Biomedical Engineering Reference
In-Depth Information
SWS/SWA in particular may play an important role in somatic and cognitive restoration, includ-
ing the consolidation of certain forms of procedural and declarative memory. A substantial dimi-
nution in the amount of SWS/SWA occurs across the human lifespan. This decline is beginning
already in adolescence and middle-aged adults have only 25% of the SWS observed in young
adults, whereas the elderly have almost none. While the clinical importance of these phenomena is
unknown, it is reasonable to speculate that they may be related to the increase of sleep complaints
associated with aging.
20.3 PHARMACOLOGICAL MODULATION OF THE SLEEP SYSTEM
The treatment of sleep disorders currently focuses at inducing and maintaining sleep. This is ensured
via the positive modulation of the GABA
A
receptor system. Other drugs with sedative side effects
(e.g., antihistamines and antidepressants) are also used, but these are often prescribed off-label, and
have not been evaluated within this indication with the same rigor as the hypnotics. In addition to
this, new pharmacological agents, such as, antagonists at orexin receptors, which are involved in
wake promotion, and 5HT
2A
antagonists, which promote SWS are in clinical development. Since
most reported studies with these compounds have included patients with primary insomnia, and
thus no comorbidity (meaning either other disease or functional consequences of the sleep distur-
bances), it still remains an open question whether these approaches might constitute an advantage
over the BzRAs in this regard. Finally, modii cation of the circadian rhythm, which in depressed
patients and in elderly patients is severely impaired, is being targeted using melatonin and melaton-
ergic agonists.
20.3.1 I
NDUCTION
AND
M
AINTENANCE
OF
S
LEEP
20.3.1.1 Benzodiazepines and Benzodiazepine Receptor Agonists
Using the benzodiazepine structure as a template, thousands of molecules with similar pharmaco-
logical activities in vivo have been developed. Structure-activity studies have identii ed essential
and forbidden areas of the structure and this analysis has led to the development of the so-called non-
benzodiazepine hypnotics (hypnotics without the 1,4 benzodiazepine ring structure) (Figure 20.4).
O
O
O
NH
N
N
OH
N
O
2
N
N
Cl
Cl
N
Cl
F
Diazepam
Flunitrazepam
Lorazepam
NC
O
N
F
N
N
N
N
O
N
N
O
N
O
N
N
O
Zaleplon
Zolpidem
Flumazenil
FIGURE 20.4
Structure of BzRAs and the competitive benzodiazepine receptor antagonist l umazenil.
