Pharmacology of Sedative-Hypnotics

What are sedative-hypnotics?

\-decrease anxiety and activity, calms the recipient.

\-produces drowsiness, facilitates onset and maintenance of sleep

What in the hypothalamus is considered the sleep promoter area?

\-VLPO

What is considered the wake promoting area in the hypothalamus?

\-TMN

How does the TMN promote wakefullness?

\-it produces histamine and the LC in the brainstem which produces norepinephrine and this causes a person to stay awake

How does VLPO promote sleep?

\-VLPO projects inhibitory GABA neurons to the TMN and the LC:

* GABA activates GABA-A receptors and has inhibitory effect on neurons in this area and this promotes sleep

What helps to balance sleep and wakefulness in people?

\-circadian and homeostasis

What is the receptor target of the benzodiazepines?

\-GABA-A receptors is the target for benzodiazepines.

MOA of benzodiazepines

\-The GABA-A receptor is where they bind but must have α, β, γ subunits are required for BZD activity.

\-GABA binds to its site between α and β subunits

\-BZDs bind to a specific recognition site located       between α and γ subunits

\-**BZDs are** __**positive allosteric modulators**__ **(PAMs) of GABAA receptors**

True/False: BZDs can work with out GABA

\-False: they must have GABA in order to work

What happens when BZDs bind to the GABA-A receptor alpha 1 subunit?

\-somnolence/hypnotic

\-amnesia

What happens when BZDs bind to GABA-A receptor alpha 2 subunit?

\-anxiolytic

\-muscle relaxation

What are some effects of BZDs in the CNS?

•Somnolence, drowsiness



•Decreased anxiety



•Muscle relaxation



•Anterograde amnesia



•Anticonvulsant activity

Which BDZ is the only prodrug?

\-clorazepate

Which BZDs do not go through phase 1 metabolism

\-Lorazepam, Oxazepam, temazepam ( they go through glucuronide)

This BZD is converted to Oxazepam by CYP3A4 and CYP2C19

\-Temazepam

What are some inhibitors of CYP3A4 that can influence the concentration of BZDs?

\-macrolides

\-antifungals

\-ritonavir

\-nefazodone

\-grapefruit juice

This drug is an competitive antagonist at the BDZ binding site of GABA-A receptors?

\-flumazenil

What is the indication of flumazenil?

\-overdose

\-reversal of BZD agonist effects

\-may cause seizures

\-not for overdose of barbiturates or TCAs

MOA of Z drug compounds?

•They are agonists that have high affinity for the α1 subunit of GABA-A receptors and bind to the BZD binding/recognition site

•Eszopiclone, zaleplon, zolpidem appear to be mostly selective for α1 containing GABA-A receptors

•Short or long term relief of insomnia

•These drugs decrease sleep latency

•Tolerance and dependence may occur with long term use

What are the two melatonin receptors in the brain?

\-MT1 and MT2

This melatonin receptor promotes sleep

\-MT1 receptor

This melatonin receptor regulates circadian rhythm

\-MT2

MOA of ramelteon

•Melatonin receptor agonist



•Activates MT1 and MT2 receptors in the suprachiasmatic nucleus



•GPCRs that have been linked to Gi and Gq



•MT1 receptor: promotes sleep onset



•MT2 receptor: regulates circadian rhythm



•Ramelteon is more selective for MT1 than MT2, and has a much higher affinity for MT1 than melatonin

Tasimelteon

•For Non-24-Hour Sleep-Wake Disorder





•Melatonin receptor agonist



•Activates MT1 and MT2 receptors, with higher affinity for MT2 receptors



•CYP1A2 and CYP3A4 are major metabolizers



•Potential drug-drug interactions with CYP1A2 inhibitors or CYP3A4 inducers

MOA of Orexin

•Orexin Receptors:



•Orexin 1 receptor (OX1R), GPCR coupled to Gq



•Orexin 2 receptor (OX2R), GPCR coupled to Gq and/or Gi



•OX1R and OX2R are found in wake promoting areas such as the locus coeruleus and tuberomammillary nucleus

What are some drug that can inhibit orexin?

\-Dual Orexin Receptor Antagonists

\-Suvorexant, Lemborexant are two drugs in this class

MOA of DORA?

•Orexin 1 receptor (OX1R), a GPCR coupled to Gq



and



•Orexin 2 receptor (OX2R), a GPCR coupled to Gq and/or Gi