1. General principles of antiepileptic drug therapy
1.1 Principle of early treatment: Recurrent seizures will lead to new brain damage, and early treatment has a high success rate and can avoid further aggravation of brain damage. However, before applying antiepileptic drugs it must be clear whether the patient is a true epileptic; the type of epilepsy to which the patient belongs; and also the cause of the patient’s epilepsy as clearly as possible. Only when these three issues are clarified can the correct treatment be given to the patient. Some patients with “epilepsy” who do not pass the treatment or whose condition progresses are eventually found to be patients with non-epileptic pseudo-seizures, and some of them are not correctly diagnosed with the type of seizure. For patients with only one seizure and normal EEG, the medication can be suspended and observed. For patients with more than 2 seizures or only 1 seizure in 1a, but with epileptiform discharges on EEG, previous history of febrile convulsions or family history of seizures, they should be treated with medication early.
1.2 Preferred medication principles: The selection of different drugs according to different seizure types is an important factor in the effectiveness of epilepsy treatment. For generalized tonic clonic seizures (GTCS), carbamazepine is preferred within 3 years of age, and valproic acid is preferred above 3 years of age. For clonic, infantile spasms, Lennox-Gas-taut (L-G) syndrome, clonazepam is preferred, followed by valproic acid. Clonazepam or valproic acid is preferred for anhedonia. For temporal lobe epilepsy and restrictive epilepsy, carbamazepine is preferred. For neonatal convulsions, phenobarbital is preferred. For vegetative seizures, scopolamine and nifedipine are preferred. Benign restrictive seizures, phenobarbital or valproic acid preferred. Carbamazepine (CBZ) is preferred for partial seizures simple and complex partial seizures. Diazepam is preferred for persistent status epilepticus.
1.3 Single medication principle: drugs in the body absorption, transport and catabolism process, may affect each other. The blood concentration monitoring shows that when multiple antiepileptic drugs are combined, they are prone to complex interactions, which may increase or decrease the concentration of a certain drug, affecting the efficacy and even causing or aggravating adverse reactions. Therefore, some authors believe that the interaction of antiepileptic drugs is a major factor in the decrease of efficacy or toxic reactions during the treatment. The mechanisms of drug interactions in vivo include hepatic enzyme induction, hepatic enzyme inhibition, competitive hepatic enzyme inhibition and competition for plasma protein binding sites. Therefore, it is important to be familiar with the possible changes in blood concentrations of different antiepileptic drugs in combination with each other. As far as possible, single medication should be used.
The dose of antiepileptic drugs is generally calculated according to body weight and is often greater in children than in adults. The use of antiepileptic drugs should start with a small dose, half or 1/3 of the dose can be used for 1 wk in the initial stage, and if there is no special reaction, it is appropriate to gradually increase the dose until the seizure is controlled without adverse reactions, so as to reduce or avoid the occurrence of adverse reactions. The half-life of different antiepileptic drugs should be noted. Generally, the steady-state blood concentration can be reached after about 5-7 half-lives after the effective dose is given. The tolerability of antiepileptic drugs varies greatly among individuals, so the dose should vary from person to person. The blood concentration should be measured regularly when available, and it should be noted that in some patients, although the blood concentration is lower than the “effective concentration”, the seizures have been controlled, so there is no need to increase the dose forcibly. Therefore, the drug dose should be adjusted according to the blood concentration and combined with the clinical situation.
1.5 Combination principle: It is best not to combine drugs. Because the interaction between AEDs is not yet well understood. Combination of drugs can be used when necessary. Principles: Firstly, according to the type of seizure, followed by consideration of the mechanism of action of the drug; again, to consider the drug interactions less. The combination of drugs is generally used to combine a traditional antiepileptic drug and a new antiepileptic drug. In general, the combination of drugs should not exceed three drugs. Commonly used combination drug regimens:
(1) carbamazepine/phenytoin sodium + sodium valproate/gabapentin/topiramate;
(2) Sodium valproate + lamotrigine/tiagabine;
(3) Lamotrigine + sodium valproate/topiramate/tiagabine;
(4) Sodium valproate/lamotrigine + topiramate;
(5) carbamazepine/gabapentin + tiagabine.
1.6 Long-term treatment principle: Most require 2-5 years of long-term treatment, and some seizure types may be treated for life.
1.7 Principle of medication change: Patients may be considered for medication change after a period of standardized treatment and if the blood concentration has reached the target range but the efficacy is not good. If the medication is not changed properly, it may aggravate the seizure or even induce a persistent status epilepticus. The principles to be followed when changing medication are: do not stop the original medication abruptly, but reduce the original medication after the additional medication has reached steady-state blood levels. The original drug should be gradually reduced to at least 10-15 days after discontinuation, and should not be increased or decreased at the same time. If a patient has a serious adverse reaction to an antiepileptic drug, the drug should be discontinued immediately. In this case, diazepam can be used as a replacement drug during the withdrawal period to avoid a sharp decrease in the blood concentration of the original drug, which may lead to an increase in the number of seizures.
1.8 Principles of increase, decrease and discontinuation: In principle, it is slow (gradual increase or decrease), especially considering the termination of treatment. The dosage of antiepileptic drugs can be reduced according to the situation, and the principles of antiepileptic drug reduction and discontinuation are as follows.
①Prohibit sudden discontinuation of medication.
The dose can be gradually reduced 3-5 years after the last seizure.
③The dose reduction period should be long enough to take six months to a year, reducing the dosage by a small amount each time and stabilizing for a period of time before the next dose reduction. A proportion of patients cannot stop the medication, and seizures will recur after stopping the medication, so the pre-dose reduction level of medication should be restored.
1.9 Drug monitoring : concentration monitoring, potency monitoring and toxic side effect monitoring.
1.10 Attention to adverse reactions Drug therapy for epilepsy needs to be maintained for several years or even for life, during which various acute or chronic toxic reactions may occur:
(1) Dose-related reactions are commonly associated with neurological and digestive symptoms, such as nausea, vomiting, dizziness, drowsiness, nystagmus, ataxia, impaired consciousness, increased seizures, or liver function impairment. They are often related to large starting doses, rapid dosing or overdose poisoning, and can be relieved by appropriate dose adjustment.
(2) Reactions related to individual idiosyncrasies such as rash, leukopenia, thrombocytopenia. Occasionally, aplastic anemia, exfoliative dermatitis and hepatotoxicity are seen. These reactions are unpredictable and unrelated to the dose of the drug, and can lead to death in severe cases, so the drug should be discontinued immediately.
(3) Teratogenic effects are common malformations such as cleft lip, cleft palate, cerebrospinal membrane bulge, spina bifida, mental underdevelopment, heart and bone malformations. Therefore, clinical attention should always be paid to close observation, regular measurement of blood concentration, blood routine and liver function, etc., timely detection and timely treatment.
2. Introduction of antiepileptic drugs
2.1 First-line antiepileptic drugs
2.1.1 Phenobarbital has been used since 1912. On the one hand, it enhances the role of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter, which binds to the GABA body, prolongs the opening of the chloride channel and promotes CI-inflow, and on the other hand, it weakens the excitatory effect of excitatory neurotransmitter glutamate. Therefore, it has anti-stunning effect at high dose, 3-6mg/kg per day, one oral dose at night before bedtime. It has good effect on tonic-clonic seizures, limited seizures and febrile convulsions, but poor effect on atonic seizures, temporal lobe epilepsy and infantile spasms. In case of persistent status epilepticus, 10mg/kg can be administered intravenously or intramuscularly to reach the loading dose rapidly, and the above maintenance dose can be given later. The effective blood concentration is 15-40mg/L (50-130μmol/L), the half-life is 96±12 hours, and the blood stability is reached in 14-21 days.
2.1.2 Phenytoin sodium has been used since 1938. It can inhibit the sodium channel on the nerve cell membrane and reduce the inward flow of Na+, and also inhibit the inward flow of Ca2+ in the calcium channel and reduce excitability.
inward flow, reducing excitability and stopping fright. It is effective for tonic-clonic seizures and limited seizures in older children, but not for myoclonus and akathisia. 5-10 mg/kg/day, divided into 2-3 doses orally after meals. The effective concentration is 10-20 mg/L (40-80 μmol/L), with a half-life of 13-46 h. It takes 5-7 days to reach blood steady state. In the case of ineffective status epilepticus, 10 mg/kg can be administered by IV.
2.1.3 Carbamazepine has been used since 1978. It is a broad-spectrum antiepileptic drug that reduces Na+ and Ca permeability in membranes and enhances GABA inhibition to stop fright. It is effective for temporal lobe epilepsy, tonic-clonic seizures and limited seizures, but not for akathisia, myoclonus, L-G syndrome, infantile spasms and febrile convulsions. 10-20 mg/kg daily, divided into two oral doses. The effective blood concentration is 4-12 mg/L (15-45 μmol/L), with a half-life of 8-20 h. The blood is stable in 5-10 days.
2.1.4 Valproic acid has been used since 1967. There are two salt base that is sodium valproate and magnesium valproate, the latter is not easy to deliquescence, release good, high bioavailability, and magnesium ions can antagonize calcium ions to strengthen the sedative effect, so magnesium salt is better than sodium salt. It can promote the activity of glutamate dehydroxylase, so that more glutamate synthesis and inhibit GABA transaminase on GABA degradation, but also can increase the concentration of glycine (another inhibitory transmitter), so there is an anti-alarm effect. 20-40mg/kg daily, divided into 3-4 doses, taken orally after meals. There are also syrup 0.2 g/5ml and extended-release tablets 0.5 g/capsule (can be taken once before bedtime). The effective blood concentration is 50-100 mg/L (300-600 μmol/L), with a half-life of 6-15 h and a steady state of blood in 4 d. It is a broad-spectrum antiepileptic drug, effective for tonic-clonic seizures, partial seizures, akathisia, infantile spasms, myoclonus, etc. and those who cannot determine the type, but less effective than carbamazepine for limited seizures. Intravenous preparations of 15 mg/kg per dose (1 mg/kg per hour) can be used for persistent status epilepticus.
2.1.5 Clonazepam (Clonazepam) has been used since 1984. It can bind to benzodiazepine BZD receptors, increase the permeability of Cl-channel, enhance GABA inhibition and stop the panic. It is a broad-spectrum antiepileptic drug with good efficacy in aphasia, myoclonus and infantile spasms. 0.05~0.2mg/kg/day orally. In persistent epilepsy, it can be given intravenously at 0.1 mg/kg per dose or by enema. The effective blood concentration is 20-60 mg/L (60-120 μmol/L), and the half-life is 20-60 h. The blood steady state is reached in 5-14 d.
2.1.6 Valium similar drugs are
①Nitrozepam (nitrozepam): the effect is only 1/5 of clonazepam, 0.5 mg/kg per day.
②Diazepam: 0.3-0.5 mg/kg each time when the epilepsy persists, slowly intravenous injection, the effect of the fastest 1 ~ 3min onset of action, injected too quickly, especially when the first use of sodium phenobarbital susceptible to respiratory depression, infants can even occur respiratory arrest.
(3) Lorazepam (chlorhexidine): in the case of persistent epilepsy, 0.05-0.1 mg/kg per time, intravenous injection, 2-3 min onset of action, more than 90% effective.
2.2 New antiepileptic drugs
2.2.1 Topiramate (TPM): first introduced into the UK market in 1995 and marketed in China in 1999, is a monosaccharide derivative containing a sulfonamide group, structurally very different from traditional antiepileptic drugs. Experimental studies have shown that it has multiple antiepileptic mechanisms of action, including.
(i) blocking voltage-dependent sodium channels;
(ii) antagonizing the erythropoietin/AMPA subtype of glutamate receptors;
③Increasing GABA activity through a non-benzodiazepine mechanism;
④Inhibition of carbonic anhydrase;
TPM is completely and rapidly absorbed orally, with low plasma protein binding (9%-17%), long half-life (19-23 hours), linear metabolism kinetics, weak enzyme inhibition and enzyme induction, and 70%-97% clearance by the kidney as a prototype. The drug was first used for the additive treatment of refractory partial seizures with good efficacy and then broadened the indications to show a better control rate for full-blown seizures (except for aphasic seizures). The most persistent Lennox-Gastaut syndrome has also shown promising results. Children were started at 0.5 mg/(kg/day) and increased by 1 mg/kg/week until reaching 4-8 mg/(kg/day). The most common adverse effects are drowsiness, fatigue, sweating disorder, vertigo, ataxia, inattention, word finding difficulties, cognitive impairment, mood swings, anorexia, weight loss, etc. Personality changes and depression may also occur. It does not affect the blood concentration of other commonly used antiepileptic drugs, but phenytoin sodium and carbamazepine can reduce the blood concentration of Toltea by 40%.
2.2.2 Lamotrigine (LTG), named Lipitor, was first marketed in Ireland in 1991 and entered the Chinese market in 1999. LTG has a broad antiepileptic spectrum and is effective in both generalized and partial seizures, especially in akathisia (typical or atypical) and atonic seizures, as well as in Lennox-Gastaut syndrome, West syndrome and other intractable epilepsies. Intractable epilepsy. It is rapidly absorbed orally, with a plasma protein binding rate of 55%, and is almost entirely metabolized in the liver without enzyme-induced effects. Children 5-15mg/(kg/day), starting with small doses, divided into 2 doses and slowly increasing. When combined with high protein binding and enzyme-inhibiting drug valproic acid, the dose should be reduced accordingly; and when combined with enzyme-inducing agent (carbamazepine phenytoin sodium phenobarbital), the dose should be increased appropriately. Adverse reactions include rash, sleepiness, vomiting and increased frequency of seizures, as well as diplopia, ataxia, headache, mood disorders and aggressive behavior. LTG does not affect the metabolism of other antiepileptic drugs, but other antiepileptic drugs can affect this drug, such as phenobarbital, phenytoin sodium, and carbamazepine. Carbamazepine can reduce its half-life to 15 hours, and valproic acid can significantly increase its half-life (up to 59 hours).
2.2.3 Oxcarbazepine (OCBZ), also known as oxycodone, is also known as trilostane. Developed by Novartis, Switzerland.
It was first marketed in Denmark in 1991 and entered China in 2004. Its chemical structure is similar to that of carbamazepine, which is a 10-ketone derivative, and therefore has similar antiepileptic mechanism of action and antiepileptic spectrum. Although the drug itself is inactive, it is rapidly metabolized to HCBZ, the main antiepileptic active ingredient, after oral absorption. although there is only a small change in structure, the half-life is relatively stable due to the absence of enzyme-induced effects. drug-drug interactions are rare and dose adjustment is simple. Because it is not metabolized by epoxide, tolerability is improved and serious adverse effects are significantly reduced. It is mainly used clinically as monotherapy or add-on therapy for partial-onset seizures, with efficacy comparable to carbamazepine, and has shown good efficacy in refractory epilepsy, especially for improving psychiatric symptoms and cognition. The maintenance dose for pediatric patients is 30-50 mg/(kg・day), and the effective blood concentration is 75-125 μmol/L, with large individual differences. Adverse reactions are similar to carbamazepine, but are rare and mild, and allergic rash is rare.
2.2.4 Gabapentin (GPB) developed by Pfizer, Inc. and approved for marketing by the FDA in 1994, is a GABA analogue, the mechanism of action is not clear. It is rapidly absorbed orally, not affected by food, basically not combined with plasma proteins, not metabolized by the liver, no drug-drug interactions, well tolerated, and therefore has good pharmacokinetic properties; however, the antiepileptic spectrum is narrow, suitable for partial seizures and secondary generalized seizures, and effective for refractory epilepsy partial seizures. Children 30-40mg/(kg/day), up to 100mg/(kg/day). Because of the short half-life, it should be divided into 3 to 4 doses. Adverse effects are rare, mainly fatigue, dizziness and drowsiness, and are dose-related.