Sedatives anxiolytic effect

Pharmacodynamic tolerance to the psychomotor effects of benzodiazepines has been demonstrated after single or multiple doses (File 1985 Greenblatt and Shader 1978 Rosenberg and Chiu 1985). Pharmacodynamic tolerance to the anxiolytic effect (over a 6-month period) has not been demonstrated (Rickels et al. 1983), and clinical experience supports the view that many patients with anxiety disorders require long-term therapy with benzodiazepines or alternative antianxiety agents. An important clinical consequence of tolerance to sedative effects is observed in benzodiazepine overdoses, when patients may initially be... 

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... 

There are now indications for the interaction of progesterone metabolites with the Cl channel of the GABAa receptor (Fig. 52-7). The A-ring-reduced steroids, especially those with the 5a,3a configuration, are particularly active on the GABAa receptor [ 12]. By facilitating chloride-channel opening, these steroids produce anesthetic, anxiolytic and sedative-hypnotic effects (see Ch. 16). 

Valerian extracts show sedative and anxiolytic effects. Whereas passionflower and chamomile have relatively specific anxiolytic effects, valerian shows more general sedative effects, but all effects occur in a dose-dependent manner (Della Logia et al. 1981 Leuschner et al. 1993). The sedative effects of valerian extract are moderate when compared to diazepam and the neuroleptic chlorpromazine (Leuschner et al. 1993). However, valepotriates reverse the anxiogenic effects of diazepam withdrawal in rats in the elevated plus maze. This effect is dose dependent, effective at 12 mg/kg but not 6 mg/kg. Interestingly, the fragrant valerian compound bornyl acetate has sedative effects in mice, but only when inhaled (Buchbauer et al. 1992). 

The functional significance of thromboxane A2 inhibition by kava is not certain. More needs to be understood about the functions of prostaglandins in the CNS, but given the inhibition of GABAA by thromboxane A2, kava s suppression of thromboxane A2 synthesis could conceivably contribute to its anxiolytic and sedative effects. More research is needed to determine if this mechanism of action is physiologically significant at normal kavalactone concentrations. 

There are a few members of the passionflower family (Passifloraceae) that have psychotropic effects. The one most studied is Pass flora incarnata, although some work has been done on Pass flora coerulea and Passiflora edulis. P. incarnata is a colorful, flowering plant with five white or lavender petals, a purple or pink corona, and five brightly colored stamen (Gruenwald et al. 1998). The parts of the plants used for medicinal effect are the whole plant or aerial parts. It is native to the mid- to southeastern United States. Passionflower has a history with Native Americans as a poultice to treat bruises, and as a tea for sedative/anxiolytic effects (Kowalchick and Hylton 1987). It is one of the most common herbs commercially available in Britain (Tyler 1994). 

Sedative and anxioiytic effects A number of flavonoids have been shown to bind to benzodiazepine receptors and have anxiolytic effects (Medina et al. 1997). The anxiolytic effects of chrysin were examined in mice (Wolfman et al. 1994). Chrysin (1 mg/kg IP) reduces behavioral measures of anxiety (elevated-plus maze) in a manner similar to diazepam (0.3-0.6 mg/kg), which was reversed by pretreatment with a benzodiazepine antagonist, Ro 15-1788. The anxiolytic effect is not likely due to sedation because there is no concurrent reduction in motor activity at the doses used. Unlike diazepam, chrysin does not produce muscle relaxation at higher doses. 

The sedative and anxiolytic effects of passionflower were examined in two other animal behavioral assays (staircase test, light/dark box choice test). Both anxiolytic and sedative effects occur, as well as potentiation... 

Despite neuropharmacolgical and animal data to support sedative and anxiolytic effects of passionflower, there have not been any such controlled studies in humans. Two studies have been published that examined the effects of combined herbal extracts on anxiety, including passionflower (Bourin et al. 1997). Although there were significant and experimentally controlled effects, a combined herbal treatment confounds the ability to selectively identify the effects of passionflower. A second controlled study was similarly confounded by the use of a three-herb combination (Gerhard et al. 1991). 

There are several members of the Geranium family (Geraniaceae), some of which have been anecdotally reported to have anxiolytic or sedative effects. However, there is a paucity of research to support the use of this herb as a CNS depressant (Manolov et al. 1977 Tasev et al. 1969). 

There are several herbs with CNS depressant effects that have been used mostly for anxiolytic and sedative effects historically. This has been supported by neuropharmacological, animal, and human studies (table 6.1). In some cases, the herbs meet Class I criteria for therapeutic treatment (table 6.4). Much work remains to be done in further testing the efficacy of these drugs and more firmly delineating their biochemical mechanisms. 

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... 

It does not cause cognitive impairment and has a low potential for abuse. It does not show withdrawal reactions and has no anticonvulsive, hypnotic, muscle relaxant and sedative effects. The anxiolytic effect gradually evolves over 1-3 weeks, it does not potentiate the sedative effects of alcohol and is indicated for the short-term management of generalized anxiety disorder. 

GABA is formed by the decarboxylation of glutamate, and is the major inhibitory neurotransmitter, hi recent years the GABAa receptor has been identified as the mediator of the anxiolytic and sedative effects of drugs such as alcohol and the benzodiazepines. Abnormahties of this receptor have been identified in humans with anxiety disorders (Nutt and Mahzia 2001). 

Buspirone is as effective as the benzodiazepines in the treatment of general anxiety. However, the full anxiolytic effect of buspirone takes several weeks to develop, whereas the anxiolytic effect of the benzodiazepines is maximal after a few days of therapy. In therapeutic doses, buspirone has little or no sedative effect and lacks the muscle relaxant and anticonvulsant properties of the benzodiazepines. In addition, buspirone does not potentiate the central nervous system depression caused by sedative-hypnotic drugs or by alcohol, and it does not prevent the symptoms associated with benzodiazepine withdrawal. 

Mechanism of Action A benzodiazepine that enhances the action of the inhibitory neurotransmitter gamma-aminobutyric acid in the CNS, affecting memory as well as motor, sensory, and cognitive function. Therapeutic Effect Produces anxiolytic, anticonvulsant, sedative, muscle relaxant, and antiemetic effects. 

Benzodiazepines act throughout the CNS. Proposed relationships between site of action and effect include the following spinal cord (muscle relaxation), brain stem (anticonvulsant effects), brain stem reticular formation (sedative effects), cerebellum (ataxia), and limbic and cortical areas (anxiolytic effects). Action outside the CNS is limited to coronary vasodilation with intravenous (IV) administration and neuromuscular blockade with very high doses of BZs. 

As with studies of many other herbs and nutritional supplements, interpretation of clinical trials of valerian is hampered by small sample sizes, suboptimal study design, lack of specified inclusion and exclusion criteria, and unknown composition of valerian extract (Plushner, 2000). Furthermore, none of the trials have included children or teenagers. Nevertheless, several studies have showed a mild hypnotic action in persons with insomnia and in normal sleepers, as well as a mild sedative effect (Leathwood and Chauffard, 1983, 1985 Balderer and Borbely, 1985). One report has described an anxiolytic effect (Kohnen and Oswald, 1988). There are suggestions that valerian may have beneficial effects on sleep latency, frequency of waking, nighttime motor activity, and overall sleep quality. 

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