Prescription Sleep Aids (Midterm II) Flashcards
what are hypnotics?
- any agents that help us fall asleep; used to treat insomnia
- the first was alcohol (tho arguably not a hypnotic if you’re just drinking so much that you literally pass out, and also doesn’t give a healthy sort of sleep), then the barbiturates (which did help you sleep, but had an incredible narrow therapeutic window)
- the newest generation has an improved safety profile, but less than ideal characteristic still linger
signals involved in the sleep/wake cycle
histamine: if receptor antagonists penetrate into the brain, they can disrupt the sleep/wake cycle
GABA: enhancing its action suppresses neuronal excitability
Orexin: an unusual peptide that seems to be linked to sleep/wake cycles
Adenosine: no true prescriptions for these systems, but we know that caffeine interrupts them to keep you awake
Melatonin: contradictory, so a less popular intervention, but available OTC
hypnotics and the sleep cycle
- for healthy sleep, we should be going through all cycles (drowsy alpha waves, stage one theta waves, stage 2 sleep spindles and k complexes, high amp. stage 3/4 delta waves, REM (low voltage, fast, and random saw-toothed waves))
- hypnotics don’t perfectly replicate this (ex benzos suppress REM and increase stage 2, but also have a rebound effect in discontinuation causes increased REM, leading to nightmares and vivid, disturbed dreams)
alcohol: hypnotic profile
- not an appropriate treatment due to inebriation, addiction, and organ damage
- while they do decrease the time it takes to fall asleep (onset), the dropping of BAC during the night ultimately leads to poor quality sleep
chloral hydrate
- chlorinated ethanol, a old hypnotic
- the original knock-out drops; was often used in robberies that turned into murders (narrow therapeutic index made it very dangerous)
hypnotics: targeting the gaba system
ex. barbiturates, benzodiazepines
- drugs that target these systems are positive allosteric modulators of certain GABA-AR, and potentiate the agonist effects of GABA at its own A receptors
- this allows even more Cl to enter through the intrinsic ion channel, hyperpolarizing neurons and dropping excitability, sometime in centres involved in sleep/wake
barbiturates
eg. pentobarbital
- allosteric modulator that binds to the transmembrane region of the GABA-AR, increasing the length of time the channel stays open
- once the most popular/common hypnotic, has now been largely replaced by benzos; danger that at high conc, it can instead directly activate the channel even in the absence of GABA which can cause respiratory depression via brainstem receptors
- linked to a number of high-profile deaths (munroe, hendrix) due to cocktail potentiation
- also used as a truth serum
benzodiazepines
eg. trazolam (halcion)
- allosteric modulators that bind at the alpha-gamma interface of GABA-AR to increase frequency of channel opening when GABA binds
- unlike barbiturates, don’t directly activate the channel at high doses bc they have a different binding site
- better safety profile that barbiturates (few ODs solely attributed to benzos), but still dangerous if used w alcohol
- also highly selective for gaba-a (show no affinity for glycine receptors which are structurally and functionally similar, or on Glue receptors either)
- can be useful for treating anxiety and convulsions due to ability to decrease neuronal firing (only in acute emergency tho normally, bc tolerance develops rapidly)
flumazenil
-a benzodiazepine antagonist; sometimes administered when someone ODs on hypnotics in an attempt to reverse depressed breathing (tried to do that for micheal jackson)
pharmacokinetics of BZs
- older BZs have long half lives, often with active metabolites too
ex. the half life of diazepam is 30-56 hrs, and that of its active metabolite nordazepam is up to 7 days - this leads to daytime impairment, making them kinda shitty drugs for treating insomnia; new drugs are designed for rapid metabolism and a shorter duration of action
triazolam (halcion)
- perhaps the most common current hypnotic, triazolam is a newer, short acting BZ (ultra short half life of only ~2 hrs, meaning it should be cleared by the time you wake)
- it potentiates the effects of GABA at the A receptor, speeding up sleep onset, but is too short-acting to be suitable to nighttime/early waking issues
- structure based on earlier BZs, but tweaked so the liver enzymes will metabolize it rapidly w/o forming any active products
- causes daytime memory impairment and lingering problems in consolidation, esp at higher doses
- banned in UK due to a number of links to violence, including murder
BZ issues
- there are many different GABA-ARs that bind BZs, and BZs aren’t particularly selective for any one kind
- some of these are hippocampal receptors, leading to issues in memory formation and storage
- they also interfere with REM sleep which is involved in memory consolidation
- bc BZs are infamous for preventing memory of events while UTI, they are used during surgeries or invasive procedures, but also assaults
- can see rebound insomnia, in which sleep quality is temporarily worse than baseline following discontinuation
- addiction and dependence are also risks (thought that 5-10% of ppl who use may develop a problematic relationship)
the Z-drugs
- zaleplon, zolpidem, zopiclone (whose s enantiomer, eszopiclone, is lunestra)
- BZ like drugs marketed as hypnotics that don’t cause tolerance or have risk of addiction (by and large false claims)
- have short half lives (1, 2.5, 6 hrs respectively)
- don’t have classic BZ structure, but bind the same site at GABA-AR, and work only when GABA is present
- carry risk or parasomnia (leaving home, driving, eating, committing crimes, etc w/o any memory/apparent knowledge of the events); maybe putting you in a pseudosleep state where you act out your dreams
- possibly less REM rebound as this stage doesn’t seem to be suppressed to the same degree
- diff side effect profiles may be due to some selectivity towards specific GABA-AR types
orexins
- A and B peptides made and secreted by neurons in the hypothalamus; important signals in control of the sleep/wakefulness cycle and are largely involved in wakefulness and vigilance
- highest lvls occur during wake, and lowest during sleep; blocking their receptors promotes sleep onset and maintenance
suvorexant (belsomra)
- the first “successful” orexin receptor antagonist and mimicked a low orexin state
- originally rejected at initial proposed marketed doses due to safety concerns from next-day somnolence (being too tired to do anything at all the next day)
- the current approved version is a lower dose, but effects are really clinically week (compared to placebo, users only fell asleep 6 min faster, slept 16 minutes longer, and still complain of feeling tired the next day); critics feel it shouldn’t have been approved
