Introduction to Levetiracetam
Levetiracetam (LEV) is a derivative of Piracetam and a new type of anti-epileptic drug that was approved in 1999. Approved by the US FDA, it was initially used for partial seizures in adults. In 2005, its oral tablets and solutions were approved for the adjuvant treatment of partial seizures in children 4 years and older. Launched in China in 2007 (trade name: Kaipu Lan), as a new type of anti-epileptic drug, LEV has a unique mechanism of action, rapid onset of action, good anti-epileptic efficacy, tolerability and safety, except for difficult-to-use drugs. In addition to the adjuvant treatment of curative epilepsy, its indications have gradually expanded to monotherapy for newly diagnosed epilepsy, and it has broad application prospects. This product has the characteristics of high bioavailability, linear pharmacokinetics, low protein binding rate, low liver metabolism, rapid acquisition of stable blood concentration, and small drug interactions. It is a relatively safe drug for clinical use.
1
Pharmacological effects of levetiracetam
Traditional anti-epileptic drugs generally act on ion channels or excitatory-inhibitory neurotransmitter systems. It works, and the mechanism of action of LEV is different from that of traditional anti-epileptic drugs. It does not act on neurotransmitters or receptors, nor does it affect neuronal gated sodium ion and calcium ion channels. Studies have shown that LEV may exert anti-epileptic effects by binding to its target, the central nervous system synaptic vesicle protein SV2A. Although the detailed mechanism of LEV action remains to be further elucidated so far, research results in recent years have shown that LEV does not affect gamma-aminobutyric acid (GABA)- and glutamatergic neurons-mediated effects at therapeutic concentrations. Synaptic transmission targets the synaptic vesicle protein SV2A in the central nervous system. SV2A is a glycoprotein with 12 transmembrane domains. It is widely distributed in the central nervous system and endocrine cells and regulates the cytotoxicity of synaptic vesicles. Exocrine function and presynaptic neurotransmitter release; research has found that SV2A is the binding site of LEV and plays an important role in epileptic seizures; other anti-epileptic drugs have not been found to bind to SV2A. LEV has an inhibitory effect on both the kindling process and the kindling state of the rat kindling model of complex partial seizures. It can inhibit burst "kindling" without affecting normal neuronal excitability, suggesting that it selectively prevents the propagation of hypersynchrony and ictal activity. . In vivo and in vitro experiments show that LEV inhibits epileptiform burst discharges in the hippocampus without affecting normal neuronal excitability, suggesting that LEV may selectively inhibit the hypersynchrony of epileptiform burst discharges and the propagation of epileptic seizures.
2
Pharmacokinetics of levetiracetam
LEV is an extremely soluble and highly permeable compound that can be almost completely absorbed after oral administration , bioavailability reaches 95 and is not affected by food. The LEV peak time is 0.6-1.3h, 2 times/day. Steady-state blood concentration can be reached within two days of administration, and it is easy to penetrate the blood-brain barrier. The drug-to-plasma protein binding rate is lt; 10. LEV is mainly hydrolyzed and metabolized by the acetamide hydrolase system in the body (accounting for 24% of the administered dose), and its hydrolysis and metabolism does not depend on the liver cytochrome P450 enzyme system. LEV has no inhibitory or inducing effect on hepatic drug enzymes, and 66 is excreted from the kidneys unchanged. The main product of hydrolysis and metabolism has no pharmacological activity and is also excreted from the kidneys. Eating can slow down its absorption, but does not affect the degree of absorption. Regardless of single dose or multiple doses, there is a linear relationship between plasma concentration and dose. In vivo experiments have confirmed that its pharmacokinetics are not affected by other antiepileptic drugs (AEDs) that are often used in combination, nor will it affect other AEDs such as phenytoin, carbamazepine, valproic acid, phenobarbital, primidone, Lamotrigine and oral contraceptives (ethinyl estradiol, levonorgestrel pills), digoxin and warfarin, etc. Most of LEV is excreted by the kidneys, so in patients with impaired renal function, its plasma concentration increases and its half-life is prolonged. The dose needs to be adjusted according to the patient's creatinine clearance rate.
3
Indications of levetiracetam
It is mainly used for the additive treatment of partial seizures in adults and children over 4 years old with epilepsy. It is used only for partial epileptic seizures and generalized seizures in adults. It also has certain effects on juvenile myoclonic epilepsy, refractory epilepsy, childhood absence epilepsy and status epilepticus. There are reports that LEV can improve the cognitive function of patients with epilepsy, and can also be used for myoclonus caused by other causes (such as encephalitis, cerebral hypoxia, etc.).
4
How to use levetiracetam
Adults (gt; 18 years old) and adolescents (12-17 years old) weight gt; 50kg, The starting dose is 500 mg, twice a day, and dosage changes should be increased or decreased by 500 mg, twice a day in 2-4 weeks. For children and adolescents aged 4-11 years (12-17 years old) weighing ≤50kg, the starting dose is 10 mg/kg, twice a day, and the dosage should be increased or decreased by 10 mg/kg, twice a day every two weeks. For children and adolescents weighing ≥50kg, the dosage is the same as for adults. Elderly people (≥65 years old) Adjust dose according to renal function status. The lowest effective dose should be used.
5
Common adverse reactions of levetiracetam
① Systemic reactions and discomfort at the administration site: The more common symptoms are fatigue.
②Nervous system discomfort: Very common symptoms include drowsiness; common symptoms include forgetfulness, ataxia, convulsions, dizziness, headache, excessive movement, and tremor.
③ Mental and psychological changes: irritability, depression, emotional instability, hostility, insomnia, neurosis, personality changes, abnormal thinking; adverse event reports include abnormal behavior, aggression, irritability, anxiety, confusion, Hallucinations, agitation, psychosis, suicide, suicidal ideation, suicide attempts.
④Digestive tract discomfort: diarrhea, indigestion, nausea, vomiting.
⑤ Metabolic and nutritional disorders: loss of appetite.
⑥ Discomfort in the ears and labyrinth system: dizziness.
⑦ Eye discomfort: diplopia.
⑧Respiratory system discomfort: increased coughing.
⑨ Abnormal changes in the skin and subcutaneous tissue: rash; adverse event reports include hair loss. In some cases, it can recover spontaneously after stopping the drug.
⑩Abnormal changes in the blood system and lymphatic system: leukopenia, neutropenia, pancytopenia, thrombocytopenia, etc.
6
Drug Interactions
In vitro data show that LEV and its major metabolites within the therapeutic dose range are neither human liver cytochrome P450, cyclic Inhibitors of oxidative hydrolases or uridine diphosphate-glucosidase are also not high-affinity substrates for them and are therefore less prone to pharmacokinetic interactions. In addition, LEV does not affect the in vitro glucosidase action of valproic acid. LEV has a low plasma protein binding rate (<10) and is not prone to clinically significant interactions due to competition with other drugs for protein binding sites.
1. Interactions between levetiracetam and other antiepileptic drugs (AEDs)
① Phenytoin: LEV has no effect on phenytoin drug metabolism; phenytoin does not affect it either Pharmacokinetic properties of LEV.
② Sodium valproate: LEV does not change the pharmacokinetic properties of sodium valproate, and sodium valproate does not change the rate or extent of LEV absorption, its plasma clearance, or urinary excretion.
③ For LEV and other anti-epileptic drugs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, deoxyphenobarbital and amprofen) obtained from placebo-controlled clinical studies Serum concentrations of LEV were evaluated and the data showed that LEV did not affect the plasma concentrations of other antiepileptic drugs; these commonly used antiepileptic drugs also did not affect the pharmacokinetic properties of LEV.
2. Interactions between levetiracetam and other drugs
① Oral contraceptives: Taking LEV does not affect oral contraceptives containing ethinyl estradiol and levonorgestrel. The pharmacokinetic properties, or levels of luteinizing hormone and progesterone, indicate that LEV does not affect the efficacy of contraceptive pills; the use of oral contraceptives does not affect the pharmacokinetic properties of LEV.
② Digoxin: Taking LEV does not affect the pharmacokinetics and pharmacodynamic properties of daily doses of digoxin; taking digoxin does not affect the pharmacokinetic properties of LEV.
③Warfarin: Taking LEV does not affect the pharmacokinetic properties of warfarin, and the coagulation time is not affected by left LEV; the application of warfarin does not affect the pharmacokinetic properties of this product.