Anxiolytics and Sedatives

Benzodiazepines are very important drugs from a turnover point of view. A large number of these compounds has been synthesized, developed and marketed (about thirty have been launched), a dozen of which contain fluorine atoms. Specific clinical indications for each compound do not result from a difference in the mechanism but from the pharmacokinetic and pharmacodynamic behavior of each one. 

Several fluorine-containing compounds are being marketed or investigated as antiepileptics, as antidegeneratives in Azheimer and Parkinson diseases, and as sleep inductors. Several of these compounds are also being developed for other indications at the same time. 

X = 0 Halazepam Anxiolytic Schering-Plough (1981) X = S Quazepam Hypnotic Schering-Plough (1987) 

Rufinamide is a structurally novel antiepUeptic agent that acts by reducing the frequency of liring of sodium-dependent neuronal action potentials. This drug is in Phase III clinical trials as a broad-spectrum anticonvulsant. 

Retigabine is a novel anticonvulsant drug in development (Phase II). It activates voltage-gated potassium channels and also affects GABA neurotransmission in the GABAyi receptor.  

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Anticonvulsants or antiepileptics are agents that prevent epileptic seizures or modulate the convulsant episodes eflcited by seizure activity. Certain of these agents, eg, the BZs, are also hypnotics, anxiolytics, and sedatives, reinforcing the possibiUty of a common focus of action at the molecular level (1). 

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Benzodiazepiaes have largely replaced barbiturates and barbiturate-like agents for use as anxiolytics and sedative—hypnotics. Because benzodiazepiaes rarely produce levels of CNS depression that require therapeutic iatervention, the need for analeptics has decreased considerably. 

Selective serotonin reuptake inhibitor antidepressant selection and anxiolytic and sedative hypnotic prescribing a multivariate analysis./ Clin Outcomes Manage 4, 16—22. 

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). 

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. 

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... 

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. 

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). 

Most anxiolytic and sedative-hypnotic drugs produce dose-dependent depression of central nervous system function. The ideal anxiolytic drug should calm the patient without causing too much daytime sedation and drowsiness and without producing physical or psycho-... 

The benzodiazepines constitute the most commonly used group of anxiolytics and sedative-hypnotics. Since the first member of this group, chlordiazepoxide, was introduced, many congeners have been marketed. Most of these drugs possess anxiolytic, sedative-hypnotic, and anticonvulsant properties. Thus, the clinical indications for specific benzodiazepines are not absolute, and their uses overlaps considerably. 

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... 

Anxiolytics and Sedative-Hypnotics. Because of their large therapeutic index, measurement of anxiolytic or sedative-hypnotic serum concentrations is not usually necessary in clinical practice, unless abuse, overdose, or inadvertent toxicity are suspected. Some data indicate that plasma alprazolam levels of 40 ng/mL may be required to manage panic disorder ( 51) (see the sections Adverse Effects of Anxiolytics and Adverse Effects of Sedative-Hypnotics in Chapter 12). 

The benzodiazepines (BZDs), which were introduced nearly 40 years ago, were hailed as a breakthrough because they have fewer of the drawbacks of prior anxiolytics and sedative-hypnotics, are effective in a range of disorders, and are safe in combination with most drugs (except other sedatives), as well as alone in overdose, and are generally mild in terms of side effects. For these reasons, BZDs quickly became, and remain, among the most widely prescribed drugs worldwide. 

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). 

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