This slide describes about the disease Narcolepsy, its causes and how the drug amphetamine overcomes it. It consist of MoA of Hypocretin (Orexin) and MoA of Amphetamine.

1. Use of Amphetamine in
Narcolepsy
Presented by:-
Maheshwor Yadav
Shailendra Shah
Suraj Chaudhary
Prakash Gurung
Subindra Danuwar
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Nobel College, Kathmandu
Pokhara University
Dec, 2018

2. What is Narcolepsy?
• Narcolepsy is a neurological sleep disorder that
causes a potentially disabling level of daytime
sleepiness. This sleepiness may occur in the form of
repeated and irresistible “sleep attacks.”
• In these episodes a person suddenly falls asleep in
unusual situations, such as while eating, walking or
driving.
• Narcolepsy as a most common causes of chronic
sleepiness, affects about 1 in 2000 people.
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3. • Despite the frequency of narcolepsy, the average
time from the onset of symptoms to diagnosis is 5
to 15 years, and narcolepsy may remain
undiagnosed in as many as half of all affected
people with narcolepsy, since many clinicians are
unfamiliar with this disorder.
• It can be characterized by disordered regulation of
rapid-eye-movement (REM) sleep.
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4. • REM sleep normally occurs only during the usual
sleep period and includes vivid, storylike dreams,
rapid (saccadic) eye movements, and paralysis of
nearly all skeletal muscles, except the muscle of
respiration.
• Narcolepsy usually begins between the ages of 10
and 20 years with the sudden onset of persistent
daytime sleepiness, although it can also develop
gradually.
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5. Clinical features of Narcolepsy
• The classic tetrad of symptoms for narcolepsy
includes excessive daytime sleepiness(EDS),
cataplexy, sleep paralysis, and hypnagogic
hallucinations.
• Not all symptoms are present in all patients and
these may vary and in frequency and intensity over
time.
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6. • In addition to the classic tetrad, patients also
describe significant problems with insomnia,
repeated awakenings, and complaints related to
their level of tiredness such as blurry vision, and
trouble with concentration and memory.
• Quite often, the diagnosis is made only after
serious problems have arisen, such as declining
grades at school, poor performance at work, or a
motor vehicle accident.
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7. • The most dramatic of these REM sleep–like states is
cataplexy — sudden episodes of partial or complete
paralysis of voluntary muscles.
• These episodes are triggered by strong emotions ,
most often by positive emotions such as those
associated with laughing at a joke or unexpectedly
encountering a friend.
• In some people, however, cataplexy can be
triggered by intense negative emotions, such as
frustration or anger.
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8. Fig.1. Stages of cataplexy
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9. Pathophysiology of Narcolepsy
• There are two subtypes of the disorder: narcolepsy
with cataplexy and narcolepsy without cataplexy.
The cause is uncertain, but there is evidence of
both genetic and environmental factors.
• The exact cause of primary human narcolepsy
remains unknown, although loss of hypocretin
appears to play a role in most cases with cataplexy.
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10. Role of Hypocretin
• Hypocretin is a peptide derived from the
dorsolateral hypothalamus that has been linked to
multiple regulatory functions including sleep/wake
cycles.
• There are currently two known variants, hypocretin
1 and 2, also known as orexin A and B, respectively.
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11. • Deficiencies of hypocretin can lead to abnormalities
in the function of these monoamine systems, which
in turn can mediate the symptoms of narcolespy.
• Autoimmune process is considered to be one of the
important part for deficiency of hypocretin.
• In the winter of 2009–2010, in China, after
vaccination against H1N1 , a dramatic
spike in new cases of narcolepsy provided the
clearest evidence so far that the disease can
be caused by an autoimmune process.
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12. • This process was found to destroy the hypocretin
(orexin) producing neurons.
• The orexin neurons are active during wakefulness, and
the orexin neuropeptides stimulate target neurons that
promote wakefulness, including those in the cortex and
basal forebrain and those in the brain stem and
hypothalamus that produce norepinephrine, serotonin,
dopamine, and histamine .
• Orexins have long-lasting effects on target neurons, and
this sustained activity may help maintain wakefulness
throughout the day.
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13. • Conversely, loss of orexin signaling in narcolepsy
may result in inconsistent activity in these
wakefulness-promoting brain regions, resulting in
frequent lapses into sleep.
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14. What are Amphetamines?
• Amphetamines are simple derivatives of
catecholamines (dopamine, norepinephrine,
epinephrine) that are made more lipophilic so that
they enter the central nervous system easily.
• These are very old chemical entities, first
made available in 1935.
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15. • Amphetamine structure is different from
methamphetamine in not having a methyl group.
• The presence of methyl group in methamphetamine
makes it more lipid soluble than amphetamines, so
centrally more available, hence more addictive.
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16. Amphetamines use in Narcolepsy
• The treatment of narcolepsy by amphetamines
was established by Prinzmetal and Bloomberg in
1935.
• They suggested the use of benzedrine, the racemic mixture
of dextro- and levo-amphetamine, would be an appropriate
treatment for narcolepsy because of its close
relationship to ephedrine and epinephrine, low toxicity
and low cost, prolonged action and lack of pronounced
sympathomimetic side effects.
• Amphetamine isomers of the D-type are more
active than isomers of the L-type, and have more effects on
dopaminergic synapses than on other monoaminergic
synapses.
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17. Neuropharmacology
• Amphetamines mimic many of the
catecholaminergic actions in the brain, primarily
substituting for monoamines in presynaptic
synapses and producing monoaminergic release .
• These are synthetic compounds having a
pharmacological profile similar to ephedrine; orally
active with relatively long duration (4–6 hours).
They exert potent CNS stimulant and weaker
peripheral cardiovascular actions.
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18. • Amphetamine occurs in indirect
sympathomimetics.
• Indirect sympathomimetics act primarily by
increasing the amount of monoamines available
within the synaptic cleft of monoamine synapses in
the and by blocking reuptake and enhancing
release of norepinephrine, dopamine and serotonin
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19. Mechanism of action of
Amphetamine
• Amphetamine (Amph) enters
the adrenergic neurone by
utilizing the neuronal
norepinephrine transporter
(NET) or dopamine
transporter (DAT)-(1), and
then the storage vesicles
through vesicular
monoamine transporter
(VMAT2).
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Fig. Illustration of the mechanisms of
noradrenaline release by amphetamine

20. • It then displaces the stored noradrenaline (NA) into
the neuronal cytoplasm, most of which is released
into the synaptic cleft by exchange diffusion-(2)
with extracellular Amphetamine, or by reverse
transport-(3), both utilizing NET.
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21. Dose
• Amphetamine: 20-40 mg/day
• More than 60mg/day is not safe.
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22. Side effects
• Few studies describe the side effects of stimulants
in children with narcolepsy; the potential side
effect of greatest concern is growth retardation. For
eg. deficits in weight gain.
• Addiction potential is high for immediate release
formulation
• Increased blood pressure and possible cardiac
complication with high doses.
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23. Contraindication
• Co-administration of an amphetamine with
MAO inhibitors is contraindicated, as it can
potentialize its effects, notably on blood
pressure.
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24. Current formulations
Desoxyn 5mg tablet
Adderall 5mg tablet
Ritalin 5,10&20 mg tablet
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25. Conclusion
• Hence, narcolepsy is a neurological disorder
manifested by sleeping disorder due to
reduced hypocretin that can be treated by
amphetamine, methamphetamine and
medonafil like drugs.
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26. Reference
1. Peacock J, Benca RM. Narcolepsy: Clinical
features, co-morbidities & treatment. 24 Nov
2008; 338-349.
2. Miller MM, Hajdukovic R, Erman MK. Treatment
of Narcolepsy with Methamphetamine. 1993
June ; 16(4): 306–317.
3. Billiarda M, Bassettib C, Dauvilliersc Y, Groseljd
LD, Lammerse GJ, Mayerf G, Cherg TP, Readingh P,
Sonkai K. EFNS guidelines on management of
narcolepsy. 2006; 13: 1035–1048.
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27. 4. Mitler MM, Aldrich MS, Koob GF, Zarcone VP.
Narcolepsy and Its Treatment With Stimulants. 1994;
17(4):352-371.
5. Scammell TE,Narcolepsy. 2015;373:2654-2662.
6. Darien IL , Narcolepsy. 2008;60561(630):737-9700.
7. Parkes JD, Fenton GW.Levo(-) amphetamine and
dextro(+)amphetamine in the treatment of
narcolepsy. 1973;36:1076-1081.
8. Tripathi KD. Essentials of Medical Pharmacology.7th
edition;9(2):134-135.
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