Seizures anticonvulsants

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. 

Anticonvulsants or antiepileptics are agents that prevent epileptic seizures or modulate the convulsant episodes eflcited by seizure activity. Certain of these agents, eg, the BZs, are also hypnotics, anxiolytics, and sedatives, reinforcing the possibiUty of a common focus of action at the molecular level (1). 

Primidone [125-33-7] C22H24N2O2 (39) is an analogue of phenobarbital that is used for the treatment of generalized tonic-clonic seizures. It is metabolized in humans to phenobarbital (6) and phenylethyLmalondiamide [7206-76-0J, C22H24N2O2 (40) and these metaboUtes are probably responsible for its anticonvulsant actions. Primidone has many of the side effect HabiUties seen with phenobarbital. 

Succinimides. Ethosuximide [77-67-8] C2H22NO2 (41) and the related succinknide, methsuximide [77-41-8] C22H23NO2 (42) are used in absence seizure treatment. Like the other anticonvulsants discussed, the mechanism of action of the succinirnides is unclear. Effects on T-type calcium channels and -ATPase activity have been reported (20). Ethosuximide has significant CNS and gastrointestinal (GI) side effect HabiUties (13). 

The anticonvulsant progabide 24) is useful in a wide variety of seizure disorders. It was synthesiied as a y-aniinobutync acid (GABA) prodrug but its activity appears to reside in the parent drug and its acid metabolite, as well as the GABA liberated [21],... 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

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. 

Occasionally, status epilepticus (an emergency situation characterized by continual seizure activity with no interruptions) can occur. Diazepam (Valium) is most often the initial drug prescribed for this condition. However, because the effects of diazepam last less than 1 hour, a longer-lasting anticonvulsant, such as phenytoin or phenobarbital, also must be given to control the seizure activity. 

The nurse obtains the vital signs at die time of the initial assessment to provide baseline data. The primary healtii care provider may order many laboratory and diagnostic tests, such as an electroencephalogram, computed tomographic scan, complete blood count, and hepatic and renal function tests to confirm the diagnosis and identify a possible cause of the seizure disorder, as well as to provide a baseline during therapy with anticonvulsants. 

Promoting an Optimal Response to Therapy When administering an anticonvulsant, the nurse must not omit or miss a dose (except by order of the primary health care provider). An abrupt interruption in ther-apy by omitting a dose may result in a recurrence of the seizures. In some instances, abrupt withdrawal of an anticonvulsant can result in status epilepticus. 

MISSELLANEOUS ANTICONVULSANTS. Valproic acid (Depakene) is unrelated chemically to the other anticonvulsants. This drug is absorbed rapidly when taken orally Tablets should not be chewed but swallowed whole to avoid irritation to the mouth and throat. The capsules may be opened and the drug sprinkled on a small amount of food, such as pudding or applesauce This mixture must be swallowed whole immediately and not chewed. Zonisamide is administered orally once a day or in divided doses. The dose may be increased by 100 mg day every 1 to 2 weeks until control of the seizures is obtained or the patient reaches the maximum dosage of 600 mg/d. 

Mr. Parks, age 32 years, has recently received a diagnosis of epilepsy. He has been taking the anticonvulsant carbamazepine, but his seizures are not yet under control. Mr. Parks asks you how long it will take to cure his epilepsy. Determine how you would respond to Mr. Parks. 

The xanHiine derivatives are contraindicated in Hiose wiHi known hypersensitivity, peptic ulcers, seizure disorders (unless well controlled with appropriate anticonvulsant medication), serious uncontrolled arrhytinnias, and hyperthyroidism. 

Similarly, convulsive seizures and a sustained epileptic state persisted after stomach contents were pumped and activated charcoal and anticonvulsive medication were administered in a 43-year-old man who ingested approximately 260 mg/kg endosulfan (Boereboom et al. 1998). At 4 days after exposure, the man was pronounced brain dead, and autopsy revealed cerebral hernia from massive cerebral edema. Eight additional accidental and/or intentional cases of acute poisoning with endosulfan resulting in adverse neurological effects have been reported in more recent studies, six by Blanco-Coronado et al. (1992), one by Lo et al. (1995), and one by Pradhan et al. (1997) two out of the eight resulted in death. Tonic-clonic convulsions were seen in the Blanco-Coronado et al. (1992) cases, whereas Lo et al. (1995) reported the development of muscle fasciculations and episodes of convulsions in their case. In the case reported by Pradhan et al. (1997), the patient had consumed about 75 mL of hquid endosulfan (35% w/v). In this case, in addition to tonic-clonic seizures and myoclonic jerks, the patient developed... 

Gardner, CR and Webster, RA (1977) Convulsant-anticonvulsant interactions on seizure activity and cortical acetylcholine release. Eur. J. Pharmacol. 42 247-256. 

The anticonvulsant activity of a drug may also be evaluated by measuring its ability to raise the convulsive threshold, i.e. the amount of applied current or infused PTZ required to just evoke a seizure. Comparison of the efficacy of drugs in the threshold and maximal seizure tests may distinguish between their abilities to raise seizure threshold or reduce seizure spread and development. 

One unwanted side-effect of phenytoin is its anti-folate activity. A programme of synthetic chemistry to manipulate the structure of the anti-folate compound pyri-methium to try to replace that property with anticonvulsant activity resulted in the synthesis of lamotrigine. It proved to be an effective AED in partial and generalised epilepsy but experience has found it also to be of value in absence seizures. 

This laboratory has utilized two approaches to define further the anticonvulsant properties of PCP. One approach involved a relatively simple convulsant model, pentylenetetrazol-induced convulsions. In this model, the administration of ketamine alone, or in combination with several known anticonvulsants, was tested. Ketamine, as a structural analog of PCP, shares many of the pharmacological properties associated with PCP. The second approach involved a more complex model, hippocampal-kindled seizures. 

Using this model, the ability of PCP, ketamine, and several anticonvulsants to antagonize hippocampal seizures and elevate seizure thresholds was tested both before and after kindling. 

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). 

TABLE 1. Effect of PCP, ketamine and selected anticonvulsants on the duration and severity of hippocampal kindled seizures... 

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