Sleep and Wakefulness Pathways

Wendy Wright and Debra Davis provide an overview of pathways and neurotransmitters involved in sleep and wake cycles.

Wendy L. Wright, DNP, ANP-BC, FNP-BC, FAANP, FAAN, FNAP: I want to hear how you explain or how you think about these different drugs and how they work. I often describe to my patients that the brain is a teeter-totter and I want them to think that come 10 o’clock at night, that circadian rhythm is starting to activate the sleep centers. All these sleep hormones, galanin, and GABA [gamma-aminobutyric acid], are being released to make you go to sleep. This is what should happen in an ideal world. But come 6 o’clock in the morning, the wakefulness center of the brain and their different neurotransmitters, for instance, orexin and histamine and serotonin and dopamine and norepinephrine, those should be kicking in to wake us up. There’s that normal teeter-tottering, but what I also say to patients is you want your brain even if it’s releasing all these sleep hormones to be able to wake up. It’s called allostatic signaling. If that fire alarm goes off or your baby cries you want to be able to have that wakefulness center turn on in a dime. What I find with a lot of the drugs, like the Z-drugs, and the benzodiazepines and trazodone, is that people’s allostatic signaling is overridden meaning they sleep through their baby crying. I’ve had patients say, “I didn’t hear the fire alarm go off.” Do you talk about that with patients as you’re explaining the mechanism of action of some of these drugs, particularly the DORAs [dual orexin receptor antagonists] that we’re about to talk about?

Debra Davis, CRNP: Yes. I do. So many times, people tell me, “My brain won’t shut off. I just can’t get my brain to stop,” and what I tell them is that an orexin inhibitor just takes all that away. It honestly removes, like you said the histamine, the serotonin, the dopamine, and the acetylcholine. It removes all that and just allows you to sleep. It doesn’t slam you to sleep. It allows you to sleep and then it has a shorter half-life, the 8-hour half-life, that allows it to turn back on in the mornings.

And what I do in hormones, I look at people’s cortisol levels. The cortisol levels should start out high. That should be 1 of the things that wake you up and then it drops as the day goes on and it drops off around 9 o’clock at night. If you test somebody and their cortisol level starts to go back up again then that’s 1 of the things that is a problem for them. Those different neurotransmitters are not shutting off and that’s what you need. You need a medication that is going to take all that away and allow them some peaceful sleep and that’s the way I present it to them.

Wendy L. Wright, DNP, ANP-BC, FNP-BC, FAANP, FAAN, FNAP: I present that very similarly. What I tell them is the DORAs are going to put you to a gentle sleep. They’re going to turn off that wakefulness center to get you to be able to go to sleep about 30 minutes sooner than you would normally with insomnia. I also say to them unlike the other drugs—I’ll joke and say they’ll put you in a coma, but they really do hit people. My fear is that those drugs based on the trials really do alter the sleep architecture. It’s 1 thing to be knocked out, but if you’re never getting into that restorative sleep is that why people wake up the next day feeling so sedative? Is it the half-life of the drug? Is it the drug itself? Or maybe a combination of all of the above? But I find with the DORAs there’s less of that hangover effect because they’re in quickly and they’re out quickly so that people can then wake up and it’s just much more of a gentle sleep.

Debra Davis, CRNP: They do get into that REM [rapid eye movement] sleep is what you want. REM sleep is when the acetylcholine makes memories attached to your brain. So many times, people come to me and they’re perimenopausal or menopausal, and they’re like, “I can’t remember anything. I can’t remember what my daughter told me yesterday. Do you think I have dementia?” “I don't think you have dementia. I think you’re not getting into REM sleep. I think you’re not getting the proper acetylcholine that you need to form memory and I don’t think that’s your problem. Let’s talk about your sleep architecture.”

Wendy L. Wright, DNP, ANP-BC, FNP-BC, FAANP, FAAN, FNAP: Excellent.

Transcript edited for clarity

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