Benzodiazepines amnestic

Anxiolytics are drugs used for the treatment of anxiety disorders. Apart from benzodiazpines, a frequently used anxiolytic is the 5HT1A (serotonin) receptor agonist buspiron, which has no sedative, amnestic or muscle-relaxant side effects, but whose action takes about a week to develop. Furthermore, it is less efficaceous than the benzodiazepines. Buspiron s mechanism of action is not fully understood. 

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... 

Mechanism of Action A benzodiazepine that enhances the action of gamma-ami-nobutyric acid, one of the major inhibitory neurotransmitters in the brain. Therapeutic Effect Produces anxiolytic, hypnotic, anticonvulsant, muscle relaxant, and amnestic effects. 

Benzodiazepines are highly effective anxiolytics and sedatives. They also have muscle relaxant, amnestic, and anticonvulsant properties. Benzodiazepines effectively treat both acute and chronic generalized anxiety and panic disorder. The high-potency benzodiazepines alprazolam and clonazepam have received more attention as antipanic agents, but double-blind studies also have confirmed the efficacy of diazepam and lorazepam in the treatment of panic disorder. Although only a few benzodiazepines are specifically approved by the... 

Zolpidem and zaleplon are hypnotics that act at the omega-1 receptor of the central GABA receptor complex. This selectivity is hypothesized to be associated with a lower risk of dependence. Unlike benzodiazepines, zolpidem and zaleplon do not appear to have significant anxiolytic, muscle relaxant, or anticonvulsant properties. However, amnestic effects may occur. 

Nevertheless, the GABAergic properties of benzodiazepines remain their most important clinical application. Over the past 30 years, the most widely used benzodiazepine drug has been diazepam (1.6). It is an anxiolytic, sedative, and muscle relaxant the anxious, depressed person becomes more outgoing and relaxed. There have been many diazepam analogs. Oxazepam (4.177) and lorazepam (4.178) have similar effects. Temazepam (4.179), flunitrazepam (4.180), and flurazepam (4.181) are useful sedative-hypnotics. Clonazepam (4.182) is a clinically useful anticonvulsant. Brotizolam (4.183), a novel benzodiazepine analog, seems to be an effective sedative-hypnotic. Midazolam (4.184) is an imidazolo-benzodiazepine that is water soluble and thus easily injectable. It is a hypnotic sedative with marked amnestic (i.e., memory loss) properties and is used in dentistry, endoscopic procedures, and induction to anesthetics in the elderly and in... 

The fact that single-dose administration of benzodiazepines could have marked amnestic effects was first recognized in anesthesiology where these drugs are used to relax and sedate patients prior to surgery. It was found that,... 

Box 7.4 Amnestic Effects of Benzodiazepines a Clinical Experiment in Anesthesiology... 

Some amnesia occurred after all three benzodiazepines, although there were pronounced differences between the three drugs with regard to the time of onset of action, peak effect and duration of action. For example the amnestic effect of diazepam occurred as soon as l min after injection but had abated completely 60 min later. 

Dorow R, Berenberg D, Duka T, et al. Amnestic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15-1788. Psychopharmacology 1987 93 507-514. 

Disadvantages of the benzodiazepines include the risk of dependence, depression of central nervous system functions, and amnestic effects. In addition, the benzodiazepines exert additive central nervous system depression when administered with other drugs, including ethanol. The patient should be warned of this possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination. In the treatment of generalized anxiety disorders and certain phobias, newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are now considered by many authorities to be drugs of first choice (see Chapter 30). 

Eszopiclone Bind selectively to a subgroup of GABAa receptors, acting like benzodiazepines to enhance membrane hyperpolarization Rapid onset of hypnosis with few amnestic effects or day-after psychomotor depression or somnolence Sleep disorders, especially those characterized by difficulty in falling asleep Oral activity short half-lives CYP substrates Toxicity Extensions of CNS depressant effects dependence liability Interactions Additive CNS depression with ethanol and many other drugs... 

Diazepam, lorazepam, and midazolam are used for preanesthetic medication and as adjuvants during surgical procedures performed under local anesthesia. As a result of their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these compounds are considered to be the drugs of choice for premedication. (The basic pharmacology of benzodiazepines is discussed in Chapter 22.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. It is important that the drug becomes lipid-soluble at physiologic pH and can readily cross the blood-brain barrier to produce its central effects. 

The most widely studied aspect of cognition with respect to benzodiazepines is memory.12 163 One of the most reliable effects of benzodiazepines is to impair recall of information presented after drug administration (anterograde amnesia). In contrast, information presented before administration of benzodiazepines is not affected. The memory decrement produced by benzodiazepines is a function of task difficulty, such that little or no impairment is observed for immediate recall of a few items, whereas more complex or delayed memory tests reveal profound impairment.12 The benzodiazepine antagonist flumazenil has been used to block the sedative effects of benzodiazepines, but the amnestic effect was not affected, suggesting that benzodiazepine-induced amnesia is independent of sedation.122,164 It has also been demonstrated that some benzodiazepines selec-... 

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). 

Clinical trials of buspirone have shown the drug to be slower in onset of action compared with diazepam, but it produces significantly less sedation and fewer detrimental effects on psychomotor function than the benzodiazepines. The main advantage of buspirone would therefore appear to be in its lack of dependence, amnestic and sedative effects. However, its slower onset of action and its lower efficacy in alleviating the somatic symptoms of anxiety make it unlikely that it will replace the therapeutically effective and proven benzodiazepines, despite the greater frequency of their side effects. Whether ipsapirone and gepirone, which are still in clinical development, will be therapeutically superior to buspirone can only be assessed after they become more widely available for clinical use. 

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