Pharmacodynamics Of Antiepileptic Drugs Research Articles

Сучасний підхід до діагностики та лікування судом у новонароджених та дітей раннього віку

The article is devoted to the topical problem of neonatology and pediatric neurology — the diagnosis and treatment of seizures in newborns and young children. The work presents an algorithm for the diagnosis and treatment of epileptic seizures in children. It is indicated that the therapeutic effect of most antiepileptic drugs consists of modulation of voltage-gated and ligand-gated channels of membranes of neurons of the cerebral cortex, enhancement of inhibitory synaptic transmission or inhibition of activating synaptic transmission. The issues of the pharmacokinetics and pharmacodynamics of antiepileptic drugs are considered, taking into account the age characteristics of the child's body, in particular, newborns and early age children. The problems of drug interaction were discussed. The properties of individual antiepileptic drugs, which are used in newborns and young children, are considered. Emphasized are «polar» differences in the work of phenobarbital, which depend on the stage of epileptogenesis, namely: suppression of epileptiform activity at the early stage of epileptogenesis and its enhancement in the already formed epileptic focus (epileptic system). The literature data on the differentiated treatment of certain epileptic syndromes are presented. The issues on the prospects for the treatment of genetically determined diseases, which are accompanied by seizures associated with metabolic disorders, are considered. The modern high-tech methods of treatment of these diseases are noted. The role of diet therapy, co-factor therapy in the treatment of hereditary metabolic disorders, in particular, the ketogenic diet as a method of alternative treatment for drug-resistant epilepsy in children, is shown. No conflict of interest was declared by the authors. Key words: newborn, epilepsy, epileptic encephalopathy, treatment, antiepileptic drugs, review.

Pathogenesis of drug resistant epilepsy

Pharmacotherapy is the first-line treatment modality for epilepsy. However, in 20-40% of patients, epilepsy is resistant to pharmacotherapy. These numbers have not changed for decades despite the development and use of antiepileptic drugs with novel mechanisms of action. Drug-resistant epilepsy is now considered a separate pathophysiologic and clinical entity. The existing hypotheses on its pathogenesis could be divided in two groups. Firstly, drug-resistance might be caused by an abnormal pharmacokinetics or pharmacodynamics of antiepileptic drugs as a result of congenital or acquired dysfunction of the transporter or receptor proteins. Secondly, it might be a consequence of inherent features of epilepsy per se, such as the so-called “intrinsic severity” or some disorder of the connectome. Taking into account the complexity of this phenomenon, the issue of drug resistance continues to remain in the focus of the current research efforts.

Treatment of epilepsy in the elderly people

The pharmacokinetics and pharmacodynamics of antiepileptic drugs (AEDs) differ in old age from those in younger patients. Age-related changes in pharmacokinetics play a role as early as the drug absorption stage, because gastric secretion, blood volume, blood flow, and gastrointestinal motility are all lower in old age. The serum concentration of the medications is heavily influenced by protein binding, mainly of serum albumin, whose concentration is markedly reduced in old age, so that the free fraction of medication in the serum is higher. This influences not only the desired medication effects, but also the undesired ones, and is particularly important in the case of highly protein-bound antiepileptic drugs such as valproic acid, phenytoin, or carbamazepine. In elderly patients a reduction of hepatic and renal function were observed. No guidelines, systematic reviews, or meta-analyses on this subject are available. There have been only three randomized, controlled, double-blind therapeutic trials of evidence class I or II regarding epilepsy in the elderly, as well as a number of smaller studies of classes IIa and III. Thus, many clinical decisions about antiepileptic treatment in old age are based on extrapolations of experience and data obtained from younger patients, combined with the general principles of pharmacotherapy in old age. The treatment of epilepsy seems to be successful in the elderly more often than in young adults. A precondition for successful treatment, however, is that the antiepileptic drug is well tolerated and does not interact with other, concurrently taken, medications. The treatment of epilepsy in an elderly patient generally requires searching for the medication that is best tolerated and least metabolized. Problems can arise because drug-drug interactions must be considered in the elderly people that often take multiple medications. It is evident that the so-called enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, phenobarbital) generally cannot be recommended for use in elderly patients because of their multifarious interaction. Moreover these AEDs may facilitate the development of osteoporosis and cannot be recommended for use in elderly woman patients. Recently, clinical studies have shown a better tolerability of never antiepileptic drugs. In conclusion numerous factors must be considered in treating elderly patients for seizures, but maximizing the ability of patients to tolerate drug therapy is often the basis for AED selection.

Treatment for epilepsy in later life

Old age is now the commonest time to develop epilepsy, often as a consequence of underlying cerebrovascular or neurodegenerative disease. Age-related physiological changes can affect the pharmacokinetics and pharmacodynamics of antiepileptic drugs. Only three double-blind, head-to-head, randomised, controlled trials have been undertaken in this patient population and so pharmacological treatment tends to be empirical, often based on what antiepileptic drug not to chose for an individual patient. The available evidence has tended to favour lamotrigine, and perhaps gabapentin, over carbamazepine, based on better tolerability rather than superior efficacy for newly diagnosed epilepsy in this population. Preliminary data with levetiracetam suggest that this drug will also be useful in older people as a consequence of its favourable side-effect profile and lack of idiosyncratic reactions and drug interactions. Despite the dearth of high quality trial evidence, published outcome data hint at a good prognosis with a single antiepileptic drug for the majority of elderly people with epilepsy. A few patients will require low dose combination therapy. Epilepsy surgery is also an occasional option in this population. As life expectancy rises, so will the likelihood of presenting with seizures in later life placing an increasing burden on healthcare resources.

Research priorities in epilepsy for the next decade—A representative view of the European scientific community: Summary of the ILAE Epilepsy Research Workshop, Brussels, 17–18 January 2008

Research priorities in epilepsy for the next decade—A representative view of the European scientific community: Summary of the ILAE Epilepsy Research Workshop, Brussels, 17–18 January 2008

Adaptive changes in the pharmacodynamics of midazolam in different experimental models of epilepsy: kindling, cortical stimulation and genetic absence epilepsy.

1. The objective of this investigation was to determine quantitatively whether experimental epilepsy is associated with a change in the pharmacodynamics of benzodiazepines in vivo. For that purpose the pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic approach in three different models of experimental epilepsy: amygdala kindling, cortical stimulation and genetic absence epilepsy. 2. The time course of the EEG effect was determined in conjunction with the decline of drug concentrations after intravenous administration of 10 mg kg(-1) midazolam. The pharmacokinetics of midazolam were most adequately described by a bi-exponential equation. No influence of epilepsy on the pharmacokinetics of midazolam was observed. 3. The increase in beta activity (11.5-30 Hz) of the EEG as derived by Fast Fourier Transformation analysis was used as pharmacodynamic endpoint. For each individual rat the increase in beta activity was directly related to the concentration in blood on the basis of the sigmoidal Emax pharmacodynamic model. In all three models a significant reduction in the maximal effect was observed, in amygdala kindling 28%, in the cortical stimulation model 49% and in genetic absence epilepsy 37%. No differences in the other pharmacodynamic parameters, E0 EC50,u and Hill factor, were observed. 4. It is inferred that in three different models of epilepsy there is a similar change in GABAergic functioning which is associated with a significant reduction in the intrinsic activity of midazolam in vivo. These models provide therefore a useful basis for further studies on the mechanism of epilepsy-induced changes in pharmacodynamics of anti-epileptic drugs.

Specific problems of children with epilepsy.

In both adults and children, the seizure type and frequency of occurrence largely determine the burden of epilepsy, for the patient and his family. Epilepsy in children can range from the severe to the relatively benign, and it is important to make the correct diagnosis as early as possible. In those under 5 years of age, epilepsy often presents as an age-related syndrome, e.g., West and Lennox-Gastaut syndromes. Later, typical absences and generalized tonic-clonic convulsions are more usual. Drug therapy should take account of the different pharmacodynamics of antiepileptic drugs in children, and phenobarbital should be avoided. Rectal diazepam has an important role in the emergency management of childhood seizures. Psychological difficulties may be manifested by both the child and the parents. They should be prevented if possible by active intervention at an early stage after diagnosis, or managed on a continuing basis by expert medical and paramedical advice. The aim of such counseling is to ensure, so far as is possible, that the epileptic child develops normally in a normal family environment.