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Transcript
Sleep Disorders
I.
Normal Sleep
a. Active suppression of the RAS
b. Sleep stages
i. Sleep is divided into two stages:
1. Non rapid eye movement (NREM)
a. A stage of sleep characterized by slowing of the EEG
rhythms, high muscle tone
b. Where night terrors can occur
c. Absence of eye movements and thought like mental
activity
d. The brain is inactive while the body is active
e. Made up of 4 stages
i. Stage 1: disappearance of alpha wave and
appearance of theta wave
1. Makes up 5% of sleep time
2. Drowsiness (actually still awake)
ii. Stage 2: K complexes (increase in voltage) and
sleep spindles (increase in frequency)
1. 12-14 cps
2. 45% of sleep
3. Light sleep
4. Longest of all sleep stages
iii. Stage 3: appearance of delta wave
1. 12% of sleep cycle
2. Deep sleep
iv. Stage 4: continuation of delta wave
1. 13%
2. Slow wave deep sleep
f. Amnesia upon waking, enuresis and somnambulism
occur and patients are hardest to arouse in stages 3
and 4
g. Stages 3 and 4 tend to disappear in the elderly
2. Rapid eye movement (REM)
a. A stage of sleep characterized by aroused EEG
patterns, sexual arousal, saccadic eye movements,
generalized muscular atony (deep paralysis) excepted
in the middle ear and the eye muscles and dreams
b. The brain is active but the body is inactive
c. Seen as bursts and sawtooth waves on the EEG
d. Makes up 25% of the sleep cycle
e. Increased BP, RR, pulse and brain RR
f.
g.
h.
i.
i. All in a irregular patter
Also called paradoxical sleep
i. The brain waves look like they do when you
are awake
ii. Patient is easiest to arouse
You remember the dreams you have
Men under go partial or full penile erections
The amount of REM increases as sleep lengthens
i. I.e. it is increased in the second half of the
night
In children, REM makes up 50% of sleep
j.
c. Sleep Cycle
i. Moves from Stage 1 to 2 to 3 to 4 to 3 to 2 to 1 and lastly to REM
ii. Normally under go 4-8 cycles per 8 hour rest
iii. REM latency is 90 minutes
1. The period of time from the moment you fall asleep to the
first REM period
2. Exception: Depression and narcolepsy
a. REM latency is 60 min or less
b. The amount of REM increases
c. Depression may be alleviated by less sleep
iv. REM rebound
1. You can catch up on lost REM but not too much
v. Sleep latency
1. The time needed before you actually fall asleep. Typically
less than 15 min in most individuals.
2. May be abnormal in many disorders such as insomnia
d. Sleep Hygiene
i. Arise at the same time daily.
ii. Limit daily in bed time to the usual amount present before the sleep
disturbance
iii. Discontinue CNS acting drugs such as caffeine, nicotine, alcohol
and stimulants
iv. Avoid daytime naps except when sleep chart shows they induce
better night sleep
v. Establish physical fitness by means of a graded program of
vigorous exercise early in the day
vi. Avoid evening stimulation and substitute radio or relaxed reading
for television
vii. Try very hot, 20 minute body temperature raising bath soaks near
bedtime
viii. Eat at regular times daily and avoid large meals near bedtime
ix. Practice evening relaxation routines such as progressive muscle
relaxation or meditation
x. Maintain comfortable sleeping conditions
e. Characteristics of Sleep
i. From infancy to old age
1. The total sleep time decreases
2. REM percentage decrease
3. Stages 3 and 4 vanish
f. Neurotransmitters of sleep, etc.
i. Serotonin
1. Secreted from the dorsal rapid (sp?)
2. Increased during sleep
3. Initiates sleep (NREM)
4. Tryptophan (precursor of serotonin) increases total sleep
time
ii. Acetylcholine
1. Increased during sleep
2. Linked to REM sleep
iii. Dopamine
1. Increased during sleep
2. Linked to arousal and wakefulness
3. Agonists produce arousal
4. Antagonists decrease arousal and produce sleep
iv. Norepinephrine
1. Decreased during sleep
2. Linked to REM sleep
3. Secreted from the Locus Ceruleus
4. Lowering norepinephrine leads to increased REM
v. Benzodiazepines
1. Suppress stage 4 and, when used chronically, increase sleep
latency
vi. Alcohol intoxication
1. Suppress REM
vii. Barbiturate intoxication
1. Suppresses REM
viii. Major depression
1. Shortens REM latency, increased REM time, suppression of
delta, multiple awakenings and early morning awakening
ix. Melatonin
1. Side effects include hypothermia or low body temperature
a. Predisposes the person to infection
2. Low in people with jetlag
g. Agents to increase sleep
II.
i. Antihistamine (OTC)
1. H1 antagonist
2. Not for use in older people or with alcohol
ii. Valarian Root
1. Calming effect
2. Decreases sleep latency and increases quality of sleep
3. Not for use in pregnant or nursing women
iii. Chamomile
1. Active ingredient is apigehin
2. Acts like a benzodiazopine
3. Also has a coumadin like effect
Sleep Disorders
a. Affects more than 40 million Americans
b. Cost over 16 billion per year
c. Classified by the diagnostic and statistical manual of mental disorders
(DSM-IV) on the basis of clinical diagnosis and criteria and presumed
etiology
d. Narcolepsy
i. A disorder characterized by excessive daytime sleepiness and
abnormalities of REM sleep for a period of greater than 3 months
ii. REM sleep occurs in less than 10-20 minutes. Patients feel
refreshed upon awakening
iii. Presenting symptoms:
1. Sleep attacks (most common)
2. Cataplexy: pathognomonic sigh consisting of a sudden loss
of muscle tone which may have been precipitated by a loud
noise or intense emotion.
a. Patient remains awake if it is a short episode
b. Treated with TCA or SSRI
3. Hypnagogic (going to sleep) and hypnopomic (after waking
up) hallucinations
4. Sleep paralysis
a. Most often occurs during waking when the patient is
awake but unable to move
5. Report falling asleep quickly at night
6. HLA-DR2 is a human lymphocyte antigen that is increased
in patients with narcolepsy
7. Hypocretin (important for appetite and alertness) is
decreased
iv. Treatment:
1. Forced naps at a regular time of day
2. Psychostimulants are preferred or if cataplexy is present
TCAs are preferred
3. Provigil is an alpha agonist used to treat sleep attacks
e. Sleep Apnea
i. 18 million Americans have sleep apnea
ii. A disorder characterized by the cessation of airflow at the nose or
mouth during sleep.
iii. Episodes last longer than 10 seconds each
iv. Characterized by a loud snore followed by a heavy pause.
v. Considered pathologic if the patient has more than 5 episodes an
hour or more than 30 episodes during the night.
vi. In severe cases, patients may experience more than 300 apneic
episodes during the night
vii. Pickwickian syndrome is the presence of sleep apnea in obese
people
viii. Presenting symptoms
1. Usually seen in obese middle aged males (~35 yr old)
2. Sometimes associated with depression, mood changes and
daytime sleepiness
3. Spouses typically complain of partner’s snoring and of
partner’s restlessness during the night
4. Complain of dry mouth in the morning
5. May have headaches in the morning due to the lack of
oxygen
6. Complain of being tired during the day
7. May develop arrhythmias, hypoxemia, pulmonary
hypertension and sudden death
8. Central alveolar hypoventilation
a. Cannot breathe because of the airways
ix. Types
1. Obstructive
a. Muscle atonia in oropharynx or nasal, tongue or
tonsil obstruction
b. Problem with the respiratory structure or due to
obesity
c. More effort for respiratory action leads to an increase
in muscle mass
2. Central
a. Due to a lack of respiratory effort
b. Problem with the respiratory center of the brain
3. Mixed
a. Central at first but prolonged disorder is due to the
collapse of the air way
x. Treatment
1. Continuous positive airway pressure (CPAP)
a. The device used to treat sleep apnea by sending
positive airway pressure at a constant continuous
pressure to help keep an open airway and allowing
the patient to breathe normal through his/her nose
and airway
2. Nasal positive airway pressure (NPAP)
3. Weight loss and surgery (for obstructive)
f. Insomnia or Dysomnia
i. A disorder characterized by difficulties in initiating or maintaining
sleep (problem with normal sleep cycle)
ii. Typically associated with some form of anxiety or anticipatory
anxiety
iii. Many patients have underlying psychiatric disorders such as
depression (more frequently in women)
iv. Other causative conditions include PTSD, OCD and eating
disorders
v. Primary lasts for at least 1 month and occurs 3x a week
vi. Secondary is due to a psychiatric disorder
vii. Can be due to jet lag (2-7 days [change meal time to fool body]),
changing jobs, pregnancy, menstrual irregularity, pain, infection,
tumor and/or vascular lesion
viii. Symptoms
1. Predominant complaint is difficulty initiation or maintaining
sleep
2. Affects the patients level of functioning
3. Frequent yawning and tiredness during the day
4. Sleep state misperceptions
ix. Treatment
1. Consider good sleep hygiene
2. Consider behavioral modification techniques such as
stimulus control
3. If medication are to be used consider benzodiazepines for a
short period of time (max = 2 wks)
a. DOC = ambian or triazolam if they can not fall asleep
and florezapan if the wake up in the middle of the
night
4. Warm socks may help some people fall asleep
x. Differential diagnosis
1. Medical:
a. Pain, CNS lesions, endocrine diseases, aging, brain
stem lesions, alcohol, diet or medications
2. Psychiatric:
a. Anxiety, tension, depression and environmental
changes or other sleep disorders
g. Parasomnias
i. Nightmares
1. Occur during REM
2. Patient has a memory of the event upon awakening
3. Increased during times of stress
4. Reported by 50% of the population
5. Usually not treated but you could use a REM suppressant
such as a TCA
ii. Night terror
1. Occurs during Stages 3 & 4
2. Awakening by scream or intense anxiety
3. NO memory of the event the following day
4. Seen more frequently in children
5. More common in boys
6. Runs in families
7. Treatment is rarely required but if medication is needed
consider benzodiazepines
8. Closely related to sleep walking and temporal epilepsy
iii. Sleep talking
1. Occurs in all stages of sleep
2. Common in children and tired people
3. Usually involves a few words
4. May accompany night terrors and sleepwalking
5. No treatment is necessary
iv. Sleepwalking
1. Also known as somnambulism
2. Occurs in stages 3 & 4
3. Sequence of behaviors with out full consciousness
4. May perform preservative behaviors
5. Usually terminates in awaking followed by confusion
6. May return to sleep without any memory of the event
7. Begins at a young age (4-8) and prevalence increases at 12
years of age
8. More common in boys
9. May find neurological condition
10. Sleep deprivation and stress my exacerbate
11. Need to assure patient safety
12. Use drugs to suppress stages 3 and 4 such as
benzodiazepines
v. Restless leg syndrome
1. Sensation of deep leg movement
III.
2. Alleviated by leg massage
vi. Sleep seizure
1. Form of epilepsy exacerbated by sleep
Sedative-hypnotic drugs
a. Includes benzodiazepines (15 types--alprazolam, diazepam, etc),
barbiturates (phenobarbital) and alcohols
b. Used to eliminate anxiety and increase sleepiness
c. Benzodiazepines are used the most
d. Barbituates were the first drugs used clinically
e. Alcohol was the first ever used
f. Most of the drugs that are used for anxiety states cause dose-dependent
depression of the CNS that extends to sleep inducing effects (hypnosis)
and possible anesthesia
g. In overdose, depression of respiratory and vasomotor centers, dose
response relationship is better for the benzodiazepines than for alcohol
and barbiturates
h. Other actions include anticonvulsant and muscle relaxing effects
i. Drug induced sleep changes REM and suppresses the amount of REM
j. All the drugs have differing levels of psychomotor depression
k. Alcohol with increase the CNS effects
l. MOA:
i. Most facilitate the action of GABA
1. GABAA receptor activation leads to increased Cl ion influx
and GABAB receptor activation causes an increase in the
efflux of K
a. Both lead to membrane hyperpolarization
ii. The pentapeptide structure of the GABAA receptor has binding
sites for benzodiazepines (BZ) and for barbiturates and alcohol
1. All different sites for each
2. Can be used to prevent OD of a specific drug
3. 5 transmembrane domains
a. Activation of any opens the Cl channel
iii. BZs potentate GABA by increasing the frequency of Cl ion channel
opening
1. This action is blocked by flumazenil, a BZ receptor
antagonist
iv. Barbiturates increase the duration of Cl ion channel opening and at
a high dose, they also open Cl ion channels and block Na channels
1. Flumazenil does not block the effects of barbiturates and
ethanol
v. BZ receptor mechanisms are heterogeneous.
1. BZ1 receptors mediate hypnotic actions
a. Zolpedidem is not an BZ but binds to the BZ receptor
2. BZ2 receptor may play a role in memory, sensor motor and
cognitive functions
m. Benzodiazepins
i. Uses and Effects
1. They enhance the function of GABA in the CNS
2. They are useful in treating the anxiety that accompines some
forms of depression and schizophrenia
3. Should not be used to alleviate the normal stress of everyday
life because of addiction potential and should only be used
for short periods of time
4. CNS depression occurs (sedation, disinhibition, nystagmus,
ataxia, respiratory depression) at very high doses
5. Additive with other CNS depressants including ethanol
6. Drug over dose is seldom lethal unless other CNS
depressants are taken concurrently
7. Flumazenil IV reverses it’s effects
a. Possible anterograde amnesia at conventional doses
ii. Flunitrozepam
1. Date rape drug
iii. Metabolites
1. Are lipophilic and are rapidly and completely absorbed after
oral administration
2. Metabolized in the liver the form active metabolites
3. They are excreted in the urine as glucoronides or oxidized
metabolites
4. Three BZ under go extrahepatic metabolism and do not form
active metabolites
a. Oxazepam, Temazepam and Lorazepan
i. OTL: outside the liver
iv. Tolerance and Dependency
1. It may occur if high doses of the drug are given over a
prolonged period.
2. Cross tolerance can occur
a. Individuals tolerant to one drug will be tolerant to
other drugs in the same class but not to drugs in other
classes
3. Abrupt discontinuation of drug results in withdrawal
symptoms after a number of days (long t ½)
4. Tolerance is possibly due to a down regulation of BZ
receptors
a. The antianxiety effects are less subject to tolerance
than the sedative and hypnotic effects
5. Drugs that are more potent and rapidly eliminated
(lorazepam and triazolam) have more frequent and severe
withdrawal problems
6. The less potent and more slowly eliminated drugs
(flurazepam and quazepam) continue to improve sleep even
after discontinuation
7. May disturb intellectual functioning and moter dexterity
v. Specific Drugs
1. Alprazolam
a. Used for short and long term treatment
b. Used for anxiety, panic disorders (DOC) and phobias
c. Most commonly used anxiolytic
2. Diazepam
a. Very similar to cholordiazepoxide, clorazepate and
oxazepam
b. Used for anxiety (primary use), preoperative
sedation, muscle relaxation (treating spasticity form
degenerative disorders such as MS and cerebral
palsy)
c. DOC for terminating grand mal epileptic seizures and
status epilepticus and acute treatment of alcohol
withdrawal
d. Longest acting BZ
e. Forms 3 metabolites
3. Lorazepam
a. Used for anxiety, preoperative sedation and status
epilepticus (primarly)
b. No active metabolites
4. Flurazepam
a. Helps people fall asleep
b. Used for sleep disorders (reduces both sleep
induction time and the number of awakenings and
increases the duration of sleep
c. Lng acting with little rebound insomnia
d. Effective up to 4 weeks
e. T ½ = 85 hours
5. Temazepam
a. Used for sleep disorders (reduces frequent awakening
and inability to stay asleep)
b. Taken several hours before bedtime
c. Intermediate acting
d. Slow oral absorption
e. Peak sedative effect occurs 2-3 hours after oral dose
IV.
6. Triazolam (Halicon)
a. Causes significant amnesia
b. Must be used carefully in elderly patients
c. Used to induce sleep in patients with recurring
insomnia and difficulty in going to sleep
d. Short acting
e. Possibility for early A.M. waking
f. Sever rebound insomnia
g. Must be used intermittently
7. Zolpidem
a. Not a BZ but acts on the BZ receptors
b. Used for sleep disorders
c. BZ1 selective
d. Causes less dependence, tolerance and abuse
e. Not effective in chronic anxiety seizure disorders or
muscle relaxation
8. Zaleplon
a. Not a BZ
b. Used for sleep disorders
c. Use possibly for early awakenings
d. Very short acting
e. Causes daytime sedation
f. Not effective in chronic anxiety seizure disorders or
muscle relaxation
g. Causes less dependence, tolerance and abuse
vi. Duration of Action
1. Short acting
a. 3-8 hours
b. Oxazepam and Triazolam
2. Intermediate acting
a. 10-20 hours
b. Alprazolam, Estazolam, Lorazepam and Temazepam
3. Long acting
a. 1-3 days
b. Clorazepate, chlordiazepoxide, diazepam,
flurazepam, quazepam
Other drugs
a. Buspirone
i. No effects on GABA systems
ii. Possible partial agonist at 5HT1A receptors
iii. There are some affinities of DA2 dopamine receptors and 5HT2
serotonin receptors
iv. No sedating and no additive CNS depression with other drugs
v.
vi.
vii.
viii.
ix.
No muscle relaxant and no anticonvulsant activity
Useful for GAD
Does not cause dependence
Should not be used with a MAOI (causes hypertension)
Useful in long term therapy of chronic anxiety with the symptoms
of irritability and hostility
b. Antihistamines
i. Hydroxylzine is useful in patients with anxiety who have a history
of drug abuse
ii. Often used for sedation prior to dental procedures or surgery
c. Opioid analgesics promote sedation and sleep
d. Barbiturates
i. Uses:
1. Dose dependent CNS depression
a. Respiratory, coma and possible mortality
b. No specific antidote for OD
2. Additive CNS depression with other drugs
3. All end in “tal” and all (except thiopental and methohexital)
end in “barbital”
ii. Metabolites
1. Hepatic metabolism leads to active metabolites
2. Induction of Cyp450 is characteristic and my lead to drug
interactions
3. Increases heme synthesis and so is contraindicated in
porphyries
iii. Tolerance and dependence
1. Occurs with chronic use
2. Withdrawal symptoms may be severe, especially with short
acting barbiturates
a. Anxiety, agitation, hyperflexia, seizures and post
seizure depression of vital functions
b. TX: long acting BZs such as diazepam
iv. Duration of Action
1. Long acting
a. 1-2 days
b. Phenobarbital
2. Short acting
a. 3-8 hours
b. Pentobarbital, secobarbital, amobarbital (useful for
unexplained muteness)
3. Ultra short acting
a. 20 minutes
b. Thiopental (anesthetic agent)
e. Alcohols
i. 1st historic use
ii. Ethylene glycol
1. Antifreeze
2. Sweet taste
3. Converted to glycoaldehyde (toxic) and then glycolic and
oxalic acid by alcohol dehydrogenase
4. Causes CNS depression, metabolic acidosis and
nephrotoxicity
5. OD treatment is fomepizole, a long acting inhibitor of
alcohol dehydrogenase and hemodialysis
a. Ethanol can be used as a competitive inhibitor
iii. Methanol
1. Converted to formaldehyde (toxic) and formic acid by
alcohol dehydrogenase
2. Causes severe anion gap metabolic acidosis, ocular damage
(blindness) and respiratory failure
3. OD treatment is fomepizole, a long acting inhibitor of
alcohol dehydrogenase and hemodialysis
a. Ethanol can be used as a competitive inhibitor
iv. Ethanol
1. Converted to acetaldehyde by dehydrogenase in the
cytoplasm
a. Causes N&V, headache, hypotension
b. Combines with foliate and inactivates it
c. Combines with thiamine to decrease availability
2. Acetaldehyde is converted to acetic acid by dehydrogenase
in the mitochondria
a. Inhibited by disulfiram
i. Used to treat alcoholism
ii. Many drugs can have a disulfiram like reaction
3. Increasing plasma levels of alcohol can lead to
a. Sociability, Gait disturbances, decreased reaction
time, ataxia, impaired motor and mental skills,
impaired memory, coma and death
b. Also causes hypoglycemia, fatty liver and lipemia,
muscle wasting (long term alcoholic and poor food
intake) and gout (lactate competes with urate for
excretion)