Benzodiazepine sedative-hypnotics pharmacologic effects

Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are different from those of other drugs described in this chapter. Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. Unlike benzodiazepines, the drug has no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HTia receptors, but it also has affinity for brain dopamine D2 receptors. Buspirone-treated patients show no... 

Some sedative-hypnotics, particularly members of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone. 

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). 

It is generally accepted that the pharmacology of benzodiazepine derivatives is identical qualitatively but varies quantitatively. In other words, the sedative, hypnotic, anticonvulsant, muscle relaxant, and anxiolytic properties reside to various degrees in all of them. Nevertheless, they do exhibit pharmacological specificity, making it necessary to select a particular drug for its desired therapeutic effect. 

Zaleplon has a pharmacological profile similar to benzodiazepines. Zaleplon is a full agonist for the benzodiazepine oq receptor located on the GABAa receptor ionophore complex in the brain, with lower affinity for the a2 and a3 subtypes. It selectively enhances the action of GABA similar to but more selectively than benzodiazepines. Zaleplon, although not benzodiazepine-like in chemical structure, induces sedative-hypnotic, anticonvulsant, and anticonflict effects via its binding to the central nervous system (CNS)-type benzodiazepine receptors [33-36]. 

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

Sedative-hypnotic agents are some of the most widely prescribed and used drugs in the developed world. They are also frequently drugs of abuse. Sedative-hypnotics are used to promote sleep, as their name implies, and to reduce anxiety. Their overall effect is to act as CNS depressants. We will consider the two major classes of drugs in this category, the benzodiazepines and the barbiturates. For a detailed discussion of the pharmacology of these agents, see Chamey et al. (2006). 

A wide difference in milligram potency exists between the benzodiazepine compounds however, when dosage adjnstments are made, all agents share similar anxiolytic and sedative-hypnotic activity. The variations in lipid solubility between componnds inflnence the pharmacokinetic properties of benzodiazepines. Different pharmacokinetic and pharmacodynamic properties can assist the clinician in choosing an appropriate anxiolytic (Table 69-9). After a single dose, the onset, intensity, and duration of pharmacological effects are important factors to consider when using benzodiazepines for the short-term, intermittent, or as-needed treatment of anxiety. 

The barbiturates have a different pharmacological and binding profile from that of the benzodiazepines. They exert a depressant effect on the cerebrospinal axis and depress neuronal activity as well as skeletal muscle, smooth muscle, and cardiac muscle activity. Depending on the compound, dose, and route of administration, the barbiturates can produce different degrees of CNS depression and have found use as sedatives, hypnotics, anticonvulsants, or anesthetics. 

In this chapter, we discuss the pharmacology of medications that are classified as anxiolytic, sedative, or hypnotic—primarily the benzodiazepines, buspirone, zolpidem, eszopiclone, and zale-plon. Subsequently, we present diagnosis-specific treatment guidelines (outlined in Table 3-1). The commonly used anxiolytics and hypnotics, together with their usual doses, are shown in Table 3-2. Many antidepressant medications are also effective in the treatment of anxiety disorders. The pharmacology of antidepressants is discussed in Chapter 2 their clinical use in anxiety disorders is addressed in the diagnosis-specific sections later in this chapter. 

The antianxiety effects of chlordiazepoxide (165) were described in 1960 and this compound was followed by diazepam (135). These two drugs have captured 75% of the market for sedatives in the USA. Other benzodiazepines used as antianxiety agents include oxazepam (166 R = H), a metabolite of diazepam that is better tolerated, lorazepam (166 R = Cl) and potassium clorazepate (167). Prazepam is the iV-cyclopropylmethyl analogue of diazepam. The benzodiazepines have other therapeutic applications, many being used for inducing sleep, diazepam and nitrazepam are anticonvulsants and flurazepam (168) is both an antianxiety agent and a potent hypnotic. Thieno- and pyrazolo-1,4-diazepinones isosteric with diazepam have similar pharmacological properties (B-81 Ml 10604). 

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