Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changing attitudes towards the use of antiepileptic drugs have led to an emphasis on monotherapy with serum concentration measurement coupled with standard, weight-adjusted starting and maintenance regimens to guide initial therapy and subsequent dosage titration. Currently, the established anticonvulsants are carbamazepine, valproic acid (sodium valproate) and phenytoin. Phenobarbital is now less commonly prescribed due to its propensity to produce sedation and impair cognitive function. The value of pharmacokinetic optimisation with valproic acid is limited by its wide therapeutic index, large fluctuations in the concentration-time profile and concentration-dependent protein binding. Thus, although serum concentrations are often measured, they are rarely subjected to pharmacokinetic interpretation. Carbamazepine has a flatter concentration-time profile than valproic acid. Its target range is more clearly defined and it undergoes autoinduction of metabolism and interacts with other drugs. Pharmacokinetic principles can, therefore, be more readily applied to carbamazepine, although, in general, a simple clinical approach to its use is usually satisfactory. Phenytoin has required the greatest pharmacokinetic input due to its nonlinear pharmacokinetics and narrow target range. Many different graphical methods, equations and computer programs have been reported, some of which demand 2 steady-state, dose-concentration pairs; others function satisfactorily with only 1. Recent attempts have been made to interpret non-steady-state data. In addition, a number of workers have demonstrated the value of altering the population parameter estimates to account for ethnic differences. A pharmacokinetic approach can also be used to tailor the use of phenytoin in the treatment of status epilepticus. Dosage alterations may be needed for specific patient groups. In particular, children generally require higher dosages on a weight-for-weight basis than adults, while equivalently lower dosages should be given to neonates. Most anticonvulsants are principally cleared by hepatic mechanisms, so dosage adjustment is not usually required in renal disease, although care must be taken in interpreting serum concentrations because of changes in protein binding. Close monitoring is required in the elderly and patients with hepatic impairment, while increased dosages may be needed in critically ill patients and during pregnancy. Pharmacokinetic principles can be used in the treatment of treat self-poisoning with anticonvulsants. There are few data available on the pharmacokinetics of vigabatrin, lamotrigine, oxcarbazepine and gabapentin in patients. Due to its mode of action in binding irreversibly to its target enzyme, serum concentration monitoring of vigabatrin plays no role in optimising therapy. The value of applying pharmacokinetic principles with the other 3 drugs remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacokinetic optimisation of anticonvulsant therapy. 151 37

The effects of clinically used anticonvulsant drugs on high-frequency sustained repetitive firing (SRF) of action potentials and on postsynaptic responses to iontophoretically applied gamma-aminobutyric acid (GABA) have been compared to establish a classification of anticonvulsant drugs based on cellular mechanisms of action. By using concentrations in the range of therapeutic cerebrospinal fluid values in humans, drugs have been separated into three categories: Phenytoin, carbamazepine, and valproic acid limited SRF, but did not alter GABA responses. Phenobarbital, clonazepam, and diazepam augmented GABA responses and limited SRF only at concentrations above the therapeutic range in ambulatory patients but that are achieved in the acute treatment of status epilepticus. Ethosuximide failed to affect SRF or GABA responses even at supratherapeutic concentrations. Ability of an anticonvulsant to limit SRF correlated well with efficacy against generalized tonic-clonic seizures clinically and against maximal electroshock seizures in experimental animals. Augmentation of GABA responses and lack of limitation of SRF correlated with efficacy against generalized absence seizures in humans and against pentylenetetrazol-induced seizures in animals. However, ethosuximide must act against generalized absence seizures and against pentylenetetrazol-induced seizures by a third, as yet unknown, mechanism. Other actions occurring at supratherapeutic concentrations correlated with clinical toxicity.
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PMID:Anticonvulsant drug mechanisms of action. 240 25

The actions of clinically used anticonvulsant drugs on sustained high frequency repetitive firing of action potentials and on responses to gamma aminobutyric acid (GABA) have been determined using mouse neurons in cell culture, and a classification of anticonvulsant drug actions has been developed based on these cellular actions. Actions of the anticonvulsant drugs were accepted as clinically relevant only if they occurred at concentrations achieved in cerebrospinal fluid or in plasma unbound to plasma proteins. Based on their cellular mechanisms of actions, drugs have been divided into 3 categories: (1) Phenytoin, carbamazepine and valproic acid limited sustained high frequency repetitive firing but did not alter GABA responses. (2) Phenobarbital and the benzodiazepines, clonazepam, diazepam and nitrazepam, augmented postsynaptic GABA responses. These drugs limited sustained high frequency repetitive firing only at concentrations above the therapeutic range in ambulatory patients, but equal to concentrations achieved in the acute treatment of status epilepticus. (3) Ethosuximide failed to reduce sustained high frequency repetitive firing or enhance GABA responses even at supertherapeutic concentrations. Limitation of sustained high frequency repetitive firing by anticonvulsant drugs correlated well with efficacy against generalized tonic-clonic seizures in man and against maximal electroshock seizures in experimental animals. Enhancement of postsynaptic GABA responses correlated with efficacy against generalized absence seizures in man and against pentylenetetrazol seizures in animals. Ethosuximide, however, did not alter GABA responses or sustained high frequency repetitive firing suggesting that its action against generalized absence seizures in man and pentylenetetrazol seizures in experimental animals occurs by an additional, as yet unknown, mechanism.
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PMID:Mechanisms of anticonvulsant drug action. 288 43

Status epilepticus (SE) is defined as a continuous seizure that lasts more than 30 minutes or as serial seizures in which the patient does not regain a premorbid level of consciousness. This condition exists primarily in two forms: convulsive (focal or generalized) and nonconvulsive (absence or partial complex) SE. Protracted or serial convulsive seizures represent a medical emergency with a current mortality rate of 10%. As in any urgent or life-threatening situation, the initial treatment is directed at support and maintenance of vital functions. Specific anticonvulsant management is usually begun with intravenous lorazepam. This benzodiazepine is replacing diazepam in many medical centers because it has a longer duration of action and causes less respiratory depression. Concurrent intravenous loading with phenytoin is usually necessary for sustained control of seizures. Phenobarbital may be required as a third drug if seizures persist or recur. In cases of refractory status epilepticus, barbiturate coma, continuous anticonvulsant intravenous infusion, or general anesthesia may be necessary.
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PMID:Status epilepticus in children and adults. 305 85

The brain uptake of phenobarbital during prolonged status epilepticus (3 h) was studied in paralyzed, ventilated sheep. The first 30 min of status epilepticus was characterized by systemic hypertension, increased CBF, increased peripheral vascular resistance, a fall in brain pH, and an elevation in brain lactate concentrations. Subsequently, hemodynamic factors normalized and brain acidosis persisted. Phenobarbital administered during the early phase of status epilepticus produced higher levels of brain phenobarbital concentration, which was greatest at the earliest sample time (5 min following infusion), compared to nonseizure controls. This elevation persisted for the first 3 h following the infusion. Phenobarbital administration during the established phase of status epilepticus, when systemic blood pressure, peripheral vascular resistance, and CBF had returned to preseizure values, resulted in attenuated brain phenobarbital uptake not different from controls for the first 30 min. These results are explained by disruption of the blood-brain barrier to phenobarbital during the early (hypertensive) phase of status epilepticus.
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PMID:Brain phenobarbital uptake during prolonged status epilepticus. 369 34

Baclofen and phenobarbital were tested for anticonvulsant efficacy against limbic seizures produced by i.c.v. infusion of kainic acid (KA) in unanesthetized rats. All rats treated with KA alone developed a prolonged status epilepticus associated with extensive neuronal degeneration. When administered immediately after the KA infusion, baclofen (5 mg/kg i.p.) protected five of six animals against the development of status epilepticus and did not alter the behavioral expression of the residual discrete electrographic seizures. Phenobarbital (40 mg/kg i.p.) given 15 min before KA also prevented the development of status epilepticus in five of six rats, but blocked the behavioral expression of the residual electrographic seizures. In two of five additional rats, baclofen prevented or reversed status epilepticus when administered 50 to 60 min after the end of the KA infusion. The ability of these drugs to prevent KA-induced neuronal degeneration correlated with their anticonvulsant action.
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PMID:Efficacy of baclofen and phenobarbital against the kainic acid limbic seizure-brain damage syndrome. 377 12

The pharmacokinetics of antiepileptic drugs used for the treatment of human epilepsies is reviewed for dogs and cats. In dogs, especially phenobarbital and primidone must be regarded as useful drugs for chronic treatment on account of their elimination rate and bioavailability. Phenytoin, carbamazepine, valproic acid and benzodiazepines are eliminated so rapidly that a therapeutic value cannot be expected. In cats, phenytoin, phenobarbital, valproic acid and diazepam must be regarded as suited for chronic treatment, but there is a definite lack of clinical experience. Phenobarbital and primidone are useful for treatment of clonic-tonic generalized seizures (grand mal) in dogs. The effect of primidone depends mostly on its metabolite phenobarbital. Since primidone, given in high dosage for longer periods of time, gives rise to liver damage, phenobarbital is regarded as the drug of first choice. A status epilepticus may be treated by i.v. injection of diazepam, clonazepam, phenytoin or lidocaine. In cats with grand mal, treatment with daily doses of about 1 mg/kg diazepam may be tried. It proved effective for longer time periods without development of tolerance. There is no reliable clinical experience with other drugs in this species.
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PMID:[Pharmacologic principles in the treatment of epilepsy in the dog and cat]. 383 46

Effects of phenobarbital, phenytoin and diazepam on cephaloridine-induced spiking activity (focal seizure) and cefazolin-induced violent seizure appearing repeatedly in EEG and general behavior (repeated generalized seizure) were studied in rats with chronically implanted electrodes. Phenobarbital, phenytoin and diazepam showed remarkable inhibition on cephaloridine-induced focal seizure and the ED50 values were 4.52 mg/kg, 9.41 mg/kg and 0.86 mg/kg, respectively. Phenobarbital and diazepam also inhibited cefazolin-induced repeated generalized seizure. The ED50s to inhibit seizure pattern in EEG were 30.5 mg/kg and 3.4 mg/kg, respectively and the ED50 values to suppress seizure behavior were 49.0 mg/kg and 4.7 mg/kg. However, phenytoin did not suppress repeated generalized seizure even at 100 mg/kg. From these results, cephaloridine-induced focal seizure and cefazolin-induced generalized seizure are thought to be useful models for evaluating the inhibitory effect of test compounds on cortical seizure and status epilepticus, respectively.
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PMID:Effects of certain antiepileptics on cephaloridine- and cefazolin-induced seizures in rats. 663 17

The pharmacokinetic parameters controlling paraldehyde elimination were determined in nine infants infused with paraldehyde at the rate of 150 mg/kg/hr in a 5% solution in 5% dextrose for the treatment of status epilepticus. The mean +/- SEM values for the observed parameters were as follows: rate constant for the disposition of paraldehyde 0.0680 +/- 0.0071 hr,-1 half-life 10.2 +/- 1.0 hr; volume of distribution 1.73 +/- 0.20 L/kg; clearance 0.121 +/- 0.023 L/hr/kg. Phenobarbital administration prior to or within 24 hours of the cessation of paraldehyde infusion decreased both paraldehyde clearance and volume of distribution in a manner linearly related to the logarithm of the phenobarbital dose. The rate constant for paraldehyde elimination was decreased as a linear function of the logarithm of the combined dose of administered phenobarbital and phenytoin. No acetaldehyde was detected in any blood samples. Paraldehyde administration was not correlated with any adverse reactions or toxicities.
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PMID:Pharmacokinetics of paraldehyde disposition in the neonate. 669 30

Phenobarbital, diazepam, lorazepam, and phenytoin are all currently used for the treatment of acute seizures, including status epilepticus. None of these drugs is considered ideal. Fosphenytoin is a new phenytoin prodrug that fulfills many of the properties of an ideal anticonvulsant drug. The safety, tolerance, and pharmacokinetics of intramuscularly administered fosphenytoin have been evaluated in three clinical trials involving patients requiring loading or maintenance doses of phenytoin. These investigations demonstrated that fosphenytoin is rapidly and completely absorbed after injection into muscle and is quickly converted to produce therapeutic phenytoin plasma concentrations within 30 min of administration. Plasma concentrations of phenytoin achieved with i.m. fosphenytoin exceeded those associated with an equimolar dose of oral phenytoin. i.m. fosphenytoin was well tolerated both locally and systemically. Only mild and transient reactions occurred at the injection site. The most common systemic adverse events reported--somnolence, nystagmus, dizziness, and ataxia--are side effects commonly seen with phenytoin and tended to be mild. Preexisting seizure disorders remained stable. Combination treatment with i.v. diazepam or lorazepam to attain rapid seizure control and i.m. fosphenytoin to maintain the anticonvulsant effect theoretically offers many advantages for control of acute seizures and should be studied.
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PMID:Intramuscular use of fosphenytoin: an overview. 864 11


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