Sedatives and Hypnotics

Question 1

Zaleplon (Sonata) - Pharamcokinetics

Answer 1

Pharmacokinetics:
* Elimination half-life = 1 hr.
* Peak plasma concentrations achieved 1 hr after oral dosing.
* Primarily metabolized to 5-oxo-zaleplon by aldehyde oxidase
* Small component of metabolism by CYP3A4

Question 2

Eszopiclone (Lunesta)

Answer 2

Enhances GABA binding to the GABA-A receptor

Question 3

Eszopiclone (Lunesta) - Pharmacokinetics

Answer 3

Elimination half-life = 6 hrs.
Peak plasma concentrations achieved 1 hr after oral dosing.
Metabolized by oxidation and demethylation (involves CYP3A4 and CYP2E1).

Question 4

Zaleplone (Sonata)

Answer 4

• Binding site is the brain omega-1 receptor, which is situated on the alpha-subunit of the GABA-A receptor complex.
• Potentiates binding of GABA to the receptor complex, thereby enhancing its biological activity.
• Sonata® reduces sleep latency, which accounts for its efficacy in patients with chronic insomnic or transient insomnia.
• Despite short half-life, next-day amnesia and impairments in cognitive performance have been reported.
• Increased risk of rebound insomnia is associated with higher doses of Sonata® - above 10 mg daily.

Question 5

Zolpidem (Ambien)

Answer 5

Produces sedative properties by binding selectively to a1-subunit.
Same site that also binds benzodiazepines.
* Evidence – pharmacological effects blocked by flumazenil
* Minimal muscle relaxing and anticonvulsant effects = less “hangover” effects as compared with benzodiazepines.
* Associated with next-day cognitive impairment – zolpidem is associated with an increased risk of motor vehicle accident
* Potential for dependence.

Question 6

The ZZZZ drugs

Answer 6

• Zolpidem, Zopiclone, and Zaleplon (i.e., the “Z” drugs)
• Act as positive allosteric modulators (PAMs) at the GABA-A receptor
• Bind to the benzodiazepine site on the GABA-A receptor and thereby enhance binding of GABA.

Question 7

Benzodiazapine properties

Answer 7

• Highly lipophilic – well-absorbed orally and easily crosses the blood-brain and blood-placental barriers.
• Hepatic metabolism – converted to hydrophilic metabolites for renal elimination.
• Metabolite = desmethyldiazepam
• Same metabolite for diazepam, chlordiazepam, prazepam, and clorazepate.
• Desmethyldiazepam itself is pharmacologically active as an anxiolytic.
• Desmethyldiazepam is converted to oxazepam in the liver.
• Short-acting metabolite.
• Directly glucuronidated (as is lorazepam and flurazepam) and excreted by the kidney.

Question 8

Benzodiazepam drug action

Answer 8

Nanomolar Concentrations
* Anxiolytic sedation – via a2 subunit.
* Action effectively blocked by flumazenil.

Micromolar Concentrations
* Anesthesia – diazepam, midazolam, lorazepam.
* Activity due to binding of benzodiazepines to low-affinity site on GABA-A receptor.