Heterocyclic sedative-hypnotics

Heterocyclic Sedative-Hypnotics, 235 4.1.4.1The First Phase, 235 4.1.4.2The Second Phase, 235... 

Current drugs on the market include barbiturates, benzodiazepines, halogenated sedative-hypnotics, heterocyclic sedative-hypnotics, antihistamines, and other sedative-hypnotics. 

The Second Phase. The second phase of the development of heterocyclic sedative-hypnotics was initiated after the development and launch of the benzodiazepine sedative-hypnotics. Although the 1,4-benzodiazepines are safe and effective drugs, they too have produced certain undesirable side effects. This compelled some companies to develop non-benzodiazepine sedative-hypnotic drugs. 

Benzodiazepines. After the first phase of the launch of heterocyclic sedative-hypnotics, as exemplified by glutethimide and methyprylone, most significant milestones were reached by Roche. In 1960, Roche launched Librium (chlordiazepoxide)and in 1963, Valium (diazepam). These two compounds were the first two 1,4-benzodiazepine class compounds launched in the world. Subsequently a number of companies launched several other 1,4-benzodiazepines for a number of indications (sedative-hypnotic, anxiolytic, anticonvulsant, and muscle relaxant). 

Specific factors to consider are both psychiatric and physical contraindications. For example, bupropion is contraindicated in a depressed patient with a history of seizures due to the increased risk of recurrence while on this agent. Conversely, it may be an appropriate choice for a bipolar disorder with intermittent depressive episodes that is otherwise under good control with standard mood stabilizers. This consideration is based on the limited data suggesting that bupropion is less likely to induce a manic switch in comparison with standard heterocyclic antidepressants. Another example is the avoidance of benzodiazepines for the treatment of panic disorder in a patient with a history of alcohol or sedative-hypnotic abuse due to the increased risk of misuse or dependency. In this situation, a selective serotonin reuptake inhibitor (SSRI) may be more appropriate. 

The benzodiazepines are widely used sedative-hypnotics. All of the structures shown in Figure 22-2 are 1,4-benzodiazepines, and most contain a carboxamide group in the 7-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position. 

Heterocyclic compounds were synthesized and tested as sedative-hypnotics with the direct purpose of substitutingthem for both barbiturates and benzodiazepines (Table 5.7). 

In quick succession, two heterocyclic non-benzodiazepine sedative/hypnotics were launched in 1985 by Rhone-Poulenc as zopi-clone and 1 88 by Synthelabo as zolpidem. In 1999, Wyeth Ayerst launched another heterocyclic non-benzodiazepine sedative/hyp-notic, zaleplon. 

Tricyclics modify peripheral sympathetic effects in two ways through blockade of norepinephrine reuptake at neuroeffector junctions and through alpha adrenoceptor blockade. Sedation and atropine-like side effects are common with tricyclics, especially amitriptyline. In contrast to sedative-hypnotics, tricyclics lower the threshold to seizures. The answer is (B). Selective serotonin reuptake inhibitors cause sexual dysfunction in some patients, with changes in libido, erectile dysfunction, and anorgasmia. Tricyclic antidepressants may also decrease libido or prevent ejaculation. Of the heterocyclic antidepressants bupropion is the least likely to affect sexual performance. The drug is also used in withdrawal from nicotine dependence. The answer is (B). 

A number of heterocyclics possessing significant hypnotic-cum-sedative activity have gained recognition in the therapeutic armanentarium. A few such compounds shall be discussed here briefly. 

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