Flashcards in Sleep and Pharm of Sleeping Meds Deck (27):
What are the two major categories of sleep?
• REM and nonREM
what are the 3 stages of nonREM sleep?
*remember, sleep is either REM or nonREM
§ Stage 1: Transition phase from being awake to falling asleep. EEG like wakefulness (α rhythm), then begins to slow down along with muscle activity. People in stage 1 may experience falling sensations, followed by sudden muscle jerks.
§ Stage 2: Light sleep; short, fragmented thoughts, EEG slower with bursts of rapid waves (sleep spindles); 50% of total.
*Slow Wave Sleep (SWS - formerly stages 3 and 4): EEG very slow (delta sleep). Deepest level of sleep (described as “best”) - most difficult stage to arouse person from and people are often groggy several minutes after awakening. Stage where somnambulism, night terrors, and nocturnal enuresis can occur.
What characterizes REM sleep?
§ REM: Active period of sleep with intense brain activity - EEG rapid and desynchronized similar to waking state. Occurrence of rapid eye movements, decreased muscle tone, increased blood pressure, pulse, and respiration. Stage of most recallable dreams.
What is sleep architecture? How does it change throughout the night?
Sleep architecture refers to the predictable alteration (right mix) of REM and NREM throughout the night.
*NREM (70-75%) and REM (25-30%) occur cyclically over 90-110 minutes (4-5 times per night).
*The first cycles each night contain short periods of REM and larger amounts of slow wave sleep. REM sleep increases throughout the night and by morning nearly all sleep is stages 1-2 and REM.
The three Z drugs are closest to the ideal hypnotic. But what would that perfect drug do?
· Should rapidly induce sleep (influenced by drug absorption)
· Duration sufficient to maintain sleep during night, but no morning “hangover” (influenced by half-life)
· Repeated use should not result in dependence or tolerance
· Abrupt discontinuation should not lead to rebound insomnia (influenced by duration of action [t1/2])
· High therapeutic index
Should normalize disturbed sleep without disturbing normal sleep
Sedative-Hypnotics can be used as therapy for sleep. However, they are nowhere near ideal. Why is that?
· Decrease latency of sleep onset (useful effect to promote onset)
· Increase duration of stage 2 sleep (useful effect for maintenance of sleep state)
· Decrease of delta sleep (deleterious effect), esp. barbiturates. (Less with flurazepam or zolpidem / zaleplon).
· Decrease duration of REM sleep (cause of REM rebound on withdrawal leading to increases in nightmares) (deleterious effect), esp. barbiturates. (Less with flurazepam, temazepam, minimal with zolpidem / zaleplon / eszoplicone).
Use for longer than 1 week generally leads to tolerance, esp. barbiturates. (Less with flurazepam, minimal with eszopiclone / zolpidem / zaleplon).
Why might antimuscarinics have an effect on sleep?
• They have effects on the pedunculopontine tegmental area cholinergic neurons
• These are active during REM and awake states
• Thus anti-muscarinics would end up suppressing REM sleep
• Muscarinic agonists activate REM
The dorsal Raphe nuclei are important for sleep how?
• these are serotonergic neurons
• active in awake
• reduced in NREM
• decrease REM on
Thus antidepressant SSRI, SNRI, TCA will increase 5HT and decrease REM
The locus ceruleus is important for sleep how?
• • Super similar to the dorsal raphe nuclei in sleep function
• these are norepinephrine using neurons
• • active in awake
• • reduced in NREM
• • decrease REM on
• Thus antidepressant SSRI, SNRI, TCA will increase 5HT and decrease REM
The ventral tegmental area (VTA) is important for sleep how?
• These are dopaminergic neurons
• Active in awake
• Increase REM off
• Thus amphetamines or methylphenidate will increase DA release and promote wakefulness
• Whereas antipsychotics will block DA and result in sedation
What is the VLPO in the brain and why is it important for sleep?
*it is part of the circadian rhythm generator
*The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain of humans and other animal
*The VLPO, together with the reticular activating system and the widely projecting orexin neuronal system that originates in the lateral hypothalamus, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states
The posterior hypothalamus is involved in sleep how?
• These are histamine neurons
• Active in awake
• Decreased when the VLPO releases GABA on them)
• They are reduced during NREM
• They are OFF during REM
• Thus antihistamines will promote drowsiness and sleep
The lateral hypothalamus is involved in sleep how?
• These neurons use the NT orexin
• Active in awake
• During awake they excite NE/5HT REM off neurons
• They are OFF during nREM
• Unknown REM activity
• Orexin antagonists like suvorexant will promote sleep by blocking excitatory actions of orexin on NE-5HT neurons
The anterior hypothalamus is involved in sleep how?
• These are GABAergic neurons
• OFF in awake
• Active in NREM
• Decreased by histamine
• Decreased by orixin
• Reduced activity in REM
• Thus, benzodiazepines enhance GABA and promote sleep onset/continuity
The basal forebrain is involved in sleep how?
• These neurons use adenosine
• Decreased cholinergic arousal centers during awake
• Thus caffeine, which is an adenosine agonist, increases alertness
What experiences qualify a patient for a dx of insomnia disorder?
(1) Difficulty in initiating sleep, maintaining sleep, or waking up too early
(2) that occurs despite adequate opportunity and circumstances for sleep and
(3) such impaired sleep produces deficits in daytime function
Which sleep drugs end up binding the same site on the GABA-a channel?
• Flumazenil (antagonist for the other two)
What does the binding of benzodiazepines and the one Z-drug that binds the same subunit of the GABA-a receptor due to the channel and neuron?
Binding of benzodiazepines (or non-BDZs like zolpidem) to the gamma subunit or an to an area of the alpha subunit influenced by the gamma unit facilitates the process of GABA channel opening, but does NOT directly initiate chloride current as does higher levels of barbiturates.
*this translates to the notion that Benzos will modulate the frequency of the GABA-a channel opening while barbiturates, which dont' bind this site, prolong the TIME the channel is open
GABA receptors in different parts of the Nervous System express different combinations of subunits. How can this be of use clinically?
*targeting the different receptor subunit combinations to give more targeted (less diffuse) effects
*§ GABA receptors with α1 subunits are highly expressed in the cortex and these receptors appear to mediate sedative (sleep), amnestic, and anticonvulsant actions of benzodiazepines
*GABA receptors with α2/α5 subunits are highly expressed in the limbic system / and brain stem and these receptors appear to mediate myorelaxant, motor impairing, anxiolytic, and ethanol-potentiating effects of benzodiazepines
What are the Z drugs and why are they more targeted for sleep than benzodiazepines?
“Z-drugs” (zolpidem, zaleplon, eszopiclone) are non-benzodiazepines - bind only to GABA-chloride channels with α1 subunits resulting in sleep without anxiolysis (reduced potential for dependence)
What's up with Triazolam?
· Triazolam (Halcion). Eliminated within 1 dosing cycle (t1/2: 1.5-5 hrs), less daytime sedation (hangover), use cautiously in elderly with dose reduction, rapidly absorbed. Can see rebound insomnia next day due to rapid elimination. Rapid oral absorption.
*remember the short-acting benzos have the "olam" at the end
What's up with Temazepam?
· Temazepam (Restoril). Intermediate t1/2 (9-13 hrs), slowly absorbed, peak concentration at 2-3 hrs, thus minimal effect on latency to sleep onset
What's up with flurazepam?
· Flurazepam (Dalmane). Long t1/2 with active metabolite (75-90 hrs), see effect at same dose for 28 consecutive days (i.e., little tolerance).
*Can accumulate in elderly due to impaired hepatic clearance leading to daytime sedation (“hangover”) / overdosage (t1/2 extended to 120-160 hrs).
What is important to note about the dangers of sleeping pills?
BLACK BOX WARNING for all members of this class relating to occurrence of strange sleep-related behavior and severe allergic reactions (anaphylaxis and facial swelling).
A. “Z”-Drugs (Nonbenzodiazepine Benzodiazepine “Receptor” Agonists). Like benzodiazepines, they are Schedule IV controlled substances.
The Z drugs in particular come with what warnings?
§ May have significant effects on next-day psychomotor performance, including driving. More likely with higher doses and longer half-life agents (eszopiclone)
§ Complex sleep-related behaviors such as sleep-walking, sleep-eating, and sleep-driving can occur without conscious awareness.
*Risk of such behaviors is increased with higher doses, use at times other than bedtime, and taking with other sedating drugs.
*Rebound effects and withdrawal and tolerance with prolonged use appear minimal, but are possible.
What sleep aids can cause anterograde amnesia?
· Anterograde amnesia is more frequent with triazolam than with temazepam. Triazolam is associated with a higher rate of confusion, bizarre behavior, agitation, and hallucinations. Emphasize use of lowest effective dose.