Sedative-hypnotic drugs mechanism

Buspirone Mechanism uncertain Partial agonist at 5-HT receptors but affinity for D2 receptors also possible Slow onset (1-2 weeks) of anxiolytic effects t minimal psychomotor impairment—no additive CNS depression with sedative-hypnotic drugs Generalized anxiety states Oral activity forms active metabolite short half-life Toxicity Tachycardia paresthesias t gastrointestinal distress Interactions CYP3A4 inducers and inhibitors... 

In contrast, acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow. Phenothiazines, tricyclic antidepressants, and sedative-hypnotic drugs are the most important drugs that interact with alcohol by this pharmacokinetic mechanism. 

A specialized form of conscious sedation is occasionally required in the ICU, when patients are under severe stress and require mechanical ventilation for prolonged periods. In this situation, sedative-hypnotic drugs or low doses of intravenous anesthetics, neuromuscular blocking drugs, and dexmedetomidine may be combined. 

An understanding of common mechanisms of death due to poisoning can help prepare the care-giver to treat patients effectively. Many toxins depress the central nervous system (CNS), resulting in obtundation or coma. Comatose patients frequently lose their airway protective reflexes and their respiratory drive. Thus, they may die as a result of airway obstruction by the flaccid tongue, aspiration of gastric contents into the tracheobronchial tree, or respiratory arrest. These are the most common causes of death due to overdoses of narcotics and sedative-hypnotic drugs (eg, barbiturates and alcohol). 

Several drugs with novel chemical structures have been introduced recently. Buspirone is an anxiolytic agent that has actions different from those of conventional sedative-hypnotic drugs. Zolpidem and zaleplon, while structurally unrelated to benzodiazepines, share a similar mechanism of action. 

The sedative-hypnotic action of chloral hydrate should be explained by the formation of trichloroethanol, which is synthesized as a result of its reduction in tissues. Despite the fact that the precise mechanism of action of chloral hydrate is not known, it evidently acts analogous to ethanol on the CNS by inCTeasing membrane permeability, which leads to sedation or sleep. Chloral hydrate can be used for insomnia as an alternative to benzodiazepines. Synonyms for this drug are aquachloral, chloradorm, chloratol, noctec, and others. 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

We have described the mesolimbic dopamine pathway and the neuropharmacology of reward and have specifically emphasized the mechanism of action of several classes of dmgs of abuse, including stimulants (cocaine and amphetamines), hallucinogens, designer drugs and phencyclidine, nicotine, marijuana, opiates, alcohol, benzodiazepines, and sedative-hypnotics. We have even mentioned how receptors and the mesolimbic dopamine pathway could play a role in the psychopharmacology of obesity. 

The mechanism of action of the benzodiazepines was discussed previously in this chapter. The antianxiety properties of these drugs involve a mechanism similar or identical to their sedative-hypnotic effects (i.e., potentiating GABAergic transmission).37 Benzo-... 

The barbitmates are the other major group of sedative-hypnotic agents. Similar to the benzodiazepines, they are a group of chemically related drugs and there are many variations in properties, particularly onset of effects and duration of action. The most recognized effects of the barbiturates are centrally mediated and include sedation, hypnosis, decreased anxiety, and, at high doses, anesthetic properties. The mechanism of... 

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