Zolpidem (Ambien)

Year of discovery: 1982 (Synthelabo)

Year of introduction: 1992
Drug Category: Nonbenzodiazepine sedative/hypnotic agent
Main Uses: short term Treatment of insomnia
related drugs: Eszopiclone (Lunesta), Zaleplon (sonata)

Insomnia the inability to fall into and maintain the state of sleep,
affects most people at one time or another, and is a chronic problem
for many, especially travelers shirt workers and the elderly. It is more
prevalent in women and patients with medical or psychiatric
conditions. Zolpidem, developed by the French company synthelabo
(later sanofi Aventis) in the early 1980s is used for the short-term
treatment of insomnia. It was introduced in the US in 1992 under the
name ambient. An extended release formulation of Zolpidem,
marketed under the name ambien cr was approved in 2005. Zolpidem
has a rapid onset of action and a half-life of ca. 1 hour. It initiates sleep
in a short period of time (usually 10-30 minutes) and prolongs total
sleep time. Extended release Zolpidem provides plasma concentrations
beyond three hours of administration, thereby improving the quality of
sleep and sustaining deep sleep. Zolpidem has little effect on the
stages of sleep.
Zolpidem has a greater safety margin than barbiturates and
benzodiazepines. Anecdotal incidents of sleep driving and eating have
been reported.
The hypnotic effect of Zolpidem is due to modulation of GABA (y-
aminobutyric acid). Receptors as is in the case of barbiturates and
benzodiazepines. GABA is an important inhibitory neurotransmitter
affecting 20-50% of all synapses of the central nervous system. There
are three types of membrane bound GABA receptors. Gaba(sub a) and
GABA(sub c) receptors are ligand-gated ion channels and Gaba (sub b)
receptors are G protein-coupled receptors that regulate other ion
channels. The Gaba(sub a) receptor is a pentameric protein complex,
most commonly containing (greek a sub n, beta sub m and y sub o)
subunits (where n+m+o=5). GABA binds to the Beta subunit of the
receptor leading to the opening of a chloride ion channel,
hyperpolarization of the membrane and reduction of neuronal activity.
Zolpidem binds to the alpha-receptor subunits (as do benzodiazepines)
and facilitates the opening of chloride channels in response to GABA.
However, unlike benzodiazepines which activate all alpha receptor
subtypes nonselectively, zolpidem binds preferentially to the alpha1
subtype which is thought to explain its reduced muscle relaxant and
antiepileptic effects. There are two other approved hypnotic agents
that also bind the a-subunit of GABA receptors. Zaleplon was
introduced in 1999 as Sonata by King Pharmaceuticals and eszopiclone
was marketed as Lunesta by Sepracor since 2004. Although
eszopiclone is less effective than benzodiazepines, it can be used for
long-term treatment of insomnia without serious withdrawal symptoms
upon discontinuation.
ISBN 978-0-470-22749-7