of epilepsy may not be suitable for another type of epilepsy. For example, absence and myoclonic seizures are aggravated by carbamazepine, which is indicated for generalized tonic-clonic and complex partial seizures.

A randomized, unblinded, multicenter, parallel-group clinical trial has compared the quality-of-life (QoL) outcomes over two years following initiation of treatment with standard versus newer antiepileptic drug in adults with new-onset epilepsy (18). QoL was reduced with failure of the initial treatment, continued seizures, and adverse drug reactions with no significant differences between drugs.

Use of anticonvulsants for prophylaxis of seizures due to disorders other than epilepsy. Decision for prophylactic use of anticonvulsants for seizures due to conditions other than epilepsy should be based on available evidence. The following are some examples:

Anticonvulsants for primary and secondary prevention of seizures in viral encephalitis. Although seizures are common in viral encephalitis, no randomized placebo-controlled trial has been reported to evaluate the efficacy of this approach (31). There is insufficient evidence in the literature to support the use of anticonvulsant drugs in viral encephalitis; therefore, there is a need for controlled clinical trials.

Anticonvulsants for seizures in brain tumors. Seizures following brain tumor surgery are well-recognized, but prophylactic use of anticonvulsants is controversial particularly in patients without previous history of seizures. A study has questioned whether the cost and risk of using prophylactic anticonvulsants in postoperative patients with convexity meningiomas and no history of seizures is worth the small benefit (38).

A study that measured the effects of selected antiepileptic drugs on glioblastoma cells lines concluded that ethosuximide, levetiracetam, and vigabatrin should not be used for prophylaxis or short-term treatment of epilepsy in glioblastoma because of their growth enhancement effects (25).

Use of anticonvulsants in preeclampsia. Seizures occurring in preeclampsia denote progression to eclampsia; these seizures are life-threatening and require control by anticonvulsants. Magnesium sulphate more than halves the risk of eclampsia, and a review of controlled clinical trials indicates that it is more effective than other anticonvulsants, such as phenytoin (09).

Use of anticonvulsants in traumatic brain injury. Prophylactic anticonvulsant therapy has been considered in traumatic brain injury because early posttraumatic seizures occur in more than one fifth of patients in the intensive care unit and are associated with secondary brain injury caused by increased intracranial pressure, brain edema, and cerebral metabolic disturbances with adverse outcomes (44).

Effect of anticonvulsants as analgesics. Similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the use of anticonvulsants in the symptomatic management of neuropathic pain. Although used for relief of neuropathic pain, anticonvulsant drugs do not seem to influence pain perception in epileptic patients (10). Pain-relieving effects require doses that are in each drug's antiepileptic dose range. Given their diverse chemistries and different patterns of activity in seizure models, it seems exceedingly unlikely that these anticonvulsants are all working on neuropathic pain via the same mechanism. Table 2 shows the mechanism of action as well as indications for use of various anticonvulsant drugs for management of pain.

Table 2. Use of Anticonvulsant Drugs for Management of Pain

Drug	Mechanism of action	Uses in pain
Carbamazepine	Slows recovery rate of voltage-gated sodium channels. Stabilization of cell membrane.	First line therapy of trigeminal neuralgia, glossopharyngeal neuralgia
Gabapentin	Inhibits repetitive firing of neurons by action at calcium channels	Neuropathic pain, migraine
Ganaxolone	An epalon that modulates GABA receptors	Migraine
Lacosamide	Modulates sodium channels and interacts with the collapsin-response mediator protein-2	Neuropathic pain, diabetic neuropathy
Lamotrigine	Inhibits repetitive firing of neurons by action at sodium channels	Neuropathic pain, migraine
Phenytoin	Enhances active sodium extrusion and inhibits passive sodium entry, leading to normalization of the sodium gradient and stabilization of the membrane.	Second line therapy of trigeminal neuralgia
Pregabalin	Enhancement of GABA-mediated inhibition	Shown to be effective in controlled studies in diabetic neuropathy and postherpetic neuralgia; fibromyalgia
Rufinamide	Inhibits repetitive firing of neurons by action at sodium channels	Neuropathic pain
Topiramate	Suppresses repetitive depolarization from injured sensory neurons.	Neuropathic pain, migraine, diabetic neuropathy
Valproic acid	Inhibits repetitive firing of neurons by action at sodium channels	Migraine

Effect of anticonvulsants in psychiatric disorders. Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, mood disorders (bipolar affective disorders in particular), and, to some extent, personality disorders. Electroconvulsive therapy can be safely and effectively administered to patients treated with various anticonvulsants, but there is no evidence that combination of the two treatment modalities augments therapeutic efficacy.

Bipolar disorders. The relative neurocognitive effects of the various psychotropic anticonvulsant drugs in patients with bipolar disorder are consistent with relative effects in patients with epilepsy.

Mood disorders. The effectiveness of anticonvulsants in mood disorders raises the question whether the analgesic effects of antiepileptic drugs in patients with neuropathic pain may result, at least in part, from their beneficial effects on mood. For example, gabapentin treatment significantly ameliorates depression, anxiety, fatigue, and other mood symptoms and improves sleep in patients with postherpetic neuralgia and painful diabetic neuropathy.

Alcohol withdrawal. Anticonvulsants have a limited role in the treatment of alcohol withdrawal syndrome. Topiramate is the most widely used anticonvulsant in the treatment of alcohol dependence (06). A systematic review of controlled clinical trials does not provide sufficient evidence in favor of anticonvulsants for the treatment of alcohol withdrawal (28).

Neuroprotective effect of anticonvulsants. Experimental studies have shown neuroprotective effect of some anticonvulsant drugs (19). A randomized trial supports neuroprotective effect of phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated Na channels selectively (33). However, clinical role of phenytoin as a neuroprotective has not been established.

Levetiracetam has been shown to have a neuroprotective effect in animal models of stroke and traumatic brain injury. Other studies have shown protective effects against cerebral edema and neuronal injury in autologous blood-induced cerebral hemorrhage (17).

Valproic acid, widely used for the treatment of epilepsy, is also used for bipolar disorder and migraine prophylaxis. Heat shock protein 70 induction in cortical neurons by valproic acid as a histone deacetylase inhibitor may contribute to its neuroprotective and therapeutic effects. One review describes the preclinical animal experimental studies as well as human clinical trials of the use of valproic acid in hemorrhagic shock and traumatic brain injury (36). Furthermore, it details the different mechanisms in which valproic acid alters gene expression and shows that valproic acid provides neuroprotection while enhancing survival in hemorrhagic shock and traumatic brain injury with potential for application in combat casualty care.

Pharmacokinetics of anticonvulsants. Pharmacokinetics is described in the articles dealing with individual anticonvulsant drugs.

Therapeutic drug monitoring. This is described along with individual anticonvulsant drugs in other articles. Considerable data have accumulated for the older first-generation antiepileptic drugs (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid), and are increasing for the new antiepileptic drugs (brivaracetam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, piracetam, pregabalin, rufinamide, stiripentol, sulthiame, tiagabine, topiramate, vigabatrin, and zonisamide). The latest review of these data has concluded that therapeutic drug monitoring is a practical approach in the management of epilepsy because dose adjustments are based on drug concentrations to optimize efficacy and safety (32).

A simple, accurate and cost-effective liquid chromatography-tandem mass spectrometric method is available for simultaneous quantification of 22 anticonvulsant drugs in case of suspected drug abuse and forensic cases (04).

Pharmacogenetics of anticonvulsants. Pharmacogenetic alterations can affect efficacy, tolerability, and safety of anticonvulsants, including variation in genes encoding drug target, drug transport, drug metabolization, and human leucocyte antigen proteins. The current studies associating genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions. However, several observations (eg, that Asian patients with the HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine) are helpful in improving our knowledge of how genetic variation affects the treatment of epilepsy. A better understanding of the genetic influences on epilepsy outcome is key to developing the much-needed new therapeutic strategies for individual patients with epilepsy.

Other categories of drugs with anticonvulsant effects. In addition to the drugs in the recognized category of anticonvulsants, there are drugs in other therapeutic categories that have anticonvulsant effects. Selective serotonin reuptake inhibitors (SSRIs) can reduce seizure frequency in humans, but no clinical trials have been done to test their value as potential anticonvulsant drugs, partly because of isolated case reports of seizures as adverse events during SSRI treatment (16).

Several herbal medicines have been used as anticonvulsants. The active medicinal components of various herbs that have shown anticonvulsant or antiepileptic activity have been reviewed and classified according to structural types such as alkaloids, flavonoids, terpenoids, saponins, and coumarins (43). This may provide the basis for development of new anticonvulsant drugs.

Cannabidiol (a component of the marijuana plant) was approved by the FDA as Epidiolex in 2018 for the treatment of seizures in Lennox-Gastaut syndrome and Dravet syndrome. It is the only form of cannabidiol available by prescription. The mechanisms for cannabidiol's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. An experimental study has shown inhibitory effects of cannabidiol on voltage-dependent sodium currents, which may partially explain its antiseizure activity (11). A double-blind, placebo-controlled trial showed that in patients with Lennox-Gastaut syndrome the addition of cannabidiol at a dose of 10 or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo (07). A double-blind, placebo-controlled, randomized clinical trial showed that cannabidiol significantly reduced seizures associated with tuberous sclerosis complex compared with placebo (NCT02544763) (40). The 25 mg/kg/day dosage had a better safety profile than the 50 mg/kg/day dosage.

Clinical trials

Numerous clinical trials in epilepsy have been conducted with newer anticonvulsant drugs, often as add-on to established older drugs. These are described in the clinical summaries for individual anticonvulsants. There are fewer clinical trials comparing monotherapies using various anticonvulsants. Remarks on specific trials are given according to indication categories such as epilepsy, pain, and psychiatric disorders.

Clinical trial databases. Information about current clinical trials can be obtained from various databases accessible on the internet. As of June 2021, the largest number of clinical trials on anticonvulsants were listed on the clinical trial database of the National Institutes of Health, which can be accessed at the following website:www.ClinicalTrials.gov. Of the 3738 clinical trials, the largest numbers involved levetiracetam (255), gabapentin (503), lamotrigine (226), pregabalin (511), and topiramate (305). The rest of the trials concern other anticonvulsants including new drugs in development.

Epilepsy. Carbamazepine has been a drug of choice for the treatment of simple or complex partial seizures and secondary generalized seizures in adults and children. After introduction of vigabatrin, an open prospective trial showed that vigabatrin is safe and effective as primary monotherapy for epilepsy in children, with a similar proportion of side effects as carbamazepine. A systematic review of randomized controlled clinical trials to compare efficacy of antiepileptic drugs for patients with generalized epileptic seizures concluded that lamotrigine, levetiracetam, and topiramate are as effective as valproate for treating generalized tonic-clonic, tonic, and clonic seizures, whereas valproate and ethosuximide are the best options for the treatment of absence seizures (02).

Status epilepticus. As of June 2021, 37 clinical trials of anticonvulsants for status epilepticus are listed on the clinical trials database, which can be accessed at the following website: www.clinicaltrials.gov. The trials compare commonly used anticonvulsant drugs and route of administration (eg, intramuscular vs. intravenous). No prospective randomized trial has shown that any agent or combination of agents is more effective for the treatment of convulsive status epilepticus than a benzodiazepine followed by phenytoin or its prodrug, fosphenytoin.

In the Established Status Epilepticus Treatment Trial (ESETT), a randomized, blinded, adaptive clinical trial on patients with benzodiazepine-refractory status epilepticus, intravenous levetiracetam, fosphenytoin, and valproate each led to cessation of seizures and improved alertness within 1 hour in approximately half the patients, and the 3 drugs were associated with similar incidences of adverse events (Kapur et el 2019). Eventually, the choice of anticonvulsant medication in status epilepticus should be guided by individual patient characteristics.

Pain. Clinical trials with individual anticonvulsant medications for pain are mentioned in the clinical summaries discussing the individual drugs. Most of the trials are in patients with pain refractory to treatment with conventional analgesics. One anticonvulsant agent is usually not compared against another in clinical trials.

Cochrane Database review of clinical trials shows that anticonvulsants reduce migraine frequency by about 1.3 attacks per 28 days compared with placebo--more than double the number of patients for whom migraine frequency is reduced by 50% relative to placebo (29). Sodium valproate/divalproex sodium and topiramate were better than placebo, whereas acetazolamide, clonazepam, lamotrigine, and vigabatrin were not.

A Cochrane review has shown some benefit of pregabalin over placebo in reducing the pain of fibromyalgia (41). No definite conclusions were drawn on the efficacy and safety of gabapentin, lacosamide, and levetiracetam.

Psychiatric disorders. Clinical trials of anticonvulsant disorders are described in the clinical summaries discussing the individual anticonvulsant agents. Few studies that compare one anticonvulsant agent against another in psychiatric disorders.

Indications

Anticonvulsant medications have been approved for the treatment of epilepsy, pain, and psychiatric disorders. Details of indications are given in the clinical summaries dealing with individual anticonvulsants.

Off-label uses

Several studies of newer anticonvulsants in epilepsy, pain and psychiatric disorders are still ongoing.

Contraindications

Contraindications are specified for each drug individually (see individual clinical summaries for each drug). There are no contraindications for anticonvulsants as a class.

Goals and duration of treatment

Goals vary according to the disease and anticonvulsant used. Anticonvulsants may be used as monotherapy or polytherapy. Duration varies for acute to chronic, with most of the indications being chronic conditions.

Personalized approach to use of anticonvulsants. Physicians try to match a drug to a patient by trial and error. The final choice may take several months and depends on the efficacy and tolerability of adverse effects. Moreover, there are problems of adverse side effects and failure to control seizures in more than 30% of patients.

Use of therapeutic drug monitoring has demonstrated pharmacokinetic variability of anticonvulsant drugs and a need to individualize the treatment for an optimal outcome. Factors that contribute to pharmacokinetic variability include external factors such as food and comedication, gender, age, and genetic factors, eg, polymorphisms of drug metabolizing enzymes (23).

Control of epilepsy with phenytoin can be a difficult and lengthy process because of the wide range of doses required by different patients and the drug's narrow therapeutic index. Similarly, appropriate doses of carbamazepine take time to determine because of the drug's variable effects on patient metabolism and its potential neurologic side effects. People with epilepsy are genetically different from one another, and some of those differences affect their responses to drugs in a predictable manner. Variants of two genes have been identified that are more likely to be found in patients who required higher dosages of the antiepileptic drugs carbamazepine and phenytoin (39). One variant of the gene that encodes CYP2C9 shows a significant association with the maximum dose of phenytoin taken by patients with epilepsy. Moreover, a variant of a second gene, called SCN1A, with activity in the brain, is found significantly more often in patients on the highest doses of both carbamazepine and phenytoin. SCN1A has been implicated in many inherited forms of epilepsy and is the drug target for phenytoin. Detection of these gene variants might determine, in advance, which patients will need the higher dose and enable a more optimal dose schedule at the start. Otherwise, it could take months to get the seizures under control. These new findings provide a direction for a dosing scheme that could be tested in a clinical trial to assess whether pharmacogenetic testing can improve dosing decisions. Such a trial might also enable physicians to identify patients who might safely take a smaller dose, thereby minimizing their risk for adverse side effects.

In search of a biomarker to predict responses to antiepileptic drugs, a study was conducted in newly diagnosed epileptic patients, drug-resistant patients, as well as healthy controls by using resting-state functional MRI tools to explore changes in spontaneous brain activity (15). Abnormally increased activity in Brodmann area 17 was associated with facilitation of seizure onset in drug-resistant patients, but this was not observed in those with successful control of seizures with an antiepileptic drug. Increased activity in Brodmann area 17 indicates imbalance between brain activation and inhibition and can be considered a predictive biomarker of poor response to antiepileptic drugs.

Anticonvulsant polytherapy. Anticonvulsant drug combinations may be used in the treatment of epilepsy but there are no definite guidelines for this. Combinations of drugs with different mechanisms of action may be more effective than combinations of drugs with the same mechanisms of action. Care should be taken to avoid combinations of drugs with additive toxicity or drug interactions. The most documented combination resulting in synergistic anticonvulsant effect against focal seizures is that of valproic acid and lamotrigine (01).

Anticonvulsants for symptomatic seizures in other neurologic disorders. Frequency of seizures attacks after stroke ranges from 3% up to 60% and there is some controversy about starting use of anticonvulsants after the first seizure. In an open comparative study, in the first group of stroke patients who took anticonvulsants for one year, repeated epileptic attacks were revealed in 27.1% of patients whereas in the other group where there was no treatment with anticonvulsants for one year, repeated attacks were observed in 53.75% of patients (30). These findings favor administration of anticonvulsants after the first seizure in patients after stroke, but controlled studies are needed.

Prophylactic use of anticonvulsants in patients undergoing neurosurgical procedures involving craniotomy, who have no history of seizures, is controversial. There is a wide variation in the rates of seizures because of the variety of lesions treated as well as the types of procedures, and 15% to 50% of patients have been reported to have at least one seizure postoperatively. Routine prophylaxis is often recommended, as a seizure may aggravate the postoperative course. Duration of prophylaxis varies from days to months, but the commonly used anticonvulsant is phenytoin. A study from one center has recommended the prophylactic use of anticonvulsants for one week as safe following uneventful procedures for extradural hematomas and extraaxial brain tumors (20). In case of intraaxial tumors, the duration depends on the nature of lesion as well as the procedure. In case of intraparenchymal hemorrhage, use of anticonvulsant is continued until blood has cleared as determined by brain imaging. Controlled studies are required to assess the usefulness of this approach.

Dosing

The doses are specified in the individual clinical summaries for each anticonvulsant.

Special considerations

Pediatric. Many of the anticonvulsants used in adults also have been used in children without any extra risk. However, safety of anticonvulsants for the treatment of psychiatric disorders in the pediatric age group is not supported by adequate clinical trials.

Geriatric. The use of anticonvulsants in the elderly for the management of epilepsy is safe.

Renal failure. Treatment of seizures in patients with renal failure, particularly those on dialysis, is challenging. Most anticonvulsants require dosage adjustment according to the degree of renal failure, and extra doses after dialysis (08).

Pregnancy. There is concern about teratogenicity as the incidence of congenital malformations in offspring of women treated with anticonvulsants during pregnancy is somewhat higher than in offspring of women not exposed to these drugs. Most anticonvulsant drugs fall into category C of the United States Food and Drug Administration. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans. Long-term developmental effects of antiepileptic drugs in children as they grow older are still uncertain. Potential benefits may warrant use of antiepileptic drugs in pregnant women despite potential risks.

Scientific data are now becoming available for the use of second generation antiepileptic drugs during epilepsy. Lamotrigine and levetiracetam are considered to have low risks for both anatomical and behavioral teratogenesis (26). Although safety issues are favorable for lamotrigine, its therapeutic concentration may be difficult to maintain during pregnancy as its clearance from the body during pregnancy is increased due to being metabolized by uridine-diphospate glucuronosyl transferase (34).

Analysis of 20 year data from the Australian Pregnancy Register of women on antiepileptic drugs for epilepsy as well other indications showed that polytherapy did not increase fetal hazard unless valproate or topiramate was involved in the combination (42). The use of these two drugs should be avoided in pregnancy unless absolutely required for seizure control. For women on anticonvulsant therapy who are breastfeeding, there are still limited data regarding the degree to which anticonvulsants penetrate into breast milk. In general, women with epilepsy can breastfeed their babies safely with some cautions (14). Phenobarbital and primidone should be avoided, and with ethosuximide, levetiracetam, lamotrigine, topiramate, and zonisamide there is a potential for significant breast milk concentrations.

Anesthesia. There are no anesthetic implications for use of anticonvulsants.

Interactions

Anticonvulsant drugs may interact with each other as well as with other drugs. These are specified in the individual clinical summaries for each agent.

Adverse effects

The adverse effects of anticonvulsants involve practically every system of the body. These are described in the separate clinical summaries of individual anticonvulsants. However, some adverse effects are common to most anticonvulsant agents, for example, adverse skin reactions, dose-related neurotoxicity, and psychiatric complications. Long-term use of anticonvulsants may lead to some metabolic and endocrine disturbances.

Anticonvulsant hypersensitivity syndrome is a rare but potentially fatal adverse drug reaction. Clinical presentations include Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS). Most commonly involved anticonvulsants are the aromatic drugs such as phenytoin, phenobarbital, carbamazepine, and lamotrigine. Nonaromatic drugs, such as benzodiazepines and levetiracetam, are the safer alternatives in these cases (05).

In 2008, the U.S. Food and Drug Administration (FDA) conducted a review of nearly 200 studies on anticonvulsant drugs and concluded that they nearly doubled the risk of suicide compared to placebo, although in absolute terms it was still quite small. The FDA recommended the black box warning, but an expert advisory panel did not support the recommendation. However, the panel agreed on the distribution of medication guides to healthcare providers, outlining the risks of antiepileptic medications and suicidal thoughts.

Drug resistance. Problems with the use of anticonvulsants include loss of efficacy and development of drug resistance. One third of patients with epilepsy develop resistance to drugs, which is associated with an increased risk of death and debilitating psychosocial consequences. The International League Against Epilepsy defined pharmacoresistant epilepsy as the “failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drugs schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (22). Some studies suggest an association of anticonvulsant drugs with increased risk of suicide in epileptic patients, whereas others have reported no association. Evaluation of this topic is complicated because observational studies show that suicide tendencies and depression are not uncommon in epilepsy, and persons with epilepsy have higher risk for suicide than healthy controls (13). However, there is a lack of prospective and longitudinal studies on suicide in epilepsy.

If epilepsy is resistant to multiple anticonvulsant drugs, the mode of resistance is nonspecific, involving drug-efflux transporters. Another mechanism underlying drug resistance in epilepsy may be the same as in cancer: a cellular pump called P-glycoprotein, which protects cells from toxic substances by actively exporting the offending compounds. In epilepsy resistant to phenytoin, low levels of phenytoin have been demonstrated in association with high levels of P-glycoprotein expression, the product of the MDR1 gene. Genotyping differences have been shown between responders and non-responders. Further studies in this direction might eventually enable the drugs to be tailored to the patient's profile.

Study of brain tissue removed during surgery for epilepsy has shown that the mechanism of action of carbamazepine, use-dependent block of voltage-dependent sodium channels, is completely lost in carbamazepine-resistant patients. Likewise, seizure activity elicited in human hippocampal slices is insensitive to carbamazepine. In marked contrast, carbamazepine-induced use-dependent block of sodium channels blocks seizure activity in vitro in patients clinically responsive to this drug. These observations suggest that the study of changes in ion channel pharmacology and their contribution to the loss of anticonvulsant drug efficacy in human epilepsy may provide an important impetus for the development of novel anticonvulsants specifically targeted to modified ion channels in the epileptic brain. It is possible to use human tissue for the demonstration of drug resistance in an in vitro preparation, providing a unique tool in the search for novel, more efficient anticonvulsants.

Studies of the properties of transmitter receptors of tissues removed during surgical treatment of drug-resistant temporal lobe epilepsy showed use-dependent downregulation of neocortical GABAA-receptor. This represents a temporal lobe epilepsy-specific dysfunction in contrast to stable GABAA-receptor function in the cell membranes isolated from the temporal lobe of temporal lobe epilepsy patients afflicted with neoplastic, traumatic, or ischemic temporal lesions and can be antagonized by brain-derived neurotrophic factor. These findings may help to develop new treatments for drug-resistant temporal lobe epilepsy.

Nanoparticulate formulations of antiepileptic drugs can be used as drug carriers to the brain with pharmacoresistant seizures and P-glycoprotein overexpression. Phenytoin carried by silica core iron oxide nanoparticles reduces the expression of pharmacoresistant seizures in rats (24).

Management. Treatment of adverse effects of anticonvulsants usually requires discontinuation of the offending agent and replacement with one that is better tolerated.

Concluding remarks and future prospects for anticonvulsants. Despite the large number of anticonvulsants available, there are considerable unmet needs in the management of epilepsy, eg, drug-resistant epilepsy. Newer drugs for epilepsy are still being approved. In 2016, the FDA approved brivaracetam as an add-on treatment to other medications to treat partial onset seizures in patients 16 years of age and older with epilepsy. Brivaracetam, a high-affinity synaptic vesicle protein 2A ligand, is reported to be 10- to 30-fold more potent than levetiracetam. It inhibits neuronal voltage-gated sodium channels as a partial antagonist (03). A multicenter, retrospective cohort study of brivaracetam in patients with genetic generalized epilepsies showed that it was well tolerated, with 50% responder rates like those observed in focal epilepsies, and that an immediate switch from levetiracetam to brivaracetam at a ratio of 15 to 1 is feasible (37).

Most conventional anticonvulsant drugs are directed at symptomatic control of seizures with much less effect on disease modification and neuroprotection. New antiepileptic drug discovery efforts aim to identify novel drugs that interfere with the underlying mechanisms of epilepsy. Advances in biotechnology with improved understanding of genetics and molecular pathophysiology of epilepsies will contribute to these efforts.