Download Insomnia - ISpatula

Mayyada Wazaify PhD
Sleep Disorders Impact
• Untreated sleep disorders, including chronic
insomnia, sleep apnea, periodic limb movements
during sleep (PLMS), and narcolepsy, are all
associated with …
diminished mental and physical functioning and
poor quality of life.
• Chronic insomnia immune system
dysregulation, release of (IL-6), TNF-α and
disruption of HPA and depletion of brain
serotonin and neurotransmitters.
Definition
• Insomnia is defined as requiring >30 minutes
to fall asleep, when individuals awaken
throughout the night and cannot immediately
return to sleep, when individuals experience
early-morning awakening, or when total sleep
time is decreased to <6 hours
Classification of Insomnia
• transient (lasting a few days),
• short-term (lasting <4 weeks),
• chronic (persisting for ≥1 month).
Disease vs. Disorder?
• A disease is a pathophysiological response to
internal or external factors.
• A disorder is a disruption to regular bodily
structure and function.
• A syndrome is a collection of signs and
symptoms associated with a specific healthrelated cause.
SLEEP STAGES
NORMAL SLEEP
Polysomnography
• Polysomnography (sleep study):
= the term used to describe three electrophysiologic
measures: the electroencephalogram (EEG), the
electromyogram (EMG), and the electrooculogram (EOG).
The pattern of brain waves, muscle tone, and eye
movements can be used to categorize sleep as
rapid eye movement (REM) sleep or nonrapid eye
movement (NREM) sleep
NREM sleep
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•
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Stages differ quantitatively and qualitatively
Stage 1: initiate sleep ‘relaxed wakefulness’
Stage 2: provides rest for muscles and brain
Stages 3 and 4: Delta sleep ‘restorative sleep’
 enhanced by serotonin, adenosine,
cholecystokinin, and IL-1  augmentation of
immune function
NREM sleep
• NREM sleep is necessary for rest and rejuvenation
• Some hormones (e.g., somatostatin, growth
hormone) are released mainly during slow-wave
sleep.
• Deep sleep is most abundant in infants and
children
• Approximately 4 hours a night during adolescence.
• At age 65, deep sleep accounts for only 10% of
sleep , at age 75, it often is nonexistent.
Normal Sleep cycles
REM Sleep
• Purpose is unknown
• REM latency: 90 minutes (throughout the
night)
• REM duration ↑ in the second half of night
• Dreaming occurs
• Paradoxical sleep: aspects of both deep and
light sleep
• Body and brain stem functions: in deep sleep
• Neurochemical processes and higher cortical
brain function: active
REM Sleep
• Numerous physiologic functions are altered
during REM sleep.
• Breathing is irregular,
• Temperature control is lost and the body
temperature typically lowers.
• REM sleep brings on variability in heart rate,
blood pressure (BP), cerebral blood flow, and
metabolism.
• Cardiac output and urine volume decrease.
• Blood may become thicker
Did you know?
• At week 32 of gestation,
the fetus spends 9095% of the time
sleeping with REM stage
dominating, an
indication of dreaming
NEUROCHEMISTRY OF SLEEP–WAKE
CYCLE
• Hypnotics (MOA) modulate brain
neurotransmitters and neuropeptides (e.g., serotonin,
norepinephrine, acetylcholine, histamine, adenosine, and GABA)
• Neuronal system: brainstem, hypothalamus, basal
forebrain, with connections in the thalamus and
cortex.
• NE, Histamine, Ach wakefulness
• Excitatory a.a: glutamate and stimulating
neuropeptides (e.g. substance P, thyrotropin-releasing factor,
corticotropin releasing factor)  wakefulness
• Hypocretin 1 and 2 (orexin a and b): deficient in
narcolepsy and primary hypersomnia
NEUROCHEMISTRY OF SLEEP–WAKE
CYCLE
• Wakefulness and sleep are antagonistic states
competing for control of brain activity.
1. Serotonin in brainstem raphe ↓ sensory input
and inhibit motor activity, promote the
emergence of slow-wave sleep.
2. Opiate peptides (e.g., enkephalin, endorphin)
and GABA  sleep
Jet Lag
• a physiological condition which results from alterations to the
body's circadian rhythms resulting from rapid long-distance
trans-meridian (east–west or west–east) travel on high-speed
aircraft.
• Circadian rhythm sleep disorder results from a mismatch
between the sleep–wake schedule required by a person’s
environment and the circadian sleep–wake pattern.
Drug-induced effects
• BZD open Cl channels GABA sleep
• BZD promote more continuous stage 2,
decrease stage 4 and suppress REM
• AH block histamine-containing neurons
• Caffeine adenosine antagonist
Pharmacologic Treatment
• Benzodiazepine hypnotics or newer “Zhypnotics,” are firstline therapies …
• because they offer significantly greater efficacy than OTC products; they
are safer than barbiturates and are more effective compared with sedating
antidepressants.
What makes the ideal hypnotic? N=4
Pharmacologic Treatment
OTC Drugs
• First generations antihistamines:
Diphynhydramine, Doxylamins, Hydroxyzine,
cholrpheniramine
• However, sometimes they are poor choice
(WHY?)
OTC product in Jordan
Based on the combination between
valerian roots and lemon balm leaves
(Melissa leaves)
Valerian
Lemon balm
Valerian roots
• Valeriana officinalis, Valerianaceae
• Contains valerenic acid, which inhibits the
enzyme system responsible for the
metabolism of GABA
• GABA: CNS depression
• Several studies have documented the
beneficial effects of valerian in humans
Melatonin
• Melatonin is a naturally occurring hormone
secreted by the pineal gland,
• Produced only during the nocturnal phase of
the circadian cycle and only in relative darkness
• mild sleep promoting properties when
administered before the period of natural
increase in endogenous melatonin (∼10 pm to
midnight).
Ramelteon
•
•
•
•
A melatonin receptor agonist
approved for treatment of sleep onset insomnia
selective for MT1 & MT2
Metabolized by the liver and should be used with
caution in patients with hepatic insufficiency.
• Contraindicated in patients taking fluvoxamine
(CYP1A2 inhibitor)
• Is more effective in treating DFA compared with
DMS
Benzodiazepines
• Relieve insomnia by ↓sleep latency and ↑ total
sleep time.
• ↑ stage 2 sleep while ↓ REM, stage 3 & stage 4
sleep
• NOT for individuals with sleep apnea, history
of substance abuse, or during pregnancy.
• Avoid concomitant alcohol and other CNS
depressants.
Pharmacokinetics of BDZ receptor
agonists
Short-Acting BDZ: Triazolam
• Appropriate for occasional difficulty in falling asleep
• Induces sleep rapidly: reaches peak plasma
concentrations in 30 minutes & has ultrashort
elimination half-life of 2-5 hours → minimal likelihood
of causing residual daytime sedation
• May be used safely on ‘as-needed basis’
• Rebound insomnia and withdrawal is likely (if
stopped abruptly after 7-10 days use)
• It is safe & effective for non-geriatric patients if used
for ≤ 1 week
Intermediate BDZs
Estazolam, lorazepam & temazepam
• Greater potential for producing daytime sedation &
performance impairment
• Temazepam is less lipophilic → slower onset of effect
(60 min)
Long acting BDZs
Flurazepam, Quazepam
• Longer-acting BDZs have side-effects that persist to next
day.
• Greater potential for producing daytime sedation &
performance impairment
• Not to be used for short term travelers (jet lag)
BDZs Elimination
• With exception of temazepam, which is
eliminated by conjugation,
 all hypnotic BDZs are metabolized by hepatic
microsomal oxidation, then glucuronide
conjugation.
• Oxidation may be inhibited in patients with
impaired liver function, advanced age, or
concurrent use of drugs that inhibit oxidation.
BDZ Side Effects
Side effects are dose dependent:
• Day time sedation & performance impairment
• Tolerance: Triazolam (after 2 weeks)
• Anterograde amnesia :Triazolam.
• To reduce it, use the lowest effective dose &
taper it before D/C .
• Rebound insomnia : occur with high dose of
Triazolam even if intermittently taken.
• CNS effects : confusion, bizarre behavior,
agitation, & hallucination.
“Z-hypnotics”
(Zolpidem and Zaleplon and Eszopiclone)
• selectively bind to GABAA receptors and
effectively induce sleepiness
• Selective for Ω-1 receptor on the BDZ receptor
complex
• Why is this selectivity important? (n=3)
“Z-hypnotics”
(Zolpidem and Zaleplon and Eszopiclone)
• Zolpidem ER and eszopiclone: For chronic
insomnia (3-6 months)
• Abrupt withdrawal of zolpidem tolerance
and withdrawal
• Although abuse potential is less, problematic
in?
Zolpidem
• Rapid absorption and short t1/2
• a low risk of residual daytime sedation in
recommended doses.
• Metabolized by CYP450 D#D interaction
• On empty stomach faster absorption
• Zolpidem CR longer duration of action
(peak= 2 hr)
Zaleplon
• Shorter t1/2 and duration
• least likely of all hypnotic agents to cause
residual daytime sedation and has the least
effect on memory and psychomotor
performance.
• metabolized primarily via aldehyde oxidase,
• CYP3A4 is a secondary route,
• no active metabolites it has less potential
for drug or food interactions
Eszopiclone
• maintains efficacy with no evidence of
tolerance after 6 months of continuous use,
resulting in an FDA approval for long-term use.
• Rapid onset of action + longer duration
• Tmax delayed to 1 hour after a heavy fatty meal
• Less receptor selectivity
• Dose related bitter taste
• Metabolized by CYP450
Treatment Algorithm
NICE guidelines
• When hypnotic drug therapy is considered appropriate, it
is recommended for short periods of time only.
• lack of evidence to distinguish between zaleplon,
zolpidem, zopiclone or shorter acting BDZ hypnotics →
drug with the lowest purchase cost should be prescribed.
• switching from one of these hypnotics to another should
only occur if patient experiences ADEs considered to be
directly related to specific agent.
• patients who have not responded to one of these
hypnotic drugs should not be prescribed any of the
others.