Now days due to various lifestyle people cannot able to sleep and having good sleep There is difficulty in initiation, maintaining, & awakening during sleep. I will try to help for understanding normal sleep, neurophysiology, sleep disorder & its Pharmacotherapy by this seminar session.

1. Sleep Disorders
and
Management
Dr. Jeenal Mistry
First year resident,
Department of Pharmacology,
Government Medical College, Surat.

2. ▰ Introduction
▰ Stages of sleep
▰ Neurophysiology of sleep and wakefulness
▰ Classification of sleep disorder
▰ Common sleep disorder and management
▰ Conclusion
▰ References
OVERVIEW

3. What is sleep?

4. ➢ Sleep is state of unconsciousness in which the brain is relatively
more responsive to internal than external stimuli.
➢ A good night’s sleep is when you fall asleep quite easily, do not fully
wake up during the night, do not wake up too early, and feel
refreshed in the morning.
➢ The origin of sleep and the meaning of dreams have fascinated people
for centuries-
Edgar allen poe described sleep as “ little slices of death”
William Shakespeare regarded it to be “chief nourisher in life’s
feast”

5. Infants 4 months to 12 months: 12 to 16 hours per 24 hours, including naps
1 to 2 years: 11 to 14 hours per 24 hours, including naps
3 to 5 years: 10 to 13 hours per 24 hours, including naps
6 to 12 years: 9 to 12 hours per 24 hours
13 to 18 years: 8 to 10 hours per 24 hours
Adults need at least 7 hour of sleep per night
Older: 6 to 7 hour of sleep per night

6. Stages of Sleep

8. ▰ Stress level
▰ Low mood and Depression
▰ Worry or Anxiety
▰ Physical health conditions
▰ Medications
▰ Worry about sleep
▰ Diet (caffeine, alcohol, excessive smoking)
Sleep patterns are impacted by:

9. Neurophysiology of sleep and wakefulness

10. Internal
clock
Melatonin &
adenosine
Zeitgebers
Circadian
Process
Need for
sleep
Time since
last adequate
sleep
Homeo-
static
Process

11. Circadian rhythm

13. Flip-Flop Switch
LC,RN,
TMN
• Monoaminergic nuclei inhibit sleep-promoting neurons in the VLPO, which in turn relieves inhibition of the
monoaminergic cells and Orexin neurons
• The Monoaminergic cells: Raphe nuclei(RN), locus coeruleus(LC), & Tubero-mamillary nucleus(TMN)
directly stimulate wakefulness
Orexin
• Orexin neurons act to promote the activity of monoaminergic nuclei
VLPO
• VLPO neurons promotes sleep
• The VLPO neurons inhibit the monoaminergic neurons & in turn, relieve their own inhibition
• The disinhibition of the VLPO neurons inhibits Orexin neurons which in turn prevents activation of
monoaminergic nuclei

14. An overview of the flip-flop switch model
Orexin
Awake
ON

15. An overview of the flip-flop switch model
Orexin
Sleep
OFF

17. Classification of Sleep disorders

19. Common sleep disorder and management

20. Insomnia Disorder

21. Insomnia is dissatisfaction with sleep, characterised by difficulty falling a
sleep (sleep latency >30 min), difficulty maintaining sleep (Total sleep
time <5.5 to 6 hr), or difficulty returning to sleep after awakenings during
the night.
Insomnia
Transient
3 days
Short-Term
3 days- 3 weeks
Chronic
3 weeks

22. ▰ Congestive heart failure
▰ COPD, Asthma
▰ Chronic renal failure, Prostatic hypertrophy
▰ Gastroesophageal reflux disease
▰ Fibromyalgia, Osteoarthritis, Rheumatoid arthritis
▰ Hyperthyroidism, Diabetes
▰ Parkinson’s disease, Cerebrovascular disease
▰ Menopause
Medical disorder & condition associated with
Insomnia:

23. ▰ Major depression, Bipolar disorder
▰ Generalised anxiety disorder, panic disorder, PTSD
▰ Schizophrenia
▰ Substance use disorder
Psychiatric condition associated with
Insomnia:

24. Diagnosis
▰ EEG: Fast β activity
during sleep,
Normally fast β
activity present only
during wakefulness
24

25. ▰ Alcohol, Caffeine
▰ Nicotine, Cannabis
▰ Anti depressant, Corticosteroids
▰ β Blocker
▰ ACE inhibitors
Medications and Substances associated with
Insomnia

26. ▰ Non Pharmacological
1) Improve sleep hygiene
2) Cognitive Behaviour therapy
3) Stimulus control therapy
4) Relaxation training
5) Sleep restriction therapy
Treatment

27. ▰ Pharmacological
1) Benzodiazepines: GABA A Chloride channel agonist
(α-γ)
DOC: Temazepam, Estazolam , Quazepam, Triazolam,
Alprazolam
2) Atypical Benzodiazepine/ Z Compounds
3) Melatonins
4) Other: 1) Suvorexant, 2) Doxepin, 3) Ritanserin
Treatment

28. Bezodiazepines
α
α1 α2
Sedation
Anxiolytics
Anti-epileptic
Muscle Relaxant

30. Triazolam
• Potent BZD
• Good for sleep induction but poor for
maintaining
• Short duration of action
• Withdrawal phenomenon- patient may
wake up early morning & feel anxious
Alprazolam
• Potent & intermediate duration of
action
• Night time hypnotic due to rapid
oral absorption
• Withdrawal phenomenon
Temazepam
• Intermediate duration of BZD
• Good for sleep onset difficulty
• Free of residual effect

31. ▰ Act on α1 subunit
▰ Addiction property
▰ Antidote: Flumazenil (Blocks α/γ {α1-α2}
subunit)
Atypical Benzodiazepines/ Z Compounds

32. Z Compounds
Zopiclone
Eszopiclone
Zolpidem
Intermediate
Zaleplon
Shortest acting
Longest acting
Use Chronic Insomnia
Transient Insomnia
Sleep onset Insomnia
JET lag Insomnia
ADR: Less/No sleep cycle distortion

33. Ramelteon
Agomelatine
Tasimelteon
• MT1 + MT2 receptor agonist (induce sleep)
• Shift workers, elderly , JET LAG
• P/K: CYP1A2
• BA:2%
• S/E: Somnolence
• MT1 + MT2 Agonist: Insomnia
• 5HT2C Antagonist: Depression
• Maintain circadian rhythm
in Blind
Melatonin agonist

34. ▰ Selective antagonist of the orexin receptor OX1R & OX2R
▰ Selectively increase REM sleep in the first 4 hour after dosing, increase
NREM N2 stage, decrease latency to sleep onset
▰ Strong effect on increasing total sleep time
▰ t1/2= 12 hours
▰ S/E: somnolence, headache, cough, dry mouth
Orexin receptor antagonist
Suvorexant (Belsomra)

35. ▰ Tricyclic anti-depressant with anti histaminic effects
▰ Doxepin inhibits the reuptake of serotonin and norepinephrine and
antagonizes cholinergic, histaminergic, and α-adrenergic activity
▰ Increase REM sleep, increase NREM N2 stage, decrease latency to
sleep onset
▰ S/E: sedation, fatigue, constipation, lethargy
Doxepin

36. Narcolepsy

37. ➢ Narcolepsy is characterised by difficulty in sustaining wakefulness,
poor regulation of REM sleep, and disturbed nocturnal sleep.
➢ Narcolepsy is caused by loss of the hypothalamic neurons that produce
the orexin neuropeptides.
Cataplexy
• Sudden bilateral loss
of muscle tone with
preserved
consciousness and
often precipitated by
strong emotion and
as laughter
Sleep paralysis
• The person
temporarily loses the
ability to talk or
move when he or she
wakes up or first
become drowsy
Hypnagogic
hallucination
• vivid dream like
experience that take
place when person is
sleeping, falling
asleep, or awakening
Automatic
behaviour
• A person continues to
function, such as
talking & putting
objects in different
places during sleep
but he or she does
not recall doing such
activity after
awakening.

38. Diagnosis
▰ Polysomnography
▰ Multiple sleep
latency test

39. ▰ Non- Pharmacological
1. Eating light meal during the day
2. Napping after meals
▰ Pharmacological
Treatment

40. Methyl-
phenidate
•It’s chemically & pharmacologically similar to amphetamine
•It blocks reuptake of norepinephrine and dopamine into presynaptic neurons, stimulate CNS
•That’s why it is used in Narcolepsy, Attention Deficit Hyperactivity Disorder
•t1/2: 4-6 hour, Central effect last much longer
•S/E: anorexia, insomnia, growth retardation, abdominal discomfort
Modafinil
•Weak dopamine reuptake inhibitor
•Indirectly activate release of orexin neuropeptide & histamine from lateral hypothalamus & TMN for contribute to heighted
arousal
•Increase attention span and improve accuracy that has been compromised by fatigue and sleepiness.
•t1/2: 15 hours
•S/E: insomnia, Headache (mainly) other: nausea, dizziness, confusion, amnesia, tremors, hypertension
Dextro-
amphetamine
•The Dextrorotary enantiomer – potent agonist of trace amine-associated receptor 1(TAAR1)
•Activation of TAAR1—Increase cAMP production via adenyl cyclase activation—inhibit function of dopamine transporter,
norepinephrine transporter, serotonin transporter
•Produce CNS Stimulation
•t1/2: 9-11 hours
•S/E: hypo/hypertension, tachycardia, erectile dysfunction, blurred vision, rhinitis

41. For Cataplexy:
1) Venlafaxine :
• Antidepressant- serotonin & noradrenaline reuptake inhibitors
• Fast onset of action
• S/E: nausea, sweating, anxiety, dizziness
2) Fluoxetine :
• Selective serotonin reuptake inhibitor (Bicyclic compound)
• Longest acting, slower onset of action
• t1/2= 2 days
• S/E: Insomnia, headache, weakness, somnolence

42. 3) Protriptyline :
• Anti-depressant, TCA
• Neurotransmitter (NE & Serotonin)
reuptake inhibitor
• Increase concentration of
neurotransmitter in the CNS
• t1/2: 54-92 hour
• S/E: headache, fatigue, agitation,
insomnia 4) Clomipramine :
• Tricyclic antidepressant
• Highest seizure precipitating potential
• Serotonin and norepinephrine uptake
affected
• t1/2= 32 hr
• S/E: headache, fatigue, xerostomia,
constipation

43. Sodium oxybate (Xyrem)
• CNS Depressant
• Taken immediately before sleep & again 2 to 4 hr later
• Increase in slow wave sleep, decrease number of nocturnal
awakening, enhanced sleep continuity
• GABA-B activation
• FDA approved in 2002 for treatment of excessive daytime
sleepiness & cataplexy in narcoleptic patients.
• S/E: headache, pharyngitis, enuresis, vomiting

44. Hyper-somnolence Disorder

45. ➢ Excessive sleepiness despite a normal sleep duration at night.
➢ Repeated episode of sleep during daytime hours, prolonged night
time sleep, typically 9 hours or longer, and/or difficulty
transitioning from sleep to wakefulness
➢ Must be present at least 3 days per week for at least 3 months.
Types of hypersomnia

46. Non-pharmacological
• Setting regular sleep-wake
schedule
• Use multiple alarms
Pharmacological
• Monoaminergic
stimulants(methylphenidate,
dextroamphetamine)
• Modafinil
• Bupropion
Treatment

47. Bupropion
▰ It is Norepinephrine-dopamine reuptake inhibitor and antagonist of
several nicotinic receptor
▰ Increase REM sleep latency
▰ Highest seizure precipitating potential
▰ t1/2= 15-25 hour
▰ S/E: dry mouth, constipation, sweating, tremor, insomnia, anxiety

48. Breathing related sleep disorder

49. Characterised by sleep disruption leading to excessive sleepiness
or insomnia caused by sleep related breathing disturbances such
as apnea , hypopnea, & oxygen desaturation.
➢ Types :
1. Obstructive Sleep Apnea Hypopnea (OSAH)-obstruction of airway
2. Central Sleep Apnea (CSA)- absence of respiratory effort
3. Sleep Related Hypoventilation (SRH)
❖ All are associated with impaired ventilation during sleep
❖ With intermittent or sustained hypoxemia
❖ Sleep disruption
❖ Result in awakening--daytime sleepiness--fatigue

50. Obstructive sleep apnea hypopnea
Diagnosis
• Polysomnography at
least an AHI: 15,
absence of symptoms
• AHI>15 with
predominantly
obstructive respiratory
events
Symptoms

51. Pharmacological
Treatment
Management of OSAH
Non-Pharmacological
Treatment
Devices such as positive airway pressure(PAP),
continuous positive airway pressure(CPAP), Bilevel
positive airway pressure(BiPAP), Nasal continuous
positive airway pressure(nCPAP).
Oral appliances such as Mandibular
advanced splints(MAS).
Surgeries such as Tracheostomy,
Uvulopalatopharyngeoplasty, Maxillo-
mandibular advancement, Tonsillectomy,
Adenoidectomy, Bariatric Surgery
Life style modification
Weight loss,
Positional Therapy,
Educational &
Behaviour Therapy

52. ▰ Characterised by variability in respiratory effort that
lead to episodes of apnea & hypopnea during sleep
Central Sleep Apnea(CSA)
1) Cheyne-strokes breathing –Heart
failure, stroke, renal failure
2) Central sleep apnea comorbid
with opioid use- such as
methadone
3) Idiopathic central sleep apnea
Subtype
• CPAP
• Adaptive servo-ventilation(ASV)
• Low flow oxygen Therapy
• CSA comorbid with opioid use
may improve with reduction in
opioid dosage
Treatment

53. ▰ Characterised by inadequate ventilation during sleep
Sleep related Hypoventilation(SRH)
Symptoms
• Fatigue
• Sleepiness
• Awakening during
sleep
• Morning headache
• Insomnia
Diagnosis
• PSG- Abnormal
elevation of Co2 level
• Obesity
hypoventilation
syndrome (BMI >30
kg/m2 Pco2>45 mmhg
Treatment
• Bi-level positive
airway pressure

54. Circadian rhythm sleep-wake disorder

55. ➢ Persistent or recurrent pattern of sleep-wake disturbance characterised
by abnormal timing of sleep or sleep propensity relative to the physical
environment
➢ Disorder of sleep timing can be either organic (i.e., due to an
abnormality of circadian pacemaker or environmental/behaviour (i.e.,
due to a disruption of environmental synchronizer).
Delayed sleep-wake
phase disorder
• Reported sleep onset and
wake times persistently
later than desired
• Actual sleep times at nearly
the same clock hours daily
• If conducted at the habitual
delayed sleep time,
essentially normal sleep on
polysomnography
Advanced Sleep-
wake phase disorder
• Individual exhibit a stable
sleep-wake cycle that is
advanced in relation to
conventional times.
• History of falling a sleep
between 6 pm to 9 pm, and
waking up between 2 to 5
pm

56. Non-24-hour sleep-wake
rhythm disorder
• N24SWRD most commonly occurs
when the primary synchronizing
input(i.e., the light-dark cycle) from the
environment to the circadian
pacemaker is lost (as occur in many
blind people with no light perception),
and the maximal phase advancing
capacity of the circadian pacemaker in
response to non-photic cues can’t
accommodate difference between the
24-h geophysical day & intrinsic period
of the patient’s circadian pacemaker,
resulting in loss of entrainment to the
24-h day.
Shift Work Disorder
•Characterised by sleep &
wake disturbances for at
least 3 months in the
context of chronic shift
work
•Excessive daytime
sleepiness
•Difficulty falling asleep
while allowed for rest
JET LAG Disorder
•With the advent of highspeed
air level, an induced
desynchrony between circadian
and environmental clocks
become possible.
•When individual rapidly travels
across many time zones, either
circadian phase advance or a
phase delay is induced,
depending on the direction of
travel.

57. Diagnosis & Treatment
• Sleep logs and/or
actigraphy measurements
for 7-14 days
• Dim-light melatonin test
• Core body temperature
• Both light & melatonin,
given at specific time can act
to reset the circadian clock
• Behavioural intervention
• Modafinil or armodafinil 30-
60 min before the start of an
8-h overnight shift for use in
shift workers with excessive
day time sleepiness

58. Non-REM sleep arousal disorder

59. These disorder is recurrent episode of partial arousals from sleep,
usually during the first third of night.
Patients affected by this disorder carry out automatic motor activities that range from simple to complex
Individuals may walk, urinate inappropriately, eat, exit the house or drive a car with minimal awareness.
Sleepwalking arise from NREM stage N3 sleep
EEG: slow cortical activity of deep NREM sleep
Treatment: Relaxation technique, Antidepressant (Benzodiazepine), Tricyclic Anti-depressant (Imipramine)
Commonly in young child
During first few hours of sleep in NREM stage N3
Child often sits up during sleep & screams, exhibiting autonomic arousal with sweating, tachycardia, large pupils, hyperventilation
Treatment: Reassuring the parents that the condition is self limited
Sleep walking(Somnambulism)
Sleep Terror

60. Bed wetting occurs during the sleep in young
Treatment: Bladder training exercise, behavioural therapy
Pharmacotherapy: Desmopressin, oxybutynin chloride or imipramine
It is an involuntary, forceful grinding of teeth during sleep
At age onset of 17-20 years and remission at age of 40 years
Treatment: Mouth guard, Stress management, Benzodiazepines
Sleep enuresis
Sleep bruxism

61. Desmopressin :
• Selective V2 agonist
• Longer acting
• Decreasing urine volume at night &
decreasing intravesicular pressure
• t1/2= 1-2 hr
Oxybutynin Chloride
• Vasico-selective anticholinergics
• High affinity for receptor in
urinary bladder & salivary glands
• Selective M3 & M1 subtype
• Used fir detrusor instability
resulting in urinary frequency &
urge incontinence

62. Nightmare disorder

63. • Bad dreams & nightmare are normal
• What differentiates Nightmare disorder from bad dreams & nightmare is
the frequency of events, degree of dysphoria, and the extent of
distress or impairment in social, occupational, or other important
areas of functioning.
• Common in physical/sexual abuse and Post Traumatic Stress Disorder
(PTSD)
• Treatment: Prazosin
Cyproheptadine, Guanfacine also helpful
Dream rehearsal therapy

64. Prazosin
•Selective α1 blockers
•Postsynaptic α- adrenergic
receptors
•Causing arterial & venous dilation
& subsequent decrease in blood
pressure
•t1/2= 2-3 hr
•S/E: Dizziness, drowsiness,
headache, weakness
Cyproheptadine
•Serotonin & histamine antagonist
•Competitively inhibits H1 receptor
•Mediating bronchial constriction,
smooth muscle contraction, CNS
depression
•Anti-5HT2 effects
•S/E: dizziness, insomnia, tremor
Guanfacine
•Selective α2-adrenergic receptor
agonist
•Bind postsynaptic α2A
adrenoceptors in the prefrontal
cortex, which may improve delay-
related firing of prefrontal cortex
neurons
•t1/2= 16 hr
•S/E: Xerostomia, somnolence,
headache

65. REM-sleep behaviour disorder

66. • Defined by repeated episode of awakening from sleep
accompanied by agitated or violent behaviours, such as shouting,
screaming, kicking, and punching.
• Commonly occurs second half of sleep period
• Patient may have injuries including- ecchymosis, laceration, fractures
• Many patient adopted self protection measures such as- tethering
themselves to bed, using sleeping bags, pillow barricades
• It is frequent harbinger of neurodegenerative disorder (Parkinson’s)
• Treatment: Clonazepam, Melatonin

67. Restless leg syndrome

68. • RLS patients report an irresistible urge to move the legs
• A creepy-crawly or unpleasant deep ache within the thighs or calves
• Much worse in evening & first half of night
• Aggravated by inactivity, sitting prolonged time caffeine, alcohol
• Relieved by movement, stretching, massage
• Causes: Iron deficiency anaemia, Vit B12 deficiency
Treatment: treat underlying cause
Pharmacotherapy:
A) Agonist of dopamine D2/3 receptors : 1) Pramipexole or
2) Ropinirole
B) Alpha-2-delta calcium channel : 1) Gabapentin
2) Pregabalin
C) Benzodiazepines
D) Opioid

69. Pramipexole or
Ropinirole
Selective Agonist of dopamine D2/3
receptors
• t1/2= 8.5 hr
• S/E: Somnolence, insomnia, dizziness
Gabapentin
• Anti-convulsant
• Binds to α2δ subunit of voltage sensitive
calcium channel
• Increase slow wave sleep without affecting
other polygraphic variables & without
causing increased drowsiness during day
time
• t1/2= 5-7 hr
• S/E: Ataxia, fatigue, somnolence
Pregabalin
• Anti-convulsant
• Binds to α2δ subunit of voltage sensitive
calcium channel
• Increase duration of NREM & REM sleep
episode & reducing their number
• S/E: Dizziness, somnolence

70. Periodic limb movement disorder

71. • PLMD also called as nocturnal myoclonus, characterised by
periodic episode of spontaneous, repetitive, highly stereotyped
involuntary limb movement that occur during sleep.
• The movement resemble a triple flexion reflex with extensions of the
great toe & dorsiflexion of the foot for 0.5-5.0 sec
• Which recur every 20-40 s during NREM sleep
• Diagnosis: Polysomnogram- recording of anterior tibialis & other
muscle, EEG
• Treatment: Benzodiazepine, Levodopa (Dopamine precursor-
important neurotransmitter regulating muscle movement)

72. Substance/Medication induced
sleep disorder

73. • This is a prominent sleep disturbance associated with
use, intoxication, or withdrawal from medication or
substance.
• Associated with depression, anxiety
• Medications and Substances associated with Insomnia
Alcohol, Caffeine
Nicotine, Cannabis
Anti depressant, Corticosteroids
β blocker
ACE inhibitor

74. ▰ This seminar will help to Learn-
▰ The term Sleep & Sleep disorder
▰ Sleep stages, their electrophysiologic correlates
▰ Basic neurophysiologic mechanism that promote brain arousal and
wakefulness, sleep onset & maintenance
▰ Basic circadian process and their interaction with sleep-wake cycle & drug
useful on it
▰ Recognize several sleep disorder & their Pharmacotherapy
▰ The rationale of certain classes of drug to treat specific sleep-related disorder
Conclusion

75. ▰ Goodman & Gillman The Pharmacological Basis therapeutics 13th
edition
▰ Harrison’s Principles of Internal Medicine 20th edition Volume1
▰ Essential of Medical Pharmacology 8th edition KD Tripathi
▰ Sleep and Sleep Pharmacology Ahmed S. BaHammam, David N.
Neubauer, Seithikurippu R. Pandi-Perumal article
▰ https://doi.org/10.1124/pr.117.014381 PHARMACOLOGICAL
REVIEWS Pharmacol Rev 70:197–245, April 2018
References

76. Good Sleep
Good Health

77. Lavender Chamomile Magnolia Bark
Valerian root
Mint Ashwagandha