Benzodiazepines anticonvulsant, anxiolytic

AHopregnanolone and similar A-ring-reduced pregnanes potentiate GABA effects at these receptors. These steroids mimic the effects of the benzodiazepines, changing chloride ion conductance and producing sedative and hypnotic behavioral effects (276,277). Neuroactive steroids can be therapeutically useful as anticonvulsants, anxiolytics, or anesthetics (qv) (see also Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Actions at benzodiazepine receptors are thought to underlie virtually all the pharmacological actions of the benzodiazepines, those that are desirable as well as those that are undesirable. This includes the desirable therapeutic actions of benzodiazepines as anxiolytics and sedative-hypnotics, as well as anticonvulsants and muscle relaxants. It also includes their undesirable side effects as amnestic agents and as agents that cause adaptations at the benzodiazepine receptor with chronic administration, which are thought to underlie the production of dependence and withdrawal from these agents (see Chapter 13). 

Benzodiazepines have anxiolytic, sedative-hypnotic, muscle relaxant, and anticonvulsant properties. They are among the most commonly prescribed drugs in the western hemisphere because of their efficacy, safety, low addiction potential, minimal side effects, and high public demand for sedative... 

Zopiclone, the first compound of the cyclopyrrolone class to be marketed, possesses anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. It causes no dependence and no rebound insomnia. Zopiclone interacts with GABA receptors (see Figure 50). It is rapidly absorbed from the GI tract, and with an oral dose of 7.5 mg, it produces a peak-plasma concentration of 50 to 80 )tg/L. Zopiclone becomes metabolized to A-demethylzopiclone (inactive) and zopiclone-iV-oxide (active). Zopiclone exhibits a high affinity for benzodiazepine-binding sites in the cerebral cortex, hippocampus, and cerebellum, but does not interact with the peripheral benzodiazepine-binding sites. 

The benzodiazepines form a group of over 40 substances, approximately half of which are available in Germany in proprietary medicines. All benzodiazepines have anticonvulsant, anxiolytic, muscle-relaxant and sedative/hypnotic properties, although the various substances differ from each other with respect to the strengths of these effects. Most substances are available as tranquilizers/ hypnotics and some as anticonvulsants or muscle relaxants. A habit-forming potential is common to all benzodiazepines, and a small number of these substances are abused extremely frequently. These are discussed further below. 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Benzodiazepines have found wide therapeutic applications as anxiolytics, sedatives, hypnotics, anticonvulsants, and central muscle relaxants. 

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

In addition to the benzodiazepine receptor agonists which, depending on the dose administered, have anxiolytic, anticonvulsant, sedative and amnestic properties, benzodiazepines have also been developed which block the action of agonists on this receptor. Such antagonists may be exemplified by... 

While the individual drugs in the benzodiazepine group differ in potency, all benzodiazepines in common use have anxiolytic, sedative-hypnotic, anticonvulsant and muscle-relaxant activity in ascending order of dose. The main clinical difference between the individual drugs lies in the time of onset of their therapeutic effect, and the intensity and duration of their clinical activity. 

The anxiolytic properties of 5-HT3 receptor antagonists have been demonstrated in several animal models of anxiety. In these models, the 5-HT3 antagonists mimic the anxiolytic effects of the benzodiazepines but differ from the latter in their lack of sedative, muscle relaxant and anticonvulsant action. These compounds appear to be extremely potent... 

Benzodiazepines modify affective responses to sensory perceptions specifically, they render a subject indifferent towards anxiogenic stimuli, i.e., anxiolytic action. Furthermore, benzodiazepines exert sedating, anticonvulsant, and muscle-relaxant (myotonolytic, p. 

The synthesis of these compounds will be described in Section 3.1, Opioid analgesics. Besides opioids, benzodiazepines (diazepam, lorazepam, and midazolam), which have anxiolytic, sedative, and anticonvulsant effects, that cause amnesia and muscle relaxation, are frequently used to relieve patients anxiety during anesthesia. 

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