Hypnotics - Drug Design and Discovery - page 329

20 Hypnotics
Bjarke Ebert and Keith A. Wafford
CONTENTS
20.1 Introduction ......................................................................................................................... 329
20.2 Sleep Basics......................................................................................................................... 330
20.3 Pharmacological Modulation of the Sleep System ............................................................. 332
20.3.1 Induction and Maintenance of Sleep ..................................................................... 332
20.3.1.1 Benzodiazepines and Benzodiazepine Receptor Agonists .................... 332
20.3.2 Modulating Slow Wave Sleep and Slow Wave Activity ........................................ 336
20.3.2.1 GABA A Receptor Agonists .................................................................... 336
20.3.2.2 5-HT 2A Antagonists................................................................................ 337
20.3.3 Orexinergics........................................................................................................... 338
20.3.4 Melatonin and Melatonergic Agonists................................................................... 338
20.4 Concluding Remarks........................................................................................................... 339
Further Readings............................................................................................................................ 339
20.1 INTRODUCTION
Problems with sleep (falling asleep, maintaining sleep, waking up early, or not feeling refreshed
after sleep) can occur in some patients as a disease in its own right and in other patients as a comor-
bidity associated with diseases like depression, stress, and pain. In addition to the impairment of
daytime alertness and reduced performance, chronic insomnia has dire consequences for the qual-
ity of life. Clinical epidemiological studies have linked poor sleep with depression, increased blood
pressure, and type 2 diabetes. The treatment of poor sleep may therefore have more wide ranging
effects than purely increase the sleep time during the night. However, when novel hypnotics have
been developed over the last decades, focus has not been on the improvement of quality of life or
day time function in general, but rather the metrics of sleep. The reason for this is probably, that the
regulatory guidelines indicate that hypnotics should be characterized in primary insomniacs, which
are insomnia patients devoid of clinical consequences of the impaired sleep. With the absence of
daytime consequences pharmaceutical companies, academia, and regulatory authorities in unison
have neglected or forgotten that sleep is not about metrics during the night but the quality of life
during the day.
Hypnotic drugs used to treat insomnia sufferers are characterized by their effects on induction
and maintenance of sleep. These hypnotics—primarily benzodiazepines and benzodiazepine recep-
tor agonists (BzRAs)—are highly effective drugs, which are able to induce and maintain sleep.
When it comes to improvement of daytime performance and thereby the quality of life; however,
existing hypnotic drugs may not improve or may even worsen these types of parameters.
This chapter will cover the basics of sleep physiology, followed by a description of different
treatment modalities from the current benzodiazepines and BzRAs to novel strategies like 5-HT 2A ,
GABA A receptor agonists, melatonergics, and orexinergics, which may advance the treatment of
sleep problems.
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