The presentation contains Introduction to Hypothalamus, functions of hypothalamus, Brain waves, Stages of sleep, Sleep disorders, Description of Orexin and its Antagonists and Conclusion.

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2. OREXIN RECEPTOR ANTAGONISTS:
A NEW CLASS OF SLEEPING PILL
PRESENTED BY
CHAITRA. N.
1ST YEAR M-PHARM.
DEPT.OF PHARMACOLOGY.
PESCP,BANGALORE.

3. INTRODUCTION TO HYPOTHALAMUS
Hypothalamus is small part of the diencephalon located inferior to thalamus.
It is composed of a dozen of nuclei.
Four major regions of hypothalamus where nuclei are located are :
 Mammillary region - located adjacent to the midbrain. It includes mammillary
bodies & posterior hypothalamic nuclei serve as relay stations for reflexes related
to the sense of smell.
 Tubular region includes the dorsomedial nucleus, ventromedial nucleus, arcuate
nucleus connects the pituitary gland to the hypothalamus.
 Supraoptic region is located superior to the optic chiasm contains the
paraventricular nucleus, supraoptic nucleus, anterior hypothalamic nucleus &
suprachiasmatic nucleus.
 Preoptic region is located anterior to the supraoptic region. It contains the medial
and lateral preoptic nuclei.
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4.  Control of the ANS.
 Production of hormones.
 Regulation of emotional and
behavioral patterns.
 Regulation of eating and drinking.
 Control of body temperature.
 Regulation of circadian rhythms and
states of consciousness.
The suprachiasmatic nucleus of the
hypothalamus serves as the body’s
internal biological clock as it establishes
the patterns of sleep-wake cycle.
FUNCTIONS OF HYPOTHALAMUS
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5. BRAIN WAVES
 Brain neurons generate millions of nerve impulses which collectively form
electrical signals called Brain waves.
 Brain waves generated by neurons can be detected by sensors called electrodes
placed on the forehead & scalp. A record of such waves is called an
Electroencephalogram (EEG).
Electroencephalogram are useful both in studying normal brain functions such
as changes that occur during sleep and in the diagnosis of various brain disorders like
epilepsy, tumors, trauma, metabolic abnormalities and degenerative diseases.
Four types of brain waves:
 Alpha waves.
 Beta waves.
 Theta waves.
 Delta waves.
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6. STAGES OF SLEEP
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7. Sleep: A natural periodic state of rest for the mind & body, in which the eyes usually
close & consciousness is completely or partially lost, so that there is a decrease in
bodily movement & responsiveness to external stimuli.
Sleep disorders are changes in sleeping patterns or habits. It can affect overall
health, safety and quality of life.
Signs and symptoms of sleep disorders include excessive daytime sleepiness,
irregular breathing or increased movement during sleep, difficulty sleeping and
abnormal sleep behaviors.
Causes for the sleep disorders
 Pain
 Cardiovascular Disease
 Psychiatric Diseases
 Neurological Diseases
 Metabolic Disorders
SLEEP DISORDERS
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8. INSOMNIA
 Sleep disorder in which there is an inability to fall asleep or to stay asleep for long
time.
 Symptoms includes prolonged night awakenings,
daytime tiredness or sleepiness, irritability,
depression or anxiety, tension headaches.
PARASOMNIAS
 Sleep disorders that involve abnormal movements, behaviors, emotions,
perceptions & dreams that occur while falling asleep, sleeping, between sleep
stages or during arousal from sleep.
 Symptoms includes sleep walking and talking,
confusional arousals, night terrors & sleep
related groaning, bed wetting.
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9. DYSSOMNIAS
 It is a primary disorder of initiating or maintaining sleep or of excessive
sleepiness & is characterized by a disturbance in the amount, quality or
timing of sleep.
 Symptoms includes abnormal amount of sleep, abnormal quality of sleep,
abnormal timing of sleep, impaired concentration.
NARCOLEPSY
 It is a neurological disorder that affects the control of sleep and
wakefulness characterized by extreme tendency to fall asleep whenever
in relaxing surroundings.
 Symptoms includes excessive daytime sleepiness, night time
wakefulness, cataplexy (loss of muscle control), hallucinations, sleep
paralysis.
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10. OREXIN
 Orexin, also called hypocretin, is a neurotransmitter that regulates arousal,
wakefulness and appetite. These are peptides found in the hypothalamus
involved in the regulation of sleep, energy homeostasis and autonomic functions.
 Orexin was discovered in 1998 by two independent groups of rat-brain
researchers. One group named it as “OREXIN” derived from orexis meaning
appetite. The other group named it “HYPOCRETIN” because it is produced in the
hypothalamus and it resembles to secretin, a hormone found in the gut.
 The brain contains the cells that produce orexin. In a human brain about 10,000
to 20,000 neurons in the hypothalamus produce orexin. Orexin-A and Orexin-B
are the active peptides derived from the prepro-orexin.
 In particular orexins function in the maintenance and stabilization of sleep and
wakefulness and inhibition of REM sleep.
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11. Prepro-orexin Orexin (hypocretin)
 Orexin constitute a novel peptide
family.
 Orexin A/Hypocretin 1 is a 33 amino
acid peptide with N-terminal
pyroglutamyl residue and two
intrachain disulphide bonds.
 Orexin B is a linear peptide of 28 amino
acids.
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12. PHYSIOLOGICAL FUNCTIONS OF OREXINS
HEART
Heart rate↑↓
Blood
pressure↑↓
INTESTINES
Bicarbonate
secretion↑
Motility↑↓
STOMACH
HCl secretion↑
Motility↑↓
OVARIES
Reproduction↑↓
PANCREAS
Insulin
secretion↑↓
TESTIS
Spermatogenesis
↑↓
ADRENALS
Sympathetic
tone↑
Epinephrine
release↑
OREXINS
CNS
Wakefulness↑
Sleep↓
Food intake↑
Metabolic rate↑
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13. OREXIN RECEPTORS
 The actions of orexins are
mediated via two types of GPCRs,
orexin 1 receptor (OX1R) and
orexin 2 receptor (OX2R).
 OX1R couples to the Gq class of G-
proteins, which results in
activation of phosopholipase C
and subsequent triggering of the
phosphatidylinositol cascade.
 OX2R couples to both Gq and Gi
classes of G-proteins in neuronal
cell lines.
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14. DISTRIBUTION OF OREXIN RECEPTORS
 OX1R and OX2R are widely distributed throughout the central nervous system.
 OX1Rs are expressed in the prefrontal & infralimbic cortex, hippocampus , bed
nucleus of the stria terminalis (BST), anterior hypothalamus, dorsal raphe nucleus
(DR) & laterodorsal tegmental nucleus (LDT).
 OX2Rs are also expressed in the amygdala, BST, DR. In addition to these regions,
OX2Rs are abundantly expressed in the dorsomedial hypothalamic nucleus,
hippocampus & medial septal nucleus.
 The histological studies suggest that orexins and their receptors are likely to play a
broad regulatory role in the central nervous system and could regulate feeding,
sleep, emotion, and reward functions.
 Additionally, OX1Rs are also distributed in peripheral tissues, such as the kidney,
adrenal gland, thyroid, testis, ovaries, and jejunum. OX2Rs are found in the adrenal
gland, lung, and pituitary.
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15. DISTRIBUTION OF OREXIN RECEPTORS
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16. OREXIN ANTAGONIST
 Sleep aids that target orexin action are known as “orexin receptor antagonists”
which means that they block the signaling of the chemical orexin in the brain.
 Orexin plays a role in keeping people awake and alert, a medication that blocks its
action has the potential to promote sleep.
Eg : Almorexant, Suvorexant.
Mechanism of action of Orexin receptor antagonists
 Orexin sleep aids affect different chemical system in the brain.
 Many of the commonly prescribed sleep aids cause sleepiness by enhancing
GABA—a wide-reaching inhibitory neurotransmitter in the brain.
 Orexin sleep aids block the brain’s receptors for the chemical orexin. Since they
target a more localized area of the brain, they will cause fewer side effects.
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17. COMPOUND ACT-078573
(Almorexant)
MK-4305
(Suvorexant)
MK-6096 SB-649868
COMPANY Actelion &
GlaxoSmithKline
Merck & Co. Merck & Co. GlaxoSmithKline
CLINICAL TRIAL Phase III,
discontinued
Phase III
completed
Phase II completed Phase II
completed
INDICATIONS Insomnia Insomnia Insomnia, migraine
prophylaxis,
diabetic
neuropathy.
Insomnia
T1/2 (HOURS) 21 12 NA 3-6
METABOLISM hepatic
CYP3A4 (S/I)
hepatic
CYP3A4 (S)
NA hepatic
CYP3A4 (S/I)
DUAL OREXIN RECEPTOR ANTAGONISTS (DORA) IN DEVELOPMENT
S=substrate; I=inhibitor; NA=not available13/2/2015 15

18. SUVOREXANT
 Suvorexant is another reversible dual orexin receptor
antagonist used in the treatment of insomnia.
 Composition
The molecular formula for suvorexant is C23H23ClN6O2 .
The molecular weight is approximately 450.932 g/mol.
 Mechanism of Action
Suvorexant is a potent dual orexin receptor antagonist
that blocks both OX1R and OX2R. It promotes sleep by
inhibition of orexin A and B neuropeptides that promote
wakefulness.
STRUCTURE OF SUVOREXANT
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19. Pharmacokinetics
Absorption: Well absorbed the onset of sleep
occurs 56 and 68 minutes after oral administration.
Distribution: Highly protein bound (99.5%).
Metabolism: Primarily metabolized by the
cytochrome P450 (CYP3A4) enzyme system.
Elimination: It is eliminated primarily via inactive
metabolites in the feces; there is no renal
elimination. The half-life is approximately 12.2
hours.
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20. ALMOREXANT
 Almorexant is a reversible, selective
dual OX1 and OX2 receptor antagonist.
 Almorexant increases deep sleep and
REM sleep.
 Commonly reported adverse effects in
the almorexant treated patients were
dizziness, nausea, fatigue, headache
and dry mouth.
 Almorexant is discontinued due to
undisclosed human tolerability issues
STRUCTURE OF ALMOREXANT
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21. SB-649868
 SB-649868 is a potent orally active orexin receptor antagonist.
 It increases total sleep time (both nREM and REM sleep) and
reduces sleep latencies.
 Compared to almorexant, the in vivo efficacy of this compound
is excellent.
 Common side effects are headaches, dry mouth and
nasopharyngitis.
 Side effects are dose dependent.
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22.  The orexin antagonists improved both sleep initiation as
well as maintenance .
 Orexin receptor antagonists are used for the management
of insomnia.
 Still more clinical trails is to be carried out to know the
important pharmacological actions of Orexin receptor
antagonist.
CONCLUSION
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23. REFERENCES
 Principles of anatomy and physiology (12th edition), Gerard J. Tortora and
Bryan H. Derrickson.
 Neurobiology of Sleep and Wakefulness, Tom Scammell, MD Neurology,
BIDMC.
 Sleep disorders. Babcock.ppt, www.mc.vanderbilt.edu.
 Orexin and orexin receptors, Takeshi Sakurai.
 The Role of Orexin/Hypocretin in the Central Nervous System and
Peripheral Tissues, Tomomi Tsunematsu and Akihiro Yamanaka.
 Orexin receptor antagonists as therapeutic agents for insomnia Ana
C.Equihua1, AlbertoK.DeLaHerrán-Arita2 and ReneDrucker-Colin1.
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