Antiepileptic drugs

Hydantoins

Hydantoins are characterized by the presence of a phenol ring linked to a five-membered ring consisting of alternating keto and nitro groups at the four corners. Substitution of the side chains attached to the nitrogen atom forming the fifth corner (located between the two keto groups) has a significant effect on the pharmacological activity of the compound. In addition to phenytoin, three other hydantoins are used as antiepileptic drugs. The first of these, 5-ethyl-5-phenylhydantoin, appeared before phenytoin. Its anticonvulsant and sedative effects have been used in the treatment of extrapyramidal disorders. However, the high incidence of drug allergy has limited its use.

Phenytoin

Phenytoin was introduced into clinical practice in 1938 as the first non-sedating antiepileptic drug. Its anticonvulsant effect was confirmed in experimental animals using the maximal electroshock model. Phenytoin remains the most widely used drug in the United States for the treatment of partial and secondarily generalized seizures.

Phenytoin has several points of application in the CNS. The final effect is to limit the spread of epileptic activity from the site of its primary generation in the cerebral cortex and to reduce maximum epileptic activity. The ability of phenytoin to block seizures in experimental animals during maximum electric shock allows us to predict its effectiveness in partial and secondarily generalized seizures. At the same time, phenytoin is not able to block seizures caused by pentylenetetrazole, which correlates with its ineffectiveness in absences.

Phenytoin blocks the development of post-tetanic potentiation, the increase in activity of neuronal systems following high-frequency stimulation. Post-tetanic potentiation is related to the processes of neuronal plasticity, which are an important feature of these cells; however, it may also participate in the amplification and propagation of epileptic discharges. Phenytoin is thought to block post-tetanic potentiation by preventing calcium ion entry into the neuron or by increasing the refractory period of neuronal sodium channels. The latter effect appears to be key to phenytoin's action, since it has been shown to attenuate prolonged high-frequency discharges in several neuronal systems.

Although phenytoin does not affect the amplitude or configuration of individual action potentials, it does reduce the rate at which neurons generate action potentials in response to brief periods of depolarizing stimulation. This effect is due to blockade of sodium channels in neurons, occurs only in depolarized cells, and is blocked by hyperpolarization. Thus, phenytoin's mechanism of action probably involves stabilization of the inactive state of neuronal sodium channels. This effect is dependent on the activity of the cell and is not observed in neurons that are not classified as rapidly discharging.

Phenytoin also inhibits synaptic transmission by inhibiting the release of some neurotransmitters, probably by blocking L-type calcium channels in presynaptic nerve terminals. At therapeutic concentrations, phenytoin also affects calcium regulatory systems in brain cells that use calmodulin.

Phenytoin remains a popular drug for the treatment of partial and secondarily generalized seizures, despite the fact that it causes a variety of side effects that can be divided into dose-dependent, idiosyncratic, and chronic.

Dose-dependent toxic effects are associated primarily with the effect of phenytoin on the central nervous system and are probably explained by its ability to block rapidly discharging neurons. Many cells in the brain normally discharge in rapid bursts of impulses and, therefore, are sensitive to the action of phenytoin at its therapeutic concentration in the blood. Thus, the vestibular nuclei, which respond to rapid changes in balance and posture, represent an example of such a system. The action of phenytoin on these cells can explain the development of ataxia. Since the oculomotor centers in the pons also consist of rapidly discharging neurons that maintain eccentric gaze direction against the resistance of the elastic forces of the orbits, the weakening of rapid discharges in this system leads to the appearance of nystagmus. Drowsiness, confusion, and dizziness are other dose-dependent side effects of phenytoin. These side effects may be observed at therapeutic blood concentrations of the drug (10-20 μg/ml) and even at lower concentrations (in patients hypersensitive to these side effects or taking several drugs simultaneously). Ataxia, dysarthria, drowsiness, confusion, and nystagmus occur more often if the blood concentration of the drug increases to 20-40 μg/ml. Very high blood concentrations (usually above 40 μg/ml) cause severe encephalopathy with the development of ophthalmoplegia, sometimes comatose consciousness.

Extrapyramidal complications with phenytoin are uncommon, although they can be severe. They may take the form of dystonia, choreoathetosis, tremor, or asterixis. Such effects may be either idiosyncratic or dose-dependent, since dose reduction sometimes results in regression of hyperkinesis.

The effects of phenytoin on cognitive function have received particular attention. Although it is generally accepted that it impairs cognitive function to a lesser extent than barbiturates, there is disagreement about whether it impairs cognitive function to a greater extent than carbamazepine. Although initial data favored carbamazepine, subsequent analysis showed that at comparable blood concentrations, the two drugs impair cognitive function to a similar extent.

Since phenytoin affects atrioventricular conduction and ventricular automaticity, rapid parenteral administration may cause cardiac arrhythmia and hypotension, although some of these effects are undoubtedly related to the action of propylene glycol, which serves as a solvent. Although dose-dependent effects on the gastrointestinal tract are rare, some patients experience nausea, vomiting, epigastric discomfort, and weight loss or weight gain while taking the drug.

The most notable idiosyncratic reaction to phenytoin is allergy, which usually manifests as a measles-like rash. More serious skin complications of the drug include exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, with an incidence of 1 in 10,000 to 50,000. Fever, arthralgia, lymphadenopathy, and influenza-like syndrome may occur alone or in combination with the rash. Lymphadenopathy may be severe enough to raise suspicion of lymphoma.

Phenytoin is metabolized in the liver, and hepatotoxicity may occur with both acute and chronic administration. Mild increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occur in approximately 10% of patients. Although signs of cholestasis with mild increases in alkaline phosphatase are common, increases in serum bilirubin are relatively rare. Induction of the cytochrome P450 enzyme gamma-glutamyl transpeptidase may occur with subacute or chronic phenytoin administration but is not indicative of liver injury. The decision to discontinue phenytoin therapy should be made based on the clinical picture and serial liver function tests rather than on a single enzyme measurement.

Adverse hematologic reactions with phenytoin are relatively rare, but can be quite serious and even fatal. These complications include leukopenia, thrombocytopenia, agranulocytosis, disseminated intravascular coagulation, and isolated red cell aplasia. Macrocytosis and megaloblastic anemia sometimes occur with prolonged use of phenytoin; these regress with folic acid. Phenytoin can also cause immunologic changes characteristic of lupus syndrome with increased levels of antinuclear antibodies, as well as interstitial nephritis, polyarteritis nodosa, and other manifestations of immune dysfunction. Rarely, phenytoin reduces the level of immunoglobulins in the serum.

The potential for chronic toxicity limits the use of phenytoin, with cosmetic defects being the most concerning. Phenytoin causes proliferation of subcutaneous tissues, which results in thickening of the skin over the bridge of the nose, coarsening of facial features, gingival hyperplasia (correction of which sometimes requires orthodontic surgery), and hair growth on the face and trunk. Gingival hyperplasia occurs in 25-50% of patients, especially with poor oral hygiene, although the cosmetic defect is more noticeable in women and children. Connective tissue proliferation occasionally causes Dupuytren's contracture, Peyronie's disease, and pulmonary fibrosis.

Phenytoin may also cause polyneuropathy, usually manifested by loss of Achilles reflexes and slight slowing of excitation conduction along peripheral nerve fibers. Clinically significant neuropathy with the development of weakness and sensory disturbances occurs rarely when taking phenytoin.

With long-term use of phenytoin, a rickets-like condition may develop due to impaired conversion of vitamin D precursors to the metabolically active form. Although nearly half of patients taking phenytoin for several years develop significant changes in bone density and serum 25-hydroxycholecalciferol levels, bone fractures or ossalgia are extremely rare. Nevertheless, some physicians recommend taking vitamin D concomitantly with phenytoin.

With prolonged use of phenytoin, the endocrine system function is often impaired, since the drug intensively binds to serum proteins, increasing the clearance of thyroid hormones. Although most patients are euthyroid and have normal blood levels of thyroid-stimulating hormone, some develop hypothyroidism. Phenytoin can also impair insulin secretion in patients predisposed to diabetes mellitus, and in extreme cases can provoke the development of hyperglycemia. Phenytoin can also increase the concentration of ACTH and cortisol in the blood, reduce the release of antidiuretic hormone, increase the secretion of luteinizing hormone, and enhance the metabolism of testosterone and estradiol. These effects, as well as the effect on epileptiform discharges, can affect the physiological processes underlying sexual activity.

Cerebellar atrophy with a decrease in Purkinje cells is common with long-term treatment with phenytoin. Whether this atrophy is caused by the seizures or by the drug itself is widely debated. Both factors appear to contribute, as the drug has been shown to cause cerebellar atrophy in healthy dogs with long-term administration. The clinical significance of this phenomenon remains unclear.

Fetal hydantoin syndrome has polymorphic manifestations: cleft lip, cleft palate, hypertelorism, atrial and ventricular septal defects, skeletal and CNS developmental anomalies, hypospadias, intestinal malformations, developmental delay, hypoplasia of the fingers and finger skin pattern, mental retardation. This syndrome is more correctly called fetal anticonvulsant syndrome, since many newborns suffering from it were exposed to a number of antiepileptic drugs in utero.

Phenytoin is available as the free acid or sodium salt. The most commonly used form, Dilantin, is available as capsules containing 30 and 100 mg of phenytoin sodium. The latter dose is equivalent to 92 mg of the free acid. Other forms of phenytoin sodium, including tablets containing 50 mg of the drug (Dilantin Infatab) and generic forms of the drug, have a shorter half-life than regular Dilantin. Phenytoin is also available as an oral suspension because it is well absorbed by this route (the half-life in this case is approximately 22 hours). More than 95% of absorbed phenytoin is metabolized in the liver, mainly by glucuronidation. Phenytoin is metabolized primarily by the CYP2C isoenzyme of the P450 family of enzymes.

The therapeutic concentration of phenytoin in the blood is usually 10-20 μg/ml. An important feature of phenytoin metabolism is its nonlinear kinetics: when the dose of the drug taken orally increases, the linear increase in the serum concentration of the drug occurs in a relatively narrow range, after which even a slight increase in the dose leads to a sharp increase in its level in the blood. This phenomenon is due to the fact that the liver stops metabolizing phenytoin at a rate proportional to its concentration in the serum (first-order kinetics) and begins to metabolize it at a constant rate (zero-order kinetics). As soon as the drug level in the blood reaches the lower limit of the therapeutic range, a further increase in the dose should be made once a week by no more than 30 mg - in order to avoid serious manifestations of intoxication.

Phenytoin is extensively bound to serum proteins, especially albumin, with approximately 10% of the total drug remaining free. Since only unbound phenytoin crosses the blood-brain barrier, changes in serum protein binding may affect the drug's effect. This is of particular importance in certain situations, such as hypoproteinemia due to malnutrition or chronic disease, and changes in serum protein levels during pregnancy. Although total serum phenytoin concentrations decrease during pregnancy, free phenytoin levels may remain unchanged.

Phenytoin is found in virtually all body fluids, including cerebrospinal fluid, saliva (which can serve as a source for measuring free phenytoin concentration), breast milk, and bile. Due to its high lipid solubility, phenytoin is concentrated in the brain, and its concentration in the brain can be 100-300% of the total serum concentration.

Phenytoin interacts with a number of other drugs. Thus, it can affect the absorption, binding to serum proteins, metabolism, pharmacodynamics of other drugs or be affected by other drugs.

The interaction between antiepileptic drugs is complex and variable. For example, phenobarbital induces liver enzymes that metabolize phenytoin, but simultaneously displaces phenytoin from its binding to serum proteins and competes with it for metabolizing enzymes. Consequently, with simultaneous administration of phenobarbital, the concentration of phenytoin can either increase or decrease. The interaction between phenytoin and carbamazepine or valproic acid is also variable, but in most cases phenytoin enhances the metabolism of other drugs, which requires an increase in their dose. Conversely, carbamazepine inhibits the metabolism of phenytoin, increasing its concentration in the serum. The interaction between phenytoin and primidone is even more complex. Phenytoin reduces the concentration of primidone itself in the serum, but increases the concentration of its metabolite, phenobarbital, in the blood. While felbamate and topiramate increase serum phenytoin levels, vigabatrin will decrease blood phenytoin levels. These changes typically occur within 10-30%.

Phenytoin is indicated for partial and secondarily generalized seizures, including status epilepticus. This list includes focal motor, focal sensory, complex partial, and secondarily generalized tonic-clonic seizures. Phenytoin can also be useful in the treatment of primary generalized tonic-clonic seizures, but it is usually ineffective in absences, myoclonic, and atonic seizures. In status epilepticus, phenytoin can be administered intravenously in a loading dose of 18-20 mg/kg. However, in this situation, it is preferable to administer fosphenoin, also in a loading dose of 18-20 mg/kg. In other situations, when the therapeutic concentration in the blood must be achieved within 24 hours, the drug is prescribed orally in a loading dose of 400 mg 3 times a day. The risk of gastrointestinal adverse effects, particularly in patients not previously treated with phenytoin, usually limits the single oral dose to 500 mg. In less urgent cases, phenytoin therapy is initiated at 300 mg/day (or 3-5 mg/kg). Because the drug has a half-life of 22 hours, this dose provides steady-state within 5-7 days. Although Dilantin capsules can be taken once daily, other forms of phenytoin may require twice-daily dosing, depending on differences in bioavailability. The phenytoin dose can be increased by 100 mg weekly until therapeutic effect or toxicity is achieved or the recommended therapeutic range of 10-20 mcg/mL is reached. After reaching the therapeutic range, further dose increases are carried out at one time by no more than 30 mg to avoid entering the nonlinear part of the metabolic curve and the associated risk of sudden toxic effects. Capsules containing 50 mg of the substance, when taken once, usually do not ensure maintenance of the therapeutic concentration of the drug throughout the day. Phenytoin suspension for oral administration contains 125 mg of the active substance in a 5-millimeter measuring spoon and 0.6% alcohol. A suspension containing 30 mg of the drug in 5 ml is also available. Since metabolism in children is faster than in adults, at this age it is advisable to take the drug twice a day.

When administered intravenously, phenytoin should not be mixed with glucose, which reduces its solubility. The rate of administration should not exceed 50 mg per minute. During and after administration, blood pressure and cardiac conduction should be monitored to promptly respond to cardiac conduction disturbances or a drop in blood pressure. Daily administration of phenytoin is possible for decades. With long-term use, it remains an effective and well-tolerated drug. Some patients have been taking phenytoin for over 50 years. Although the drug remains generally effective, tachyphylaxis has been observed in some individuals. The drug is discontinued gradually over 1-3 months, unless side effects require more rapid cessation of the drug.

Treatment with phenytoin is recommended to begin with a dose of 3-7 mg/kg per day, most often 5 mg/kg/day (in the average adult - 300 mg/day). This dose is usually prescribed in 1-2 doses. Long-acting capsules containing 100 mg and 30 mg of the active substance, or a suspension containing 125 mg or 30 mg of the active substance in 5 ml can be used for treatment. When taking generics or short-acting forms, the daily dose should be prescribed in 2-3 doses. Phenytoin for parenteral administration is available as a solution containing 50 mg/ml of sodium phenytoin in ampoules or vials of 2 ml. Sodium phenytoin for parenteral administration should not be administered intramuscularly due to its irritating effect on tissues.

Fosphenytoin

Fosphenytoin is a phosphate ester of phenytoin that is more soluble in water than the parent compound. Fosphenytoin is broken down by phosphatases in the lungs and blood vessels to form phenytoin, with a half-life of 10 minutes. Because fosphenytoin is more soluble in aqueous solutions than phenytoin, it does not require the presence of propylene glycol and ethanolamine to stabilize the solution, as phenytoin does. It is believed that some of the side effects of intravenous phenytoin are related to these solvents.

Fosphenytoin causes less pain and irritation at the injection site than intravenous phenytoin. In addition, fosphenytoin appears to cause less hypotension, abnormal heart rhythms, and tissue necrosis when injected extravascularly than phenytoin. These advantages are supported by clinical trials and clinical experience.

Although the fosphenytoin molecule is 50% heavier than phenytoin, doses of phenytoin and fosphenytoin are considered equivalent. Therefore, administration of 1000 mg fosphenytoin will result in the same serum phenytoin concentration as administration of 1000 mg phenytoin. Fosphenytoin can be safely administered at a rate of 150 mg per minute, three times faster than phenytoin. This allows for faster administration and more favorable protein binding characteristics, resulting in blood levels of free phenytoin rising as rapidly with fosphenytoin as with phenytoin alone. Fosphenytoin can also be administered intramuscularly.

The side effects of fosphenytoin are essentially the same as those of phenytoin, but appear to be less severe. An exception is pruritus of the face, trunk, or genitals associated with rapid administration of fosphenytoin, which is probably due to the formation of formic acid during metabolism. Other important problems associated with the use of fosphenytoin are its higher cost (compared to phenytoin) and its limited availability. In addition, there is a risk of confusion: phenytoin may be confused with fosphenytoin, which may lead to overly rapid and potentially dangerous intravenous administration of phenytoin.

Ethotoin

Ethotoin has been used since 1956. It is usually used in situations where phenytoin has been effective but its toxic effects have made further use impossible. Ethotoin almost never causes cosmetic defects and causes ataxia to a lesser extent than phenytoin. The disadvantages of ethotoin include a short half-life, which requires taking the drug 3-4 times a day, and, apparently, lower efficacy than phenytoin. Ethotoin is available in tablets of 250 and 500 mg. Its mechanism of action is probably similar to phenytoin. Treatment is initiated with a dose of 250 mg 4 times a day (1 g/day) or by replacing 100 mg of phenytoin with 250-500 mg of ethotoin daily. The dose of ethotoin can be increased by 250-500 mg once a week until the effect is achieved or intolerable side effects appear. The total dose can reach 2-3 g/day. The therapeutic serum concentration is usually 15-45 mcg/ml. Ethotoin causes the same side effects as phenytoin, but their probability is lower. The only relatively unique side effect of ethotoin is distortion of visual perception, expressed as increased brightness of perceived light. Gingival hyperplasia and cosmetic changes caused by phenytoin may regress when phenytoin is replaced by ethotoin.

Another clinically important hydantoin is mephenytoin, 3-methyl-5-ethyl-5-phenylhydantoin. The therapeutic effect is exerted by the active metabolite of mephenytoin, 5-phenylhylantoin, formed from mephenytoin by demethylation. In terms of properties, mephenytoin is similar to hydantoins and barbiturates and is active in both the maximum electric shock model and the pentylene hetrazole seizure model in experimental animals. Introduced in 1945, it is used to treat partial and secondarily generalized seizures. Mephenytoin is available in 100 mg tablets. The daily dose ranges from 200 to 800 mg. Since the active metabolite of mephenytoin has an elimination half-life of approximately 3-6 days, it is prescribed once a day. Although mephenytoin is effective in partial and secondarily generalized seizures, it is not the drug of choice due to toxicity. Compared with phenytoin, mephenytoin is more likely to cause rash, lymphadenopathy, fever, serious and even fatal hematological complications.

Barbiturates

Introduced into clinical practice in 1912, phenobarbital remained the most widely used antiepileptic drug for several decades. It is currently the drug of choice for some seizure types in countries where cost and ease of administration of antiepileptic drugs are high priorities. In the United States, phenobarbital use has declined due to its pronounced sedative effects and negative effects on cognitive function. Chemically, phenobarbital is 5-ethyl-5-phenylbarbituric acid. Due to differences in physicochemical properties, the actions of different barbiturates vary greatly. Long-acting barbiturates (such as phenobarbital) are antiepileptic, while short-acting barbiturates (such as thiopental and methohexital) are relatively ineffective against epileptic seizures and may even increase epileptiform activity. Phenobarbital and primidone are the two barbiturates most widely used in the treatment of epilepsy.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Phenobarbital

Phenobarbital is active in a number of experimental models of epilepsy, including the maximal electroshock and pentylenetetrazole seizure models. Although studies in experimental models indicate that phenobarbital has a broader spectrum of activity than phenytoin and carbamazepine, clinically phenobarbital is most useful in the same types of seizures as these drugs, namely, partial and secondarily generalized seizures.

Phenobarbital enhances GABA-receptor-mediated inhibitory postsynaptic potentials by increasing the duration of opening of receptor chloride channels in response to GABA. In addition to enhancing inhibitory postsynaptic potentials, phenobarbital weakens the excitatory response to glutamate in neuronal culture, blocks fast neuronal discharges (probably by acting on their sodium channels), and blocks the entry of calcium ions into neurons in certain situations.

Phenobarbital is well absorbed after oral or intramuscular administration. Therapeutic blood levels of phenobarbital range from 5 to 40 μg/ml, but most often lie in the range of 10 to 30 μg/ml. Approximately 45% of phenobarbital in the blood is bound to serum proteins, but only the free fraction (55%) is able to penetrate the brain. Phenobarbital is metabolized by the hepatic cytochrome P450 enzyme system. Although phenobarbital induces liver microsomal enzymes, this does not lead to significant autoinduction. A significant proportion (25%) of unchanged phenobarbital is eliminated by the kidneys; the remainder is metabolized in the liver, mainly converting to beta-hydroxyphenobarbital. The elimination of phenobarbital and its metabolites is linear, with the half-life of the drug ranging from 72 to 120 hours. In neonates, the half-life may be as long as 150 hours, gradually shortening during the first years of life. Due to the long half-life, phenobarbital can be administered once daily, and there is no reason other than force of habit to recommend taking it three times daily. If treatment is not initiated with a loading dose of phenobarbital, several weeks of administration are required to achieve steady-state serum concentrations of the drug.

The addition of valproic acid rapidly increases the blood level of phenobarbital by 20-50%, while the simultaneous administration of phenytoin has a variable effect on the concentration of phenobarbital in the blood. Carbamazepine, topiramate, and benzodiazpines usually do not affect the blood level of phenobarbital. Since phenobarbital induces hepatic microsomal enzymes, the metabolic transformation of other antiepileptic drugs is accelerated when phenobarbital is added. Although phenobarbital increases the metabolism of phenytoin, the serum level of hydantoin may not change, since both drugs compete for the same metabolic pathways. Phenobarbital may cause a small decrease in the concentration of carbamazepine in the blood, variable changes in the level of 10,11-carbamazepine epoxide metabolite, and a minimal decrease in the concentration of valproic acid in the blood. A number of drugs can affect the blood level of phenobarbital, including propoxyphene and phenothiazines, which increase the concentration of the barbiturate in the blood. In contrast, phenobarbital can decrease the blood concentration of theophylline, tetracyclines, coumadin, phenothiazines, and vitamin D. Like phenytoin and carbamazepine, phenobarbital can decrease the level of endogenous estrogens - this leads to the fact that low-dose oral contraceptives may lose their effectiveness. In combination with other sedatives and hypnotics, including alcohol and benzodiazepines, phenobarbital can cause life-threatening respiratory depression.

Phenobarbital is used for the acute and chronic treatment of partial and secondarily generalized seizures. Although it is also useful in primarily generalized tonic-clonic seizures, atonic seizures, absences, and myoclonic seizures, its effectiveness in these cases is more variable. To achieve therapeutic blood levels, the daily dose of phenobarbital in adults should be 1–1.5 mg/kg; in children, 1.5–3.0 mg/kg. In status epilepticus, phenobarbital may be given intravenously in a loading dose of 18–20 mg/kg at a rate not exceeding 100 mg/min. If a loading dose is not used, steady-state blood levels are achieved after many weeks.

Phenobarbital is as effective as phenytoin and carbamazepine in controlling partial seizures and may be the drug of choice for neonatal epileptic seizures and febrile seizures in children. However, in the latter case, phenobarbital often leads to the development of hyperactivity and learning difficulties.

One of the main dose-dependent side effects of phenobarbital is drowsiness. The sedative effect is most pronounced in the first 1-2 months of treatment. Patients taking phenobarbital for years often do not notice the sedative effect and fatigue until the drug is gradually discontinued. Other side effects caused by the drug's action on the central nervous system - ataxia, dysarthria, dizziness, nystagmus, cognitive impairment - are relatively common, especially against the background of high concentrations of the drug in the blood.

Children and the elderly who take phenobarbital sometimes experience paradoxical hyperactivity rather than sedation. All patients may experience some depressive symptoms when taking phenobarbital, which increases the risk of suicidal behavior.

Idiosyncratic adverse effects associated with phenobarbital include hypersensitivity, rash, and uncommon hematologic and hepatic complications. Sexual dysfunction may occur in men taking phenobarbital, and decreased libido may occur in women. Liver necrosis, cholestasis, and gastrointestinal disturbances are rare.

Phenobarbital-induced increase in liver microsomal enzyme activity may affect vitamin D metabolism, leading to osteomalacia, and may cause folate deficiency and megaloblastic anemia. Furthermore, long-term phenobarbital administration may induce connective tissue proliferation, although the cosmetic defect is usually not as noticeable as with phenytoin. Phenobarbital-induced connective tissue proliferation may lead to Dupuytren's contracture of the hand, Peyronie's disease, frozen shoulder, and diffuse joint pain with or without palmar fibromatosis (Ledderhouse syndrome).

Phenobarbital has adverse effects on cognitive function, and these effects may persist even after the drug is discontinued. Farwell (1990) found that children taking phenobarbital had an IQ 8.4 points lower than controls, and 6 months after the drug was discontinued, it was 5.2 points lower than controls.

Although phenobarbital is recommended by the American College of Obstetricians and Gynecologists for the treatment of epilepsy during pregnancy, there is little convincing evidence that it is safer than most other antiepileptic drugs in this situation. Phenobarbital use during pregnancy has been associated with fetal malformations, including tracheoesophageal fistulas, small bowel and lung hypoplasia, digital anomalies, ventricular septal defects, hypospadias, meningomyelocele, mental retardation, and microcephaly. There is no direct evidence that these malformations are related to phenobarbital use; they may be attributable to other concomitant antiepileptic drugs, epilepsy itself, or other underlying medical conditions.

Phenobarbital and other agents that induce liver enzyme activity (eg, phenytoin and carbamazepine) accelerate the metabolism of coagulation factors, including prothrombin, leading to hemorrhagic complications in the newborn. These complications can be prevented by prescribing vitamin K to the expectant mother at a dose of 10 mg orally one week before delivery. Since the exact date of birth cannot be predicted, vitamin K should be taken after the 8th month of pregnancy.

Phenobarbital is available as 15, 30, 60, and 100 mg tablets. Special care is needed when taking phenobarbital, since tablets of different strengths are often perceived by patients as the same "little white pill" and may mistakenly take a tablet with a different strength. In adults, treatment is usually initiated with a dose of 90-120 mg per day (unless a loading dose is used). Although the 100 mg tablets are more convenient, it is better to take 3-4 30 mg tablets at the beginning of treatment; this facilitates gradual titration of the dose. The 15 mg tablets may be useful for fine titration of the dose or for gradual withdrawal of phenobarbital, which may extend over several months unless a serious side effect requires more rapid withdrawal. Phenobarbital for intravenous administration is available in several strengths. Intravenous administration should be done at a rate not exceeding 100 mg/min, taking into account the possibility of respiratory and cardiac depression. Some parenteral phenobarbital preparations contain propylene glycol, an ingredient that is a tissue irritant.

Primidone

It is a 2-deoxy analogue of phenobarbital. It is effective against epileptic seizures, probably due to its two active metabolites - phenylethylmalonic acid (PEMA) and phenobarbital. Under experimental conditions, primidone is as effective as phenobarbital in the model of seizures induced by maximal electric shock, but is less effective in seizures induced by pentylenetetrazole. At the same time, it has an advantage over phenobarbital in models of myoclonic epilepsy.

Primidone and FEMC are relatively short-lived compounds with half-lives of 5-15 hours. Approximately half of the primidone dose is excreted unchanged by the kidneys. The attainment of steady-state serum phenobarbital concentrations appears to correspond to the onset of the therapeutic effect of primidone. Primidone is well absorbed when taken orally. Approximately 25% is bound to serum proteins. Primidone has the same drug interactions as phenobarbital.

Primidone is used to treat partial seizures, secondarily generalized seizures, and occasionally myoclonic seizures. Although most comparative studies have shown primidone to be equally effective as phenobarbital, patients taking primidone dropped out of the study more often than those taking phenobarbital, as well as carbamazepine and phenytoin. This is because side effects (drowsiness, nausea, vomiting, dizziness) occur significantly more often with primidone, especially during the first week of treatment. Patients who continued taking primidone for more than 1 month dropped out of the study no more often than those taking other drugs. No significant differences in the frequency of side effects and effectiveness were noted between the drugs during this period. Approximately 63% of patients taking primidone were seizure-free after 1 year of treatment, compared with 58% of patients taking phenobarbital, 55% of patients taking carbamazepine, and 48% of patients taking phenytoin.

An important feature of the use of primidone is the need for slow titration of the dose. Some patients experience severe drowsiness after taking the first dose. Severe drowsiness may persist for several days. In this regard, it is advisable to begin treatment with a test dose of 50 mg. If the patient tolerates this dose, he can be prescribed the next dose - 125 mg, which should be taken at night for 3-7 days. Subsequently, the dose is increased by 125 mg every 3-7 days. The effective dose in adults is usually 250-500 mg 3 times a day. Given the short half-elimination period of primidone and its metabolite FEMC, the drug is recommended to be taken fractionally throughout the day. In case of nocturnal seizures, the entire daily dose can be prescribed at night. With this treatment regimen, the phenobarbital level will be constant throughout the day.

The therapeutic level of primidone in the blood varies from 4 to 15 mcg/ml, most often 12 mcg/ml. Due to the short half-life, the concentration of primidone may change during the day. Some doctors ignore the level of primidone in the blood and evaluate only the equilibrium concentration of phenobarbital, which, due to its long half-life, does not depend on how much time has passed from taking the drug to the moment of blood sampling.

Due to the high risk of withdrawal seizures, the drug should be discontinued with extreme caution. The drug is usually discontinued gradually over several months (with a switch to tablets containing 125 mg and 50 mg), unless serious side effects require more rapid withdrawal.

Side effects of primidone are the same as those seen with phenobarbital. These include drowsiness, ataxia, cognitive impairment, depression, irritability, hyperactivity, and gastrointestinal disturbances. Idiosyncratic and chronic side effects are identical to those seen with phenobarbital.

Primidone is available as 50-, 125-, and 250-mg tablets and as an oral suspension (250 mg in 5 ml). Primidone is not available parenterally in the United States. Patients unable to take primidone orally may be given parenteral phenobarbital as a temporary measure. When switching from one drug to another, it should be noted that 250 mg of primidone is equivalent to approximately 30 mg of phenobarbital.

Other barbiturates

Mephobarbital (methylphenobarbital) is indicated for the treatment of partial and secondarily generalized seizures and possibly primary generalized seizures. However, it appears to be ineffective in absence seizures.

When administered orally, mephobarbital is not absorbed as completely as phenobarbital, so its dose should be 50-300% higher than the phenobarbital dose. It should also be taken into account that there are two racemic forms of the compound, which differ in absorption, potency, and metabolism. Approximately 66% of mephobarbital is bound to serum proteins, with an elimination half-life of approximately 48 hours for the bound enantiomers. Mephobarbital is metabolized in the liver, and its metabolites are excreted in the urine. Most of the drug is demethylated in the liver to phenobarbital, which allows for the measurement of therapeutic levels of phenobarbital after reaching equilibrium with mephobarbital. Although other compounds are formed as a result of mephobarbital metabolism by aromatic hydroxylation, it is not known whether they contribute to the therapeutic effect of the drug. The therapeutic concentration of mephobarbital in the blood ranges from 0.5 to 2.0 μg/ml, but the concentration of phenobarbital in the blood is considered a more reliable indicator, better correlating with the clinical effect.

Mephobarbital has the same indications and side effects as phenobarbital. Although some physicians believe that mephobarbital has a less pronounced sedative effect than phenobarbital in some cases, this has not been confirmed in clinical trials. Like other barbiturates, mephobarbital can cause drug dependence.

In adults, the effective dose of mephobarbital is 400-600 mg/day. Mephobarbital is available in tablets of 32, 50 and 100 mg. Children under 5 years of age are prescribed mephobarbital at a dose of 50-100 mg/day, children over 5 years of age - at a dose of 100-300 mg/day. Treatment usually begins with a dose that is a quarter of the usual effective dose. Then, if the drug is well tolerated, the dose is increased every week to the therapeutic dose. Since the duration of action of mephobarbital ranges from 10 to 16 hours, it is usually prescribed 3 times a day.

Other barbiturates (such as pentobarbital or secobarbital) are sometimes used in acute situations. Barbiturates that are shorter acting than phenobarbital are not as effective as antiepileptics and are rarely used for long-term therapy.

Carbamazepine

The drug of choice for partial and secondarily generalized tonic-clonic seizures. Although it is also capable of suppressing primarily generalized tonic-clonic seizures, carbamazepine is not effective against absence, myoclonic, and atonic seizures. Although carbamazepine was developed in the 1950s as a chemical analogue of tricyclic antidepressants, it is chemically an iminostilbene. Carbamazepine was initially tested as an antidepressant, then for pain syndromes associated with depression, and finally for trigeminal neuralgia. The drug's effectiveness in trigeminal neuralgia served as the basis for testing its effectiveness in epilepsy, which was also characterized by rapid, uncontrolled neuronal discharges.

Carbamazepine is active in the maximal electroshock model but is of little use in pentylenetetrazole seizures. However, it is more effective than phenytoin in blocking seizures induced by kindling activation of the amygdala in experimental animals. Since carbamazepine blocks bursts of fast neuronal discharges in hippocampal slices, it probably blocks sodium channels in neurons, as does phenytoin. Carbamazepine is thought to bind to inactivated sodium channels, slowing their transition to the active state. Carbamazepine also affects the response of neurons to excitatory amino acids, monoamines, acetylcholine, and adenosine. Blockade of presynaptic fibers caused by the effect on sodium channels may reduce the release of transmitter from them and disrupt calcium transport into neurons.

Carbamazepine is slowly and incompletely absorbed after oral administration. Plasma concentrations peak within 4-8 hours after administration, but this period is sometimes extended to 24 hours, which is especially important in carbamazepine overdose. Approximately 80% of carbamazepine binds to plasma proteins, with the concentration of the substance in the brain being proportional to the content of the free fraction in the blood. Carbamazepine is metabolized to form several compounds, the most important of which is 10,11-epoxide, which probably contributes to the development of the therapeutic and toxic effects of the drug. Simultaneous administration of other agents increases the proportion of carbamazepine-carbamazepine converted to epoxide, which may explain the development of a toxic effect even against the background of a relatively low level of carbamazepine in the blood. If necessary, the blood level of 10,11-epoxide can be measured.

Therapeutic blood levels of carbamazepine range from 4 to 12 mcg/ml, although some patients require higher oxcarbazepine levels of 8 to 12 mcg/ml. The total blood levels of bound and unbound drug fractions are usually measured, but unbound drug concentrations can be measured separately. The epoxide metabolite accounts for 10-25% of carbamazepine levels, but this ratio may be higher with concomitant administration of other drugs.

Carbamazepine induces liver microsomal enzymes. Autoinduction of its own metabolism may occur during the first few weeks of treatment. The CYP3A4 enzyme system is the major metabolic pathway for both carbamazepine and 10,11-epoxide.

The interaction of drugs with carbamazepine is complex. Some agents are capable of changing the concentration of 10,11-epoxide without affecting the blood level of carbamazepine itself. Carbamazepine is capable of variably decreasing the concentration of phenytoin. After the addition of carbamazepine, a greater portion of primidone is converted into phenobarbital. Carbamazepine also increases the metabolic clearance of valproic acid, decreasing its equilibrium concentration. In addition, carbamazepine decreases the blood level of benzodiazepines and other drugs, including phenothiazines, fentanyl, tetracycline, cyclosporine A, tricyclic antidepressants, coumadin, and oral contraceptives. Acceleration of the metabolism of oral contraceptives may lead to unexpected pregnancy in a woman taking a contraceptive containing less than 50 mcg in terms of ethinyl estradiol.

Serum concentration of carbamazepine is affected by a number of other drugs, the most significant of which are erythromycin, propoxyphene, cimetidine, isoniazid, antidepressants - selective serotonin reuptake inhibitors. The experimental antiepileptic drug stiripentol significantly inhibits the clearance of carbamazepine and 10,11-epoxide, causing an increase in the concentration of carbamazepine in the blood. A similar effect was noted with the simultaneous administration of valproic acid and acetazolamide with carbamazepine. Drugs that induce liver microsomal enzymes (for example, phenytoin, phenobarbital, primidone and felbamate) enhance the metabolism of carbamazepine, reducing its concentration in plasma by 10-30%.

Carbamazepine is effective in partial and secondarily generalized seizures and is one of the drugs of choice for these conditions. In a large clinical trial comparing the effectiveness of various antiepileptic drugs, carbamazepine provided complete seizure freedom in a significantly higher proportion of patients than other drugs. Although carbamazepine also has an effect on primarily generalized tonic-clonic seizures, it is rarely effective in absence and myoclonic seizures. It is also relatively ineffective in febrile seizures. In the United States, carbamazepine is officially approved for use in children over 6 years of age, but is also used to treat partial seizures in younger children.

The therapeutic dose of carbamazepine should be achieved slowly because of the risk of gastrointestinal and CNS side effects. The initial dose is usually 100 mg 3 times daily, then it is increased by 100-200 mg every 3-7 days to a dose of 400 mg 3 times daily (1200 mg/day). Although dose increases to 1600 mg/day or even higher are sometimes recommended, these higher doses are usually used only by experienced physicians in resistant cases. Sequential increases in the dose of carbamazepine may be necessary during the first few weeks due to hepatic autoinduction. The drug can be used as monotherapy or in combination with other antiepileptic drugs.

Carbamazepine is particularly often combined with phenytoin (although this often results in severe ataxia), valtroic acid, gabapentin, lamotrigine, and sometimes phenobarbital.

Although carbamazepine itself rarely causes side effects, it may cause the same idiosyncratic, dose-dependent, and chronic side effects as other antiepileptic drugs. The most serious idiosyncratic effect of carbamazepine is a hypersensitivity reaction with skin rashes, most often in the form of a maculopapular rash. Less common are erythema multiforme, Stevens-Johnson syndrome, and epidermal necrolysis. Lymphadenopathy, vasculitis-like syndrome, including the clinical picture of lupus, and nephritis occasionally occur with carbamazepine treatment. Hematological side effects are quite serious and occur in 5-10% of patients. They consist of a decrease in the number of granulocytes and leukocytes (sometimes up to 2000-4000 in 1 mm ³ ). Moreover, the number of platelets may also decrease. Such changes in the blood are usually transient and regress during the first weeks of treatment. They respond to a reduction in the dose of carbamazepine and depend on the rate of dose titration. Aplastic anemia occurs with a frequency of 1:50,000-200,000 and is a very rare side effect that should be distinguished from the more common transient leukopenia.

Acute side effects of carbamazepine are mainly related to its adverse effects on the gastrointestinal tract and central nervous system. These include nausea, diarrhea, ataxia, dizziness, double vision, drowsiness, and cognitive impairment. All of these can be minimized by slowly increasing the dose. Double vision is a very common, although not unique, side effect of carbamazepine. In addition, carbamazepine has a pronounced anticholinergic effect, causing dry mouth, decreased lacrimation, tachycardia, urinary retention, and constipation. Elderly patients are especially sensitive to these side effects.

Although increased liver enzymes are common with carbamazepine, hepatotoxicity is rare. Such toxicity may take the form of allergic granulomatous hepatitis with cholestasis or direct toxic hepatitis with liver necrosis without cholestasis. This complication usually occurs within the first month of treatment. Carbamazepine also increases the secretion of antidiuretic hormone, which leads to a decrease in the concentration of sodium in the blood.

Patients taking carbamazepine are advised to have regular clinical blood tests. Because of early reports of possible leukopenia, the initial recommendations suggested more frequent blood tests; currently, less frequent blood tests are recommended, depending on the individual situation. The proposed regimen includes testing before prescribing the drug at 1 and 3 months, and thereafter as needed. Blood tests include a clinical blood test with platelet count, sodium concentration, liver enzymes, and total carbamazepine in the blood.

Carbamazepine may cause subclinical or, less commonly, clinically apparent polyneuropathy. Some patients develop chronic thyroid dysfunction with decreased levels of the corresponding hormones and, less commonly, clinical signs of hypothyroidism. With prolonged use, carbamazepine increases free cortisol levels and decreases luteinizing hormone and free sex hormones, which may explain the development of sexual dysfunction with the use of the drug. Carbamazepine makes low-hormone oral contraceptives ineffective and alters vitamin D metabolism (although there are only a few reports of clinically apparent osteomalacia caused by carbamazepine). Carbamazepine may impair cardiac conduction, both with acute and chronic administration. Cardiac rhythm disturbances may be represented by sinus tachycardia (a manifestation of the cholinolytic effect), bradyarrhythmia, or blockade of the cardiac conduction system. Cardiac disorders are more common in older patients or people with heart disease.

The extent to which carbamazepine impairs cognitive function has not been clearly defined. It is generally accepted that carbamazepine has less adverse effects on cognitive function than barbiturates and benzodiazepines. Although earlier studies indicated that carbamazepine impairs cognitive function to a lesser extent than phenytoin, subsequent analyses of these results showed that the effects of both drugs on cognitive function are comparable. Encephalopathy, delirium, and paranoid psychosis may also occur with acute and chronic administration of carbamazepine.

Carbamazepine is a teratogenic drug that sometimes causes so-called minor malformations, consisting of malformations of the face and fingers. These tend to regress in the first few years of life. Spinal dysraphism occurs in no more than 1% of children born to mothers who took carbamazepine. Although the administration of folic acid (0.4-1.0 mg) can prevent the teratogenic effect of carbamazepine on the development of the fetal spine, this effect has not been confirmed in controlled clinical trials.

Carbamazepine is available in the United States as 100 mg chewable tablets, 200 mg tablets, and a suspension containing 100 mg in 5 ml. More recently, slow-release capsules of carbamazepine have been introduced that can be taken twice daily. They contain 100, 200, and 400 mg. Other oral forms of carbamazepine should be given 3 to 4 times daily. Treatment is recommended to begin with a dose of 100 mg 3 times daily, then the daily dose is increased by 100 to 200 mg every 3 to 7 days if well tolerated, up to 1200 mg in 3 doses. The dose may be increased to 1600 mg/day or higher, but only in special cases and by specialists experienced in the use of this compound. Although a clinical form of carbamazepine for parenteral administration has been developed, it is not currently used in clinical practice.

[ 5 ], [ 6 ], [ 7 ], [ 8 ]

Oxcarbazepine

Structurally similar to carbamazepine. The keto group contained in the molecule of this substance prevents the metabolization of carbamazepine with the formation of 10,11-epoxide, which reduces the risk of side effects. Clinical trials have shown that oxcarbazepine is an effective and relatively safe drug that can be prescribed to patients who are intolerant to carbamazepine. Although in general the side effects of oxcarbazepine are similar to carbamazepine, they occur less frequently. The exception is hyponatremia, which occurs more often with oxcarbazepine than with carbamazepine.

A recent pre-operative study in hospitalized patients showed that oxcarbazepine prolonged the time to the fourth seizure compared with placebo. The drug is approved for use in both Europe and the United States.

Valproic acid (valproate) is 2-propylvaleric acid, a fatty acid analogue with a terminal carboxyl group. The antiepileptic properties of valproic acid were discovered by accident. Initially, the substance was used as a solvent for compounds with supposed antiepileptic action. When all the tested drugs turned out to be effective, which was impossible, the researchers reasonably assumed that the active ingredient was actually the solvent. The first clinical trials of valproic acid were conducted in France in 1964. In France, the drug entered the pharmacological market in 1967, and in the United States it began to be used since 1978. A special dosage form in an enteric-coated shell, divalproex sodium, has been used in practice since 1983, and since 1990 the drug has been available for children in the form of capsules with microgranules. A form for intravenous administration has also appeared relatively recently.

Although valproic acid has been shown to be a broad-spectrum antiepileptic drug in experimental models and animals, it is a low-potency drug with an effective dose of several hundred milligrams. Valproic acid inhibits seizures in the maximal electroshock and pentylenetetrazole seizure models in laboratory animals, with a therapeutic index of 4-8, equivalent to phenytoin, carbamazepine, and phenobarbital. Valproic acid is somewhat more effective in pentylenetetrazole seizures than in the maximal electroshock model, which predicts its efficacy in absence epilepsy. It also inhibits chemically induced seizures and seizures resulting from the kindling effect.

At high doses, valproic acid inhibits succinylsemialdehyde dehydrogenase, an enzyme involved in GABA metabolism. However, this effect requires a higher concentration of valproate than is normally produced in the brain. Variable effects are also observed in the ability to potentiate GABA-receptor-mediated inhibitory postsynaptic potentials. The effect of valproate is similar to that of phenytoin and carbamazepine. All of these drugs inhibit fast repetitive discharges of depolarized neurons, possibly by interacting with sodium channels on neurons. Interaction with the low-threshold calcium current responsible for repetitive discharges of thalamic pacemakers may underlie the drug's efficacy in absences. Other possible effects of the drug are currently being investigated, including its effect on calcium channels and its ability to block excitatory amino acid-mediated transmission.

Sodium valproate and divalproex are readily absorbed after oral administration, with peak plasma concentrations occurring 1-2 hours after administration. Although absorption is also good when taken with food, the peak concentration is delayed by 4-5 hours. The ease of absorption makes it possible to administer a loading dose of valproic acid through a nasogastric tube in critical conditions. In this case, the dose is approximately 20 mg/kg. When administered rectally, valproic acid is also readily absorbed and administered at the same dose. After absorption, sodium valproate is 85-95% bound to plasma proteins, but only the unbound form penetrates the brain. The elimination half-life from plasma ranges from 5 to 16 hours. The therapeutic serum level is usually in the range of 50 to 100 μg/ml. However, in severe seizures, higher blood concentrations may be required - up to 150 mcg/ml.

Valproic acid is metabolized by conjugation with glucuronic acid in the liver and subsequent excretion in the urine. The parent compound is also conjugated with carnitine, glycine, and coenzyme A. Part of valproic acid is also oxidized in the mitochondria to form two oxidative metabolites, 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid, which have antiepileptic activity. The former, also known as 2-N-valproic acid, is thought to be partly responsible for the therapeutic and toxic effects of valproate. Although efficacy often persists for 1 to 2 weeks after the parent compound has disappeared from the blood, it is unknown whether this is due to accumulation of 2-N-valproic acid, tissue binding of valproic acid, or metabolites with some long-term physiological changes.

Valproic acid differs from most traditional antiepileptic drugs in its ability to block, rather than induce, hepatic microsomal enzymes, which increases the likelihood of some drug interactions. Thus, when prescribing valproic acid, the serum concentration of phenobarbital, unbound phenytoin, lamotrigine, and sometimes ethosuximide increases. Given this, when adding valproic acid to phenobarbital, the dose of the barbiturate should be reduced by about a third. At the same time, at steady state, valproate reduces the serum concentration of carbamazepine, total phenytoin, and increases the fraction of carbamazepine metabolized to form 10,11-epoxide. Most other antiepileptic drugs increase the hepatic clearance of valproate, reducing its blood level. Therefore, the addition of phenytoin, phenobarbital, primidone, carbamazepine or felbamate may be associated with a decrease in valproic acid concentrations.

Valproic acid is a broad-spectrum antiepileptic drug indicated for absences, partial and secondarily generalized seizures, and some myoclonic and atonic seizures. It is the drug of choice for the treatment of generalized seizures in patients with juvenile myoclonic epilepsy. Valproic acid can be used both as ionotherapy and in combination with other antiepileptic drugs, most commonly phenytoin or carbamazepine.

Treatment with valproate should be initiated gradually, primarily because of the potential for gastrointestinal side effects, which can be severe if the drug is given at high doses. Although the usual starting dose is 15 mg/kg/day given three times daily, given the available dosage forms, it is more convenient to initially give 125 mg 2 or 3 times daily. The dose is then increased by 125-250 mg every 3-7 days, depending on the severity of seizures and side effects. The effective dose in adults is 250-500 mg orally 3 times daily, or approximately 30 mg/kg/day. The recommended maximum dose is 60 mg/kg/day. The therapeutic serum concentration is 50-100 mcg/mL, although in severe cases it may be necessary to increase it to 150 mcg/mL.

Valproate causes skin rashes in 1-5% of patients. The rashes are sometimes accompanied by fever and lymphadenopathy. Hepatotoxicity is a more serious idiosyncratic effect, usually developing within 3 months of starting treatment. Although liver enzyme elevations are common, hepatotoxicity is rare. An analysis of liver-related deaths has shown that they occur at a rate of 1:50,000 per year. Although this rate is relatively low overall, in patients under 3 years of age taking multiple drugs, the risk of death due to severe liver damage is as high as 1:600. This circumstance should be taken into account when prescribing valproic acid in this age group. In contrast, no fatal hepatotoxic effects have been reported in adults receiving valproic acid monotherapy.

Sporadic cases of hemorrhagic pancreatitis and cystic fibrosis have also been reported with valproic acid therapy. Acute idiosyncratic hematological effects consist primarily of thrombocytopenia and inhibition of platelet aggregation. Neutropenia and bone marrow suppression are rare side effects of valproic acid.

At the beginning of treatment, side effects are associated primarily with gastrointestinal dysfunction and include nausea, vomiting, epigastric discomfort, and diarrhea. When using enteric-coated tablets and taking the drug with food, these side effects are less common. CNS side effects are less pronounced than with phenobarbital, phenytoin, or carbamazepine, although some patients experience sedation, ataxia, double vision, dizziness, or, less commonly, encephalopathy or hallucinations. Postural tremor is more pronounced with valproic acid than with other antiepileptic drugs.

With prolonged use, the main side effect that limits further use of the drug is a tendency to increase body weight, less often its decrease is observed. The mechanism of weight gain remains unclear. Some experts believe that the main role is played by inhibition of beta-oxidation of fatty acids and increased appetite. With prolonged use of valproate, peripheral edema and alopecia are possible, some patients also note amenorrhea and sexual dysfunction.

Valproic acid often causes hyperammonemia, which does not necessarily reflect liver dysfunction and may be due to blockade of nitrogen metabolism. Carnitine, which is involved in the transport of fatty acids across mitochondrial membranes, may restore nitrogen balance, although there is no evidence that administration of this compound is effective in the absence of its deficiency.

Valproic acid is teratogenic. Reports of neural tube defects in children whose mothers took valproic acid during pregnancy first appeared in 1981. Overall, dysraphic syndrome occurs in 1-2% of children whose mothers took the drug during the first trimester of pregnancy. Taking folic acid is thought to reduce the risk of this complication. A small percentage of offspring also develop other minor malformations of the face and fingers.

In the USA, valproic acid is available as 250 mg tablets and a syrup containing 250 mg sodium valproate in 5 ml of solution. The valproic acid derivative divalproex sodium is available as 125 mg microgranulated capsules and 125, 250, and 500 mg sustained-release tablets. A parenteral formulation (100 mg/ml in a 5 ml vial) has also been recently developed. The drug is administered parenterally by infusion at a rate of 20 mg/min at a dose equivalent to that prescribed orally.

Succinimides

Ethosuximide, chemically related to phenytoin, is the drug of choice for absence seizures (petit mal).

Ethosuximide blocks pentylenetetrazole-induced seizures but not seizures induced by maximal electric shock or kindling activation of the amygdala. It is also relatively ineffective against seizures induced by bicuculline, N-methyl-D-aspartate, strychnine, or allylglycine.

The spectrum of action of ethosuximide is narrower than that of most other antiepileptic drugs. It is effective primarily in absence seizures and, to a lesser extent, in myoclonic and atonic seizures, but has no effect on other types of seizures. This selectivity of action suggests that the drug primarily affects the thalamocortical regulatory system that generates rhythmic spike-wave activity. Neurons of the thalamic system have a special type of ion channel, the low-threshold T-type calcium channels, which cause neurons to discharge when the membrane potential changes - at the moment when hyperpolarization is replaced by relative depolarization. Ethosuximide partially blocks these low-threshold calcium channels and, as a result, can inhibit the spike-wave activity generated by the thalamocortical system.

Although various hypotheses have been proposed to explain the positive effect of ethosuximide in absences, none of them have been confirmed. Thus, it has been suggested that the effect of ethosuximide is related to its ability to inhibit GABA synthesis in the brain, as well as the activity of sodium-potassium ATP-dependent channels in the membrane, but this effect is observed only at very high concentrations, which are not usually achieved in the brain when taking the drug. The effect on GABAergic, glutamatergic, and dopaminergic transmission is not sufficient to explain the action of ethosuximide.

Ethosuximide is a water-soluble substance that is readily absorbed after oral administration. Maximum blood concentration is reached 1-4 hours after administration. When using syrup, the drug is absorbed faster than when taking capsules. Ethosuximide is distributed in a space equivalent to the total volume of water in the body, with less than 10% of the drug bound to serum proteins. It easily crosses the blood-brain barrier, so the concentration in the cerebrospinal fluid is approximately equal to the concentration in the serum. In children, the half-elimination period of ethosuximide is 30-40 hours, in adults - 40-60 hours. Approximately 20% of ethosuximide is excreted unchanged in the urine, the remainder is metabolized, mainly by oxidation. Four metabolites formed with the participation of the hepatic CYP3A enzyme system have been identified. All of them are pharmacologically inactive. Ethosuximide interacts with other drugs to a much lesser extent than other antiepileptic drugs, since it binds to serum proteins only to a small extent. Variable interactions have been noted between ethosuximide, on the one hand, and phenytoin, phenobarbital, carbamazepine, and valproic acid, on the other hand, but such interactions are inconsistent and usually have no clinical significance. The insert to the drug notes the possibility of increasing the serum concentration of phenytoin when adding ethosuximide.

Ethosuximide is indicated for absences. Although there is no formal age limit for this indication, such seizures usually occur in children, to whom ethosuximide is most often prescribed. Previously, ethosuximide was also used for a combination of absences and tonic-clonic seizures, usually in combination with phenytoin. Currently, in this case, as a rule, resort is made to motonotherapy with valproic acid. In view of the possible hepatotoxic effect in children when using valproic acid, its relatively high cost, ethosuximide remains the drug of choice for epilepsy manifested only by absences. Valproic acid is the drug of choice for a combination of absences with other types of seizures or for atypical absences.

In patients aged 3-6 years, the initial dose of ethosuximide is 250 mg once daily (as capsules or syrup). Every 3-7 days, the dose is increased by 250-500 mg, usually to 20 mg/kg/day. The therapeutic concentration in the blood is usually from 40 to 100 μg/ml, but in resistant cases it has to be increased to 150 μg/ml. This indicator is close to the therapeutic concentration of valproic acid. Due to the long half-elimination period, ethosuximide can be taken once daily. However, if side effects (nausea, vomiting) occur, it is advisable to switch to 2-4 times a day. Fractional administration is useful at the beginning of treatment, allowing to minimize side effects. The most common dose-dependent effect of ethosuximide is abdominal discomfort. In addition, the drug may cause anorexia, weight loss, drowsiness, dizziness, irritability, ataxia, fatigue, and hiccups. A small proportion of children experience psychiatric side effects in the form of behavioral changes, aggression, and, less commonly, hallucinations, delusions, or severe depression. The effects of ethosuximide on cognitive function have been assessed in only a few studies. They appear to be less significant than those of barbiturates.

Idiosyncratic side effects associated with ethosuximide include skin rashes, erythema multiforme, and Stevens-Johnson syndrome. Rarely, ethosuximide, like other antiepileptic drugs, causes a lupus-like syndrome. Among the most serious but rare side effects of ethosuximide, hematopoietic depression, including aplastic anemia and thrombocytopenia, should be avoided. Because of this possibility, periodic clinical blood counts are recommended during treatment with the drug. The decrease in granulocyte count is more likely to be a dose-dependent transient reaction than the initial manifestations of aplastic anemia; however, regular monitoring is necessary for this side effect.

Side effects with long-term use of ethosuximide are observed less frequently than with other antiepileptic drugs. There are isolated descriptions of cases of thyroiditis, immune damage to the kidneys, decreased serum corticosteroid levels, and extrapyramidal disorders. There are cases where ethosuximide contributed to an increase in seizure frequency. This effect may occur in patients with atypical absences and lead to the development of previously absent generalized tonic-clonic seizures, but more often the worsening of the condition is noted in patients with myoclonic and partial seizures.

Ethosuximide can cause a teratogenic effect, which is facilitated by the lack of binding to serum proteins and hydrophilicity, facilitating the penetration of the drug through the placenta and into breast milk. Although there is no clear evidence of the ability of ethosuximide (in isolation from other antiepileptic drugs) to induce teratogenesis, this drug should be used during pregnancy only if its therapeutic effect clearly outweighs the risk of possible complications.

Ethosuximide should be withdrawn gradually to avoid worsening absences or development of absence status.

In the United States, ethosuximide is available as 250 mg capsules and a syrup containing 250 mg per 5 ml. The initial dose for children aged 3 to 6 years is 250 mg per day, for those over 6 years old - 500 mg. The daily dose is increased by 250 mg every 3-7 days until a therapeutic or toxic effect is achieved, up to a maximum of 1.5 g/day. Although treatment usually begins with 2-3 doses of the drug, if the patient tolerates it well, it can be transferred to a single dose. The optimal dose is usually 20 mg/kg/day.

Other succinimides

In addition to ethosuximide, two other succinimides are used in clinical practice - methsuximide and fensuximide. Ethosuximide is somewhat more active than other succinimides in the model of pentylenetetrazole seizures in experimental animals and, accordingly, is more effective in absences in humans. In contrast, methsuximide is the most effective of the succinimides in seizures provoked by maximum electric shock. This allows it to be recommended as a second-line drug in the treatment of partial seizures.

Methsuximide is well absorbed after oral administration, with peak blood concentrations occurring 1–4 h after administration. The drug is rapidly metabolized in the liver and excreted in the urine. The active metabolite, N-desmethylmethsuximide, has a half-life of 40 to 80 h. Several other metabolites may also have a clinical effect. Methsuximide is likely similar in its mechanism of action to ethosuximide.

Methsuximide is indicated for absence seizures and is used as a second- or third-line drug for this condition. Methsuximide is also used in the treatment of treatment-resistant complex partial seizures. Treatment is usually initiated at 300 mg/day, then increased by 150-300 mg/day every 1-2 weeks until a therapeutic or toxic effect is achieved, up to a maximum of 1200 mg/day. Serum concentrations of methsuximide are usually so low as to be unmeasurable; therapeutic concentrations of N-desmethylmethsuximide range from 10 to 50 μg/mL. Methsuximide increases serum concentrations of phenytoin and phenobarbital and enhances the conversion of carbamazepine to 10,11-epoxide.

Side effects of methsuximide are relatively common and include drowsiness, dizziness, ataxia, gastrointestinal disturbances, decreased blood cell counts, skin rashes (including Stevens-Johnson syndrome). Other side effects of the same kind as those caused by ethosuximide are also possible.

Phensuximide is indicated for absences, but can sometimes be used as a second- or third-line drug for other types of seizures. The drug is available in 500 mg capsules. The initial dose is usually 500 mg/day, then it is increased every 3-7 days until the effect is achieved, up to 1 g 3 times a day in adults. Side effects are the same as with ethosuximide and methsuximide.

Felbamate

Felbamate - 2-phenyl-1,3-propanediol dicarbamate - was the first antiepileptic drug to be widely introduced after valproic acid. Currently, before prescribing the drug, it is necessary to warn the patient about possible side effects and obtain informed consent from him. In recent years, the popularity of the drug has increased somewhat.

Felbamate was developed as an analogue of meprobamate, a tranquilizer widely used before the advent of benzodiazepines. Felbamate is active against seizures induced by maximal electric shock in mice and rats, as well as against pentylenetetrazole-induced seizures, although it is less effective in the latter case. Felbamate also blocks seizures induced by other convulsants, inhibits kindling activation of the amygdala, and reduces focal motor seizures in mice induced by the action of aluminum hydroxide on the cerebral cortex. Felbamate has been shown to be safe in animal toxicology studies, leading to false confidence in the drug's good tolerability.

Felbamate interacts with sodium channels of neurons and receptors of excitatory amino acids. The effect of felbamate on sodium channels is similar to the action of carbamazepine and phenytoin. Felbamate inhibits prolonged neuronal discharges, probably due to the fact that it prolongs the period during which the channel is in an inactive state. Felbamate also blocks the glycine-binding site, which regulates the activity of NMDA-type glutamate receptors in the brain. In addition, felbamate directly blocks quisqualate glutamate receptors. Due to these effects, felbamate may have neuroprotective and antiepileptic effects.

Felbamate is well absorbed after oral administration despite limited water solubility. Due to its lipophilicity, it readily crosses the blood-brain barrier, and its levels in the cerebrospinal fluid approximately correspond to serum concentrations. Approximately 25% of the administered dose is bound to serum proteins; the elimination half-life varies from 1 to 22 hours. Although the drug does not appear to induce the enzymes responsible for its own metabolism, the elimination half-life of felbamate may decrease from 20 to 14 hours when other agents induce microsomal enzymes. The approximate volume of distribution of felbamate is 0.8 L/kg. Although a clear correlation between drug concentration and therapeutic effect has not been established, clinical trials indicate that therapeutic concentrations may lie in the range of 40 to 100 μg/mL.

Felbamate undergoes first-order metabolism by the hepatic microsomal enzyme system. It induces hepatic microsomal enzymes and may enhance the metabolism of other drugs that are substrates for these enzymes. The metabolites of felbamate include the monocarbamate and conjugated felbamate, as well as several other compounds formed in smaller amounts. Approximately 50% of the absorbed dose is excreted unchanged in the urine.

Interaction of felbamate with other drugs may be of clinical importance. In general, it increases the serum concentration of other antiepileptic drugs, especially phenytoin, valproic acid and barbiturates, by 20-50%. When combined with carbamazepine, the concentration of carbamazepine itself decreases, but the level of 10,11-epoxide usually increases. Some of these interactions occur at the level of the epoxide hydrolase enzyme, which is involved in the metabolism of carbamazepine, 10,11-epoxide and phenytoin. On the other hand, phenytoin and carbamazepine increase the metabolism of felbamate, which leads to a decrease in its serum level by 15-30%. Felbamate also affects the serum concentration of some other drugs, especially if they compete for the same microsomal enzymes. Of particular note is the fact that felbamate slows the metabolism of coumadin and may enhance its effect.

The efficacy of felbamate was assessed primarily in partial seizures with or without secondary generalization. It was the first antiepileptic drug used for a preoperative test - it was administered to a patient at the end of preoperative monitoring. The drug had a positive effect in 40-45% of patients with partial seizures. The efficacy of felbamate in partial seizures compared with valproic acid was demonstrated in a study conducted in outpatients. Another study showed its efficacy in Lennox-Gastaut syndrome in patients with polymorphic (tonic, atonic, and other) seizures resistant to previously used antiepileptic drugs. Small clinical trials have also shown that felbamate may also be useful in absences and juvenile myoclonic epilepsy, which allows it to be considered a broad-spectrum antiepileptic drug.

Felbamate is available in 400 and 600 mg tablets. Due to the risk of serious toxic effects, the drug should be prescribed only after other therapeutic options have proven ineffective. Depending on the urgency of the situation, treatment begins with a dose of 300 or 600 mg 2 times a day. Subsequently, the dose is increased by 300-600 mg every 1-2 weeks, most often up to 1200 mg 3 times a day. Some patients require lower doses to achieve the effect, while others need to increase the dose to 4800 mg/day or the threshold of individual tolerance. In children, the initial dose is 15 mg/kg/day, subsequently it is increased weekly by 30-45 mg/kg/day, up to a maximum of 3000 mg/day. Taking the drug with food can reduce the likelihood of side effects from the gastrointestinal tract. Patients taking felbamate should have regular clinical blood tests and liver function tests.

In toxicology studies on rats, it was not possible to determine the lethal dose of felbamate, since even a large dose of the drug did not cause any dangerous complications. However, after its introduction into practice, it turned out that the drug can cause very serious side effects in patients. Dose-dependent side effects include gastrointestinal dysfunction, weight loss, headache, insomnia, and behavioral changes in children. Felbamate has less adverse effects on cognitive function and overall activity level than other antiepileptic drugs. In fact, it can even improve learning and memory. While weight loss may be a desirable effect for some patients, for others this effect is unfavorable. If insomnia occurs, the last dose of the drug often has to be moved to daytime. Due to the possibility of nausea, the drug must be taken with food or sucralfate. For headaches, conventional analgesics are used. The likelihood of side effects when taking felbamate is significantly higher when it is combined with other drugs, which is determined by the possibility of drug interactions.

Approximately 1,500 patients were enrolled in clinical trials of felbamate prior to its marketing, including 366 patients who received the drug in two monotherapy studies. On average, patients were treated with the drug in these studies for approximately 1 year. Twelve percent of patients withdrew from the clinical trials because of adverse events. Furthermore, no significant abnormalities in blood counts or liver function tests were observed, except for a few cases of transient leukopenia, thrombocytopenia, or anemia. No cases of aplastic anemia were observed in the clinical trials. However, to date, 31 cases of aplastic anemia associated with felbamate have been reported. All occurred in 1994. No additional cases were reported by the manufacturer between 1995 and 1997. On average, aplastic anemia was diagnosed 6 months after initiation of felbamate (range, 2.5 to 12 months). Most patients who developed this complication had preexisting immunological disorders, others had serious illnesses or previous episodes of hematological complications with other antiepileptic drugs. However, no specific prognostic factor was found that predetermines the development of aplastic anemia. Of the 31 patients with aplastic anemia, 8 died from this complication.

In 14 patients, severe hepatotoxicity developed after 0.5-10 months of treatment with felbamate. Although most of these patients were taking several drugs at the same time, several were taking felbamate alone.

The risk of aplastic anemia and liver damage has significantly limited the use of felbamate and almost led to its withdrawal from the market. However, many patients and their support groups believed that it was the only effective and well-tolerated treatment in some cases and urged that felbamate remain available. Nevertheless, given the risks, patients are asked to sign an informed consent form before felbamate is prescribed. The manufacturer recommends regular complete blood counts and liver function tests every 1 to 2 weeks while taking felbamate, although this is inconvenient for most patients. The risk of complications is thought to decrease after 1 year of treatment, and therefore the need for laboratory monitoring is reduced thereafter. Furthermore, there is no evidence that laboratory monitoring will reduce the incidence of aplastic anemia or hepatotoxicity. However, the clinician and patient should develop a laboratory monitoring schedule that is acceptable to both. Patients and their relatives should also be warned about the need to promptly report any unusual infectious manifestations, bleeding, bruising, pallor or jaundice.

Felbamate is available in the form of tablets of 400 and 600 mg and a suspension for oral administration containing 600 mg in 5 ml.

[ 9 ], [ 10 ], [ 11 ], [ 12 ], [ 13 ], [ 14 ]

Gabapentin

Gabapentin - 1-aminomethylcyclohexane acetate - was introduced into practice in the United States in 1993. The drug is an analogue of GABA, and its cyclohexane ring structure is designed to facilitate penetration into the brain. Gabapentin is used as an adjuvant in partial and secondarily generalized seizures, as well as in a number of non-epileptic conditions, including pain syndromes, bipolar disorder, and restless legs syndrome.

Although gabapentin was developed as a GABA analogue, it has low affinity for GABA receptors and the enzymes responsible for the synthesis and degradation of this neurotransmitter. It also has minimal effects on GABA-mediated inhibitory postsynaptic potentials. Gabapentin is thought to act by increasing intracellular GABA concentrations through its effects on the amino acid transport system. This system, which transports large neutral amino acids such as L-phenylalanine and leucine, is found in the membranes of neurons and glial cells. The mechanism by which gabapentin interacts with the transporter in the small intestine and brain is still being studied. The binding sites of radioactive gabapentin in the brain are distinct from those of known neurotransmitters and neuromodulators. Gabapentin is highly bound to the superficial layers of the neocortex, dendritic regions of the hippocampus, and the molecular layer of the cerebellum. In experimental models, it has been noted that the maximum anticonvulsant effect develops several hours after intravenous administration. This time may be required for gabapentin to be converted to another substance or to achieve an effective concentration of the drug in a critically important sector of the cell. Although gabapentin has some effect on neuronal sodium channels, monoamine release, and calcium ion channels in the brain, it is unlikely that its therapeutic effect is related to these mechanisms. It is assumed that gabapentin is able to interact with amino acids of the Krebs cycle, affecting the amount of glutamate released by neurons. It is also believed that gabapentin may also have a neuroprotective effect in some situations.

In experimental models, gabapentin is as potent as phenytoin in blocking seizures induced by maximal electric shock. However, it has only a moderate effect on pentylenetetrazole seizures and is ineffective in absence models in rats and myoclonic seizures in photosensitive baboons. Gabapentin increases the epileptic threshold and reduces mortality when administered to rodents with N-methyl, D-aspartate. In addition, it attenuates epileptic seizures induced by kindling activation of limbic structures in rodents. These data indicate that gabapentin should be most effective in partial and secondarily generalized seizures.

Although the absorption of gabapentin increases with increasing dose, the proportion of drug absorbed decreases. This nonlinear relationship is thought to be due to saturation of the L-aromatic amino acid transporter in the gastrointestinal tract that mediates drug absorption. Thus, increasing the dose above 4800 mg/day results in only a small increase in serum drug concentrations. Gabapentin is virtually not bound to serum proteins and is excreted unchanged in urine and feces. Since gabapentin is not metabolized, it does not inhibit or induce hepatic microsomal enzymes. These properties result in a low potential for drug interactions, as demonstrated by both pharmacokinetic studies and clinical experience. Other antiepileptic drugs do not significantly affect gabapentin blood levels, and vice versa. Although concomitant administration of antacids reduces the absorption of gabapentin by approximately 20%, and cimetidine increases serum gabapentin levels by 10%, these interactions are generally not clinically significant. Gabapentin does not alter the metabolism of estrogens and thus does not weaken their contraceptive effect.

The half-life of gabapentin varies from 5 to 8 hours, so the drug must be taken 3-4 times a day. The level of gabapentin in the blood does not clearly correlate with clinical efficacy, although it is believed that the therapeutic concentration is in the range of 2 to 4 mcg / ml. In some cases, the concentration of the drug in the blood must be increased to 10 mcg / ml or the threshold of individual tolerance.

At least five controlled studies have been conducted to evaluate the efficacy of gabapentin at doses ranging from 600 to 1800 mg and several long-term safety studies. Approximately 20-30% of patients with seizures resistant to previously prescribed medications respond well to the addition of gabapentin, that is, to a reduction in seizure frequency of 50% or more compared with baseline. Clinical experience shows that the percentage of patients with a good response to the drug increases with the use of the drug at doses of 2400-4800 mg/day, while maintaining a favorable therapeutic ratio, but these data need to be confirmed by controlled trials. Small clinical trials have failed to demonstrate the efficacy of gabapentin in absence, myoclonic, and atonic seizures. Although the drug is not officially approved for use as monotherapy in the United States, two studies of the efficacy of gabapentin monotherapy have been completed. In one study, hospitalized patients were rapidly titrated to 3600 mg/day using preoperative monitoring. Monotherapy with gabapentin was more effective than placebo in partial and secondarily generalized seizures. However, the study in outpatients failed to demonstrate efficacy. This is believed to be due to errors in the study protocol, as a significant proportion of patients experienced an increase in seizures when carbamazepine was discontinued, which affected the efficacy of gabapentin.

Gabapentin is available in tablets of 100, 300, and 400 mg. A liquid form for oral or parenteral use has not been developed. The manufacturer recommends taking 300 mg once a day on the first day of treatment, the same dose twice a day on the second day; starting from the third day, the drug is taken three times a day. However, more rapid titration of the dose, for example, if treatment is started with a dose of 300 mg 3 times a day, is usually well tolerated. If well tolerated, the daily dose can be increased by 300 mg every 3-7 days until the effect is achieved - usually up to 1800 mg / day. Nevertheless, clinical experience shows that higher doses are effective in some patients - 3600 mg / day and more. Although monitoring the serum concentration of the drug does not help in selecting an effective dose, it is sometimes determined to assess patient compliance or for other indications. The range of therapeutic concentrations is from 2 to 10 mcg / ml. The addition of gabapentin generally does not require dose adjustments of other antiepileptic drugs, although these should be individualized. Pharmacodynamic interactions (eg, increased dizziness when gabapentin is added to carbamazepine or increased drowsiness when gabapentin is combined with most other antiepileptic drugs) sometimes occur when gabapentin is added to other drugs, even though blood levels of the drugs do not change. Frequent monitoring of complete blood counts is generally not necessary with gabapentin; however, some physicians find it useful to periodically perform complete blood counts and liver enzyme tests.

Animal toxicology studies have shown that gabapentin is well tolerated in rats when administered acutely at doses up to 8 g/kg and in monkeys at doses up to 1.25 g/kg. Male Wistar mice given gabapentin develop tumors of pancreatic acinar cells that are considered hyperplasia or benign. However, these tumors do not contribute to mortality and appear to be a species-specific complication. There is no evidence that gabapentin increases the risk of pancreatic cancer in humans.

Dose-related side effects include drowsiness, ataxia, dizziness, and fatigue. Gastrointestinal disturbances have been reported in some cases. In double-blind, placebo-controlled trials, gabapentin-treated patients dropped out of the study at a rate not significantly higher (<5%) than placebo-treated patients, indicating excellent tolerability of the drug.

To date, gabapentin has been used for approximately 450,000 patient-years. Although there have been isolated reports of idiosyncratic side effects, including skin rashes and decreased blood cell counts, serious allergic reactions are extremely rare. The safety of this drug in pregnancy is unknown. Overall, gabapentin is significantly superior to other antiepileptic drugs in terms of tolerability and safety.

Lamotrigine

Lamotrigine - 3,5-diamino-6-2,3-dichlorophenyl-1,2,4-triazine - is another recently introduced antiepileptic drug. It was initially developed as an inhibitor of folic acid synthesis, since it was believed that this effect was associated with the antiepileptic action of phenytoin and phenobarbital. However, it has now become clear that the effect on folic acid metabolism is not the main mechanism of action of lamotrigine.

Lamotrigine blocks seizures induced by maximal electroshock, kindling activation, and photosensitive seizures in laboratory animals. It also has an effect, although relatively weak, on pentylenetetrazole-induced seizures.

Lamotrigine blocks sustained high-frequency neuronal discharge in a manner similar to phenytoin and carbamazepine. This effect is thought to be due to an effect on voltage-dependent sodium channels in neurons and prolongation of the cell's refractory period. Lamotrigine also inhibits glutamate release, suggesting a possible neuroprotective effect of lamotrigine. It does not appear to affect chloride channels or the GABAergic, dopaminergic, noradrenergic, muscarinic, or adenosine systems in the brain.

Lamotrigine is well absorbed after oral administration (with or without food). Its bioavailability is close to 100%. Serum concentrations peak 2-3 hours after administration. Lamotrigine is 55% bound to serum proteins. Its distribution volume is 0.9-1.3 l/kg. Lamotrigine is metabolized in the liver, primarily by conjugation with glucuronic acid. Its main metabolite, the 2-N-glucuronic acid conjugate, is excreted in the urine. Elimination of lamotrigine is linear with respect to dose, corresponding to first-order kinetics.

Although lamotrigine has only a minimal effect on serum levels of other antiepileptic drugs, agents that enhance or inhibit liver enzyme activity may significantly affect the metabolism of the drug. Thus, when administered alone, the half-life of lamotrigine is 24 hours, but when taken simultaneously with drugs that induce liver enzymes (eg, phenytoin, carbamazepine, and phenobarbital), the half-life is reduced to 12 hours. In contrast, valproic acid, an inhibitor of the liver microsomal enzyme system, prolongs the half-life of lamotrigine to 60 hours. Thus, the frequency of lamotrigine administration during the day depends on the drugs with which it is combined. Although lamotrigine induces its own metabolism, it remains unclear whether this has clinical significance.

In the United States, lamotrigine was introduced into clinical practice in 1994, but it had been used in other countries for some time. Clinical trials in the United States have confirmed the efficacy of lamotrigine as an adjuvant in partial and secondarily generalized seizures. Three large studies have reported a greater than 50% reduction in seizure frequency compared with baseline in 20-30% of patients. On average, seizure frequency was reduced by 25-35% with 300-500 mg/day. Several recent clinical trials have shown that lamotrigine can also be used as monotherapy. Small clinical trials and clinical experience suggest that it may be effective not only in partial and secondarily generalized seizures, but also in absence, myoclonic, atonic, and polymorphic seizures. A clinical trial has also shown that lamotrigine is effective in Lennox-Gastaut syndrome. Although the drug is primarily used for partial and secondarily generalized seizures, some clinicians consider it a useful alternative for treatment-resistant primary generalized seizures. There are isolated reports of the drug's use in non-epileptic disorders, including chronic pain syndromes, bipolar disorder, movement disorders, and neurodegenerative diseases. However, the efficacy and safety of lamotrigine in these conditions has not been formally proven.

Lamotrigine is available as 25, 100, 150, and 200 mg tablets. In monotherapy, the effective dose is usually 300-500 mg/day. When combined with valproic acid, which can double the serum concentration of the drug, the lower limit of the specified range should be followed when choosing a dose. However, the upper limit of the dose range has not yet been clearly defined. In some cases, it is prescribed at a dose of 1 g/day or even higher. Although the serum level of the drug correlates poorly with the therapeutic or toxic effect, experience shows that it should be maintained in the range of 2 to 10 mcg/ml (according to other data - from 2 to 20 mcg/ml).

Treatment with lamotrigine should be initiated gradually to avoid skin rashes. The manufacturer recommends that patients over 16 years of age begin treatment with a dose of 50 mg daily, increasing the dose to 100 mg/day after 2 weeks. This dose is also maintained for 2 weeks, after which it is increased by 100 mg every 1-2 weeks to the required level. Skin rashes may occur if titration is too rapid. With slower titration, treatment is initiated with a dose of 25 mg, which is taken for 1 week, and then the dose is increased by 25 mg every week until 100-200 mg/day is reached. Then switch to 100 mg tablets and then increase the dose by 100 mg/day every 2 weeks until the desired clinical effect is achieved. If the patient is taking valproic acid simultaneously, then treatment with lamotrigine is started with a dose of 25 mg every other day, after 2 weeks they switch to daily intake of 25 mg, and after another 2 weeks they begin to further increase the dose by 25-50 mg every 1-2 weeks until the clinical effect is achieved. During the period of titration of the lamotrigine dose, the intake of other antiepileptic drugs is usually continued at the same dose, and only after the lamotrigine dose reaches the lower limit of the effective dose range (200-300 mg/day), the dose is adjusted or the other drug is discontinued. In monotherapy and in combination with valproic acid, lamotrigine can be prescribed once a day. In combination with phenytoin, phenobarbital, carbamazepine, felbamate and other drugs that induce liver microsomal enzymes, lamotrigine is prescribed twice a day.

The main adverse reaction with lamotrigine is skin rash, which may take the form of a simple morbilliform or maculopapular rash or more widespread and severe lesions such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. In controlled clinical trials, the incidence of skin complications in adults was 10% (5% in the placebo group). It should be noted that this rate is consistent with that seen in some clinical trials of carbamazepine and phenytoin. A recent warning has been issued about the possibility of serious skin complications in children, who may be more sensitive to the effects of lamotrigine. This may include Stevens-Johnson syndrome or toxic epidermal necrolysis. In several small clinical trials, the incidence of serious skin complications was as high as 1 in 40 children, and 1 in 200 in the group as a whole. Therefore, before prescribing the drug to children under 16 years of age, patients and their relatives should be warned about the possibility of skin rashes, having obtained their informed consent to use the drug. The risk of rashes increases when taking lamotrigine in combination with valproic acid. In adults, the likelihood of developing rashes depends on the rate of dose increase, sometimes they disappear with a decrease in the dose and subsequent slower titration of the dose.

The main dose-dependent toxic effects of lamotrigine are related to CNS dysfunction and include ataxia, accommodation disorder, dizziness, confusion, and fatigue. Nausea and vomiting are also occasionally reported. In studies evaluating the efficacy of adding lamotrigine to previously taken antiepileptic drugs, the drug had to be discontinued in 10% of subjects (with placebo, this figure was 8%). In monotherapy studies in Europe, the drug was well tolerated, with the only relatively common significant adverse effect being skin rash. Hematologic and hepatotoxic complications with lamotrigine are rare. Other adverse effects, which are usually rare, include delirium, delusions, choreoathetosis, changes in libido and sexual function, and a paradoxical increase in seizure frequency. In toxicology studies, lamotrigine caused cardiac arrhythmias in dogs, presumably due to the N-2-methyl conjugate, which is not formed in humans. Although there are isolated reports of cardiac arrhythmias in humans, the incidence of this complication is low.

Lamotrigine is available as 25, 100, 150, and 200 mg tablets and 5 and 25 mg chewable tablets. The drug is not available in solution. Although lamotrigine is not officially approved for use in individuals under 16 years of age in the United States (except in cases of Lennox-Gastaut syndrome), it is used in this age group in other countries. In children taking liver enzyme inducers without valproic acid, lamotrigine treatment should be initiated at a dose of 2 mg/kg/day. After two weeks, it is increased to 5 mg/kg/day, and after another two weeks, the dose is increased by 2-3 mg/kg/day every 1-2 weeks until the clinical effect is achieved. The maintenance dose usually ranges from 5 to 15 mg/kg/day. For monotherapy, it is recommended to take 0.5 mg/kg/day for the first two weeks, then 1 mg/kg/day for another two weeks, after which the dose is gradually increased to 2-10 mg/kg/day. When combined with valproic acid, lamotrigine treatment in children should be started with a dose of 0.2 mg/kg/day (two weeks), then the dose is increased to 0.5 mg/kg/day, which is also prescribed for two weeks, after which the dose is increased by 0.5-1 mg/kg/day every 1-2 weeks until the clinical effect is achieved. The maintenance dose is usually from 1 to 15 mg/kg/day. The daily dose is usually divided into two doses.

Topiramate

Topiramate - 2,3:4,5-bis-0-(1-methylethylbenzene)-beta-0-fructopyrazone sulfamate - has a chemical structure that is significantly different from other antiepileptic drugs. It was developed by the R.W. Johnson Pharmaceutical Research Institute in collaboration with the Epilepsy Branch of the National Institutes of Health (USA). Topiramate is used for partial and secondarily generalized seizures, but has potential for use in a wider range of seizures. In some cases, its use may be limited due to the possibility of adverse effects on cognitive function.

Topiramate is active against seizures induced by maximal electric shock in rats and, to a lesser extent, against seizures induced by pentylenetetrazole, bicuculline, or picrotoxin. Although topiramate inhibits carbonic anhydrase, this effect does not appear to be the primary mechanism of its antiepileptic action. More important are its ability to increase GABA receptor-mediated chloride influx and to block the AMPA subtype of glutamate receptors in the brain.

Topiramate is well absorbed after oral administration (with or without food). Peak serum concentrations are reached 2-4 hours after administration. Approximately 15% of the drug is bound to serum proteins. Only a small amount of topiramate is metabolized in the liver, while approximately 80% of the drug is excreted unchanged in the urine. Since the half-life is 18-24 hours, the drug must be taken twice daily. The range of therapeutic blood concentrations of the drug has not yet been established. Phenytoin and carbamazepine increase the clearance of the drug and, therefore, decrease its serum concentration. In turn, topiramate increases the concentration of phenytoin and carbamazepine by approximately 20%, but reduces the level of estrogens in the blood.

Topiramate has been studied primarily as a treatment for partial and secondarily generalized seizures. Three multicenter, double-blind, controlled studies have been conducted with topiramate added to existing antiepileptic drugs and with flexible dosing from 20 to 1000 mg/day. Other studies have tested topiramate at doses up to 1600 mg/day. The results show that the drug's efficacy does not increase significantly with doses above 400 mg/day, in contrast to gabapentin and lamotrigine, which have been tested at doses significantly lower than those considered optimal in clinical practice. At doses above 400 mg/day, topiramate can cause serious side effects such as confusion or speech delay, but does not further enhance efficacy. There are, of course, exceptions to this rule.

Small clinical trials and isolated clinical observations show that topiramate has a broad spectrum of antiepileptic activity and may be effective in absence, atonic, myoclonic and tonic seizures. However, the drug's effectiveness in these types of epilepsy should be proven in controlled clinical trials. In recent years, topiramate has been shown to be effective in children with infantile spasms and Lennox-Gastaut syndrome, resistant to other antiepileptic drugs.

The manufacturer recommends starting topiramate treatment with a dose of 50 mg twice daily. However, many clinicians believe that increasing the dose too quickly can lead to cognitive impairment. Therefore, treatment is often started with a dose of 25 mg/day, after which the daily dose is increased by 25 mg every 1-2 weeks. In some adults, the drug has a therapeutic effect at a dose of 100 mg/day, but it is most often effective at doses of 200 to 400 mg/day. The daily dose should be divided into 2 doses. Under these conditions, approximately 40-50% of patients with treatment-resistant seizures note a more than 50% decrease in seizure frequency compared to baseline. It is assumed that topiramate may also be effective as monotherapy, but clinical trials investigating this possibility have not yet been completed.

Topiramate's side effects are primarily related to its action on the central nervous system. They include confusion, drowsiness, ataxia, dizziness, and headache. The risk of side effects is higher when using multiple medications and when titrating the dose rapidly. The incidence of cognitive impairment with topiramate reaches 30%. These include slowness of thought and speech, memory loss, impaired speech comprehension, disorientation, and other symptoms. These symptoms may decrease over time or with a reduction in dose.

There have been isolated reports of gastrointestinal dysfunction, skin rashes, urolithiasis, and serious psychiatric complications associated with topiramate. Topiramate cannot be considered safe during pregnancy. It has been shown to cause some fetal malformations in laboratory animals.

Topiramate is available in tablets of 25, 100 and 200 mg. The drug is not produced in solution.

Benzodiazepines

The benzodiazepines most commonly used to treat epileptic seizures include diazepam, clonazepam, lorazepam, and clorazepate. The advantage of these drugs is their rapid action, which does not require loading (shock) doses. Diazepam and lorazepam for parenteral (intravenous) administration are the drugs of choice for status epilepticus. Benzodiazepines are not usually used for long-term antiepileptic therapy, since their effectiveness decreases after several weeks of use, which requires increasing the dose to maintain the effect. However, long-term use of benzodiazepines is sometimes necessary for atonic, myoclonic, or seizures resistant to other treatment methods, when there are no alternatives. Booster administration of benzodiazepines for 1-2 days can be useful during periods of a sharp increase in seizure frequency. This approach is also used when it is known that one seizure may be followed by a second seizure quickly or during menstruation. The usual antiepileptic drug used is diazepam, 2-5 mg every 4-6 hours. Clonazepam is usually given 0.5-2 mg orally 3 times a day. Lorazepam can be given 0.5-1.0 mg, repeated if necessary, until seizures are controlled. The daily dose can be as high as 4 mg/day.

[ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ]

Tiagabine

Tiagabine has recently received official status in the United States as a drug for the treatment of partial and secondarily generalized seizures and is similar in its profile of action to phenytoin, carbamazepine, and gabapentin. It appears to be ineffective in absences and myoclonic seizures. Approximately 20-30% of patients resistant to other anti-seizure drugs respond to tiagabine. The drug is well tolerated. There are only isolated reports of drowsiness, impaired thinking, and dizziness. There are also reports of increased seizure frequency due to tiagabine use and a few serious psychiatric complications, but it is unclear whether these phenomena are related to tiagabine use or are explained by the severity of the underlying disease. The short half-life requires the drug to be administered 3-4 times daily. Treatment is started with a dose of 4 mg/day. Then it is increased weekly by 4-8 mg until the effect is achieved, up to a maximum of 56 mg/day.

Vigabatrin

Although vigabatrin, a structural analog of GABA, has been used in European countries since 1989, it was not until 1997 that it received FDA approval for use in the United States. Vigabatrin appears to be most effective in partial and secondarily generalized seizures, but is also commonly used in several other epileptic syndromes, such as in children with infantile spasms that are uncontrolled by other drugs. Vigabatrin is most often used as an add-on drug in patients with refractory partial seizures; it is effective in 40–50% of such patients. Overall, it is better tolerated than many other antiepileptic drugs.

Side effects of vigabatrin include dizziness, unsteadiness when walking, drowsiness, and impaired thinking and memory, although the side effects are generally less severe than those of many more traditional drugs. A small proportion of patients develop depression and other serious psychiatric complications, which regress when the drug is discontinued. Visual field defects, possibly caused by damage to the optic nerves or retina, occur in some patients taking vigabatrin and may be irreversible. Registration of the drug in the United States was delayed due to toxicology data in animals showing that the drug causes myelin edema in the brain. Although this has been seen with high doses of the drug in rats and dogs, and possibly in monkeys, no similar complication has been observed in humans. The effect is reversible and is detectable by magnetic resonance imaging and evoked potential studies. The clinical experience of the drug is estimated at more than 200,000 patient-years, but there have been no cases of myelin damage. Treatment begins with a dose of 500 mg 2 times a day, then it is increased over several weeks until the effect is achieved. In most cases, the effective dose is 2000-3000 mg/day (in 2 doses).

Other drugs for the treatment of epilepsy

Several other antiepileptic drugs are currently undergoing clinical trials, including zonisamide, remacemide, UCB L059, losigamon, pregabalin, rufinamide, ganaxalone, stiripentol. It is unlikely that all of these drugs will be introduced into widespread practice, since any new drug must demonstrate obvious advantages in efficacy, safety, tolerability, ease of use, and cost over currently used drugs.

Although none of the newly available drugs offers significant advantages over more traditional agents, patients with epilepsy now have a wider range of drug therapy options than they did 5-10 years ago. As clinical experience with these drugs increases, safer and more effective treatment regimens for epilepsy will be developed.