ICL 8.6: Psychopharmacology of Sleep Flashcards
what is primary insomnia?
- too much arousal during the night and day
- not feeling sleepy despite not sleeping at night
- most of the medications are studies with primary insomnia –> most medications are tested in people who have primary insomnia, not secondary insomnia from a psychiatric disorder
- studies with depression and anxiety show better remission rates
- treat chronic insomnia chronically- long term treatment
which FDA drugs are used for insomnia?
- benzodiazepines (flurazepam, temazepam, triazolam)
- nonbenzodiazepine (zolpidem, eszopiclone, zaleplon) = 3Zs of sleep
- orexin-receptor antagonist (suvorexant)
- melatonin receptor agonists (ramelteon)
- antidepressants (doxepin)
what are H1 receptors?
G protein coupled- phosphatidyl inositol and transcription cFOS
responsible for wakefulness, alertness and precognition
blockage of H1 receptors causes drowsiness, sedation or sleep
this is why antihistaminergics are sedatives
what are H2 receptors?
action on gastric acid secretion
G protein coupled- phospholipase A and transcription CREB
what are H3 receptors?
presynaptic, auto receptors-inhibition of histamine release
no known drug-clinical developmental stage
what is the main nucleus that releases histamine?
tuberomammillary nucleus in the hypothalamus
which drug types of histamine H1 antagonists?
- popular over the counter drugs, diphenhydramine
2. tricyclic antidepressants
what are the side effects of TCAs?
anticholinergic side effects = blurred vision, constipation, memory, dry mouth, hangover
it causes histamine blockage –> difficult to separate antihistamine actions from antimuscarinic, and or alpha blockage
ex. amitriptyline (elavil)
what is doxepin?
doxepin at low doses is a potent H1 blocker (1-6 mg) –> if you up the doge to 150-300 mg it can have antidepressant action
so it causes rapid sleep induction with all-night sleep maintenance without hangover
no tolerance or withdrawal; no weight gain –> H1 blockers usually only cause weight gain if they’re also paired with something that blocks serotonin
which drugs are benzodiazepine receptor agonists?
- zolpidem
- zaleplon
- eszopiclone
3Zs of sleep
what are the benefits of using benzodiazepine receptor agonists?
- fewer hangover symptoms than benzodiazepines
- fewer problems with dependency, though still an issue
- do not show deleterious effects to the sleep cycle
- generally a longer half-life than benzodiazepines so help with sleep maintenance
one is approved for long-term use: Eszopiclone (but the others have open label studies)
which subunits of the GABA(A) receptor do benzodiazepines interact with?
BZDs interact at the α 1, 2, 3 and 5 subunit
zolpidem, zaleplon and eszopiclone are positive allosteric modulator (PAM) of GABAA receptor, at the alpha 1 subunit –> this selectivity may be why there is a lower risk of dependence
what is the function of the α1 subunit in the GABA(A) receptor?
α1 is critical for sedation
also linked to daytime sedation, anticonvulsant and amnesia
what is the function of the α2 and α3 subunit in the GABA(A) receptor?
- anxiolytic
- muscle relaxant
- alcohol potentiating
what is the function of the α5 subunit in the GABA(A) receptor?
hippocampus- cognition and other function
what are melatonergic hypnotics?
melatonin is neurotransmitter secreted by pineal glad that acts on SCN
they help restore circadian rhythm and help with phase delay
can be used in depressed patients, teenagers and people with jet lag
melatonergic hypnotics work at the M1, M2 and M3 receptors
which drugs are melatonergic hypnotics?
- agomelatonin (antidepressant) (M1, M2 and 5HT2B, 5HT2C)
- melatonin (M1, M2, M3)
- Ramelton (M1/M2 agonist)
- tasimelteon (M1/M2)
they shift circadian rhythm and help with phase delay
what’s the different between M1 and M2 melatonin receptors?
M1 mediated inhibition of neurons at SCN promotes sleep-lowering alerting signals of SCN
found in brain / pituitary / supra-chiasmatic nuclei of hypothalamus; Associated with circadian rhythm and reproductive functioning
M2: phase shifting and circadian rhythm-SCN
found in the retina
what is the MOA of ramelteon?
rozerem selectively binds both MT1 and MT2 and is an agonist
helps with sleep initiation insomnia
what is trazodone?
a serotonergic hypnotic but it’s used as a sleep medication!
to work as antidepressant high doses are needed to recruit 5HT2A and serotonin reuptake blocking properties
sedating action is due to H1 antihistamine and α antagonism
by giving it at night and lowering dose H1 antihistamine and α blocking and 5HT2A are retained.
which antidepressants are commonly used as sedatives?
- amitriptyline (used with pts. who also have pain)
- trazodone (used with pts. who also have MDD or hypotension)
- doxepin/silenor (sleep maintenance insomnia)
- mirtazepine
what is mirtazepine?
an antidepressant used for sleep that works on noradrenergic and serotonergic receptor
smaller doses used for depression
significant weight gain**
what are orexin antagonists?
orexin neurons are located on lateral hypothalamus, perifornical area and posterior hypothalamus
orexin A and orexin B keep you awake –> orexin 2 activates TMN histaminergic neurons
lack of orexin causes narcolepsy!
what are DORAs?
DORA = dual orexin receptor antagonists
DORAs are orexin receptor antagonists at orexin 1 and 2 receptors
can also be used for drug abuse and weight loss
helps with initiation and maintenance of sleep without the benzodiazepines side effects; but in theory it could cause narcolepsy since you’re blocking orexin but it doesn’t actually happen in practice oddly enough
ex. Almorexant, Suvorexant (Belsomra)
