Sedative-hypnotics pharmacology

Miller NS, Gold MS. Sedative-hypnotics pharmacology and use. J Fam Pract 1989 29 665-670. 

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. 

The continuing search for molecules that possess the sedative-hypnotic properties of the barbiturates but show a better pharmacologic ratio has, as shown above, taken many directions. To name only two variants, the ring has been contracted and even opened entirely in each case some activity of the parent was retained. Although at one time the acylurea functional array was thought necessary for activity, the work below shows that even... 

Metabolism converts a lipophilic molecule into a more hydrophilic (water-loving) metabolite that can be excreted in urine by the kidneys. In the majority of cases the drug is detoxified, or made pharmacologically inactive by this metabolic breakdown. However, a few drugs need to be metabolised to become psychoactive for instance, the sedative-hypnotic chloral hydrate is converted to the active metabolite trichloroethanol. In this case the parent molecule is referred to as a prodrug. With many drugs, both the parent compound and its metabolites are psychoactive. An example of this is the tricyclic antidepressant imipramine which is metabolised to desipramine, with... 

Chronic insomnia calls for careful assessment for a medical cause, non-pharmacologic treatment, and careful use of sedative-hypnotics (intermittently to prevent tolerance and dependence). 

Dating back to the 1800s, some of the earliest snccessfnl psychiatric medications were those nsed to promote sleep. Sleep-promoting medications, called sedative-hypnotics, have remained an important component of onr pharmacological armamentarium. Over the past 100-plus years, as we have learned more abont both pharmacology and sleep physiology, a series of refinements have improved the safety and effectiveness of sleep medications. 

Nabitan (39) is a cannabis-inspired analgesic whose nitrogen atom was introduced in order to improve water solubility and perhaps to affect the pharmacological profile as well. The phenolic hydroxyl of benzopyran synthon is esterified with 4-(l-piperidino)butyric acid under the influence of dicyclohexyl carbodi mi de. In addition to being hypotensive and sedative-hypnotic, nabitran (39) is a more potent analgesic than codeine. The preparation of synthon begins with aceto-... 

Pharmacodynamics, antipsychotics also differ in their pharmacodynamics, i.e. their pharmacological and clinical profiles of action. A rough distinction is made between highly sedative, hypnotic antipsychotics (e.g. clopenthixol, levomepromazine) and other products with weaker initial sedative action (e.g. fluphenazine and haloperidol). Sedative antipsychotics are prescribed for states of major unrest, often combined with insomnia, whereas the less sedative antipsychotics are preferred for patients suffering from delusions and hallucinations but in whom heavy sedation during daytime is undesirable. 

Available evidence indicates that systematic desensitization and in vivo exposure are the most effective treatment methods available. Pharmacological treatment has not been well investigated, but studies involving antidepressants suggest that TCAs and MAOIs are ineffective ( 85, 86 and 87). In addition, three studies suggest that sedative-hypnotic anxiolytics may undermine the behavioral treatment of specific phobias (88, 89 and 90). In another study, volunteers with animal phobias were exposed to their phobic object 1.5 hours after administration of either tolamolol, diazepam, or placebo in a double-blind crossover design. Tolamolol abolished the stress-induced tachycardia but had no beneficial behavioral or subjective effects ( 91). 

Basic and Clinical Pharmacology > Chapter 22. Sedative-Hypnotic Drugs > ... 

The chemical structures of some older and less commonly used sedative-hypnotics, including several barbiturates, are shown in Figure 22-3. Glutethimide and meprobamate are of distinctive chemical structure but are practically equivalent to barbiturates in their pharmacologic effects. They are rarely used. The sedative-hypnotic class also includes compounds of simpler chemical structure, including ethanol (see Chapter 23) and chloral hydrate. 

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. 

CLINICAL PHARMACOLOGY OF SEDATIVE-HYPNOTICS TREATMENT OF ANXIETY STATES... 

Pharmacodynamic interactions are also of great clinical significance. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics, is most important. Alcohol also potentiates the pharmacologic effects of many nonsedative drugs, including vasodilators and oral hypoglycemic agents. 

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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