Seizures anticonvulsant drugs

The fundamental neurobiological importance of the GABA A receptor is underscored by observations that even more receptor sites exist at or near this complex (Fig. 8—20). This includes receptor sites for nonbenzodiazepine sedative-hypnotics such as zolpidem and zaleplon, for the convulsant drug picrotoxin, for the anticonvulsant barbiturates, and perhaps even for alcohol. This receptor complex is hypothetically responsible in part for mediating such wide-ranging CNS activities as seizures, anticonvulsant drug effects, and the behavioral effects of alcohol, as well as the known anxiolytic, sedative-hypnotic, and muscle relaxant effects of the benzodiazepines. 

Generally, anticonvulsants reduce the excitability of the neurons (nerve cells) of the brain. When neuron excitability is decreased, seizures are theoretically reduced in intensity and frequency of occurrence or, in some instances, are virtually eliminated. For some patients, only partial control of the seizure disorder may be obtained with anticonvulsant drug therapy. 

We have evaluated the dose-related effects of PCP, ketamine, and selected anticonvulsant drugs on seizure activity in the hippocampal model of kindled seizures. The hippocampal model is particularly well suited for the study of the anticonvulsant effects of drugs because of the slow rate of acquisition of the fully kindled seizure. Electrical stimulation of the dorsal hippocampus initially evokes a stereotyped sequence of behavior, accompanied by a characteristic EEG pattern. Repeated electrical stimulation eventually results in generalized kindled seizures. This allows the testing of drugs on the unkindled hippocampal seizure (afterdischarge) to be compared to effects on the fully kindled seizure in the same rats. 

Anticonvulsant drugs such as carbamazepine, diazepam, valproic acid, and phenobarbital also slightly increased the duration of the initial AD. However, the effects of these drugs on the other associated seizure events were quite different from PCP and ketamine. The effects of carbamazepine and diazepam, typical of the four compounds, are illustrated in figure 4. These compounds either suppressed the rebound spiking (diazepam, valproic acid, and phenobarbital) or lengthened the total seizure duration with no rebound suppression (carbamazepine). 

On the other hand, the results using the hippocampal seizure model revealed an interesting profile of anticonvulsant effects for PCP and ketamine, compared to several classical anticonvulsant compounds. When tested against the unkindled hippocampal seizure, the effects of behaviorally equivalent doses of PCP and ketamine were remarkably similar, but differed substantially from the effects of the anticonvulsant drugs. The compression of the entire EEG seizure episode to a shorter duration was unique to PCP and ketamine, and suggests an anticonvulsant effect. Conversely, the small prolongation of the initial AD episode, and the decreased duration of the postictal depression, could be reflective of pro-convulsive influences. There were, however, no other indications of enhanced seizure activity, such as the appearance of motor convulsions or spread of seizure activity to the cerebral cortex. 

Alcohol withdrawal seizures do not require anticonvulsant drug treatment unless they progress to status epilepticus. Patients with seizures should be treated supportively. An increase in the dosage and slowing of the tapering schedule of the BZ used for detoxification or a single injection of a BZ may be necessary to prevent further seizure activity. 

Anticonvulsives. Drugs used to prevent seizures. Antihypertensives. Drugs used to lower blood pressure. 

While regular monitoring of plasma phenytoin levels can result in improved seizure control, the benefit derived from measuring other commonly prescribed anticonvulsant drugs is difficult to assess. Phenobarbitone, primidone, and carbamazepine will be discussed briefly. 

Little is known as yet about the pharmacokinetics of carbamazepine in humans although preliminary reports suggest slow absorption (M21) and marked variations in blood levels during a day in some subjects (M15). Blood levels varying from trace quantities to 12 /ig/ml have been found in patients taking 400-1000 mg daily (P3), but no relation between the level observed and the dose was apparent. In the studies so far published carbamazepine blood levels have not correlated with seizure control (P3), but all the subjects wore receiving additional anticonvulsant drugs. 

Head trauma, meningitis, childhood fevers, brain tumors, and degenerative diseases of the cerebral circulation are conditions often associated with the appearance of recurrent seizures that may require treatment with anticonvulsant drugs. Seizures also may be a toxic manifestation of the action of central nervous system (CNS) stimulants and certain other drugs. Seizures often occur in hyperthermia (febrile seizures are very common in infants) sometimes in eclampsia, uremia, hypoglycemia, or pyridoxine deficiency and frequently as a part of the abstinence syn-... 

Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Most authorities now recommend prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug, although diazepam is also effective. Phenytoin and carba-mazepine are ineffective, and valproic acid may cause hepatotoxicity in very young patients. 

Benzodiazepines and barbiturates are used as anticonvulsant drugs in the treatment of epilepsy. Epilepsy, a medical disorder characterized by recurrent seizures, has many different forms. The four most common seizure types are generalized tonic-clonic seizures (old name grand mal seizures), generalized absence seizures (petit mal seizures), complex partial seizures (psychomotor or temporal lobe seizures), and simple partial seizures (focal seizures). 

BD and other forms of NCL are relatively rare, occurring in an estimated two to four of every 100,000 live births in the US [www.ninds.nih.gov]. There is currently no specific treatment for BD and current therapy simply alleviates the symptoms of the disease. Anticonvulsant drugs alleviate the associated seizures, and occupational therapy helps individuals compensate for the loss of vision, physical and mental abilities. Because BD involves the deterioration of neuronal cell tissue, it is a candidate for cellular therapy. 

ANTICONVULSANTS Drugs that relieve or prevent seizures. 

Problem 20.8 Dilantin (5,5-diphenylhydantoin), an anticonvulsant drug used in the treatment of epileptic seizures, is a pyrrole with the molecular formula C 5H 2N202. What is the structural formula for Dilantin ... 

Table 1 Test results for dose-dependent suppression of sound-induced tonic seizures in mice. Experimental agents used show a comparable/superior binding affinity to the a2S subunit similar to that of the anticonvulsant drug, Neurontin a...

Siris JH, Pippenger CE, Werner WL, Masland RL. Anticonvulsant drug-serum levels in psychiatric patients with seizure disorders. Effects of certain psychotropic drugs. NY State J Med 1974 74(9) 1554-6. 

Many biochemistry laboratories no longer undertake routine measurement of the plasma concentration for most anticonvulsant drugs because plasma concentrations are insufficiently stable to serve as a useful guide to change of dose. The exception is phenytoin, where a small increase in dose may lead to a disproportionate rise in the plasma drug concentration (see zero-order pharmacokinetics, p. 99) and plasma monitoring is essential. With other drugs the dose is increased to the maximum tolerated level and, if seizures continue, it is replaced by another. 

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