Sleep-Wake Disorders (6208)

-Adenosine

-GABA (Y-aminobutyric acid)

-Opiate peptides (enkaphalin, endorphin)

Promotes Sleep

-NE

-Dopamine

-Histamine

-ACh

-Glutamate

-Substance P, Thyrotropin-releasing factor, Corticotropin releasing factor

-Serotonin

Promotes Wakefullness

-Orexin A and B

-Melatonin

Modulates Sleep-Wake Cycle

-Enkaphalin

-Endorphin

Opiate peptides to promote sleep

What is Y-aminobutyric acid?

GABA

-INC sleep onset latency

-DEC sleep time

ALSO:

-DEC REM sleep

Cocaine

-1st half of sleep: DEC sleep onset latency (yay)

-2nd half of sleep: INC arousals and sleep fragmentation (yikes)

Alcohol effect on Sleep

-Electroencephalogram (EEG)

-Electromyogram

-Electrooculogram of each eye

Measures of Sleep Function that use Pattern of Brain Waves, Muscle Tone, and Eye Movements

Dissatisfaction w/ sleep quality or quantity associated w/ ≥1 of the following:

-Difficulty initiating sleep

-Difficulty maintaining sleep (frequent awakenings/problems returning to sleep)

-Early morning awakening w/ inability to fall back to sleep

-Sleep disturbances causes clinically sig stress or impairment in social, occupational, educational, behavioral, or etc. areas of functioning

-Sleep difficulty occurs despite adequate opportunity for sleep

-Sleep difficulty occurs ≥3 nights/week

-Sleep difficulty present for ≥3 months

-Occurs in absence of co-morbid mental/medical conditions or substance use

DSM-5 Diagnosis for Insomnia

-Female

-Stress

-Precipitating major life events (illness, separation, unemployment)

-Poor sleep habits

-Irregular sleep scheudling

-Comorbid psychological or Medical Conditions

-Medications

-Diet

-Jet lag

-Shift work

Risk Factors for Insomnia

-Mood disorders (e.g. depression, mania)

-Anxiety disorders

-Substance misuse and withdrawal

Psychiatric Etiology for Insomnia

-CV (e.g. angina, arrhythmias, HF)(HTN)

-Respiratory (asthma, sleep apnea)

-Chronic pain

-Endocrine (e.g. diabetes, hyperthyroidism)

-GI (GERD, ulcers)

-Neurologic (e.g. delirium, epilepsy)

-Pregnancy

Medical Etiology for Insomnia

-Anticonvulsants

-Central adrenergic blockers

-SSRIs

-Steroids

-Stimulants

Insomnia can be Induced by These Rx

Cognitive Behavioral Therapy (CBT)

1st-Line for Insomnia

-BZDs

-Z-drugs (non-BZDs)

-Sedating antidepressants

-Melatonin agonist

-Dual Orexin receptor antagonist (DORAs)

2nd-Line for Insomnia Tx

-Behavioral and Cognitive factors

-Sleep restriction

-Stimulus control

-Counter-arousal measures and relaxation

Multicomponent Approach of CBT-I

Binds allosterically to GABA-A receptor

-INC freq of Cl- channel opening

-Potentiates GABA

→ DEC sleep latency and INC total sleep time (Stage 2 and Delta)

MoA of BZDs

-Flurazepam (Dalmane)

-Quazepam (Doral)

→ Long half life. AVOID USING these BZDs in the Elderly and Hepatic Impairment

This BZD is ONLY for Sleep Onset, not for Maintenance

Triazolam (Halcion)

-Typically not used for Insomnia due to risk and long t1/2, but we can use if there's acute trauma

-Used for Sleep onset & Maintenance

BZDs Indication

-Combined with Opioids → Profound Sedation, Respiratory Depression, Coma, and DEATH

-Exposes users to Risk of Abuse, Misuse, and Addiction...

-Continued use may lead to Physical Dependence

Boxed Warning for BZD

-Pregnancy

-Untreated Sleep apnea

-Hx of Substance use disorder

-Concurrent use of alcohol, opioids, or other CNS depressants

Contraindications to Using BZDs

-Eszopiclone (Lunesta)

-Zaleplon (Sonata)

-Zolpidem (Ambien, Intermezzo, Edluar, Zolpimist)

Z-Drugs List

This Z-drug has the shortest half-life and is only used for Sleep Onset

Zaleplon

This Zolpidem formulation is used for Sleep Onset only

-Sublingual Tab (Edluar)

-Regular Oral Tab (Ambien) **not the ER version

This Zolpidem formulation is used for Middle-of-the-Night awakenings

Sublingual Tab (Intermezzo)

This Z-drug is an intermediate-acting one with a half-life of 6 hours, beating most of the rest; it is labeled for LONG-TERM USE (up to 6 months)

Eszopiclone

-Cimetidine

-Rifampin

Zaleplon DDIs

-Somnolence

-Unpleasant taste

-Headache

-Dry mouth

SEs of Eszopiclone

-Drowsiness

-Amnesia*

-Dizziness

-Headache

-GI upset (dose-related)

SEs of Zolpidem

Complex Sleep Behaviors:

-Sleep-walking

-Driving

-Preparing and eating food

-Making phone calls

-Having sex

Boxed Warning for Z-Drugs

≥4 hours

Sleep needed for Zaleplon

7-8 hours

Sleep needed for Zolpidem and Eszopiclone

-Sedative

-Anxiolytic

-Muscle Relaxant

-Anticonvulsant

Therapeutic Effects of BZDs

-Used off label for Insomnia

-0.5 to 5 mg

-OTC, not regulated by the FDA

-Use products w/ USP verified mark

-NOT recommended for CHRONIC insomnia ***

Melatonin

-For sleep-onset insomnia

-Highly selective agonist at MT1 and MT2 receptors

-***Useful in patients w/ COPD & Sleep Apnea !!! <3 b/c it doesn't cause CNS depression/breathing issues

-Avoid in severe hepatic impairment

-CYP1A2 substrate → avoid w/ Fluvoxamine

Ramelteon (Rozarem)

-Daridorexant

-Suvorexant

-Lemborexant

Dual Orexin Receptor Antagonists (DORAs) - List

Worsening of Mood & Suicide ideation (dose-dependent)

Boxed Warning for DORAs

-CYP3A4 substrate

-Contraindicated in Narcolepsy !!

-Not recc'd in Severe Hepatic Dysfunction

Clinical Considerations for DORAs

-NOT used as first-line

-Reserved for ppts who did not do well on 1st lines or cannot take other medications

Sedating Antidepressants' Place in Therapy

-Trazodone

-Doxepin

-Amitriptyline

-Nortriptyline

-Mirtazapine

Sedating Antidepressants List/Options

-Trazodone

-Amitriptyline/Nortriptyline

-Mirtazapine

Contraindicated in Angle-Closure Glaucoma

-For: Sleep Maintenance

-BOXED: Risk of suicide ideation & behavior in kids and young adults

-DO NOT take within 3 hours of meal !! (will delay absorption)

-Low risk for impaired alertness/next-morning impairment :)

-MoA: 5-HT, NE reuptake inhibitor (also H1, M1, and A1)

Doxepin (Silenor)

-Agranulocytosis

-Serotonin Syndrome

-Cardiac arrhythmias / QT prolongation

-SEIZURES (may DEC threshold)

-Risk of Activating Mania/Hypomania

-Hyponatremia

Precautions for Amitriptyline and Mirtazapine

-Serotonin Syndrome

-Cardiac arrhythmias / QT prolongation

-*Bleeding risk* (INC w/ ASA, NSAIDs, warfarin, antiplatelets/anticoags)

-Risk of Activating Mania/Hypomania

Precautions for Trazodone

-Z-drugs or Ramelteon

-Diff Z-drug or Ramelteon if initial agent no good

-Sedating antidperessants (esp if treating comorbid depression/anxiety)

Med Trial Sequenece for Insomnia

-Dozepin

-Ramelteon

Has the LOWEST CNS Depression

-DORAs

-Doxepin

-Ramelteon

Preferred for Insomnia if patient is on Opioids

-Slumber Camp

-Sleepio

-GO! To Sleep

-Oura Ring

-AirSense 10

CBT-I Technology

Upper airway collapse and obstruction

Obstructive Sleep Apnea (OSA)

Impairment of Respiratory Drive

Central Sleep Apnea

Characterized by repetitive episodes of cessation of breathing during sleep; we get desaturation of blood O2 which causes brief arousal from sleep to restart breathing

Sleep Apnea

-Positive Airway Pressure (PAP)

-Weight Reduction

-Surgery

-Positional therapies, Oral appliances, Hyopoglossal nerve stimulators

Non-Pharm Tx for OSA

-CNS Depressants (alcohol, hypnotics)

-Meds that promote Weight Gain

AVOID These in OSA

Tirzepatide (Zepbound)

Rx Tx for OSA

-Risk of Thyroid C-cell Tumors

-Contraindicated in ppts w/ personal or Fam Hx of MTC or in patients w/ MEN 2 (multiple endocrine neoplasia syndrome type 2)

Boxed Warning for Tirzepatide

-With Cataplexy

-WITHOUT Cataplexy

Types of Narcolepsy

Excessive Daytime Sleepiness

-Cataplexy

-Hallucinations (hypnagogic, hyponopompic)

-Sleep paralysis

Signs and Symptoms of Narcolepsy

-Mofafinil

-Armodafinil

-Pitolisant

-Solriamfetol

1st Lines for Narcolepsy Tx

-Sodium Oxybate*

-Methylphenidate

-Amphetamines

2nd lines for Narcolepsy Tx (due to the fact that they cause more sympathomimetic SEs)

-Pitolisant (Wakix)

-Sodium Oxybate (Xyrem)

Use if the patient has Excessive Daytime Sleepiness AND Cataplexy

-Fluoxetine (Prozac) *will see benefits sooner than antidepressant effects

-Venlafaxine (Effexor) *may INC BP

Agents for Cataplexy ALONE

Parethesias that are felt in the calf, thigh, or arm muscles resulting in urge to keep limbs in motion

**Urge to move the limbs that are associated w/ uncomfortable sensations, characterized by ALL of these:

-Sx begin or worsen during rest

-Sx are exclusively present or worse in the evening or night

-Sx are temporarily relieved by movement

-Occurrence of Sx is not accounted for as Sx of another medical condition

Restless Leg Syndrome AKA Willis-Ekbom Syndrome

-Chronic Kidney Disease

-Pregnancy

-Iron defeciency in the Substantia Nigra in CNS

These are Associated w/ RLS

-Caffeine

-Stress

-Alcohol

-Fatigue

Things that Exacerbate RLS

U =Urge to move limbs

R = Rest worsens the sensation

G = Getting up to move offers temporary relief

E = Evening is worse for symptoms

Sx for RLS

-Gabapentin

-Pregabalin

(alpha-2-delta ligands)

1st Line for RLS

-Ropinirole

-Pramipexole

-Rotigotine

(Dopamine agonists)

2nd Lines for RLS

-Opioids (e.g. codeine, tramadol, methadone)

-Sedative-Hypnotics (e..g clonazepam, temazepam, zolpidem, zaleplon)

3rd Lines for RLS

When do we use PO Iron Therapy in RLS?

-Ferritin <75 mcg/L or

-TSAT <20%

-Gabapentin

-Pregabalin

-BZDs

-Z-Drugs

-TCAs (e.g. Doxepin >6 mg, Amitriptyline, Nortriptyline)

-Mirtazapine (can use w/ caution)

Beer's List

-BZDs

-Z-Drugs

AVOID these in Substance Use Disorders