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Sleep Disorders
Spring 2004
Sue Gielow Bollmeier, Pharm.D., AE-C
Assistant Professor of Pharmacy Practice
Sleep Disorders
• Introduction
• Epidemiology
– 1/3 adults
– Women, unemployed, lower socioeconomic
status, elderly, seperated or widowed
– Concurrent psyc disorder
Pharmacoeconomics
• QOL
• Costs
• Sleep deprivation
– Job
– Endangerment
Sleep deprivation
• Drowsy during the day
• Fall asleep within 5 minutes of lying down
• Sleep deprived individuals
– Perform hand-eye coordination tasks worse
than patients intoxicated
– Magnifies alcohols effects on the body
– Driver fatigue
• Caffeine / stimulants cannot overcome
effects of sleep deprivation
Sleep requirements
• Infants • 1st trimester of
– 16hrs/day pregnancy
• Teenagers – Requirements increase
– 9hrs/day • SLEEP DEPRIVED
• Adults INDIVIDUALS
– 7-8 hrs/day – Increased need
– 5-10 hrs/day RANGE
Sleep physiology
• Circadian rhythm
• NREM
• REM
• Neurotransmitters
Circadian Rhythms
• Latin for “around a day”
• Regulate changes in mental and physical
characteristics
• Follow 24 hour cycle of the sun
• Controlled by body’s “biological clock”
– Suprachiasmatic nucleus (SCN)
Suprachiasmatic nucleus (SCN)
• Contains 20,000 neurons
• Located in hypothalamus
Sleep / wake cycle
LIGHT REACHES
RETINA
Optic nerve carries
signal to the SCN
SCN
SIGNAL sent to pineal helps regulate body temp,
gland hormone secretion, urine production,
blood pressure associated
with sleep cycle
pineal gland responds to light by
halting production of melatonin
Sleep / wake cycle
Darkness falls
external cues: "bedtime",
end of day routine
sleep promoting neurons neurons controlling
become active alertness/ being
awake start to weaken
5HT, GABA, adenosine NE, Ach, H
Sleep cycle initiated >>>> signals sent to
hypothalamus/pineal gland >>>> ↑ secretion of melatonin
Sleep physiology
Neurotransmitter Effect
Norepinephrine Arousal
Dreaming
Acetylcholine Promotes wakefulness
Serotonin Slow wave sleep
Non-dreaming
Histamine Promote wakefulness
GABA Inhibitory NT,
promotes sleep
Sleep cycle
• Waking
– Low voltage brain waves
– +REM
• Stage 1
– Transient between wakefulness and sleep
– 5-7 minutes
– Low voltage brain waves
Sleep cycle
• Stage 2
– High voltage brain waves
– “light sleep”
– Provides rest for muscles and brain
– 15-20 minutes
– No eye movement
Sleep cycle
• Stage 3 & 4
– High voltage, slow, delta brain waves
– Refreshing, restorative sleep “deep sleep”
• REM
– Low voltage brain waves
– Dreaming occurs
Sleep cycle
• Each cycle lasts approximately 90-100
minutes
• New cycle will occur 4-6 times / night
• Last half of the night
– REM time period gets longer
– Deep sleep time period lessens
Factors affecting sleep cycle
• Foods
• Drugs
Etiologies of insomnia
• Situational
– Work
– Interpersonal
– Life events
– Jet lag, shift work
Etiologies of insomnia
• Medical
– CV
– Respiratory
– Pain
– DM,
hyperthyroidism
– GI
– pregnancy
Etiologies of insomnia
• Psychiatric
– Mood disorders
• Depression
• Bipolar disorder
– Anxiety disorders
– Substance abuse
Etiology of insomnia
• Pharmacologically induced
– Anticonvulsants
– Diuretics
– Adrenergic blockers
• Clonidine
– SSRI
– Steroids
– stimulants
Types of insomnia
• Transient
– Few consecutive nights
– Sporatic
• Short-term
– Few weeks – month
• Long-term (chronic)
– >1 month
Non-pharmacologic therapy
• Should be considered first line for all
patients complaining of insomnia
• Stimulus control procedures
• Sleep hygiene recommendations
Pharmacologic Therapy
Before initiating therapy 1) Distinguish between:
Difficulty Difficulty
maintaining Early morning
falling
sleep (DMS) awakenings
asleep
(DFA)
3) Non rx 4) Assess
2) Consider therapy –only patient
possible partially
etiologies effective?
Age, size, dx, organ
function, DI, Abuse
potential?
Transient insomnia
• Few nights
• Sporatic
• Jet leg
– Reset watches
– Participate in activities that
correspond to new time
zone
– Stay active until new time
zone bedtime
• BZ
– Short term use
– Use only PRN
Short term insomnia
Distinguish
between
Difficulty falling asleep Early morning awakenings
Difficulty
maintaining sleep
Short term use of BZ
7-14 DAY TRIAL
Chronic insomnia
TREATMENT
Non-benzodiazepine Benzodiazepine
hypnotics hypnotics
Antidepressants Flurazepam
Antihistamines Traizolam
Zolpidem Temazepam
Zaleplon Quazepam
Herbal medications Estazolam
Nonbenzodiazepine hypnotics
• Antidepressants
– TCA
• Amitriptyline 10-75mg
• Doxepin 75-150mg
– Trazodone
• 50-200mg
• Adverse effects
Nonbenzodiazepine hypnotics
• Antihistamines
– Diphenhydramine
– MOA: blocks H1 receptors resulting in
drowsiness
– 25-50mg nightly
– “hungover” effect
– Tolerance
Nonbenzodiazepine hypnotics
• Zolpidem
• Selective for BZ 1 receptor
• 10-20mg
• Elderly / hepatic dysfunction: 5mg/day
• Lasts 6-8 hours
• Adverse effects: n/v/d common
Nonbenzodiazepine hypnotics
• Zaleplon
• Binds selectively to BZ 1 receptor
• Claim to fame: rapid onset, quick
elimination
• Useful if patient wakes up in the middle of
the night
• Dose: 10mg, elderly: 5mg
Nonbenzodiazepine hypnotics
• Herbal / dietary supplements
– Melatonin
• Hormone
– Valerian root
• Increase GABA
• Not regulated by FDA
• Promoted as sleep aid
BENZODIAZEPINE (BZ)
HYPNOTICS
• 5 marketed in the U.S.
• Flurazepam
• Triazolam (Halcion)
• Temazepam (Restoril)
• Quazepam
• Estazolam
– Differ with regard to onset of effect,
elimination T1/2
BZD MOA for insomnia
BZ compound attaches to
BZ-Cl-ionophone complex
Chloride channels open
GABA increases
Overexcited areas inhibited;
calming effect
BZ hypnotics
• Will reduce time to sleep onset
• Decrease # of awakenings
• Increase total sleep time by decreases stages
1 & 4 and increases stage 2
Estazolam
• ProSom
• Intermediate-elimination T1/2 BZ
– 12-15 hours
• Metabolized via oxidation in liver
• Can accumulate in the elderly
• Discontinue – abruptly, may lead to
transient rebound insomnia
• Long term efficacy not known
Flurazepam
• Dalmane
• Long elimination T1/2 BZD
• Has active metabolite – relies on for most
clinical activity
• 1st night of use – unlikely to induce sleep
• Rapidly absorbed, intermediate fat
solubility
• Oxidized via liver
• Daytime anxiety efficacy
Quazepam
• Doral
• Long elimination T1/2 BZ
• T1/2 39 hours
• Greater lipid solubility compared to
flurazepam – will induce sleep on first night
of use
• Oxidized via liver
Temazepam
• Restoril
• Intermediate elimination T1/2 BZD
• Moderate fat solubility
• Long dissolution time
• Eliminated via conjugation – lacks hepatic
metabolism
• *intermediate duration of effect
• *no accumulation
• *decreased potential for daytime somnolence or
cognitive impairment
Triazolam
• Halcion
• Short elimination T1/2 BZD
• Rapidly absorbed; highly lipophilic
• Short duration of effect – highest risk of
rebound insomnia, withdrawal
• Oxidized via liver
Tolerance / dependence
• Tolerance
– Efficacy is not sustained
– Usually develops if take BZD –1 month
• (2 weeks with triazolam)
• Dependence
– Insomnia worsens without BZD
– Usually with continued BZD use over 2-4
months
Treatment algorithm for chronic insomnia
Assess:
Identify and -type of pt
manage medical, Sleep hygiene
-age, -size – other dx –
ψ, p’col causes ineffective
organ function-potential
DI’s, -abuse potential
Distinguish between
Early morning
Difficulty falling Difficulty awakenings
asleep maintaining
sleep Intermed-
Rapid onset, long elim.
short duration Intermediate T1/2 BZ
BZ elimination t1/2 -AD?
BZ
Treatment algorithm for chronic insomnia
Intermediate Intermed-long
Rapid onset, short elim. T1/2 BZ
elimination t1/2
duration BZ
BZ -AD?
*temazepam *temazepam
*Triazolam
*estazolam *estazolam
*zaleplon
*zaleplon *quazepam
*zolpidem
*flurazepam
*Trazodone
Sleep apnea
• Cessation of airflow at the nose and mouth
lasting at least 10 seconds
• High risk of morbidity / mortality
• Periods of breathing cessation (when
sleeping) coupled with snoring and gasping
for breath
• Etiology: obesity, polyps, enlarged tonsils,
adenoids or tongue
Sleep apnea
• Treatment
• Weight loss
• Treat cause of obstruction
• Avoid supine sleep position
• CPAP – continuous positive airway
pressure during sleep
• Avoid CNS depressants
Narcolepsy
• Abnormality in regulatory mechanisms of
REM
• Excessive daytime sleepiness
– “sleep attacks”
– May last up to 30 minutes
• Cataplexy
– Episode of sudden bilateral loss of muscle tone
resulting in collapsing
Narcolepsy
• Treatment
• Psychostimulants – daytime sleepiness
• Antidepressants - cataplexy
Restless leg syndrome
• Discomfort, crawling sensation, or
cramping in the calves
• Occurs only at rest
• Relieved by walking or moving legs
Restless leg syndrome
• Treatment
• BZ – first line for less severe cases
• Other options are available
• Tolerance
