Barbiturates

FIGURE 19-2 Enhanced GABA synaptic transmission. In the presence of GABA, the GABAa receptor (structure on left) is opened, allowing an influx of Cl-, which in turn increases membrane polarization (see Chapter 16). Some antiseizure drugs (shown in larger blue text) act by reducing the metabolism of GABA. Others act at the GABAa receptor, enhancing Cl- influx in response to GABA. As outlined in the text, gabapentin acts presynaptically to promote GABA release; its molecular target is currently under investigation. GABA-T, GABAtransaminase; GAT-1, GABAtransporter.

FIGURE 19-2 Enhanced GABA synaptic transmission. In the presence of GABA, the GABAa receptor (structure on left) is opened, allowing an influx of Cl-, which in turn increases membrane polarization (see Chapter 16). Some antiseizure drugs (shown in larger blue text) act by reducing the metabolism of GABA. Others act at the GABAa receptor, enhancing Cl- influx in response to GABA. As outlined in the text, gabapentin acts presynaptically to promote GABA release; its molecular target is currently under investigation. GABA-T, GABAtransaminase; GAT-1, GABAtransporter.

GENERALIZED-ONSET EPILEPSIES: ABSENCE SEIZURES In contrast to partial seizures, which arise from localized regions of the cerebral cortex, generalized-onset seizures arise from the reciprocal firing of the thalamus and cerebral cortex. For absence seizures, the electroencephalogram (EEG) hallmark is generalized spike-and-wave discharges at a frequency of 3/sec (3 Hz) that represent oscillations between the thalamus and neocortex. The EEG spikes are associated with the firing of action potentials; the following slow wave is associated with prolonged inhibition. One intrinsic property of thalamic neurons that is involved in the generation of the 3-Hz discharges is a particular form of voltage-regulated Ca2+ current, the low threshold ("T") current. In contrast to its small size in most neurons, the T current in many thalamic neurons has a large amplitude. Indeed, bursts of action potentials in thalamic neurons are mediated by activation of the T current. The T current plays an amplifying role in thalamic oscillations, with one oscillation being the 3-Hz spike-and-wave discharge of the absence seizure. Drugs effective against absence seizures (e.g., ethosuximide, valproic acid) are thought to act by inhibition of the T current (Figure 19-3). Thus, inhibition of voltage-regulated ion channels is a common mechanism of action of antiseizure drugs, with anti-partial-seizure drugs inhibiting voltage-activated Na+ channels and anti-absence-seizure drugs inhibiting voltage-activated Ca2+ channels.

GENETIC APPROACHES TO THE EPILEPSIES Most patients with epilepsy are neuro-logically normal; elucidating mutant genes underlying familial epilepsy in otherwise normal individuals has led to the identification of genes implicated in distinct, albeit rare, idiopathic epilepsy syndromes that account for <1% of all human epilepsies. Interestingly, almost all of the mutant genes encode ion channels that are gated by voltage or ligands. Mutations have been identified in voltage-gated Na+ and K+ channels and in channels gated by GABA and acetylcholine. The cellular electrophysiological consequences of some of these mutations may relate to mechanisms of seizures and antiseizure drugs. For example, generalized epilepsy with febrile seizures is caused by a point mutation in the p subunit of a voltage-gated Na+ channel (SCN1B) that appears to interfere with channel inactivation.

ANTISEIZURE DRUGS: GENERAL CONSIDERATIONS

THERAPEUTIC ASPECTS The ideal antiseizure drug would suppress all seizures without causing any unwanted effects. Drugs used currently not only fail to control seizure activity in some patients, but frequently cause unwanted effects that range in severity from minimal impairment of the central nervous system (CNS) to death from aplastic anemia or hepatic failure. The task is to select the drug or combination of drugs that best controls seizures in an individual patient at an acceptable level of untoward effects. Complete control of seizures can be achieved in up to 50% of patients, while another 25% can be improved significantly. Success varies as a function of seizure type, cause, and other factors. To minimize toxicity, treatment with a single drug is preferred. If seizures are not controlled with the initial agent at adequate plasma concentrations, substitution of a second drug is preferred to concurrent administration of a second agent. However, multiple-drug therapy may be needed, especially when two or more types of seizure occur in the same patient.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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