Antiepileptic drugs

Hydantoins

Hydantoins are characterized by the presence of a phenolic ring bound to a five-membered ring, consisting of alternating keto- and nitro groups in four corners. Replacement of the side chains attached to the fifth nitrogen atom forming the nitrogen atom (located between the two keto groups) has a significant effect on the pharmacological activity of the compound. In addition to phenytoin, the other three hydantoins are used as anti-epileptics. The first of these, 5-ethyl-5-phenylhydantoin, appeared before phenytoin. His anticonvulsant and sedative actions were used in the treatment of extrapyramidal disorders. However, the high incidence of drug allergy limited its use.

Phenytoin

Phenytoin was introduced into clinical practice in 1938 as the first non-sedative antiepileptic agent. Its anticonvulsant effect was confirmed in experimental animals using the model of maximum electric shock. Phenytoin is currently the most widely used drug in the US for the treatment of partial and secondarily generalized seizures.

Phenytoin has several application points in the central nervous system. The final effect is to limit the spread of epileptic activity from the place of its primary generation in the cerebral cortex and to reduce the maximum epileptic activity. The ability of phenytoin to block seizures in experimental animals with maximum electroshock makes it possible 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 - an increase in the activity of neuronal systems after high-frequency stimulation. Post-tetanic potentiation is related to the processes of plasticity of neurons, which are an important feature of these cells; but at the same time it can participate in the amplification and dissemination of epileptic discharges. It is believed that phenytoin blocks post-tetanic potentiation, preventing the entry of calcium ions into the neuron or increasing the refractory period of the sodium channels of the neurons. The latter effect appears to be key in the action of phenytoin, as it is shown that it weakens long-duration high-frequency discharges in several neuronal systems.

Although phenytoin does not affect the amplitude or configuration of individual action potentials, it reduces the rate at which neurons generate action potentials in response to short periods of depolarizing stimulation. This effect is associated with the blockade of sodium channels in neurons, occurs only in depolarized cells and is blocked by hyperpolarization. Thus, the mechanism of action of phenytoin is probably to stabilize the inactive state of the sodium channels of neurons. This effect depends on the activity of the cell and is not observed in neurons that do not belong to the category of rapidly discharging.

Phenytoin also suppresses synaptic transmission, inhibiting the release of certain neurotransmitters, probably due to the blockade of L-type calcium channels in the presynaptic nerve endings. In therapeutic concentrations, phenytoin also has an effect on calcium regulatory systems in brain cells using calmodulin.

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

Dose-dependent toxic effects are mainly associated with the effects of phenytoin on the central nervous system and are probably due to its ability to block rapidly discharged neurons. Many cells in the brain are normally discharged with rapid flashes of impulses and, consequently, are sensitive to the action of phenytoin at its therapeutic concentration in the blood. Thus, the vestibular nuclei, reacting to rapid changes in balance and posture, are 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 bridge also consist of rapidly discharging neurons that support the eccentric direction of the eye against the resistance of the elastic forces of the eye sockets, the weakening of fast discharges in this system leads to the appearance of nystagmus. Drowsiness, confusion and dizziness are other dose-related side effects of phenytoin. These side effects can be observed with the therapeutic concentration of the drug in the blood (10-20 μg / ml) and even at a lower concentration (in patients hypersensitive to these side effects or simultaneously taking several drugs). Ataxia, dysarthria, drowsiness, confusion and nystagmus occur more often if the concentration of the drug in the blood increases to 20-40 μg / ml. Very high concentrations in the blood (usually above 40 μg / ml) cause severe encephalopathy with the development of ophthalmoplegia, sometimes coma consciousness.

Extrapyramidal complications in the use of phenytoin do not occur often, although sometimes they are very severe. They can take the form of dystonia, choreoathetosis, tremor or asterixis. Similar effects can be both idiosyncratic and dose-dependent, since a decrease in dose sometimes leads to regress of hyperkinesis.

The influence of phenytoin on cognitive functions attracts special attention. Although it is generally acknowledged that it has less effect on cognitive functions than barbiturates, there is no consensus that it disrupts cognitive function more than carbamazepine. Although the initial data indicated the benefit of carbamazepine, subsequent analysis showed that, with comparable concentrations in the blood, both drugs had approximately equal effects on cognitive performance.

Since phenytoin affects atrioventricular conduction and ventricular automatism, with rapid parenteral administration, cardiac rhythm disturbance and arterial hypotension may occur, although some of these effects are undoubtedly associated with the action of propylene glycol, which serves as a solvent. Although a dose-dependent effect on the gastrointestinal tract is rare, some patients have nausea, vomiting, epigastric discomfort, and a decrease or increase in body weight.

The most noticeable idiosyncratic reaction when taking phenytoin is an allergy, which is usually manifested by skin rashes resembling a measles rash. More serious skin complications when taking the drug - exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis - occur at a frequency of 1 to 10-50 thousand. Fever, arthralgia, lymphadenopathy and influenza-like syndrome can occur separately or in combination with skin rashes. Lymphadenopathy can be so severe that it causes suspicions about the presence of lymphoma.

Phenytoin is metabolized in the liver, and hepatotoxicity can occur with both acute and prolonged administration. A slight increase in the level of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT) is observed in approximately 10% of patients. Although signs of cholestasis with a slight increase in the level of alkaline phosphatase is observed frequently, an increase in the serum bilirubin level is relatively rare. Induction of the enzyme gamma-glutamyl transpeptidase belonging to the cytochrome P450 system can be observed with subacute or chronic administration of phenytoin, but does not indicate a liver damage. The decision to discontinue phenytoin treatment can be made on the basis of the clinical picture and the data on the level of hepatic enzymes in dynamics, and not on the basis of a single study of the activity of one of the enzymes.

Adverse hematological reactions with phenytoin are relatively rare, but can be severe and even lethal. These complications include leukopenia, thrombocytopenia, agranulocytosis, disseminated intravascular coagulation and isolated red blood cell aplasia. With long-term administration of phenytoin, macrocytosis and megaloblastic anemia sometimes occur, which regress when folic acid is taken. Phenytoin can also cause immunological changes that are characteristic of lupus syndrome with an increase in the level of antinuclear antibodies, as well as interstitial nephritis, nodular polyarteritis, and other manifestations of immune dysfunction. Occasionally, phenytoin reduces the level of immunoglobulins in the serum.

The possibility of chronic toxic effects limits the use of phenytoin, with the greatest concern is a cosmetic defect. Phenytoin induces the proliferation of subcutaneous tissue, which leads to thickening of the skin on the bridge of the nose, coarsening of facial features, gingival hyperplasia (correction sometimes requires operative orthodontic intervention), hair growth on the face and trunk. Hyperplasia of gums occurs in 25-50% of patients, especially with poor oral hygiene, although the cosmetic defect is more visible in women and children. Proliferation of connective tissue occasionally causes Dupuytren's contracture, Peyronie's disease and pulmonary fibrosis.

Phenytoin can also cause polyneuropathy, usually manifested by the loss of achilles reflexes and a slight slowdown in the excitation of peripheral nerve fibers. Clinically significant neuropathy with the development of weakness and sensitivity disorders when taking phenytoin occurs rarely.

With the long-term administration of phenytoin, the development of a rachitis-like state associated with a disruption in the conversion of vitamin D precursors to a metabolically active form is possible. Although almost half of patients taking phenytoin for several years develop significant changes in bone density and serum levels of 25-hydroxycholecalciferol, bone fractures or ossalgia are extremely rare. Nevertheless, some physicians recommend taking vitamin D simultaneously with phenytoin.

With long-term administration of phenytoin, the function of the endocrine system often suffers, since the drug intensively binds to whey proteins, increasing the clearance of thyroid hormones. Although most patients have euthyroidism and a normal level of thyroid-stimulating hormone, some develop hypothyroidism. Phenytoin can also disrupt insulin secretion in patients predisposed to developing diabetes, and in extreme cases can provoke the development of hyperglycemia. Phenytoin is also able to increase the concentration in the blood of ACTH and cortisol, 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 influence the physiological processes underlying sexual activity.

With prolonged treatment with phenytoin, cerebellar atrophy often develops with a decrease in the number of Purkinje cells. The question is widely debated whether this atrophy is caused by seizures or the drug itself. Apparently, both factors contribute to this, since it is shown that with prolonged administration, the drug causes cerebellar atrophy in healthy dogs. The clinical significance of this phenomenon remains unclear.

The hydantoin syndrome of the fetus has polymorphic manifestations: hare lip, wolf mouth, hypertelorism, atrial and interventricular septal defects, skeletal and central nervous system anomalies, hypospadias, malformation of the intestine, developmental lag, hypoplasia of the fingers and skin pattern neither of them, mental underdevelopment. This syndrome is more correctly called an anticonvulsant fetus syndrome, because many of the newborns suffering from it have been in utero tested by a number of antiepileptic drugs.

Phenytoin is available as a free acid or sodium salt. The most commonly used form - dilantin - is available in the form of capsules containing 30 and 100 mg of phenytoin sodium. The last dose is equivalent to 92 mg of free acid. Other forms of sodium phenytoin, including tablets containing 50 mg of the drug (Dilatin Infatab), and generic forms of the drug have a shorter half-life than the conventional dilantine. Phenytoin is released and the form of the suspension for oral administration, because it is well absorbed in this way of administration (the half-elimination period in this case is approximately 22 hours). More than 95% of the absorbed phenytoin is metabolized in the liver, mainly by glucuronization. The metabolism of phenytoin is provided mainly 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 the metabolism of phenytoin is nonlinear kinetics: with an increase in the dose of the drug taken orally, a 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 ceases to metabolize phenytoin at a rate proportional to its serum concentration (first-order kinetics), and begins to metabolize it at a constant rate (kinetics of zero order). Once the level of the drug 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 binds intensely to serum proteins, especially albumin, with approximately 10% of the total amount remaining free. Since only unbound phenytoin penetrates the blood-brain barrier, changes in binding to serum proteins can affect the effect of the drug. This becomes particularly important in certain situations, for example, hypoproteinemia due to malnutrition or chronic diseases, as well as changes in serum protein levels during pregnancy. Although the total serum concentration of phenytoin decreases during pregnancy, the level of free phenytoin may remain the same.

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

Phenytoin interacts with a number of other drugs. So, it can affect absorption, binding to serum proteins, metabolism, pharmacodynamics of other drugs or to experience the corresponding influence of other drugs.

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

Phenytoin is indicated for partial and secondarily generalized seizures, including epileptic status. This list includes focal motor, focal sensory, complex partial and secondarily generalized tonic-clonic seizures. Phenytoin is useful in the treatment of primary generalized tonic-clonic seizures, but with absences, myoclonic and atonic seizures, it is usually ineffective. With epileptic status, phenytoin can be administered intravenously in a loading dose of 18-20 mg / kg. However, in this situation, it is preferable to administer phosphoentoin, also in a loading dose of -18-20 mg / kp. In other situations, when the therapeutic concentration in the blood needs to be reached within 24 hours, the drug is prescribed inside at a loading dose of 400 mg 3 times per day. The risk of a side effect on the part of the gastrointestinal tract, especially high in patients who have not previously taken phenytoin, usually limits the oral dose to a single 500 mg dose. In less urgent cases, phenytoin treatment starts at a dose of 300 mg / day (or 3-5 mg / kg). Since the half-elutation period of the drug is 22 hours, this dose ensures an equilibrium state within 5-7 days. Although dilantine capsules can be taken once a day, other forms of phenytoin may require a double intake, depending on the differences in bioavailability. The dose of phenytoin can be increased by 100 mg per week until a therapeutic effect or toxic effect is achieved or a recommended therapeutic range of 10-20 μg / ml is reached. After reaching the therapeutic range, a further increase in the dose at a time is carried out by no more than 30 mg at one time to avoid the occurrence of a toxic effect in the nonlinear portion of the metabolic curve and the associated risk. Capsules containing 50 mg of substance, with a single admission, usually do not ensure the maintenance of the therapeutic concentration of the drug throughout the day. Suspension of phenytoin for oral administration contains 125 mg of active substance in a 5-millimeter measuring spoon and 0.6% alcohol. A suspension containing 5 mg of 30 mg of the drug is also produced. Since children metabolism is faster than in adults, at this age it is advisable to take the drug twice a day.

When administered intravenously, phenytoin can not be mixed with glucose, which reduces its solubility. The rate of administration should not exceed 50 mg per minute. During and after administration, the blood pressure and the conduction state of the heart should be monitored in order to respond in a timely manner to a violation of conduction of the heart or a drop in blood pressure. Daily intake of phenytoin is possible for decades. With prolonged admission, it remains an effective and well tolerated drug. Some patients take phenytoin for more than 50 years. Although overall the effectiveness of the drug is preserved, individuals have tachyphylaxis. The withdrawal of the drug is carried out gradually within 1-3 months, if the side effects do not require a faster 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 divided doses. For the treatment, long-acting capsules containing 100 mg and 30 mg of active substance or a suspension containing 125 mg or 30 mg of active substance in 5 ml may be used. When taking generics or forms with a short action, the daily dose should be prescribed in 2-3 doses. Phenytoin for parenteral administration is available as a solution containing 50 mg / ml phenytoin sodium in ampoules or 2 ml vials. Phenytoin sodium for parenteral administration can not be administered intramuscularly due to irritant effects on the tissue.

Phosphenytoin

Phosphenytoin is a phosphate ester of phenytoin, which dissolves more readily than the parent compound. Phosphenytoin is cleaved by phosphatases in the lungs and blood vessels to form phenytoin, with a half-life of 10 minutes. Since phosphenytoin is better soluble in aqueous solutions than phenytoin, unlike phenytoin, it does not require the presence of propylene glycol and ethanolamine to stabilize the solution. It is suggested that some of the side effects of intravenously administered phenytoin are associated with these solvents.

Phosphenytoin causes less pain and irritation at the injection site than intravenous phenytoin. In addition, phosphenytoin, apparently to a lesser degree than phenytoin, causes arterial hypotension, cardiac rhythm disturbance, and necrosis of tissues when it hits the vessel. These benefits are proven by clinical trials and clinical experience.

Although the molecule of phosphenytoin is 50% heavier than the phenytoin molecule, it is considered that the doses of phenytoin and phosphenytoin are equivalent. Therefore, the administration of 1000 mg of phosphenytoin provides the same concentration of phenytoin in the serum as the administration of 1000 mg of phenytoin. Phosphenytoin can be safely administered at a rate of 150 mg per minute, that is, three times faster than phenytoin. Thanks to this, the administration becomes faster and more favorable binding characteristics are provided to the proteins, as a result of which the level of free phenytoin in the blood with the administration of phosphenytoin rises as rapidly as when phenytoin is administered. In addition, phosphenytoin can also be administered intramuscularly.

The side effects of phosphenytoin are basically the same as phenytoin, but appear to be less pronounced. An exception is the itching in the face, trunk or genitals associated with the rapid administration of phosphenytoin, which is probably due to the formation of formic acid during metabolism. Other important problems associated with the use of phosphenytoin are the higher cost of the drug (compared to phenytoin) and its limited availability. In addition, there is a risk of error: phenytoin can be confused with phosphenytoin, which can lead to an excessively fast and potentially dangerous intravenous injection of phenytoin.

This is the

It has been used since 1956. It is usually used in situations where phenytoin was effective, but because of the toxic effect, its further administration became impossible. It almost never causes cosmetic defects and to a lesser degree causes ataxia than phenytoin. To the shortcomings of etotoin is a short period of half-elimination, which requires taking the drug 3-4 times a day, and, apparently, a lower efficacy than phenytoin. It is available in tablets of 250 and 500 mg. By the mechanism of action, it is probably similar to phenytoin. Treatment begins with a dose of 250 mg 4 times a day (1 g / day) or daily changing 100 mg of phenytoin to 250-500 mg of etotoin. The dose of etotoin can be increased by 250-500 mg once a week before the onset of the effect or the appearance of intolerable side effects. The total dose can reach 2-3 g / day. The therapeutic serum concentration is usually 15-45 μg / ml. It causes the same side effects as phenytoin, but their probability is lower. The only relatively unique side effect of etotoin is the distortion of visual perception, expressed in the increased brightness of perceived light. Hyperplasia of the gums and cosmetic changes caused by phenytoin, when the phenytoin is replaced by ethytoin, may regress.

Another clinically important hydantoin is mefenitoin, 3-methyl-5-ethyl-5-phenylhydantoin. The therapeutic effect has an active metabolite of mephenitine - 5-phenylgilantoin, formed from mephenytoin by demethylation. On the properties of mephenytoin is similar to hydantoins and barbiturates and is active both on the model of maximum electric shock and on the model of pentylengetrazole seizures in experimental animals. Introduced in 1945, it is used to treat partial and secondarily generalized seizures. Mephenytoin is available in tablets of 100 mg. The daily dose ranges from 200 to 800 mg. Since the active metabolite of mephenitoin has a half-elimination period of about 3-6 days, it is prescribed 1 time per day. Although the effectiveness of mephenytoin in partial and secondarily generalized seizures is beyond doubt, it does not apply to drugs of choice due to toxicity. Compared with phenytoin, mephenitoin often causes rash, lymphadenopathy, fever, severe and even lethal haematological complications.

Barbiturates

Introduced in clinical practice in 1912, phenobarbital for several decades remained the most widely used antiepileptic drug. Currently, it is still the drug of choice for some types of seizures in countries where the cost and ease of use of antiepileptic drugs are the main priorities. In the US, the use of phenobarbital has decreased because of a pronounced sedative effect and a negative effect on cognitive function. Chemically, phenobarbital is 5-ethyl-5-phenylbarbituric acid. Due to differences in physical and chemical properties, the effect of different barbiturates is very different. Barbiturates with long-term action (such as phenobarbital) are antiepileptic drugs, while short-acting barbiturates (such as thiopental and methohexital) are relatively ineffective in epileptic seizures and even can exacerbate epileptiform activity. Phenobarbital and primidone are the two barbiturates most widely used in the treatment of epilepsy.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]

Phenobarbital

Phenobarbital is active on a number of experimental models of epilepsy, including the model of maximum electric shock and pentylenetetrazole seizures. Although the study on experimental models shows that phenobarbital has a broader spectrum of action than phenytoin and carbamazepine, phenorbarbital is most useful in the clinic for the same types of seizures as the indicated drugs, namely, partial and secondarily generalized seizures.

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

Phenobarbital is well absorbed after ingestion or intramuscular injection. The therapeutic level of phenobarbital in the blood ranges from 5 to 40 μg / ml, but most often lies in the range of 10 to 30 μg / ml. Approximately 45% of phenobarbital in the blood is associated with serum proteins, but only a free fraction (55%) is able to penetrate the brain. Phenobarbital is metabolized by the hepatic cytochrome-P450 enzyme system. Although phenobarbital induces microsomal liver enzymes, this does not result in significant autoinduction. A significant proportion (25%) of unchanged phenobarbital is eliminated by the kidneys, the rest is metabolized in the liver, mainly turning into beta-hydroxy-phenobarbital. Elimination of phenobarbital and its metabolites is linear, and the period of half-elimination of the drug ranges from 72 to 120 hours. In newborns, the half-elimination period can reach 150 hours, gradually shortening during the first years of life. Due to the long period of half-elimination, phenobarbital can be administered once a day, and nothing else but the force of habit is conditioned by the recommendation to take it three times. Structural formula once a day. If the treatment is not started with a loading phenobarbital dose, then achieving an equilibrium concentration of the drug in the serum requires several weeks of administration.

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

Phenobarbital is used for acute and chronic treatment of partial and secondarily generalized seizures. Although it is also useful for primary generalized tonic-clonic seizures, atonic seizures, absences and myoclonic seizures, in these cases its effectiveness is more variable. To create a therapeutic drug concentration in the blood, the daily dose of phenobarbital in adults should be 1-1.5 mg / kg, in children 1.5-3.0 mg / kg. With epileptic status, phenobarbital may be administered intravenously at a loading dose of 18-20 mg / kg at a rate not exceeding 100 mg / min. If the loading dose is not applied, the equilibrium concentration of the drug in the blood is reached after many weeks.

Phenobarbital is not inferior in effectiveness to phenytoin and carbamazepine in the control of partial seizures and can serve as a drug of choice in case of epileptic seizures in newborns, as well as in 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. Sedation is most pronounced in the first 1-2 months of treatment. Patients taking phenobarbital for years often do not notice sedation and fatigue until the drug is gradually canceled. Other side effects caused by the drug on the CNS - ataxia, dysarthria, dizziness, nystagmus, cognitive impairment - are relatively common, especially against the background of a high concentration of the drug in the blood.

In children and the elderly, taking phenobarbital, sometimes there is paradoxical hyperactivity, not sedation. In all patients with the use of phenobarbital may occur some manifestations of depression, which increases the risk of suicidal actions.

Idiosyncratic side effects associated with taking phenobarbital include hypersensitivity, rash, and not often occurring hematologic and hepatic complications. In men taking phenobarbital, sexual functions can be violated, and in women - sexual desire may decrease. Necrosis of the liver, cholestasis and gastrointestinal disorders are rare.

Phenobarbital-induced increase in the activity of microsomal liver enzymes can affect the metabolism of vitamin D, which leads to osteomalacia, as well as causing folate deficiency and megaloblastic anemia. Moreover, long-term use of phenobarbital can induce proliferation of connective tissue, although cosmetic defect is usually not as noticeable as when taking phenytoin. The proliferation of connective tissue caused by the use of phenobarbital can lead to the development of Dupuytren's contracture in the hand, Peyronie's disease, the frozen shoulder syndrome, diffuse joint pain with or without palmar fibromatosis (Ledderhoez syndrome).

Phenobarbital has an adverse effect on cognitive function, and this effect can persist even after the drug is discontinued. Farwell (1990) found that in children taking phenobarbital, the intelligence factor (IQ) is 8.4 points lower than in the control group, and 6 months after drug withdrawal it is 5.2 points lower than in control.

Although phenobarbital is recommended by the American College of Obstetrics and Gynecology for the treatment of epilepsy during pregnancy, there is too little convincing evidence that in this situation it is safer than most other anti-epileptic drugs. The intake of phenobarbital during pregnancy is associated with the appearance of fetal malformations, including tracheoesophageal fistulas, small intestine and lung hypoplasia, abnormality of the fingers, ventricular septal defects, hypospadias, meningomyelocele, mental retardation and microcephaly. There is no direct evidence that these malformations are associated with the use of phenobarbital - they can be attributed to other concomitant antiepileptic drugs, epilepsy itself, or other concomitant diseases.

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

Phenobarbital is available in tablets of 15, 30, 60 and 100 mg. When taking phenobarbital requires special care, because tablets with different doses of patients are often perceived as the same "small white pills" and may mistakenly take a pill with a different dose. In an adult, treatment is usually started at a dose of 90-120 mg per day (if not taken to a loading dose). Although 100 mg tablets are more convenient, at the beginning of treatment it is better to take 3-4 tablets of 30 mg: this facilitates a gradual titration of the dose. Tablets of 15 mg can be useful for a thin titration dose or for the gradual withdrawal of phenobarbital, which can last for several months, if any serious side effect does not require a faster withdrawal of the drug. Phenobarbital for intravenous administration is available in several doses. Intravenously, the drug should be administered at a rate not exceeding 100 mg / min, while the possibility of respiratory depression and cardiac activity should be considered. Some phenobarbital preparations for parenteral administration contain propylene glycol, an ingredient that irritates tissue.

Primidone

It is a 2-deoxy-analogue of phenobarbital. It is effective in epileptic seizures, probably due to its two active metabolites - phenyethylmalonic acid (FEMC) and phenobarbital. Under experimental conditions, primidone is not inferior in effectiveness to phenobarbital on the model of seizures caused by maximal electroshock, but 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 few living compounds with a half-elimination period of 5-15 hours. Approximately half the dose of primidone is excreted unchanged by the kidneys. Achieving the equilibrium concentration of phenobarbital in the serum appears to correspond to the onset of the therapeutic effect of primidone. Primodon is well absorbed when taken orally. Approximately 25% binds to serum proteins. Primodon also interacts with other drugs, like phenobarbital.

Primidone is used to treat partial seizures, secondarily generalized seizures and sometimes myoclonic seizures. Although most comparative studies have shown equal efficacy of primidone and phenobarbital, patients taking primidone were more likely to drop out of the study than patients taking phenobarbital, as well as carbamazepine and phenytoin. The reason for this is that when taking primidon, side effects (drowsiness, nausea, vomiting, dizziness) occur more often, especially in the first week of treatment. Patients who continued to receive primidone more than 1 month, dropped out of the study no more often than with the reception of other funds. During this period, there were no significant differences between the drugs in terms of frequency of side effects and efficacy. Approximately 63% of patients taking primidone did not have seizures after 1 year of treatment-for comparison: seizures completely regressed in 58% of patients taking phenobarbital, 55% of patients taking carbamazepine, and 48% of patients taking phenytoin.

An important feature of primidon application is the need for slow titration of the dose. At some patients already after reception of the first dose the sharp drowsiness develops. Severe drowsiness may persist for several days. In this regard, treatment is advisable to start with a trial dose of 50 mg. If the patient is taking this dose, then he can be given 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. Considering the short half-life of primidone and its metabolite FEMK, the drug is recommended to be taken fractionally within 24 hours. At night seizures, the whole daily dose can be prescribed for the night. With this scheme of treatment, the level of phenobarbital will be constant throughout the day.

The therapeutic level of primidone in the blood varies from 4 to 15 μg / ml, most often 12 μg / ml. Due to the short semi-elimination period, the concentration of the primidone during the day can vary. Some doctors ignore the level of primidone in the blood and estimate only the equilibrium concentration of phenobarbital, which, because of its long half-elimination period, does not depend on how long it took from taking the drug to the time of blood sampling.

In view of the high risk of abstinence seizures, the drug should be discontinued with extreme caution. Usually the drug is canceled gradually, for several months (with switching to tablets containing 125 mg and 50 mg), if serious side effects do not require more rapid cancellation.

Side effects when taking primidone are the same as in the treatment with phenobarbital. These include drowsiness, ataxia, cognitive impairment, depression, irritability, hyperactivity, gastrointestinal disorders. Idiosyncratic and chronic side effects are identical to those observed with phenobarbital.

Primidone is available in tablets of 50, 125 and 250 mg, as well as a suspension for oral administration (250 mg in 5 ml). The form of primidone for parenteral administration in the United States does not apply. Patients who are not able to take primidone inside, as a temporary measure can be parenterally assigned phenobarbital. When switching from one drug to another, it should be borne in mind that 250 mg of primidone is equivalent to about 30 mg of phenobarbital.

Other barbiturates

Mephobarbital (methylphenobarbital) is indicated for the treatment of partial and secondarily generalized seizures and, possibly, primary generalized seizures. At the same time, it seems to be ineffective in absences.

When administered orally, mefobarbitol does not get as full as phenobarbital, so its dose should be 50-300% higher than the dose of phenobarbital. It should also be taken into account that there are two racemic forms of the compound that differ in absorption, efficiency and metabolism. Approximately 66% of mefobarbital binds to serum proteins, while the semi-elimination period for bound enantiomers is approximately 48 hours. Mephobarbital is metabolized in the liver, and its metabolites are excreted in the urine. Most of the drug is demethylated in the liver with the formation of phenobarbital, which makes it possible to measure the therapeutic level of phenobarbital after reaching an equilibrium state with mefobarbital. Although the metabolism of mefobarbital produces other compounds that result from aromatic hydroxylation, it is not known whether they contribute to the therapeutic effect of the drug. The therapeutic concentration of mefobarbital in the blood ranges from 0.5 to 2.0 μg / ml, but the concentration in the blood of phenobarbital is considered a more reliable indicator, better correlating with the clinical effect.

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

In adults, the effective dose of mefobarbital is 400-600 mg / day. Mephobarbital is available in tablets of 32, 50 and 100 mg. Children under 5 years mefobarital prescribed in a dose of 50-100 mg / day, children over 5 years - in a dose of 100-300 mg / day. Treatment usually starts 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 a therapeutic dose. Since the duration of action mefobaritala varies from 10 to 16 hours, it is usually prescribed 3 times a day.

Other barbiturates (for example, pentobarbital or secobarbital) are sometimes used in acute situations. Barbiturates with a shorter action than phenobarbital, are not as effective as antiepileptic drugs and are practically not used for long-term therapy.

Carbamazepine

The drug of choice for partial and secondarily generalized tonic-clonic seizures. Although it is able to suppress also primary generalized tonic-clonic seizures, carbamazepine is not effective in absences, myoclonic and atonic seizures. Although carbamazepine was developed in the 1950s as a chemical analog of tricyclic antidepressants, from the point of view of its chemical structure, it is an iminostilbene. Carbamazepine was originally tested as an antidepressant, then with pain syndromes associated with depression, and, finally, with neuralgia of the trigeminal nerve. The effectiveness of the drug in trigeminal neuralgia served as a basis for testing its effectiveness in epilepsy, which was also characterized by rapid uncontrolled discharges of neurons.

Carbamazepine shows activity on the model of maximal electroshock, but it is not effective for pentylenetetrazole seizures. At the same time, it is more effective than phenytoin, in blocking seizures caused by the winding activation of the amygdala in experimental animals. Since carbamazepine blocks outbreaks of rapid discharge of neurons in the hippocampal slices, it probably blocks sodium channels in neurons, as does phenytoin. It is suggested that carbamazepine binds to inactivated sodium channels, slowing their transition into the active state. Carbamazepine also affects the response of neurons to excitatory amino acids, monoamines, acetylcholine and adenosine. The blockade of presynaptic fibers, caused by exposure to sodium channels, can reduce the release of a mediator from them and disrupt the transport of calcium into neurons.

Carbamazepine is slowly and not completely absorbed after ingestion. The concentration in the plasma reaches a maximum within 4-8 hours after administration, but sometimes this period stretches to 24 hours, which is especially important in case of an overdose of carbamazepine. Approximately 80% of carbamazepine binds to plasma proteins, while the concentration of the substance in the brain is 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 a background of relatively low levels of carbamazepine in the blood. If necessary, the blood level of 10,11-epoxide can be measured.

The therapeutic level of carbamazepine in the blood varies from 4 to 12 μg / ml, although some patients require a higher oxcarbazepine level - from 8 to 12 μg / ml. Usually, the total content of the bound and unbound drug fractions in the blood is measured, but the concentration of the unbound drug can be examined separately. The content of epoxide metabolite is 10-25% of the level of carbamazepine, but this ratio can be higher with simultaneous reception of other agents.

Carbamazepine induces microsomal enzymes of the liver. During the first few weeks of treatment, autoinduction of one's own metabolism can occur. The enzyme system CYP3A4 is the main pathway of metabolism for both carbamazepine and 10,11-epoxide.

The interaction of drugs with carbamazepine is complex. Some agents are able to change the concentration of 10,11-epoxide, without affecting the blood level of carbamazepine itself. Carbamazepine is capable of variable in reducing the concentration of phenytoin. After the addition of carbamazepine, a larger portion of the primidone is converted to phenobarbital. Carbamazepine also increases the metabolic clearance of valproic acid, reducing its equilibrium concentration. In addition, carbamazepine reduces blood levels of benzodiazepines and other drugs, including phenothiazines, fentanyl, tetracycline, cyclosporin A, tricyclic antidepressants, coumadin, and oral contraceptives. The acceleration of the metabolism of oral contraceptives can lead to an unexpected pregnancy in a woman taking a contraceptive drug containing less than 50 μg in terms of ethinylestradiol.

The 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 styipentol 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 observed with simultaneous administration of carbamazepine valproic acid and acetazolamide. Drugs that induce hepatic microsomal enzymes (eg, phenytoin, phenobarbital, primidone and felbamate) increase the metabolism of carbamazepine, reducing its plasma concentration by 10-30%.

Carbamazepine is effective for partial and secondarily generalized seizures and is one of the drugs of choice in these conditions. In a large clinical study comparing the efficacy of various anti-epileptic agents, carbamazepine provided complete elimination of seizures in a much larger proportion of patients than other drugs. Although carbamazepine also affects primarily generalized tonic-clonic seizures, with absences and myoclonic seizures, it rarely has an effect. It is relatively ineffective in febrile seizures. In the US, carbamazepine is officially approved for use in children older than 6 years, but is used to treat partial seizures and in younger children.

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

Carbamazepine is especially often combined with phenytoin (although this often leads to severe ataxia), valtroic acid, gabapentin, lamotrigine and sometimes with phenobarbital.

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

Acute side effects with carbamazepine are mainly associated with its adverse effects on the gastrointestinal tract and CNS. These include nausea, diarrhea, ataxia, dizziness, double vision, drowsiness, and cognitive impairment. All of them can be minimized with a slow increase in the dose. Doubling is a very characteristic, though not unique, side effect of carbamazepine. In addition, carbamazepine has a pronounced anticholinergic effect, causing dry mouth, reducing tearing, tachycardia, urinary retention, constipation. Elderly patients are particularly sensitive to these side effects.

Although carbamazepine is often detected as an increase in blood levels of liver enzymes, hepatotoxic effects are rare. Such a toxic effect can take the form of allergic granulomatous hepatitis with cholestasis or direct toxic hepatitis with liver necrosis without cholestasis. This complication usually occurs in 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, it is recommended to conduct a regular blood test. Because of early reports of the possibility of leukopenia, the initial recommendations suggested more frequent blood control, currently it is recommended to be conducted less often - depending on the specific situation. The proposed scheme includes a study before the appointment of the drug at 1 and 3 months, then - if necessary. The blood test includes a clinical blood test to determine the number of platelets, the determination of the sodium concentration, the level of liver enzymes and the total content of carbamazepine in the blood.

Carbamazepine can cause subclinical or, more rarely, clinically pronounced polyneuropathy. Some patients develop chronic thyroid dysfunction with a decrease in the level of the corresponding hormones and, more rarely, clinical signs of hypothyroidism. With prolonged admission, carbamazepine increases the level of free cortisol and reduces the level of luteinizing hormone and free sex hormones, which can explain the development of sexual dysfunction with the drug. Carbamazepine makes oral contraceptives with low hormones ineffective and alters the metabolism of vitamin D (although there are only a few reports of clinically expressed osteomalacia caused by carbamazepine). Carbamazepine can disrupt the conductivity of the heart, both in acute and chronic administration. Violation of the heart rhythm can be represented by sinus tachyacardia (manifestation of cholinolytic action), bradyarrhythmia or blockade of the conduction system of the heart. Heart disorders often occur in elderly patients or those suffering from heart disease.

The degree of disruption of cognitive functions under the action of carbamazepine is still not clearly defined. It is generally recognized that carbamazepine has a less pronounced adverse effect on cognitive function than barbiturates and benzodiazepines. Although earlier studies indicated that carbamazepine less violates cognitive functions than phenytoin, a subsequent analysis of these results showed that the effect of both drugs on cognitive function is comparable. In case of acute and chronic administration of carbamazepine, encephalopathy, delirium and paranoid psychosis may also occur.

Carbamazepine is a teratogenic drug, sometimes causing so-called small developmental anomalies, consisting in the developmental defects of the face and fingers. They tend to regress in the first few years of life. Spinal dysphasia 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 formation of the fetal spine, this effect is not confirmed in controlled clinical trials.

Carbamazepine is available in the US in the form of chewable tablets of 100 mg, 200 mg tablets and a suspension containing 100 mg in 5 ml. More recently, carbamazepine sustained release capsules have been used, which can be taken twice a day. They contain 100, 200 and 400 mg. Other dosage forms of carbamazepine for oral administration should be prescribed 3-4 times a day. Treatment is recommended to begin with a dose of 100 mg 3 times, then the daily dose is increased by 100-200 mg every 3-7 days with good tolerability to 1200 mg in three divided doses. The dose can be increased up to 1600 mg / day and higher, but only in special cases and specialists having experience of using this compound. Although a clinical form of carbamazepine for parenteral administration has been developed, it is not currently used in clinical practice.

[15], [16], [17], [18], [19], [20], [21], [22], [23]

Oxcarbazepine

Structurally close to carbamazepine. The keto group contained in the molecule of this substance prevents carbamazepine from being metabolized to form 10,11-epoxide, which reduces the risk of side effects. Clinical trials have shown that oxcarbazepine is an effective and relatively safe remedy, which can be prescribed to patients who do not tolerate carbamazepine. Although in general, the side effects of oxcarbazepine are similar to carbamazepine, they occur less frequently. The exception is hyponatremia, which is more common with oxcarbazepine than with carbamazepine.

A recent preoperative study in hospitalized patients showed that oxcarbazepine prolongs the time until the onset of the fourth fit compared with placebo. The drug is approved for use in 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 accidentally. Initially, the substance was used as a solvent for compounds with an expected antiepileptic effect. When all the tested drugs proved to be effective, which was impossible, the researchers reasonably assumed that the active ingredient was actually a solvent. The first clinical trials of valproic acid were conducted in France in 1964. In France, the drug entered the pharmacological market in 1967, in the United States it began to be used since 1978. Special dosage form in the shell, soluble in the intestine, is sodium divalproex - has been used in practice since 1983, since 1990 the preparation is produced for children in the form of capsules with microgranules. A form for intravenous administration appeared comparatively recently.

Although experimental models and animals have demonstrated that valproic acid is a broad-spectrum antiepileptic drug, it is a low-potential agent with an effective dose of several hundred milligrams. Valproic acid inhibits seizures in the model of maximum electric shock and pentylenetetrazole seizures in laboratory animals, with the therapeutic index of the drug in this case being 4-8, which is equivalent to phenytoin, carbamazepine and phenobarbital. Valproic acid is somewhat more effective in pentylenetetrazole seizures than in the maximal electroshock model, which makes it possible to predict its efficacy in absence of epilepsy. It also inhibits chemically induced seizures, as well as seizures that result from the Kindling effect.

In high doses, valproic acid inhibits succinemeli-aldehyde dehydrogenase, an enzyme involved in the metabolism of GABA. However, this effect requires a higher concentration of valproate than that usually created in the brain. A variable effect is also observed with respect to the ability to potentiate GABA-receptor mediated inhibitory postsynaptic potentials. The effect of valproate is in many respects similar to the effect of phenytoin and carbamazepine. All these drugs inhibit fast repeated discharges of depolarized neurons, possibly due to interaction with the sodium channels of neurons. Interaction with the low-threshold calcium current responsible for repeated discharges of thalamic pacemakers can underlie the effectiveness of the drug in absences. Currently, other possible effects of the drug are being investigated, including its effect on calcium channels and the ability to block transmission mediated by excitatory amino acids.

Valproate sodium and divalproex easily absorbed after ingestion, while the concentration in the plasma reaches a peak 1-2 hours after ingestion. Although absorption is good when taken with food - in this case, the concentration reaches a peak with a delay of 4-5 hours. The ease of absorption makes it possible to administer a loading dose of valproic acid through a nasogastric tube in critical states. In this case, the dose is about 20 mg / kg. When rectal administration of valproic acid is also easily absorbed and administered in the same dose. After absorption, sodium valproate is 85-95% bound to plasma proteins, but only the unbound form penetrates the brain. The half-elimination period from plasma varies from 5 to 16 hours. In this case, the therapeutic level in the serum usually lies in the range from 50 to 100 μg / ml. However, severe seizures may require higher concentrations in the blood - up to 150 μg / ml.

Valproic acid is metabolized by conjugation with glucuronic acid in the liver and subsequent excretion in the urine. The starting compound is also conjugated to carnitine, glycine and coenzyme A. Partially 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. It is believed that the former, also known as 2-N-valproic acid, is partly responsible for the therapeutic and toxic effects of valproate. Although efficacy often persists for 1-2 weeks after the parent compound has disappeared from the blood, it is not known whether this is due to the accumulation of 2-N-valproic acid, the binding of valtroic acid or metabolites to tissues with some long-term physiological changes.

Valproic acid differs from most traditional antiepileptic drugs by blocking, rather than inducing, hepatic microsomal enzymes, which increases the likelihood of certain drug interactions. Thus, with the appointment of valproic acid, the serum concentration of phenobarbital, unbound phenytoin, lamotrigine, and sometimes ethosuximide is increased. Given this, when adding valproic acid to phenobarbital, the dose of barbiturate should be reduced by about a third. At the same time, in an equilibrium state, valproate decreases the serum concentration of carbamazepine, the total phenytoin, and increases the fraction of carbamazepine metabolized to form a 10,11 epoxide. Most other antiepileptic drugs increase the hepatic clearance of valproate, reducing its level in the blood. Therefore, the addition of phenytoin, phenobarbital, primidone, carbamazepine or felbamate may be accompanied by a decrease in the concentration of valproic acid.

Valproic acid is an antiepileptic drug with a wide spectrum of action, shown in absences, partial and secondarily generalized seizures, as well as some myoclonic and atonic seizures. It is the drug of choice in the treatment of generalized seizures in patients with juvenile myoclonic epilepsy. Valytric acid can be used both as ionotherapy and in combination with other antiepileptic drugs, most often phenytoin or carbamazepine.

Treatment with valproic acid should be started gradually, mainly because of the possibility of side effects from the gastrointestinal tract, which are severe if the drug is immediately prescribed in a high dose. Although usually treatment is recommended to start at a dose of 15 mg / kg / day in three divided doses, given the existing dosage forms of the drug, it is more convenient to first prescribe 125 mg 2 or 3 times a day. Subsequently, the dose is 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 a day, or about 30 mg / kg / day. The recommended maximum dose is 60 mg / kg / day. The therapeutic concentration in the serum is 50-100 μg / ml, although in severe cases it sometimes has to be increased to 150 μg / ml.

Valproate causes skin rashes in 1-5% of patients. Rashes are sometimes accompanied by fever and lymphadenopathy. Hepatotoxic effect is a more serious idiosyncratic effect, usually developing within 3 months after initiation of treatment. Although elevated hepatic enzymes are often detected, hepatotoxicity is rare. Analysis of deaths caused by liver damage showed that they occur at a frequency of 1:50 000 per year. Although in general this indicator is relatively low, in patients under 3 years of age who take several drugs, the probability of a lethal outcome due to severe liver damage is 1: 600. The 9th circumstance should be taken into account when administering valproic acid in this age group. In contrast, in adults who are on monotherapy with valproic acid, there is no hepatotoxic effect with a lethal outcome.

Against the background of valproic acid therapy, sporadic cases of hemorrhagic pancreatitis and cystic fibrosis were also noted. Acute idiosyncratic hematologic effects consist, mainly in 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 primarily associated with gastrointestinal dysfunction and include nausea, vomiting, epigastric discomfort, diarrhea. When using tablets in a shell dissolving in the intestine, and taking the drug with food, these side effects are less common. Side effects from the central nervous system are less pronounced than when taking phenobarbital, phenytoin, or carbamazepine, although some patients have sedation, ataxia, doubling, dizziness, or, rarely, encephalopathy or hallucinations. Postural tremor with valproic acid is more pronounced than with other antiepileptic drugs.

With long-term admission, the main side effect limiting the further use of the drug is a tendency to increase in body weight, less often it decreases. The mechanism of increasing body weight remains unclear. Some experts believe that the main role is played by the inhibition of beta-oxidation of fatty acids and an increase in appetite. With prolonged use of valproate, peripheral edema and alopecia are possible, some patients also experience amenorrhea and impairment of sexual function.

Valproic acid often causes hyperammonemia, which does not necessarily reflect hepatic dysfunction and may be associated with a blockade of nitrogen metabolism. Carnitine, involved in the transport of fatty acids through mitochondrial membranes, can restore nitrogen balance, although there is no evidence that the purpose of this compound is effective in the absence of its deficiency.

Valproic acid has a teratogenic effect. Reports of neural tube development defects in children whose mothers received valproic acid during pregnancy first appeared in 1981. In general, disfunctional syndrome occurs in 1-2% of children whose mothers took the drug during the first trimester of pregnancy. It is believed that taking folic acid reduces the risk of this complication. A small percentage of the offspring also have other small anomalies in the development of the face and fingers.

In the United States, valproic acid is available in the form of 250 mg tablets and a syrup containing 250 mg of the sodium salt of valproate in 5 ml of the solution. Valproic acid derivative divalproex sodium is available in the form of capsules with 125 mg microgranules and 125, 250, 500 mg sustained-release tablets. Recently, a form for parenteral administration (100 mg / ml in a 5 ml vial) has also been developed. Parenterally, the drug is administered by infusion at a rate of 20 mg / min at a dose equivalent to that given orally.

Succinimides

Ethosuximide, chemically close to phenytoin, is the drug of choice for absences (petit mal).

Ethosuximide blocks pentylenetetrazole seizures, but not seizures caused by maximal electroshock or winding activation of the amygdala. It is also relatively ineffective in seizures caused by bicuculline, N-methyl-D-aspartate, strychnine or allylglycine.

The spectrum of action of ethosuximide is narrower than that of most other anti-epileptic drugs. It is effective, mainly with ethosuximide absences and, to a lesser extent, with myoclonic and atonic seizures, but does not have an effect in other types of seizures. This selectivity of action indicates that the drug predominantly affects the thalamocortical regulatory system that generates rhythmic peak-wave activity. The thalamic system neurons have a special type of ion channel - low-threshold calcium channels of the T-type, which cause the discharge of neurons when the membrane potential changes - at a time when hyperpolarization is replaced by relative depolarization. Ethosuximide partially blocks these low-threshold calcium channels and, due to this, can inhibit the peak-wave activity generated by the thalamocortical system.

Although various hypotheses were suggested that explain the positive effects of ethosuximide in absences, none of them could be confirmed. Thus, it was suggested that the effect of ethosuximide is related to its ability to inhibit the synthesis of GABA in the brain, as well as the activity of sodium-potassium ATP-dependent channels in the membrane, but this effect is observed only at a very high concentration, which is usually not achieved in the brain upon admission preparation. The effect on GABA -ergic, glutamatergic and dopaminergic transmission is not sufficient to explain the action of ethosuximide.

Ethosuximide is a water-soluble substance that is easily absorbed after ingestion. The maximum concentration in the blood is reached 1-4 h after administration. When the syrup is used, the drug is absorbed more quickly than when taking the capsules. Ethosuximide is distributed in a space equivalent to the total volume of water in the body, while less than 10% of the drug binds to serum proteins. It easily crosses the blood-brain barrier, so the concentration in the CSF 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. About 20% of ethosuximide is excreted unchanged in urine, the rest is metabolized, mainly by oxidation. Identified 4 metabolites formed with the involvement of the hepatic CYP3A-enzyme system. All of them are pharmacologically inactive. Ethosuximide, to a much lesser extent than other antiepileptic drugs, interacts with other drugs, as it only binds to a small extent with serum proteins. Variable interaction was noted between ethosuximide, on the one hand, and phenytoin, phenobarbital, carbamazepine, valproic acid on the other hand, however, such interaction is not constant and does not usually have no clinical significance. In the insert to the preparation, the possibility of increasing the serum concentration of phenytoin with the addition of ethosuximide was noted.

Ethosuximide is indicated in absences. Although there are no formal age limits in connection with this indication, such seizures usually occur in children who are most often prescribed ethosuximide. Earlier, ethosuximide was also used in combination of absences and tonic-clonic seizures, usually together with phenytoin. Currently, in this case, as a rule, resort to motor therapy with valproic acid. In view of the possibility of a hepatotoxic effect in children with valproic acid, its relatively high cost, ethosuximide remains the drug of choice for epilepsy, manifested only by absence. Valproic acid is the drug of choice when combinations of absences with other types of seizures or atypical absences.

In patients 3-6 years, the initial dose of ethosuximide is 250 mg once a day (in the form of capsules or syrup). Every 3-7 days the dose is increased by 250-500 mg, usually up to 20 mg / kg / day. The therapeutic concentration in the blood is usually 40 to 100 μg / ml, but in resistant cases it must be increased to 150 μg / ml. This ratio is close to the therapeutic concentration of valproic acid. Due to the long half-elimination period, ethosuximide can be taken once a day. However, when side effects (nausea, vomiting) occur, it is advisable to switch from 2 to 4 times. Fractional administration is useful at the beginning of treatment, allowing to minimize side effects. The most frequent dose-dependent effect of ethosuximide is discomfort in the abdomen. In addition, the drug can cause anorexia, weight loss, drowsiness, dizziness, irritability, ataxia, fatigue, hiccup. A small proportion of children experience psychiatric side effects in the form of behavioral changes, aggression, less hallucinations, delusions, or severe depression. The effect of ethosuximide on cognitive functions was evaluated in only a few studies. It is, apparently, less significant than that of barbiturates.

Idiosyncratic side effects associated with the use of ethosuximide include skin rashes, erythema multiforme, Stevens-Johnson syndrome. Occasionally, ethosuximide, like other antiepileptic drugs, causes a lupus-like syndrome. Among the most serious, but rare side effects of ethosuximide, it is necessary to reverse the oppression of hematopoiesis, including aplastic anemia and thrombocytopenia. In view of this possibility, periodic clinical blood analysis is recommended in the treatment of drugs. The decrease in the number of granulocytes is rather a dose-dependent transient response, rather than the initial manifestations of aplastic anemia, however, this side effect requires regular monitoring.

Side effects with prolonged use of ethosuximide are observed less frequently than with the use of other antiepileptic drugs. There are separate descriptions of cases of thyroiditis, immune renal damage, a decrease in the serum level of corticosteroids, extrapyramidal disorders. There are cases when ethosuximide contributed to the increase in seizures. This effect can occur in patients with atypical absences and lead to the appearance of previously missing generalized tonic-clonic seizures, but more often the condition is worsened in patients with myoclonic and partial seizures.

Ethosuximide is capable of causing 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 (separately from other antiepileptic drugs) to induce teratogenesis, in pregnancy this drug should be used only if its therapeutic effect clearly outweighs the risk of possible complications.

Ethosuximide should be withdrawn gradually to avoid increasing absences or the appearance of an absence status.

In the US, ethosuximide is available in capsules of 250 mg and a syrup containing 250 mg in 5 ml. The initial dose in children from 3 to 6 years is 250 mg per day, in individuals over 6 years, 500 mg. The daily dose is increased by 250 mg every 3-7 days until a therapeutic or toxic effect is reached, up to a maximum of 1.5 g / day. Although treatment usually begins with a 2-3-fold administration of the drug, in the future, with good tolerability of the patient can be transferred to a single dose of the drug. The optimal dose is usually 20 mg / kg / day.

Other succinimides

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

Metsuximide is well absorbed after ingestion, with the concentration in the blood becoming maximal 1-4 hours after administration. The drug is rapidly metabolized in the liver and excreted in the urine. The active metabolite, N-desmethylmetussuximide, has a semi-elimination period of 40 to 80 hours. Several other metabolites can also have a clinical effect. The mechanism of action of metsuximide is probably similar to ethosuximide.

Metsuximide is indicated for absences and is used as a second- or third-line drug in this condition. Metsuximide is also used in the treatment of complex partial seizures resistant to therapy. Treatment usually begins with a dose of 300 mg / day, then it is increased by 150-300 mg / day every 1-2 weeks until therapeutic or toxic effects are reached, up to 1200 mg / day. The serum concentration of metsuximide is usually so small that it can not be measured; the therapeutic concentration of N-desmethylmethoxysuimide ranges from 10 to 50 μg / ml. Metsuximide increases the serum concentration of phenytoin and phenobarbital, and also enhances the conversion of carbamazepine to 10,11-epoxide.

Side effects associated with taking metsuximide are relatively common and include drowsiness, dizziness, ataxia, gastrointestinal disorders, a decrease in the number of blood cells, skin rashes (including Stevens-Johnson syndrome). Other side effects are possible from those that are caused by ethosuximide.

Fensuksimid shown at absences, but can sometimes be used as a second or third-line drug for other types of seizures. The drug is available in capsules of 500 mg. The initial dose is usually 500 mg / day, subsequently it is increased every 3-7 days until the effect is obtained, maximum in adults up to 1 g 3 times a day. Side effects are the same as when taking ethosuximide and metsuximide.

Felbamat

Felbamate - 2-phenyl-1,3-propanediol-dicarbamate - was the first antiepileptic drug introduced into the wide practice after valproic acid. At present, before prescribing the drug, it is necessary to warn the patient of possible side effects and obtain informed consent from him. In recent years, the popularity of the drug has slightly increased.

Felbamate was developed as an analogue of meprobamate, a tranquilizer widely used before the appearance of benzodiazepines. Felbamate is active against seizures caused by maximal electroshock in mice and rats, as well as with pentylenetetrazole seizures, although in the latter case it is less effective. Felbamate also blocks seizures caused by other convulsants, inhibits winding activation of the amygdala, reduces focal motor attacks in mice, caused by exposure of aluminum hydroxide to the cerebral cortex. In toxicological studies on animals, felbamate safety was noted, which led to false confidence in the good tolerability of the drug.

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

Felbamate is well absorbed after ingestion, despite limited solubility in water. Due to its lipophilicity, it easily crosses the blood-brain barrier, and its level in the cerebrospinal fluid corresponds approximately to the concentration in the serum. Approximately 25% of the dose is associated with serum proteins; the half-elimination period varies from 1 to 22 hours. Although the drug does not appear to induce enzymes responsible for its own metabolism, against the background of the administration of other means inducing microsomal enzymes, the half-elimination period of felbamate can decrease from 20 to 14 hours. The approximate volume of felbamate distribution is 0.8 l / kg. Although there was no clear correlation between the concentration of the drug and the therapeutic effect, clinical trials suggest that the therapeutic concentration may range from 40 to 100 μg / ml.

Felbamate undergoes first-order metabolism with the hepatic microsomal enzyme system. It induces hepatic microsomal enzymes and can enhance the metabolism of other drugs that serve as substrates for these same enzymes. Among the metabolites of felbamate are monocarbamate and conjugated felbamate, as well as several other compounds formed in a smaller amount. Approximately 50% of the absorbed dose is excreted unchanged in the urine.

Interaction of felbamate with other medicinal products may be of great 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 epoxide hydrolase enzyme level, 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 can enhance its effect.

The effectiveness of felbamate was evaluated, mainly, with partial seizures with or without secondary generalization. This was the first antiepileptic drug used to conduct the preoperative test - he was prescribed to the patient at the end of preoperative monitoring. The drug caused a positive effect in 40-45% of patients with partial seizures. The effectiveness of felbamate in partial seizures in comparison with valproic acid was demonstrated in a study conducted in outpatients. In another study, it was shown to be effective in patients with Lennox-Gastaut syndrome in patients with polymorphic (tonic, atonic and other) seizures resistant to previously used antiepileptic drugs. In small clinical trials, it has also been shown that felbamate can also be useful in absences and juvenile myoclonic epilepsy, which allows it to be considered an antiepileptic broad-spectrum drug.

Felbamate is available in tablets of 400 and 600 mg. In view of the danger of a serious toxic effect, the drug should be administered only after other therapeutic options have proved ineffective. Depending on the urgency of the situation, treatment starts 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 require an increase in the dose to 4,800 mg / day or an individual tolerance threshold. In children, the initial dose is 15 mg / kg / day, then it is weekly increased by 30-45 mg / kg / day, maximum to 3000 mg / day. Taking the drug along with food can reduce the likelihood of side effects from the gastrointestinal tract. In patients taking felbamate, a regular clinical analysis of blood and liver samples is necessary.

In toxicological studies in rats, the fatal dose of felbamate was not determined, since even a large dose of the drug did not cause any dangerous complications. Nevertheless, after the introduction into practice, it turned out that the drug is capable of causing very serious side effects in patients. Dose-related side effects include gastrointestinal dysfunction, weight loss, headache, insomnia, behavioral changes in children. Felbamate has a lesser adverse effect on cognitive function and overall activity than other antiepileptic drugs. In fact, it can even improve learning and memory. While for some patients, weight loss may be a desirable effect, for others this effect is unfavorable. When insomnia appears, 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. With a headache, use conventional analgesics. The probability of side effects when taking felbamate is much higher when it is combined with other drugs, which is determined by the possibility of drug interaction.

Approximately 1500 patients were involved in clinical trials of felbamate prior to release to the market, including 366 people taking the drug in two studies evaluating the effectiveness of monotherapy. On average, in these studies, patients took the drug for about 1 year. 12% of patients withdrew from clinical trials because of side effects. Moreover, there were no significant abnormalities in clinical blood tests or liver function tests, except for a few cases of transient leukopenia, thrombocytopenia, or anemia. In clinical trials, no case of aplastic anemia was noted. However, to date, 31 cases of aplastic anemia associated with felbamate have been reported. All of them date back to 1994. For the period 1995-1997 the manufacturer did not inform about any additional case. On average, aplastic anemia was diagnosed 6 months after the initiation of felbamate (the spread was 2.5 to 12 months). Most patients who developed this complication had previous immunological abnormalities, others had serious illnesses or previous episodes of hematologic complications while taking other antiepileptic drugs. Nevertheless, no specific prognostic factor predetermining the development of aplastic anemia was found. Out of 31 patients with aplastic anemia, 8 died from this complication.

In 14 patients with felbamate treatment, a severe hepatotoxic effect developed in 0.5-10 months. Although most of these patients simultaneously took several drugs, several took only felbamate.

The risk of aplastic anemia and liver damage significantly limited the use of felbamate and almost led to withdrawal of the drug from the market. However, many patients and their support groups believed that in some cases it was the only effective and tolerable remedy, and insisted that felbamate remain available. However, given the risk, patients are required to sign an informed consent prior to the appointment of felbamate. The manufacturer recommends taking a clinical blood test and liver tests every 1-2 weeks on a background of taking felbamate, although this is inconvenient for most patients. It is assumed that the risk of complications decreases after a year of treatment, and, consequently, the need for laboratory monitoring is subsequently reduced. Moreover, there is no evidence that laboratory monitoring will reduce the likelihood of developing aplastic anemia or a hepatotoxic effect. Nevertheless, the clinician and the patient should develop a laboratory control schedule that would suit them both. Patients and their relatives should also be warned about the need to promptly report when unusual infections, bleeding, bruising, pallor, or jaundice occur.

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

[24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]

Gabapentin

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

Although gabapentin was developed as an analog of GABA, it has a low affinity for GABA receptors and enzymes responsible for the synthesis and degradation of this neurotransmitter. It also has minimal effect on the brake postsynaptic potentials mediated by GABA. It is suggested that the action of gabapentin is associated with an increase in the intracellular concentration of GABA, due to the effect on the amino acid transport system. This system, which carries large neutral amino acids, such as L-phenylalanine and leucine, is found in the membranes of neurons and glial cells. The mechanism of interaction of gabapentin with a carrier in the small intestine and brain continues to be studied. The binding sites of radioactive gabapentin in the brain are different from those with which known neurotransmitters and neuromodulators interact. The highest binding of gabapentin is observed in the surface layers of the neocortex, the dendritic regions of the hypocamp and the molecular layer of the cerebellum. On experimental models, it is noted that the maximum anticonvulsant effect develops a few hours after intravenous administration. This time may be required to convert gabapentin to another substance or to achieve an effective drug concentration in a critical sector of the cell. Although gabapentin has some effect on the sodium channels of neurons, the release of monoamines and calcium ion channels in the brain, it is unlikely that its therapeutic effect was associated with these mechanisms. It is suggested that gabapentin is able to interact with the amino acids of the Krebs cycle, affecting the amount of glutamate released by neurons. It is also believed that gabapentin in some situations may have neuroprotective effects.

On experimental models, gabapentin also actively blocks seizures caused by maximal electroshock, like phenytoin. At the same time, it has only a mild effect with pentylenetetrazole seizures and is ineffective in absences models in rats and myoclonic seizures in photosensitive baboons. Gabapentin increases the epileptic threshold and reduces mortality when administered to rodents N-methyl, D-aspartate. In addition, it weakens epileptic seizures caused by handling activation of limbic structures in rodents. These data suggest that gabapentin should be most effective in partial and secondarily generalized seizures.

Although absorption of gabapentin increases with increasing doses, the proportion of the absorbable drug is reduced. It is assumed that this nonlinear regularity is due to the saturation of the carrier of L-aromatic amino acids in the gastrointestinal tract, which ensures the absorption of the drug. Thus, an increase in the dose of more than 4,800 mg / day leads only to a slight increase in the concentration of the drug in the serum. Gabapentin practically does not bind to whey proteins and is excreted unchanged in urine and feces. Since gabapentin is not metabolized, it does not inhibit or induce hepatic microsomal enzymes. These features predetermine a low potential for drug interaction, which is confirmed by both pharmacokinetic studies and clinical experience. Other antiepileptic drugs have no significant effect on the level of gabapentin in the blood, and vice versa. Although simultaneous administration of antacids reduces the absorption of gabapentin by about 20%, and when cimetidine is prescribed, the serum level of gabapenin is increased by 10%, these interactions are usually not clinically relevant. Gabapentin does not change the metabolism of estrogens and does not weaken, thus, their contraceptive effect.

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

At least five controlled studies of the efficacy of gabapentin in doses ranging from 600 to 1800 mg and several long-term drug safety studies have been carried out. Approximately 20-30% of patients with seizures resistant to previously prescribed drugs, the addition of gabapentin gives a good effect, that is, reduces the incidence of seizures by 50% or more, compared with the baseline level. Clinical experience shows that when a drug is administered at a dosage of 2400-4800 mg / day, the percentage of persons with a good response to the drug increases while maintaining a favorable therapeutic ratio, but this data should be confirmed by controlled trials. In small clinical trials, it has not been possible to demonstrate the efficacy of gabapentin in absences, myoclonic and atonic seizures. Although the drug is not officially approved in the US for use as monotherapy, two studies of the efficacy of monotherapy with gabapentin have been completed. In one of them, a quick titration of the dose up to 3600 mg / day with the use of the preoperative monitoring technique was carried out in hospitalized patients. Monotherapy with gabapentin proved to be more effective, in comparison with placebo, with partial and secondarily generalized seizures. However, in the study of outpatients, the effectiveness of the drug could not be demonstrated. It is suggested that this can be explained by miscalculations in the study protocol, since a significant proportion of patients noted an increase in seizures amid the withdrawal of carbamazepine, which affected the performance of gabapentin.

Gabapentin is available in tablets of 100,300 and 400 mg. A liquid form for oral or parenteral administration has not been developed. The manufacturer recommends 300 mg once a day on the first day of treatment, on the second day - the same dose, but twice a day; starting from the third day the drug is taken three times a day. However, a quicker titration of the dose, for example, if treatment starts with a dose of 300 mg 3 times a day, is usually well tolerated. With good tolerability, 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 in some patients higher doses are effective - 3600 mg / day or more. Although monitoring the serum concentration of the drug does not help in selecting the effective dose, it is sometimes determined to assess the patient's compliance or other indications. The range of therapeutic concentrations is from 2 to 10 μg / ml. The addition of gabapentin, as a rule, does not require correction of the dose of other antiepileptic drugs, although they must be individualized. When gabapentin is added to other drugs, pharmacodynamic interactions are sometimes observed (for example, increased dizziness when gabapentin is added to carbamazepine or drowsiness increases when gabapentin is combined with most other antiepileptic drugs), even if the concentration of drugs in the blood does not change. When gabapentin is used, there is usually no need for frequent monitoring of clinical blood analysis, however, some clinicians consider it appropriate to conduct clinical blood tests from time to time and examine the level of hepatic enzymes.

Toxicological studies in animals have shown that gabapentin is well tolerated by rats with acute administration at a dose of up to 8 g / kg, and in monkeys - in a dose of up to 1.25 g / kg. In male Wistar gabapentin, the growth of tumors from pancreatic acinar cells, which are regarded as hyperplasia or benign neoplasm, has been observed. However, these tumors do not affect mortality and, apparently, are a species-specific complication. There is no evidence that people taking gabapentin increases the risk of developing pancreatic cancer.

Dose-dependent side effects include drowsiness, ataxia, dizziness, fatigue. In some cases, gastrointestinal disorders are noted. In double-blind, placebo-controlled trials, patients taking gabapentin did not go out much more often (<5%) than those taking placebo, which indicates an excellent tolerability of the drug.

To date, the experience with gabapentin has an estimated 450,000 patient-years. Although there are some reports of idiosyncratic side effects, including skin rashes and a decrease in the number of blood cells, serious allergic reactions are extremely rare. The degree of safety of this drug in pregnancy is unknown. In general, for portability and safety gabapentin significantly exceeds other antiepileptic drugs.

Lamotrigine

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

Lamotrigine blocks seizures induced by maximum electroshock, handling activation, and photosensitive seizures in laboratory animals. In addition, it has an effect, albeit relatively weak, on pentylenetetrazole seizures.

Lamotrigine blocks the long-term high-frequency discharge of neurons in the same way as phenytoin and carbamazepine. It is believed that this effect is explained by the action on the potential-dependent sodium channels of neurons and the elongation of the refractory period of the cell. Lamotrigine also inhibits the release of glutamate, which indicates a possible neuroprotective effect of lamotrigine. Apparently, it does not affect the chlorine canals, as well as GABAergic, dopaminergic, noradrenergic, muscarinic and adenosine systems in the brain.

Lamotrigine is well absorbed when taken orally (both with and without food). Its bioavailability is close to 100%. Concentration in the serum reaches a peak 2-3 hours after taking the drug. Lamotrigine is 55% bound to serum proteins. The volume of its distribution is 0.9-1.3 l / kg. Lamotrigine is metabolized in the liver, mainly by conjugation with glucuronic acid. Its main metabolite, the 2-N-glucuronic acid conjugate, is excreted in the urine. Elimination of lamotrigine is linear in relation to the dose, which corresponds to the kinetics of the first order.

Although lamotrigine has only a minimal effect on the level of other antiepileptic agents in serum, agents that enhance or inhibit the activity of liver enzymes can significantly affect the metabolism of the drug. So, with monotherapy, the half-elimination period of lamotrigine is 24 hours, but with a simultaneous reception with drugs inducing hepatic enzymes (eg, phenytoin, carbamazepine and phenobarbital), the half-elimination period is reduced to 12 hours. In contrast, valproic acid, an inhibitor of the hepatic microsomal enzyme system, extends the half-elimination period of lamotrigine to 60 hours. Thus, the frequency of lamotrigine during the day depends on the drugs with which it is combined. Although lamotrigine induces its own metabolism, it remains unclear whether this is clinically relevant.

In the United States lamotrigine was introduced into clinical practice in 1994, but in other countries it has been used before. Clinical trials in the United States have confirmed the efficacy of lamotrigine as an adjuvant for partial and secondarily generalized seizures. In three large studies, there was a more than 50% reduction in the incidence of seizures compared to baseline in 20-30% of patients. On average, when taking the drug at a dose of 300-500 mg / day, the frequency of seizures decreased by 25-35%. Several recent clinical trials have shown that lamotrigine can also be used as a monotherapy. Small clinical studies and clinical experience indicate that it can be effective not only with partial and secondarily generalized seizures, but with absences, myoclonic, atonic and polymorphic seizures. A clinical study also showed that lamotrigine is effective in Lennox-Gastaut syndrome. Although the drug is mainly used in partial and secondarily generalized seizures, some clinicians consider it to be a useful alternative in primary generalized seizures that are resistant to conventional therapy. There are separate reports on the use of the drug in non-epileptic disorders, including chronic pain syndromes, bipolar disorder, movement disorders, neurodegenerative diseases. However, formally, the efficacy and safety of lamotrigine under these conditions has not been proven.

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

Treatment with lamotrigine should be started gradually to avoid skin rashes. The manufacturer recommends that patients older than 16 years begin treatment with a dose of 50 mg daily, after 2 weeks the dose is increased to 100 mg / day. This dose is also preserved for 2 weeks, after which it is increased by 100 mg every 1-2 weeks to the required level. If the titration is too rapid, skin rashes may occur. With a slower titration, treatment starts with a dose of 25 mg, taken for 1 week, and then the dose is increased by 25 mg every week until 100-200 mg / day is reached. After that, go 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 at the same time, lamotrigine is started with a dose of 25 mg every other day, after 2 weeks they switch to a daily intake of 25 mg, and after 2 weeks they begin to increase the dose by 25-50 mg every 1-2 weeks until reaching clinical effect. For the titration period of the lamotrigine dose, the administration 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), dose correction or other remedy is initiated. With monotherapy and in combination with valproic acid, lamotrigine can be given once a day. When combined with phenytoin, phenobarbital, carbamazepine, felbamate and other drugs inducing hepatic microsomal enzymes, lamotrigine is prescribed twice a day.

The main side reaction when taking lamotrigine is skin rashes, which can take the form of a simple corneal or maculopapular rash or a more common and severe lesion, such as erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis. In controlled clinical trials, the incidence of skin complications in adults was 10% (in the placebo group, 5%). It should be noted that this figure corresponds to the value obtained in some clinical trials of carbamazepine and phenytoin. Recently, a warning has been made about the possibility of serious skin complications in children, as they may be more sensitive to lamotrigine. This can be expressed in the development of Stevens-Johnson syndrome or toxic epidermal necrolysis. In several small clinical trials, the incidence of serious skin complications reached 1 case per 40 children, and in the group as a whole, 1 for 200. Therefore, before prescribing a drug under 16 years of age, patients and their relatives should be warned about the possibility of skin rashes, consent to use the drug. The risk of rashes increases with lamotrigine in combination with valproic acid. In adults, the probability of developing rashes depends on the rate of dose build-up, sometimes they disappear when the dose is lowered and then the titration of the dose is slower.

The main dose-related toxic effects of lamotrigine are associated with central nervous system dysfunction and include ataxia, discomfort, dizziness, confusion and fatigue. Sometimes there are nausea and vomiting. In studies evaluating the efficacy of adding lamotrigine to antiepileptic drugs previously taken, 10% of patients had to cancel the drug (with the addition of placebo, the figure was 8%). In the study of monotherapy in Europe, a good tolerability of the drug was noted, the only relatively significant significant side effect was skin rashes. Hematologic and hepatotoxic complications with lamotrigine are rarely observed. Other side effects, usually rare, include delirium, delirium, choreoathetosis, changes in libido and sexual functions, a paradoxical increase in the frequency of seizures. In toxicological studies, lamotrigine caused heart rhythm disturbances in dogs, apparently due to the action of N-2-methyl-conjugate, which is not formed in humans. Although there are some reports of cases of heart rhythm disturbances in humans, the incidence of this complication is not high.

Lamotrigine is available in tablets of 25, 100, 150 and 200 mg and chewable tablets of 5 and 25 mg. The drug is not released in solution. Although in the United States lamotrigine is not officially approved for use in persons younger than 16 years (with the exception of Lennox-Gastaut syndrome), in other countries it is also used in this age group. In children taking inducers of hepatic enzymes without valproic acid, lamotrigine should be started at a dose of 2 mg / kg / day. After two weeks, it is increased to 5 mg / kg / day, and after two weeks they begin to increase the dose by 2-3 mg / kg / day every 1-2 weeks until the clinical effect is reached. The maintenance dose usually varies from 5 to 15 mg / kg / day. With 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 in children should be started at a dose of 0.2 mg / kg / day (two weeks), then increase the dose to 0.5 mg / kg / day, which is also prescribed for two weeks, after which the dose is increased at 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, as a rule, is divided into two doses.

Topiramate

Topiramate 2,3: 4,5-bis-O- (1-methylethylvden) -beta-0-fructopyrazone sulfamate - differs significantly in chemical structure from other antiepileptic agents. It was developed by the RW Johnson Pharmaceutical Research Institute in collaboration with the Department of Epilepsy of the National Institutes of Health (USA). Topiramate is used for partial and secondarily generalized seizures, but is potentially useful for 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 electroshock in rats, and to a lesser extent with seizures caused by pentylenetetrazole, bicuculline or picrotoxin. Although topiramate inhibits carbonic anhydrase, apparently this effect is not the main one in the mechanism of its antiepileptic action. More important is its ability to increase GABA-mediated stimulation of chlorine ions into the cell and block the AMPA subtype of glutamate receptors in the brain.

Topiramate is well absorbed after oral administration (with or without food). The maximum concentration in the serum is reached after 2-4 hours after administration. Approximately 15% of the drug binds 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-elimination period is 18-24 hours, the drug should be taken twice a day. The range of therapeutic concentrations of the drug in the blood has not yet been established. Phenytoin and carbamazepine increase the clearance of the drug and, consequently, reduce its concentration in the serum. In turn, topiramate increases the concentration of phenytoin and carbamazepine by about 20%, but decreases the level of estrogens in the blood.

Topiramate has been studied, mainly, as a drug for the treatment of partial and secondarily generalized seizures. Three multicenter, double-blind, controlled studies were performed with the addition of topiramate to previously prescribed antiepileptic drugs and flexible dosing from 20 to 1000 mg / day. In other studies, topiramate was tested at doses up to 1600 mg / day. The results show that the effectiveness of the drug does not increase significantly with increasing doses above 400 mg / day, unlike gabapentin and lamotrigine, which were tested at doses substantially lower than those considered optimal in clinical practice. In doses above 400 mg / day, topiramate can cause serious side effects, such as confusion or slowness of speech, but the effectiveness does not increase. From this rule, of course, there are exceptions.

Small clinical trials and individual clinical observations show that topiramate has a broad spectrum of antiepileptic activity and can be effective in absences, atonic, myoclonic and tonic seizures. However, the efficacy of the drug in these epilepsy variants should be demonstrated in controlled clinical trials. In recent years, it has been shown that topiramate can be effective in children with infantile spasms and Lennox-Gastaut syndrome, resistant to other antiepileptic drugs.

The manufacturer recommends starting treatment with topiramate from a dose of 50 mg 2 times a day. Nevertheless, many clinicians believe that too rapid a dose increase is fraught with the development of cognitive impairment. In this regard, treatment is usually started with a dose of 25 mg / day, after which the daily dose is increased every 1-2 weeks by 25 mg. In some adults, the drug has a therapeutic effect at a dose of 100 mg / day, but the bowl is effective at doses of 200 to 400 mg / day. The daily dose should be divided into 2 divided doses. Under these conditions, approximately 40-50% of patients with treatment-resistant seizures report a more than 50% decrease in seizure frequency compared to baseline. It is assumed that topiramate can be effective as a monotherapy, but clinical trials that investigate this possibility have not yet been completed.

The side effects of topiramate are mainly related to its effect on the central nervous system. These include confusion, drowsiness, ataxia, dizziness and headache. The risk of side effects is higher with the use of several drugs and rapid titration of the dose. The incidence of cognitive impairment when taking topiramate reaches 30%. They consist in slowness of thinking and speech, memory loss, violation of speech understanding, disorientation and other symptoms. These symptoms may decrease with time or with a lower dose.

There are some reports of gastrointestinal dysfunction, skin rashes, urolithiasis and serious psychiatric complications associated with taking topiramate. Topiramate can not be considered a drug safe in pregnancy. It is shown that it can 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.

Benzodiazenines

The benzodiazepines most commonly used in the treatment of epileptic seizures include diazepam, clonazepam, lorazepam, clorazepate. The advantage of these drugs is a rapid action that does not require the introduction of loading (shock) doses. Preparations of diazepam and lorazepam for parenteral (intravenous) administration are the means of choice for epileptic status. Benzodiazepines are usually not used for prolonged antiepileptic therapy, because their effectiveness decreases after several weeks of use, which requires an increase in dose to maintain the effect. Nevertheless, the long-term use of benzodiazepines sometimes has to resort to atonic, myoclonic or resistant to other methods of treatment of seizures, when there are no alternatives left. Booster administration of benzodiazepines for 1-2 days is useful in the period of a sharp increase in seizures. This approach is also used in cases where it is known that after a seizure a second seizure may occur quickly either during menstruation. Usually, as an antiepileptic drug, diazepam is given in a dose of 2-5 mg every 4-6 hours. Clonazepam is usually taken for 0.5-2 mg orally 3 times a day. Lorazepam can be administered at 0.5-1.0 mg, if necessary, repeatedly, until the seizures stop. In this case, the daily dose can reach 4 mg / day.

[35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46]

Tiagabin

More recently, I received the official status of the drug in the United States for the treatment of partial and secondarily generalized seizures and is close to phenytoin, carbamazepine and gabapentin by the action profile. With absences and myoclonic seizures, this drug appears to be ineffective. Approximately 20-30% of patients resistant to other anti-inflammatory drugs respond to tiagabine. The drug is well tolerated. There are only isolated reports about the development of drowsiness, disturbance of thinking and dizziness. There are also reports of increased seizures due to tiagabine and a few serious psychiatric complications, but it is unclear whether these phenomena are associated with taking tiagabine or due to the severity of the underlying disease. A short period of semi-elimination requires the administration of the drug 3-4 times per day. Treatment begins with a dose of 4 mg / day. Then it is increased weekly by 4-8 mg until the effect is reached, up to a maximum of 56 mg / day.

Vigabatrin

Although vigabatrin, which is a structural analogue of GABA, has been used in European countries since 1989, it was only in 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 it is often used in some other epileptic syndromes: for example, in children with infantile spasms that can not be controlled with other drugs. Most often, vigabatrin is prescribed as an additional drug in patients with resistant partial seizures; while it is effective in 40-50% of these patients. In general, it is better tolerated than many other antiepileptic drugs.

Side effects of vigabatrin include dizziness, unsteadiness in walking, drowsiness, disturbance of thinking and memory, although overall side effects are less pronounced than many other, more traditional drugs. A small proportion of patients develop depression and other serious psychiatric complications that regress when the drug is withdrawn. Some of the patients taking vigabatrin have visual field defects, possibly caused by damage to the optic nerves or retina, which may be irreversible. Registration of the drug in the United States was delayed in connection with these toxicological studies on animals showing that the drug causes myelin edema in the brain. Although this manifestation was noted with the administration of the drug in a high dose to rats and dogs and, possibly, monkeys, there was no development of a similar complication in humans. This effect is reversible and identifies with magnetic resonance imaging and the study of evoked potentials. The clinical experience of the drug is estimated at more than 200 000 patient-years, but no cases of damage to myelin have been recorded. Treatment begins with a dose of 500 mg 2 times a day, then it is increased for several weeks until the effect is achieved. In most cases, the effective dose is 2000-3000 mg / day (in 2 divided doses).

Other drugs for the treatment of epilepsy

Currently, several other antiepileptic drugs are being clinically tested, including zonisamide, remacemide, UCB L059, losigamone, pregabalin, rubinamide, ganaxalone, and styipentol. It is unlikely that all these drugs will be introduced into wide practice, because for this any new drug should demonstrate obvious advantages in efficiency, safety, tolerability, convenience of use, cost before the currently used funds.

Although none of the recently developed drugs have significant advantages over more traditional drugs, patients with epilepsy currently have broader options for choosing drug therapy than it was 5-10 years ago. As the clinical experience of clinical use of these drugs is enriched, safer and more effective treatments for epilepsy will be developed.