Sleep disorders Flashcards
Describe the nature of the normal sleep cycle
The sleep cycle consists of two primary stages Rapid Eye movement (REM) sleep and Non-rapid Eye movement (NREM).
A complete sleep cycle takes approximately 90 – 110 minutes. A typical night’s sleep consists of 4 to 5 sleep cycles.
Describe the role of NREM sleep
NREM sleep has a role in recuperation of the body
NREM sleep serves essential physical and mental functions such as aiding in memory consolidation, physical growth and repair of body tissues, particularly during the period of deep sleep that occurs in stage 3.
Describe NREM sleep
Non-rapid Eye movement (NREM) is divided into stages 1,2,3 (4)
NREM stage 1: acts as a transition between wakefulness and the deeper stages of sleep. During stage 1, brain waves begin to slow. Breathing, heartbeat, and body movements are also slow. While muscles become more relaxed. Stage one is the briefest stage of sleep, lasting just five to 10 minutes.
Brain activity on the EEG in stage 1 transitions from wakefulness (marked by rhythmic alpha waves) to low-voltage, mixed-frequency waves.
NREM stage 2: characterised by slowed body activity and decreased awareness.
During this stage, the brain produces two distinct patterns of brain waves; sleep spindles (short spikes in brain activity) and K-complexes (sharp waves).
Stage 2 lasts approximately 10 to 25 minutes in the initial cycle and lengthens with each successive cycle, eventually constituting between 45 to 55 percent of the total sleep episode.
*sleep spindles are important for memory consolidation
NREM stage 3 (and 4): Slow-wave sleep
Mostly occurs during the first third of the night. Each has distinguishing characteristics. Stage 3 lasts only a few minutes and constitutes about 3 to 8 percent of sleep. Stage 3 is characterised by delta waves.
Stage 4 lasts approximately 20 to 40 minutes in the first cycle and makes up about 10 to 15 percent of sleep. The arousal threshold is highest for all NREM stages in stage 4. This stage is characterized by increased amounts of high-voltage, slow-wave activity.
- Stage N1: The lightest stage of sleep, lasting a few minutes, characterized by slow eye movements and reduced muscle activity.
- Stage N2: A deeper sleep stage where eye movements stop, heart rate slows, and body temperature drops. Sleep spindles and K-complexes are seen in EEG recordings.
- Stage N3: Also known as slow-wave sleep (SWS) or deep sleep, marked by delta waves in EEG. It is the most restorative stage, essential for physical and mental recovery.
Describe the role of REM sleep
REM sleep has roles in memory, learning and creativity
Describe REM sleep
During the initial cycle, the REM period lasts only 1 to 10 minutes, however, it becomes progressively prolonged as the sleep episode progresses and makes up 25% of total sleep time.
REM sleep is associated with dreaming and memory consolidation.
State the brain regions important to sleep and sleep/wake cycle
The reticular activating system. This contains the:
- Locus coeruleus
- Raphe nuclei
The Suprachaismatic nucleus regulates sleep-wake cycle (it projects to pineal where levels of melatonin peak at night)
The hypothalamus is important in sleep regulation:
* The lateral hypothalamus: orexin (hypocretin - neuropeptide) promotes wakefulness when it connects with sleep/wake pathways such as the Raphe nuclei and locus corelus.
Which region of the brain promotes sleep
Raphe nuclei
Which region of the brain is active during wakefulness
Locus coeruleus
State important sleep disorders
- Insomnia: difficulty in falling or remaining asleep that impairs daytime functioning (affects up to 1/3 of adults) – can be sleep onset, sleep maintenance or mixed. Causes include stress, pregnancy, premenstrual syndrome. May co-exist with other conditions (eg depression, anxiety)
- Narcolepsy: a severe and persistent daytime sleepiness
- Sleep apnoea: a sleep related breathing disorder
- Restless leg syndrome: uncomfortable feelings in the legs with symptoms becoming worse when inactive
Define Insomnia
difficulty in falling or remaining asleep that impairs daytime functioning (affects up to 1/3 of adults) – can be sleep onset, sleep maintenance or mixed. Causes include stress, pregnancy, premenstrual syndrome. May co-exist with other conditions (eg depression, anxiety)
Discuss how insomnia disrupts the normal sleep cycle
- insomnia prevents entry into deeper stages of sleep, reducing restorative benefits.
Insomnia disrupts the normal sleep cycle by causing difficulty in falling asleep, frequent awakenings, and reduced time in deep sleep (NREM stage 3) and REM sleep. This results in fragmented sleep, preventing the progression through the necessary sleep stages for physical and mental restoration. Consequently, individuals with insomnia experience impaired cognitive function, emotional instability, and physical health issues due to the lack of restorative sleep.
State potential treatment options for insomnia
Optimising sleep hygiene: promoting an environment that allows an individual to fall asleep and remain asleep.
Light therapy, herbal remedies (Valerian), Cognitive behavioural therapy
Hypnotics: Z-drugs, Benzodiazepines and melatonin
Describe the mechanism of Benzodiazepines and Z drugs
Benzodiazepines and Z drugs potentiate GABA-ergic activity.
GABA is an inhibitory neurotransmitter.
Benzodiazepines and Z drugs are allosteric modulators
It binds at BDZ site to potentiate action at GABA binding site,
GABA binds opening of chloride ion channel CL plugs into the cell, hyperpolarising it.
Therefore, it is less likely to be excited, dampening down activity within target cell that has a GABA-a(?) receptor
what are some considerations for using benzodiazepines as hypnotics
NICE guidelines recommend that these are prescribed short-term for insomnia. Due to side effects (+ withdrawal symptoms)
Relatively short duration of action is preferable (for insomnia, unlike anxiety)
E.g. Lormetazepam and temazepam (have a shorter duration of action, no hangover)
Whereas flurazepam and nitrazepam have a longer duration of action.
Benzodiazepines reduce sleep latency
However, disrupt sleep architecture, which reduces REM sleep
Which benzodiazepines are typically prescribed/used for insomnia?
Lormetazepam and temazepam
List examples of Z-drugs
Zolpidem and Zopiclone
Why are Z-drugs more advantageous than benzodiazepines?
Z-drugs are designed to exploit the beneficial hypnotic properties of benzodiazepine, but with fewer adverse effects.
How/where do Z-drugs bind?
What influences binding?
zolpidem: binds to the α1 subunit
zopiclone: binds to the alternate site
Binding can be influenced by overall subunit combination of GABAA receptor (eg γ subunit type)
Benzodiazepines versus Z-drugs
- Both have adverse effects
- All have abuse potential
- All have potential for rebound insomnia
- All can cause amnesia and block memory consolidation (benzodiazepines worse than Z drugs because of effect on REM sleep)
- Greater suicidal risk with benzodiazepines
- Impaired driving performance with both (enough to warrant advice from the EMA and FDA)
- Falls are an issue (especially in the elderly)
List findings from behavioural pharmacology studies of benzodiazepines and Z-drugs
- EEG studies in rodents show that zolpidem causes less REM disruption than triazolam
- Tolerance to both benzodiazepines and Z drugs develops resulting in rebound EEG changes
- Zolpidem causes motor impairment in open field tests, but less effect on grip strength than benzodiazepines
- Zolpidem has similar reinforcing effects to benzodiazepines
Give examples of alternative therapies for insomnia
Eszopiclone: S-enantiomer of zopiclone developed for a more favourable PK and side-effect profile.
Dual orexin receptor antagonist (DORA): Suvorexant
Describe orexins
Orexins (OXs/ hypocretins) are excitatory neuropeptide hormones produced by neurons in the lateral hypothalamus. Orexins hormones are categorised into two types, A (OXA) and B (OXB), which bind to their specific G-protein coupled receptor, orexin receptor type 1(OX1R) and orexin receptor type 2 (OX2R). This interaction promotes locomotor activity, behavioural arousal, and wakefulness.
Describe the mechanism of Dual orexin receptor antagonists (DORA)
Dual orexin receptor antagonists (DORA) inhibits binding of orexin A and B to OX1R and OX2R. Thus, Inhibiting the neurons that control wake-promoting regions of the brain such as the lateral hypothalamus, locus coeruleus, and the dorsal raphe nucleus. DORA inhibits arousal-promoting neuropeptides, inducing sleep.
Suvorexant
Suvorexant is a selective dual orexin receptor antagonist (DORA) for the treatment of sleep onset and sleep maintenance insomnia. Suvorexant inhibits binding of orexin A and B to OX1R and OX2R. Thus, Inhibiting the neurons that control wake-promoting regions of the brain such as the lateral hypothalamus, locus coeruleus, and the dorsal raphe nucleus. Suvorexant is effective for insomnia management.
List some critical evaluation points (Insomnia pharmacology)
- Pharmacotherapy is often a secondary option due to potential side effects, risk of dependence, and altered sleep architecture.
- Cognitive Behavioural Therapy for Insomnia (CBT-I) is considered first-line treatment.
- Long-term use of medications should be closely monitored and combined with non-pharmacological strategies.
