Integrated Pharmacotherapy 4: Sleep Disorders

• RHCHP School of Pharmacy offers Integrated Pharmacotherapy 4 in Spring 2025, focusing on sleep disorders.

Facilitators

• Dan Berlau, PhD ([email protected], 303-964-6178)
• Katie Tuck, PharmD, BCPP, BCPS ([email protected], 303-964-5327)

Learning Objectives

• Define and explain bolded items in the notes
• List physiological parameters recorded during polysomnography, e.g., brain and skeletal muscle electrical activity, heart rate, body temperature
• Discuss features of REM and non-REM sleep stages in a normal sleep cycle
• Describe the function of the biological circadian rhythm
• Identify anatomical regions regulating circadian rhythm
• Discuss the influence of melatonin and adenosine on sleep
• Describe the structure and function of GABA and GABA receptors
• Discuss the pathophysiology of major sleep disorders
• Apply DSM-5 classification and diagnostic criteria for sleep-wake disorders
• Differentiate between insomnia disorder, narcolepsy, obstructive sleep apnea/hypopnea, and circadian rhythm sleep-wake disorders
• Describe acute, short-term, and chronic insomnia
• Identify situational, medical, psychiatric, and pharmacologic etiologies of insomnia
• Compare clinical presentation of circadian rhythm sleep disorders, specifically jet lag and shift work disorder
• Describe clinical presentation and secondary causes of restless legs syndrome
• Describe the clinical presentation of narcolepsy
• Describe the clinical presentation of obstructive sleep apnea
• Discuss psychological and behavioral interventions for primary insomnia, specifically stimulus control and sleep hygiene therapy
• Describe nonpharmacologic approaches to managing circadian rhythm disorders, restless legs syndrome, and narcolepsy
• Describe medical, behavioral, and surgical approaches to managing obstructive sleep apnea
• Match sleep disorder medications to pharmacologic classifications: benzodiazepine receptor agonist, benzodiazepine, non-benzodiazepine GABA agonist, melatonin agonist, orexin receptor antagonist, antihistamine, atypical antidepressant, or wakefulness-promoting agent
• Compare dosage formulations of zolpidem
• Describe first-pass metabolism and discuss its role with sleep disorder medications
• Describe the effect of food on oral medications for sleep disorder and explain how it impacts patient counseling
• Explain aspects of drug distribution important to the efficacy of sleep disorder medications
• Define these terms: sedative, hypnotic, anxiolytic
• Recognize the chemical structure of a benzodiazepine
• Describe the mechanism of action and pharmacologic effects of sleep disorder medications
• Compare the GABA subunit binding spectrum of benzodiazepines and non-benzodiazepine GABA agonists and explain how their respective binding spectrums affects pharmacologic action in the body
• Discuss the safety profile of sleep disorder medications both with and without concomitant administration of other CNS depressants
• Explain the relationship between melatonin and melatonin agonists with regard to drug design
• Identify antihistamines and an atypical antidepressant used for sleep disorders
• Identify CNS stimulants useful for management of narcolepsy
• Identify the CYP450 isoforms most important to the metabolism of benzodiazepines, zolpidem, and eszopiclone
• Describe the metabolism profile common to most benzodiazepines
• Identify benzodiazepines that are eliminated only by glucuronidation and explain how this may affect the choice of benzodiazepines
• Describe the impact of elimination half-life on benzodiazepine therapy
• Apply benzodiazepine elimination half-life data to providing appropriate therapy decisions for management of sleep disorders
• Identify common adverse effects of sleep disorder medications and apply this knowledge to drug therapy decisions in a patient case
• Describe the abuse potential and identify the Controlled Substance Schedule for sleep disorder medications
• Identify potentially inappropriate sedatives and hypnotics in older adults and their rationale according to the 2019 Beers criteria
• Screen a patient drug profile and social history for important drug-drug interactions involving sleep disorder medications
• Explain the rationale used in selecting each nonpharmacologic, complementary and alternative medicine, and pharmacologic intervention used to treat sleep disorders
• Discuss considerations and precautions with sedative-hypnotic medications related to adverse effects, comorbid conditions and concomitant therapies, and special populations
• Recommend psychological, behavioral, and pharmacological therapies according to the American Academy of Sleep Medicine clinical guidelines on the management of chronic insomnia in adults
• Formulate an evidence-based therapeutic plan that includes nonpharmacologic, complementary and alternative medicines, and pharmacologic therapies to manage sleep disorders
• List medications recommended by the AASM for sleep onset insomnia and sleep maintenance insomnia

Introduction to Sleep Disorders

• Sleep disorders are conditions that disturb sleep and wakefulness

Definitions

• Dyssomnias: abnormalities in the amount, quality, or timing of sleep, e.g., insomnia, narcolepsy
• Parasomnias: abnormal behavioral or physiologic events associated with sleep, e.g., nightmare disorder
• Anxiolytic: A drug used to reduce anxiety.
• Cataplexy: Sudden loss of muscle tone triggered by emotional stimuli such as laughter, fear, or anger.
• DSM-5: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
• EEG (Electroencephalogram): A test that records electrical activity in the brain.
• EMG (Electromyogram): A test measuring electrical activity in skeletal muscles.
• EOG (Electrooculogram): A test recording eye movement and electrical activity in the retina.
• GABA (Gamma-aminobutyric acid): The major inhibitory neurotransmitter in the CNS.
• GABAergic Drug: A drug that enhances GABA’s inhibitory effects, either by directly activating GABA receptors or enhancing its action.
• Hypnotic: A drug that promotes sleep.
• Narcolepsy: A sleep disorder characterized by excessive daytime sleepiness and uncontrollable episodes of falling asleep.
• OSA (Obstructive Sleep Apnea): A disorder where the airway collapses during sleep, causing breathing pauses.
• PAP (Positive Airway Pressure): A treatment for sleep apnea using air pressure to keep the airway open.
• Paresthesia: An abnormal sensation, such as tingling or burning, often due to nerve damage.
• PLMS (Periodic Leg Movements during Sleep): Repetitive limb movements occurring during sleep.
• PSG (Polysomnography): A comprehensive sleep study measuring brain waves, oxygen levels, heart rate, and body movements.
• REM (Rapid Eye Movement): A stage of sleep associated with dreaming and brain activity similar to wakefulness.
• RLS (Restless Legs Syndrome): A disorder causing an irresistible urge to move the legs, usually at night.
• SCN (Suprachiasmatic Nucleus): A region in the hypothalamus that controls circadian rhythms.
• Sedative: A drug that calms or relaxes without necessarily inducing sleep.
• Sleep Latency: The time it takes to transition from wakefulness to sleep.
• TST (Total Sleep Time): The total amount of sleep achieved during a sleep period.

Epidemiology

• 65% of people report a sleep problem a few nights a week
• 44% report sleep problems nightly or almost every night
• 29% report falling asleep or being sleepy at work
• 36% report falling asleep or nodding off while driving
• Insomnia life prevalence is estimated at 80-90%
• Insomnia onset typically occurs in early or middle adulthood
• Insomnia and sleep deprivation impact quality of life and physical health
• Insomnia is associated with an increased number of physician visits, hospitalizations, missed workdays, and poor performance

Physiology/Biochemistry

• Sleep timing is controlled by the biological circadian clock

Sleep and the Brain

• The biological circadian clock mediates changes in metabolic output and behavior according to the time of day
• It follows a roughly 24-hour cycle synchronized by the natural light-dark cycle
• The suprachiasmatic nucleus (SCN) in the hypothalamus coordinates circadian rhythms
• Direct neuronal connections between the SCN and the retina relay ambient light information to the brain
• The SCN synchronizes regulatory signals, transmitting a signal via the spinal cord to the pineal gland
• The pineal gland secretes melatonin

The Sleep Cycle

• The sleep cycle consists of four recurring stages defined by predictable physiological changes
• One stage is defined by rapid eye movements (REM)
• Three stages are referred to as non-REM stages
• Sleep progression is monitored by polysomnography
  • Polysomnography provides data on electrical activity, eye movement, and heart rate.

Physiological Parameters Recorded During Polysomnography (PSG)

• Electroencephalogram (EEG): Measures brain electrical activity.
• Electromyogram (EMG): Measures skeletal muscle activity.
• Electrooculogram (EOG): Measures eye movement.
• Heart Rate: Monitored to assess cardiac activity during sleep.
• Blood Oxygen Levels: Determines oxygen desaturation events, crucial for diagnosing sleep apnea.
• Respiratory Effort & Airflow: Identifies breathing disturbances.
• Body Temperature: Assessed in some cases to observe temperature fluctuations in sleep.
• Limb Movements: Detects periodic limb movements related to RLS or PLMS.

NON-REM Sleep Stages

• Consists of stages 1 through 3 (N1-N3) and typically lasts from 90 to 120 minutes

REM Sleep Stage

• Characterized by rapid eye movements and paralysis of voluntary muscle groups
• Dreaming occurs because of heightened brain activity
• Accounts for ~25% of total sleep time, affecting memory consolidation
• Heart rate and respiration are irregular with rapid fluctuations
• The REM sleep stage lengthens with each recurrence of the sleep cycle

Features of REM and Non-REM Sleep Stages

• Non-REM Stages:
  • N1: Light sleep; muscle activity decreases, slow rolling eye movements.
  • N2: Sleep spindles and K-complexes appear; body temperature drops, heart rate slows.
  • N3 (Deep Sleep): Characterized by delta waves; essential for physical recovery and immune function.
• REM Sleep:
  • Occurs approximately 90 minutes after sleep onset.
  • Characterized by rapid eye movements, vivid dreams, and paralysis of voluntary muscles.
  • Plays a role in memory consolidation and emotional regulation.
  • Heart rate and respiration become irregular.

EEG Waves and Neuronal Synchrony

• Cortical neurons fire independently when awake, leading to high-frequency, low-amplitude EEG waves
• EEG waves show increased amplitude and decreased frequency during sleep stages

Sleep Regulating Factors

Melatonin

• Hormone that is serotonin-related, synthesized from tryptophan
• Secretion, inhibited by light, adheres to circadian control of the SCN
• Melatonin levels peak in the middle of the night
• G protein-coupled receptors for melatonin exist on SCN neurons facilitating feedback regulation
• Melatonin promotes sleep onset by decreasing alertness

Adenosine

• Nucleoside acts as neurotransmitter at synaptic junctions in the brain
• Post-synaptic adenosine receptors elicit inhibitory potentials
• Adenosine levels rise due to ATP use
• Clearance occurs during restful sleep
• Complex mechanism involving GABA neurons in the preoptic area of the brain promotes sleep
• Adenosine builds up during wakefulness, inhibits wake-promoting neurons, and promotes sleep drive

Gamma-Amino Butyric Acid (GABA)

• Main inhibitory neurotransmitter in the central nervous system
• Neurons are active during REM and non-REM
• Promotes sleep by binding to the GABA receptor
• Regulation of GABA neurons by adenosine receptors determines the timing of GABA influence via sleep-wake cycle

Structure and Function of GABA and GABA Receptors

• Structure: GABA is an inhibitory neurotransmitter that binds to GABA_A receptors, leading to chloride influx and neuronal hyperpolarization.
• Function:
  • Reduces excitatory neurotransmission.
  • Induces sedation and muscle relaxation.
  • GABAergic drugs (e.g., benzodiazepines, non-benzodiazepine GABA_A agonists) enhance sleep induction.

Orexin

• It is a neurotransmitter peptide released by cells in the lateral hypothalamus
• Contributes to wakefulness
• Orexin activates monoaminergic and cholinergic neurons in the hypothalamus and brainstem to maintain waking period
• Mutations in orexin linked to narcolepsy symptoms
• Patients exhibit low/absent orexin levels in cerebrospinal fluid

Pathophysiology of Sleep Disorders

• The sleep cycle can be affected through several agents, these include: quality, duration, and onset of sleep
• Sleep deprivation is a factor
• Stress and environment are factors
• Dysfunction may also be caused through the use of artificial lighting
• Disruption may also be caused through breathing by infection or age

Insomnia Disorder

• Disturbance during waking periods due to challenges during sleeping periods
• Primary Insomnia may be marked by incomplete or turbulent sleep

Primary Insomnia

• May occur when known elements may lead to its on set

Circadian Rhythm Sleep-Wake Disorders

• Disorders are caused by problems with circadian rhythms that is dictated by the SCN
• Clock is not exactly 24 hours (can be 23-25 hours)
• Disease is considered to be Non-24
• Common form is time zone change syndrome
• Another form is shift work disorder

Restless Legs Syndrome (RLS)

• Characterized by the urge to move one's limbs, worsening at night.
• High familial incidence, suggesting genetic cause
• Causes include iron deficiency, neurologic disorders, pregnancy, uremia, and medications
• Involves homeostatic mechanisms regulating iron influx/efflux

Narcolepsy

• Characterized by sudden, uncontrollable sleep bouts during waking hours, disturbed REM
• Likely cause of cataplexy
• Recent evidence: orexin peptide involved

Sleep Apnea

• Breathing-related sleep disorder during sleep, incomplete sleep, daytime drowsiness
• Most common: obstructive sleep apnea, airway collapse at pharynx
• More common in men, advanced age, and obesity
• Airflow ceases for ~10 seconds through nose and mouth

Classification

• DSM-5 classifies sleep-wake disorders by disorder/groups, including:
  • Insomnia Disorder
  • Narcolepsy
  • Breathing-Related Sleep Disorders
  • Circadian Rhythm Sleep-Wake Disorders
  • Restless Legs Syndrome

Insomnia Disorder - A type of clinical diagnosis

• Endogenous disorder caused by potential neurochemical abnormalities
• Hyperarousal
• Considered a chronic disorder from the DSM-5

Restless Legs Syndrome (RLS)

• Is a neurologic sensorimotor disease with parathesias
• One feels the irresistible urge to shake their limbs
• 5-10% of adults have this condition

Pathophysiology of Major Sleep Disorders

• Insomnia: Increased cortical activity; linked to hyperarousal.
• Narcolepsy: Dysfunction in orexin (hypocretin) signaling.
• Obstructive Sleep Apnea (OSA): Airway collapse causing intermittent hypoxia.
• Restless Legs Syndrome (RLS): Dopaminergic dysfunction, possibly related to iron deficiency.
• Circadian Rhythm Sleep Disorders: Mismatch between endogenous circadian rhythm and environmental cues.

Narcolepsy

• Neurologic disorder that detrimental effect on personal safety
• Excessive daytime sleepiness (EDS) is a key feature

Sleep Apnea

• Can range from narrowing of the wind pipe to full obstructions

Apply DSM-5 Classification and Diagnostic Criteria for Sleep-Wake Disorders

• Based on specific DSM-5 criteria:
  • Insomnia: Sleep difficulty ≥3 nights per week for ≥3 months.
  • Narcolepsy: Excessive daytime sleepiness with cataplexy, sleep paralysis, hypnagogic hallucinations.
  • OSA: Breathing pauses, excessive daytime sleepiness.
  • RLS: Urge to move legs, worse in the evening.
  • Circadian Disorders: Mismatch between desired and actual sleep schedules.

Differentiate Between Insomnia Disorder, Narcolepsy, OSA, and Circadian Rhythm Sleep-Wake Disorders

• Feature Insomnia Narcolepsy OSA Circadian Rhythm Disorders
• Primary Issue Difficulty falling/staying asleep Excessive daytime sleepiness Repeated airway collapse Mismatch between sleep-wake schedule & environment
• Key Symptoms Sleep latency > 30 min, frequent awakenings Sudden sleep attacks, cataplexy Loud snoring, gasping, daytime fatigue Difficulty adjusting to shifts, time zone changes
• Pathophysiology Hyperarousal, decreased sleep drive Orexin deficiency Airway obstruction SCN desynchronization
• Diagnosis Sleep history, sleep diaries PSG + Multiple Sleep Latency Test PSG, apnea-hypopnea index Sleep logs, actigraphy

Describe Acute and Short-Term Insomnia and Chronic Insomnia

• Acute Insomnia: Lasts less than 3 months, often due to situational stressors (e.g., job loss, grief, exams).
• Short-Term Insomnia: Lasts between 1 to 3 months, often due to a temporary condition like hospitalization or major life events.
• Chronic Insomnia:
  • Lasts ≥3 months.
  • Occurs ≥3 times per week.
  • Associated with hyperarousal, psychiatric conditions, or medical disorders.
  • Leads to daytime impairments such as fatigue, poor concentration, and mood disturbances.

Identify Common Situational, Medical, Psychiatric, and Pharmacologic Etiologies of Insomnia

• Etiology Examples
  • Situational: Stress, jet lag, shift work, major life changes (e.g., divorce, bereavement)
  • Medical: Cardiovascular (CHF, angina), respiratory (COPD, asthma), pain disorders (arthritis, fibromyalgia), GERD, hyperthyroidism, pregnancy
  • Psychiatric: Anxiety, depression, PTSD, schizophrenia, bipolar disorder
  • Pharmacologic: Caffeine, stimulants (amphetamine, methylphenidate), antidepressants (bupropion, SSRIs, MAOIs), steroids, diuretics, alcohol withdrawal

Compare and Contrast the Clinical Presentation of Circadian Rhythm Sleep Disorders

• Feature Jet Lag Disorder (JLD) Shift Work Disorder (SWD)
  • Cause: Rapid travel across ≥2 time zones, Night shifts, early morning shifts, rotating shifts
  • Symptoms: Insomnia, excessive sleepiness, impaired performance, Sleepiness during shifts, insomnia on off-days
  • Duration: Lasts 2-3 days (up to 7-10 days if >8 time zones), Chronic if schedule remains misaligned
  • Risk Factors: Frequent travelers, older age (>35), Healthcare workers, emergency personnel
  • Management: Light therapy, melatonin, gradual sleep schedule adjustment, Sleep hygiene, planned naps, timed light exposure

Goals of Therapy

• Normalize patterns
• Improve sleep quality and quantity
• Improve daytime impairments and life quality
• Prevent further progression

Describe the Clinical Presentation and Secondary Causes of Restless Legs Syndrome (RLS)

• Symptoms:
  • Urge to move legs, worsening at rest or during sleep.
  • Relief with movement (e.g., walking, stretching).
  • Worse in the evening and night.
• Secondary Causes:
  • Iron Deficiency (low CSF ferritin levels).
  • Neurologic Disorders (Parkinson’s, multiple sclerosis).
  • Medications (SSRIs, antipsychotics, diphenhydramine, metoclopramide).
  • Pregnancy (especially in the third trimester).
  • Chronic Kidney Disease (CKD)/Uremia.

Describe the Clinical Presentation of Narcolepsy

• Excessive Daytime Sleepiness (EDS): Uncontrollable sleep attacks.
• Cataplexy: Sudden loss of muscle tone, triggered by emotions.
• Hypnagogic/Hypnopompic Hallucinations: Vivid, dream-like hallucinations at sleep onset or awakening.
• Sleep Paralysis: Temporary inability to move upon waking.
• Abnormal REM Onset: REM occurs

NONPHARMACOTHERAPY

Insomnia Disorder

• Psychological and behavioral interventions enhance self efficiacy

Stimulus control therapy

• Reinforce association to enhance schedule

Relaxation Training

• lower somatic

Sleep Restriction

• Improve sleep by enhancing drive

Medical Sleep Disorders and Therapies

Circadian Rhythm Sleep-Wake Disorders

• Approaches such scheduled sleep are useful to mitigate problems

Restless Legs Syndrome

• Management of RLS by managing/identifying secondary causes

Narcolepsy

• Treatment balances the daily lifestyle to improve

Sleep Apnea

• OSA can be managed through different approaches

Therapeutic Agents for Sleep Disorders

• Sedative effect is an effect many hypnotics achieve to relax
• However drugs of this sort require that one is careful and cautious
• Drugs of this kind may also be misused

Drug Formulation, Delivery and Absorption

• Most drugs are delivered through oral consumption
• There are instances where drugs may also have extended release

Pharmacologic Mechanisms for Management of Sleep Disorders

• Can enhance sleep by means of increased activation in particular pathways
• Can target insomnia in the body
• Can be enhanced through use of certain drugs

Benzodiazepines (Schedule C-IV)

• Have short term indications used for managing sleeping in particular conditions

NONBENZODIAZEPINE GABA AGONISTS

• ZOLPIDEM
• ZALEPLON
• ESZOPICLONE
• Schedule IV

Melatonin Agonists

• New class of medication used to treat issues with sleeping
• Melatonin agonists were tested to be a mimic
• It makes sense to design drugs to chemically mimic melatonin when creating new methods

Orexin Antagonists

• Block the binding of certain orexin in the body
• These help the body rest due to lower wakefulness in the body

Antihistamines

• The use is controversial due to the increased effect of anticholinergic elements in the body

Wakefulness-Promoting Agents for Narcolepsy

• First line of medications can be used

Algorithm For Treatment of Dyssomnias

• The algorithm that is provided is a general summary to describe

Complementary and Alternative Medicines

• Have sedative hypnotic properties
• May reduce sleep and improve sleep quality

Therapeutic Applications of Evidence Based Management of Sleep Disorders

• Treatment for insomnia is based on the clinical history only
• Can treat with a cognitive behavioral treatment
• Short term insomnia can be managed through a proper sedative