PHR 936 - Block 1 Sleep

functions of sleep

metabolism

learning & memory

cardiovascular health

emotional regulation

immune function

brain health

hippocampal-cortical memory consolidation

occurs during sleep

memories are moved from short-term, low capacity storage into long-term, high capacity storage

- this solidifies memories after learning and opens storage space in the hippocampus for new memories

consequences of sleep deprivation

decreased immune function

- increased risk of infections

- potential increase risk of cancer

- inflammatory neurodegenerative diseases

- autoimmune diseases

- inflammatory metabolic & vascular disease

- decreases vaccine response

- decreased number of NK cells

risk for mental illness

buildup of toxins/ waste products

NREM stage 1

the initial stage of NREM sleep, which is characterized by low-amplitude brain waves (4-6 Hz) of irregular frequency, a slow heart rate, and reduced muscle tension

- lasts 5-10 minutes

- transition period between wake and sleep

NREM stage 2

the start of true sleep

body temperature drops & heart rate slows

brain begins to produce sleep spindles

- lasts 20 minutes

NREM stage 3

deepest sleep occurs

muscles relax, breathing rate drops

REM sleep

rapid eye movement sleep, a recurring sleep stage during which vivid dreams commonly occur

body becomes relaxed & immobilized

brain becomes more active

circadian rhythm

Process C

"about a day"

homeostatic process informed by outside environment

melatonin

a hormone secreted by the pineal gland, regulated by the SCN

- MT1 receptors: entrainment to light-dark cycles

- MT2 receptors: phase-shifting

functions in the body:

inflammatory regulation

epigenetic regulation

oxidative stress

glucocorticoid programming

RAS regulation

cortisol

stress hormone released by the adrenal cortex

heightens memory and attention

functions in the body:

increases blood pressure

increases blood glucose

decreases pain sensitivity

suppresses immune response

sleep pressure

Process S

driver of sleep

cellular metabolism generates adenosine -> adenosine receptor stimulation promotes sleep

adenosine is recycled in sleep -> improved wakefulness the next day

ATP ⇌ adenosine ⇌ sleep

other sleep/ wake promoting neurotransmitters

wake:

acetylcholine

histamine

monoamines (dopamine, norepi, serotonin)

orexin

sleep:

GABA galanin

orexin

neuropeptide involved in regulations of feeding behavior, sleep-wake cycles, and autonomic function

- orexin A binds both OXR1 and OXR2

- orexin B is selective for OXR2

- OXR1: wakefulness

- OXR2: sleep, suppresses motor activity during dreams

sleep trends across life

newborns: sleep sporadically throughout the day

1 y/o: SCN is developed, child syncs with circadian rhythm

adolescence: increase in deep NREM sleep for synaptic pruning

midlife/ old age: sleep decreases, but need for sleep does not

- substantial reductions in deep NREM sleep (stage 3&4)

assessing sleep

#1: polysomnography: multi-parameter sleep test

actigraphy: at home device (watch) that estimates sleep stages

- variable reliability

2 categories of sleep disorders

1. dyssomnias

- trouble falling asleep, staying asleep, or excessive sleepiness

- insomnia, OSA, narcolepsy, sleep movement disorders

2. parasomnias

- abnormal activities or behaviors during sleep

- nightmares, sleepwalking, sleep paralysis, sleep terrors, bruxism

insomnia

dyssomnia

difficulty falling and/or staying asleep

- occurs at least 3 nights per week for at least 3 months (chronic)

- occurs despite adequate sleep opportunity

- most common

- notable in: military/ veterans, psychiatric disorders, eldery

insomnia pathology

genetic vulnerability

+ precipitating event/ stressor and moderators (age, medications, comorbidities)

↓

abnormalities in neurobiological processes

- co-activation of wake and sleep promoting areas

↓

neurophysiological hyperarousal, psychological and behavioral processes

↓

insomnia

↓

adverse health outcomes

benzodiazepines

oldest class of sleep drugs

positive allosteric modulator of GABAa receptors (inhibitory NT)

- GABA binding -> Cl entry -> decreased likelihood of an action potential

commonly used for insomnia: temazepam (Restoril), triazolam (Halcion)

caution: pregnancy X, causes dizziness/ drowsiness, abuse potential, should be limited to short term use (<2 weeks)

Z-hypnotics

similar to benzos, has increased specificity for GABAa1 receptors and LESS MUSCLE RELAXANT ACTIVITY (=less potential for respiratory depression, the diaphragm is a muscle!!)

commonly used for insomnia: zolpidem (Ambien)

caution: pregnancy C, dizziness/drowsiness, abuse potential, sleep related behaviors (eating, walking, sex)

orexin receptor antagonists

block OXR1 and OXR2

commonly used for insomnia: sucorexant (Belsomra)

caution: pregnancy C, obesity, abnormal dreams

antihistamines & antidepressants

some use in insomnia

antihistamines: MUST cross BBB = 1st generation only

- diphenhydramine (Benadryl)

> short term only

antidepressants: MUST have antihistamine activity

- trazadone (Desyrel), amitriptyline (Elavil), doxepin (Silenor)

> lower dose than for depression

caution: significant anticholinergic effects, including delirium

- activity on the H1 receptor

melatonin (drug)

only appropriate for sleep onset insomnia

- ramelteon (Rozerem): melatonin receptor agonist

narcolepsy

excessive daytime sleepiness with

- cataplexy: emotionally triggered transient muscle weakness

- hypnagogic hallucinations: vivd, frightening hallucinations occurring at sleep onset

- sleep paralysis: inability to move for 1-2 minutes at sleep onset/waking

diagnosis includes Epworth sleepiness scale: objective questionnaire, asks "how likely are you to fall asleep in these scenarios"

narcolepsy pathophysiology

progressive loss of orexin neurons

> ↓orexin = motor off switch is hit outside of REM sleep

- early = excessive sleepiness

- later = cataplexy, rapid daytime transition into REM sleep

likely other mechanisms related to histamine and other brain areas

modafinil, armodafinil

Provigil, Nuvigil

CIV CNS stimulants

for narcolepsy

MOA: likely acts via increased dopamine signaling

lower abuse potential than amphetamines

ADE: headache, nausea, dry mouth, anorexia, diarrhea

solriamfetol

Sunosi

CIV CNS stimulant

for narcolepsy

similar to (ar)modafanil in efficacy and ADEs

MOA: dual norepinephrine and dopamine reuptake inhibition

methylphenidate, amphetamines

CII CNS stimulants

for narcolepsy

MOA: increased synaptic dopamine (& norepi)

- methylphenidate: blocks DAT/NET (signal that says to stop releasing DA and NE)

- amphetamines: does what methylphenidate does + reverses DAT/NET to flood system with more DA and NE

- IR and ER formulations

- may reduce cataplexy, hallucinations, and sleep paralysis

pitolisant

Wakix

for narcolepsy

MOA: H3 receptor antagonist/ inverse agonist

- binds presynaptic H3 receptors, preventing histamine from binding AND increasing histamine release

- basically, blocks signal that says to stop releasing histamine = increased histamine

- may reduce cataplexy

sodium oxybate

Xyrem

CIII for narcolepsy

MOA: gamma-hydroxybutyrate (GHB) -> GABA metabolite

- likely related to GABAb activity to increase REM sleep

[BLACK BOX]: risk of abuse, misue, death; REMS

- must take at bed time and 2.5-4 hours later

- date rape drug

oveporexton

not approved yet, for narcolepsy

MOA: selective OXR2 agonist

obstructive sleep apnea (OSA)

soft palate airway obstruction during sleep

- apnea = no airflow

- hypoapnea = decreased airflow with desaturation

symptoms: snoring/ snorting, EDS, hypertension, morning headaches, depression, anxiety, short term memory loss

OSA diagnosis

apnea/ hypopnea index (AHI)

- mild = 5-15 events/hr

- moderate = 15-30

- severe = >30

polysomnography used

OSA device based therapy

continuous positive airway pressure (CPAP) - forces steady flow of pressurized air into nose/ mouth

mandibular repositioning device - removable device that physically moves the jaw forward

Inspire upper airway stimulation - implamted device that sends electrical signals to hypoglossal nerve

restless leg syndrome (RLS)

the urge to move legs, often accompanied by discomfort

symptoms occur at rest and are relieved by movement

- worsen at night

- more common in: women, 30+

RLS pathophysiology

- brain iron deficiency

genetic predisposition, exposure to certain medications/ withdrawal from anticonvulsants, benzos, barbituates

↓

dopaminergic dysfunction and cortico-striato-spinal dysfunction

↓

RLS

iron replacement

for restless leg syndrome

MOA: iron is a cofactor for tyrosine hydroxylase, which is necessary for dopamine creation

gabapentinoids

gabapentin (Neurontin) and pregablin (Lyrica)

for restless leg syndrome

MOA: bind α2∆ subunit of presynaptic volatge-gated Ca channels (blocks signal) -> destabilization, internalization, and recycling

Horizant: gabapentin encarbil prodrug -> higher levels in the body

dopamine agonists

pramipexole (Mirapex)

for restless leg syndrome

MOA: D2 receptor agonism

ADE: somnolence, dizziness, headache, nausea

caution: augmentation (higher highs & lower lows), have to increase dose as body tolerates, may increase impulsive behaviors

- not a 1st line