Sleep disorders

Question 1

Describe the nature of the normal sleep cycle

Answer 1

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.

Question 2

Describe the role of NREM sleep

Answer 2

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.

Question 3

Describe NREM sleep

Answer 3

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.

1. Stage N1: The lightest stage of sleep, lasting a few minutes, characterized by slow eye movements and reduced muscle activity.
2. 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.
3. 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.

Question 4

Describe the role of REM sleep

Answer 4

REM sleep has roles in memory, learning and creativity

Question 5

Describe REM sleep

Answer 5

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.

Question 6

State the brain regions important to sleep and sleep/wake cycle

Answer 6

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.

Question 7

Which region of the brain promotes sleep

Answer 7

Raphe nuclei

Question 8

Which region of the brain is active during wakefulness

Answer 8

Locus coeruleus

Question 9

State important sleep disorders

Answer 9

• 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

Question 10

Define Insomnia

Answer 10

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)

Question 11

Discuss how insomnia disrupts the normal sleep cycle

Answer 11

• 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.

Question 12

State potential treatment options for insomnia

Answer 12

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

Question 13

Describe the mechanism of Benzodiazepines and Z drugs

Answer 13

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

Question 14

what are some considerations for using benzodiazepines as hypnotics

Answer 14

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

Question 15

Which benzodiazepines are typically prescribed/used for insomnia?

Answer 15

Lormetazepam and temazepam

Question 16

List examples of Z-drugs

Answer 16

Zolpidem and Zopiclone

Question 17

Why are Z-drugs more advantageous than benzodiazepines?

Answer 17

Z-drugs are designed to exploit the beneficial hypnotic properties of benzodiazepine, but with fewer adverse effects.

Question 18

How/where do Z-drugs bind?
What influences binding?

Answer 18

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)

Question 19

Benzodiazepines versus Z-drugs

Answer 19

• 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)

Question 20

List findings from behavioural pharmacology studies of benzodiazepines and Z-drugs

Answer 20

• 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

Question 21

Give examples of alternative therapies for insomnia

Answer 21

Eszopiclone: S-enantiomer of zopiclone developed for a more favourable PK and side-effect profile.

Dual orexin receptor antagonist (DORA): Suvorexant

Question 22

Describe orexins

Answer 22

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.

Question 23

Describe the mechanism of Dual orexin receptor antagonists (DORA)

Answer 23

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.

Question 24

Suvorexant

Answer 24

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.

Question 25

List some critical evaluation points (Insomnia pharmacology)

Answer 25

• 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.