Z-Drugs – Non-Benzodiazepines

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The Z-Drugs

If you get a prescription from a doctor for insomnia medicine, it will probably be one of the Z-drugs.  The Z-drugs, which include Lunesta, Ambien, and Sonata, are benzodiazepine receptor agonists.  That means they work in a similar way to the benzodiazepine drugs inside the brain.  They are GABA agonists meaning they somewhat mimic the action of gamma-Aminobutyric acid, the inhibitory neurotransmitter and thereby induce sleepiness.

In the historical timeline of insomnia treatment, these drugs came along after the benzodiazepines.  They are better because the side effects are less severe and the not as habit forming. (Benzodiazepines still have a place in medicine for treatment of anxiety and are still used for insomnia, too.)

These drugs are sometimes referred to as non-benzodiazepine hypnotics or just non-benzodiazepines.  That’s a dumb name, if you ask us.  Too unspecific and vague, especially if you are not in the context of sleep medicine.  Further, even within sleep medicine, there are compounds that are non-benzodiazepine hypnotics that would not be considered part of this class: antihistamines and ramelteon, for instance.

One problem is that the chemists don’t have a category that these drugs all fall into which is narrow enough to signify what medical practitioners are talking about.  These drugs are in the categories pyrazolopyrimidines, imidazopyridines or cyclopyrrones, but they are not all in the same category.

Therefore, we prefer the term Z-drugs.  The generic names for these drugs all contain the letter Z, and it is as good a name as any.

Eszopiclone is sold under the brand name Lunesta® (manufactured by Sepracor). It is less effective than some other insomnia treatments, but has several unique advantages. Eszopiclone has a much smaller chance of causing user dependence than other sleep aids, and is less likely to be used recreationally. It also works well for long-term use. The most frequent side effects reported are loss of coordination and dizziness.

Zaleplon is mainly used to treat insomnia, and is manufactured by King Pharmaceuticals under the brand name Sonata®. Although zaleplon is not a benzodiazepine, it produces many of the same side effects: anterograde amnesia (inability to remember, especially during the period of the drug’s use), confusion, daytime drowsiness, agitation, and hallucinations. Zaleplon is a habit-forming drug.

Zolpidem is manufactured under several trade names; the most familiar being Sanofi-Aventis’ Ambien®. It is indicated for short-term insomnia treatment. Prescription Ambien is used as a “no-go” pill by the U.S. Air Force to facilitate sleep for pilots after a mission. Zolpidem is also used off-label to manage restless legs syndrome. If taken for an extended period, zolpidem has the potential to become addictive or at least to induce dependence. It produces many side effects, among them: hallucinations and/or delusions, anterograde amnesia, decreased motor coordination, and impaired judgement.

Zopiclone is a short-acting hypnotic drug first developed by Sepracor, and currently produced by Sanofi-Aventis. In the United States, it is sold under the analogue of eszopiclone (see above), and sold under multiple other brand names worldwide. The most commonly reported side effects are a bitter metallic taste, dry mouth, and headache.

The Difference between Z-drugs and Benzodiazepines

Both benzodiazepine drugs and these non-benzodiazepine sedatives work in the brain on the gamma-aminobutyric acid-A (GABA-A) receptors, as do many drugs used to induce sleep. They may not be formal agonists (in the sense that they don’t directly compete with GABA for biochemical sites in the neurons), but they bind to other places near or in the receptors. Benzodiazepines act on GABA-A receptors that include subunits of the alpha-1, alpha-2, alpha-3, and other classes. The Z-drugs are more selective for the alpha-1 subclass which seems to drive sleepiness but not anti-anxiety.

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