Barbiturates GABA receptors

Saunders PA, Ho IK Barbiturates and the GABA receptor complex. Prog Drug Res 34 261-286, 1990... 

This area has been covered in a review by Eldefrawi and Eldefrawi [23]. The GABA -receptor channel is activated by GABA (Fig. 2), avermectin, muscimol, taurine (Fig. 2) and j -alanine (Fig. 2). The activation by agonists is potentiated by benzodiazepines and barbiturates. The channel is blocked by the competitive... 

Historically, the treatment of alcohol use disorders with medication has focused on the management of withdrawal from the alcohol. In recent years, medication has also been used in an attempt to prevent relapse in alcohol-dependent patients. The treatment of alcohol withdrawal, known as detoxification, by definition uses replacement medications that, like alcohol, act on the GABA receptor. These medications (i.e., barbiturates and benzodiazepines) are cross-tolerant with alcohol and therefore are useful for detoxification. By contrast, a wide variety of theoretical approaches have been used to reduce the likelihood of relapse. This includes aversion therapy and anticraving therapies using reward substitutes and interference approaches. Finally, medications to treat comorbid psychiatric illness, in particular, depression, have also been used in attempts to reduce the likelihood of relapse. 

Benzodiazepines. Like the barbiturates, benzodiazepines bind to the GABA receptor and are therefore cross-tolerant with alcohol. As a result, they also make suitable replacement medications for alcohol and are widely used for alcohol detoxification. Theoretically, any benzodiazepine can be used to treat alcohol withdrawal. However, short-acting benzodiazepines such as alprazolam (Xanax) are often avoided because breakthrough withdrawal may occur between doses. Intermediate to long-acting benzodiazepines including chlordiazepoxide (Librium), diazepam (Valium), oxazepam (Serax), lorazepam (Ativan), and clonazepam (Klonopin) are more commonly utilized. 

Figure 2.12. Diagrammatic representation of the GABA-benzodiazepine supra-molecular complex. Compounds that increase inhibitory transmission may do so either by directly activating the GABA receptor site (e.g. muscimol) or by acting directly on the chloride ionophore (e.g. barbiturates). Benzodiazepines (e.g. diazepam) enhance the sensitivity of the GABA-A receptor to GABA. Compounds that decrease inhibitory transmission may do so by activating the picrotoxin site, which closes the chloride ionophore, or by blocking the GABA-A receptor.

Sedation is an intermediate degree of CNS depression, while hypnosis is a degree of CNS depression similar to natural sleep. From the chemical point of view, soporific, sedative, and hypnotic drugs are classified as barbiturates, benzodiazepine hypnotics, and so on. Except for a few rare exceptions, any one of these compounds can be used for acquiring a sedative effect or state of sleep. Presently, the less toxic benzodiazepines are edging out the class of barbiturates more and more because of the possibility of chronic dependence associated with the use of barbiturates. Drugs of both classes are primarily CNS depressants, and a few of their effects, if not all, are evidently linked to action on the GABA-receptor complex. 

Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986) Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232 1004-1007... 

Mechanism of Action A barbiturate that enhances the activity of gamma-aminobutyric acid (GABA) by binding to the GABA receptor complex. Therapeutic Effect Depresses CNS activity. 

Mechanism of Action A barbiturate that depresses the central nervous system (CNS) activity by binding to barbiturate site at the GABA-receptor complex enhancing GABA activity and depressing reticular activity system. Therapeutic Effect Produces hypnotic effect due to CNS depression. 

Figure 4.1 Benzodiazepines interact with the GABA receptor in the brain and activate the ceii membrane of neurons to open and allow negative chioride ions (Cl ) to enter the neuron (a, ), y subunits form the Cl- ion). This entry inhibits that neuron s ability to fire an action potential. The GABA receptor also has binding sites for other substances, such as steroids, barbiturates, and alcohol.

Our knowledge of the binding sites of the other ligands at the GABA receptor is more limited. The barbiturates and neurosteroids act through distinct binding sites, but the specific subunits involved have not been clearly determined. Unlike the benzodiazepines, they do not seem to require the y subunit to function and may just require a and (5 subunits. 

In the next section, we describe the other known main ligands of the GABA receptor, that is, neurosteroids, alcohol, and the barbiturates. (The neurosteroid section is only a summary for completeness for a more comprehensive overview, the reader is referred to Siegfried, Chapter 33, in this volume.)... 

Because alcohol and barbiturates also act, in part, via the GABA receptor-mediated chloride ion channel, benzodiazepines show cross-tolerance with these substances. Thus, benzodiazepines are used frequently for treating alcohol or barbiturate withdrawal and detoxification. Alcohol and barbiturates are more dangerous than benzodiazepines because they can act directly at the chloride ion channel at higher doses. In contrast, benzodiazepines have no direct effect on the ion channel the effects of benzodiazepines are limited by the amount of endogenous GABA. 

Buspirone is a partial agonist at serotonin type 1A (5-HTj ) receptors. Unlike benzodiazepines, barbiturates, and alcohol, buspirone does not interact with the GABA receptor or chloride ion channels. Thus, it does not produce sedation, interact with alcohol, impair psychomotor performance, or pose a risk of abuse. There is no cross-tolerance between benzodiazepines and buspirone, so benzodiazepines cannot be abruptly replaced with buspirone. Likewise, buspirone cannot be used to treat alcohol or barbiturate withdrawal and detoxification. Like the antidepressants, buspirone has a relatively slow onset of action. 

Like benzodiazepines, barbiturates bind to the GABA receptor— however, at a different site from the benzodiazepines. Measurements of mean ion channel open times show that barbiturates act by increasing the proportion of channels opening to the longest open state (i.e., 9 msec), resulting in an overall increase in CL flux into the neuron. 

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