Lecture 14 Sleep Disorders and Sleep Medications

Question 1

What are the stages of sleep grouped into?

Answer 1

Non-REM sleep and REM sleep

Question 2

What are the characteristics of non-REM sleep?

Answer 2

• Reduced muscle tension throughout body
• Minimal movement – body capable of movement, but brain rarely sends motor commands
• Some mentation
• Reduced body temperature, metabolism, heart rate, respiration
• Divided into Stages 1-4 (1=light sleep, 4=deep sleep)

Question 3

What are the characteristics of REM sleep?

Answer 3

• Rapid eye movements
• Dreaming
• EEG/brain activity high (almost indistinguishable from that of being awake)
• Increased and irregular heart rate & respiration
• Skeletal muscle atonia

Question 4

What are three mechanisms to measure sleep cycles?

Answer 4

• Electroencephalogram (EEG)
• Electromyogram (EMG)
• Electrooculogram (EOG)

Question 5

Atonia

Answer 5

Little control of muscles, muscles have lost their strengths.

Question 6

What can occur to sleep stages as people age?

Answer 6

The sleep patterns are altered and sleep gradually decreases throughout age

Question 7

Name the 2 orexin peptides and what are they also referred to?

Answer 7

Orexin A and orexin B

They are also called hypocretins

Question 8

What are the pharmacological treatments of insomnia?

Answer 8

• Barbituates
• BZPs
• Non-BZP hypnotics
• Antihistamines
• Melatonin
• Orexin receptor agonists

Question 9

Name a few non-BZP hypnotics

Answer 9

• i.e., zolpidem (Ambien), eszopiclone (Lunesta), zaleplon (Sonata), etc.
• Chemically distinct from benzodiazepines but act in the same manner, generally with short half-lives

Question 10

How do BZPs work?

Answer 10

Primarily act as positive allosteric modulators at GABA(A) receptors to suppress general neuronal activity

Question 11

What is a danger of BZPs?

Answer 11

Daily use of long half-life BZPs can result in drug accumulation and toxicity. i.e. Flurazepam (Half life 24-150 hours)

Daily use of moderate half-life BZPs can result in daytime “hangover” i.e. estazolam & temazepam (Half life 15-30 hours)

Question 12

Whats an issue with hypnotics?

Answer 12

Hypnotics with short half-lives can wear off in the middle of the night
i.e. ambien (half life 1-3 hours)

Question 13

What is the ideal hypnotic half life?

Answer 13

approximately 6 hours

Lunesta, zolpidem CR

Question 14

What is melatonin and where is melatonin synthesized and secreted?

Answer 14

Meltonin is a hormone and is produced andsecreted in the pineal gland

Question 15

Where does melatonin act?

Answer 15

• Acts in suprachiasmatic nucleus (SCN) to regulate biological rhythms
• Has 3 receptors (MT1-MT3); MT1 and MT2 are thought to be involved in sleep regulation

Question 16

What are some melatonin analogues?

Answer 16

ramelteon, tasimelteon and agomelatine

Question 17

How do antihistamines create drowsiness

Answer 17

• Cause drowsiness by blocking histamine H1 receptors

- Also block M1 mAChRs to cause anticholinergic effects (blurred vision, amnesia, dry mouth, constipation)

Question 18

What is a common active ingredient in most antihistamines for sleep?

Answer 18

Primary active ingredient in most antihistamines (i.e., Benadryl) is diphenhydramine

Question 19

How many orexins receptors are there and what are the names?

Answer 19

2

OX1R & OX2R

Question 20

What does SORA and DORA stand for?

Answer 20

Single orexin receptor antagonists (SORA1/SORA2) & dual orexin receptor antagonists (DORA)

Question 21

What receptors is caffeine active at?

Answer 21

-Caffeine is an antagonist at adenosine receptors

Question 22

Explain caffiene’s action?

Answer 22

• Adenosine is an endogenous neurotransmitter that acts on adenosine (also called purine) receptors (A1, A2, A3), and normally reduces neuronal activity
• Adenosine receptors share similar signal transduction cascades with D2 receptors and are often physically linked
• When adenosine binds to its receptors, it inhibits the binding of dopamine to its receptors
• Caffeine is an antagonist at adenosine receptors, so when it blocks adenosine receptors, dopamine can bind to its receptors and cause stimulatory effects

Question 23

What are the symptoms of narcolepsy

Answer 23

-Intrusive sleep attacks
-Excessive daytime sleepiness regardless of amount of sleep obtained
-Cataplexy (sudden muscular paralysis while conscious, triggered by emotion, surprise or laughter)
-Sleep paralysis (awakening while REM atonia is still occurring)
Hypnagogic hallucinations (dream-like mental activity due to immediate onset of REM sleep)
-Automatic behavior (doing without thinking)

Question 24

What is the cause of narcolepsy and when does it usually develop?

Answer 24

Due to genetic loss of orexin

Usually develops between ages of 7 and 25

Question 25

What are the treatments of narcolepsy?

Answer 25

• Excessive daytime sleepiness is treated with stimulants such as amphetamines, Ritalin, Provigil
• Cataplexy is treated with antidepressants or sodium oxybate (GHB, Xyrem), a non-selective GABA agonist

Question 26

Narcolepsy and swine flu

Answer 26

A dramatic rise in the number of people <20 yrs old diagnosed with narcolepsy was observed in some European countries where the swine flu (H1N1) vaccination Pandemrix was given.

A 2013 study showed that the vaccine (possible in combination with the adjuvant) caused immune cells to generate antibodies against orexin

Question 27

What is cataplexy?

Answer 27

sudden muscular paralysis while conscious, triggered by emotion, surprise or laughter

Question 28

What are hypnagogic hallucinations?

Answer 28

dream-like mental activity due to immediate onset of REM sleep