This slide share is all about the sleeping-pills available to the practitioners of modern medicine. Hypnotics, the drugs used to treat insomnia (difficulty in falling asleep, staying asleep, frequent awakenings in the night, morning awakening without feeling fresh) are described with special reference to drugs based on New Concepts (orexin/hypocretin antagonism, melatonin agonism, GABA-agonism) in the back-drop of old drugs. This way all the hypnotic drugs, including the new as well old, and drugs having sedating effects, such as, some anti-histaminics, used in insomnia, are included in this presentation, with the hope that medical students and those studying pharmacology in pharmacy and ayurvedic colleges will find it useful.

1. HYPNOTICS : BASED ON NEW CONCEPTS
(orexin/hypocretin antagonism, melatonin agonism, GABA-
agonism) in the back-drop of old drugs
Dr. Ashok Kumar Batham, MB,BS,MD,DCR,
Chief Consultant, Dr Batham Pharma Consultants,
EMAIL: ASHOKPHARMACOL@GMAIL.COM
TELEPHONE:0919328018777

2. INSOMNIA
Insomnia is defined as repeated difficulty with sleep initiation,
maintenance, consolidation, or quality that occurs despite adequate time
and opportunity for sleep and that results in some form of daytime
impairment.
Specific criteria vary, but common ones include taking longer than 30
minutes to fall asleep, staying asleep for less than 6 hours, waking more
than 3 times a night, or experiencing sleep that is chronically
nonrestorative or poor in quality.
Dr.Ashok Kumar Batham 2

3. INSOMNIA (DSM-5)
DSM-5 defines insomnia as dissatisfaction with sleep quantity
or quality, associated with one (or more) of the following
symptoms:
• Difficulty initiating sleep
• Difficulty maintaining sleep, characterized by frequent
awakenings or problems returning to sleep after awakenings
• Early-morning awakening with inability to return to sleep
Dr.Ashok Kumar Batham 3

4. INSOMNIA (DSM-5)
• Other criteria include the following:
• The sleep disturbance causes clinically significant distress or impairments in social, occupational,
educational, academic, behavioral, or other important areas of functioning
• The sleep difficulty occurs at least 3 nights per week
• The sleep difficulty is present for at least 3 months
• The sleep difficulty occurs despite adequate opportunity for sleep
• The insomnia cannot be explained by and does not occur exclusively during the course of another
sleep-wake disorder
• The insomnia is not attributable to the physiological effects of a drug of abuse or medication.
• Coexisting mental disorders and medical conditions do not adequately explain the predominant
complaint of insomnia
Dr.Ashok Kumar Batham 4

5. INSOMNIA(DSM-5)
The Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5) makes no distinction between primary
and comorbid insomnia.
Insomnia is Insomnia whether it is Primary or Secondary or
associated with other diseases.
Dr.Ashok Kumar Batham 5

6. HYPNOTICS APPROVED FOR USE IN INSOMNIA
• Benzodiazepines: flurazepam, temazepam, quazepam, estazolam, and
triazolam.
• Non-Benzodiazepines acting on GABAergic Benzodiazepine receptors:
zaleplon, zopiclone, eszopiclone, zolpidem
• Melatonin receptor agonists: ramelteon, tasimelteon
• Orexin or Hypocretin receptor antagonists: Suvorexant, Lemborexant
• Barbiturates: Secobarbital , Butabarbital (almost obsolete)

7. DRUGS WITH SEDATIVE EFFECTS USED IN INSOMNIA
• Benzodiazepines: diazepam, chlordiazepoxide, alprazolam,
lorazepam etc.
• Antidepressants: amitriptyline, nortriptyline, trimipramine,
imipramine, doxepine
• Atypical antipsychotics: quetiapine
• OTC anti-histaminics: doxylamine, diphenhydramine

8. MELATONIN
• Natural hormone produced by pineal gland, the levels of which rise
and fall in a circadian fashion in the suprachiasmatic nucleus.
• Melatonin levels start increasing in the evening as the individual
prepares for sleep, peaking between 11 pm and 3 am, reaching the
plateau and start falling sharply before daylight (daytime levels are
about 10 times lower than nighttime).
• Responsible for maintaining wake-sleep cycle (biological-clock).
Dr.Ashok Kumar Batham 8

9. MELATONIN (CONTD.)
• Light at night blocks production of melatonin and can lead to sleep disturbances.
• Advancing age is associated with declining levels of melatonin, which may
contribute to insomnia in elderly people.
• Melatonin acts on:
• MT1 receptors to promote onset of sleep
• MT2 receptors to shift the timing of circadian system, and
• MT3 receptor (quinone reductase 2)
• Melatonin is reported to possesses anti-oxidative, immuno-modulating and anti-
tumor activities.
Dr.Ashok Kumar Batham 9

10. MELATONIN (CONTD.)
• Synthetic melatonin available as an over-the-counter (OTC) dietary supplement in
the US.
• Melatonin supplementation has been suggested for sleep disorders, Jet-Leg, and
sleep cycle adjustment in shift-workers, and blind people.
• Effective starting doses for jet lag range from 0.3 to 0.5 mg.
• Lower doses may work for some people, while others may need a higher dose, up to
3 to 5 mg.
• Doses over 5 mg appear to be no more effective than lower doses.
Dr.Ashok Kumar Batham 10

11. RAMELTEON
• Synthetic tricyclic analog of Melatonin. Binds to M1 and M2 receptors.
• MT1 and MT2 are thought to promote sleep and to be involved in maintenance of the
circadian rhythm and normal sleep-wake cycle.
• Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal
firing (reduces alerting effect of the SCN), and stimulation of the MT2 receptor in the SCN
affects the circadian rhythm, causing a phase advance (earlier sleep time).
• Does not bind to M3 receptors and receptors of other neurotransmitters, such as nicotinic
acetylcholine, neuropeptide, dopamine, opiate, benzodiazepine-binding sites on GABAA
receptors.
• Appears to act by producing a phase advance of the endogenous circadian rhythm.Dr.Ashok Kumar Batham 11

12. RAMELTEON (CONTD.)
• Appears to act by producing a phase advance of the endogenous circadian rhythm.
• Rapidly absorbed on oral administration reaching peak concentration within 1-hour.
• Undergoes significant first-pass metabolism, therefore its bioavailability is less than
2%.
• Half-life ~2 hours.
• Plasma protein biding of the drug is 80%.
• Metabolized by CYPs 1A2, 2c, and 3A4. Of the 4-metabolites, one M-II is active.
Dr.Ashok Kumar Batham 12

13. RAMELTEON (CONTD.)
• Approved for the treatment of insomnia, specifically sleep onset
difficulties.
• Shortens sleep latency, and increases sleep time.
• Does not produce impairment of cognitive functions on next-day.
• Beneficial effects found to be sustained up to 6-months in clinical trials.
• No development of Tolerance and Dependence.
• No reports of withdrawal reactions and rebound insomnia on
discontinuation.
• Administered in doses of 8, 16 mg up to 64 mg.Dr.Ashok Kumar Batham 13

14. TASIMELTEON (HETLIOZ)
• Tasimelteon is a selective agonist for the melatonin receptors MT1 and MT2, similar to
ramelteon (2005).
• Approved by the US FDA in January 2014 for the treatment of non-24-hour sleep–wake
disorder (Non-24, N24 and N24HSWD).
• Approved in Europe by EME in July 2015 for the treatment of non-24-hour sleep-wake
rhythm disorder in totally blind adults, but not in the rarer cases of non-24 in people with
normal eyesight.
• Treatment of N24HSWD with Tasimelteon leads to improved sleep timing while taking the
drug. Reversion to baseline sleep performance occurs within a month of discontinuation.

15. HYPOCRETIN (OREXIN): HYPOTHALAMIC NEUROPEPTIDE
Hypocretin/Orexin was independently discovered by two groups using different
techniques.
• de Lecea et al.(1998) identified the pro-hormone pre-prohypocretin, and its peptide products- Hypocretin-1 (Hcrt-1)
and Hypocretin-2 (Hcrt-2), and
• Sakurai et al (1998) reported discovery of the orexins, orexin-A (Orx-A) and orexin-B (Orx-B).
Hypocretin/Orexin systems have roles in:
• sleep–wake cycle,
• arousal state,
• regulating feeding and drinking behavior,
• metabolism, and
• endocrine system.

16. HYPOCRETIN (OREXIN) RECEPTORS
• Receptors for these neuropeptides Hcrtr1 [Orxr1] and Hcrtr2 [Orxr2]) have been
identified as G-protein coupled receptors (GPCR).
• Hcrtr1 receptor has a much higher (100 to 1000-fold) affinity for Hcrt-1 than for
Hcrt-2.
• Hcrtr2 receptor seems to have equal affinities for both neuropeptides.
• Hcrtr1 is hypothesized to have a sleep-specific role.
• Hcrtr2 receptor is hypothesized to have more general role.
• The receptors have been mapped on human chromosome 1p33 and 6cen,
respectively.

17. HYPOCRETIN (OREXIN) IN SLEEP AND OTHER DISORDERS
• Strong evidence indicates that narcolepsy is associated with abnormalities of the hypocretin
neurotransmitter system.
• Low or undetectable levels of hypocretin are found in most patients of Narcolepsy.
• Some patients of Narcolepsy may have ‘hypocretin resistance’ which may lead to overproduction of
hypocretin.
• Hypocretin/orexin system may be involved in other sleep disorders, such as primary
hypersomnolence, insomnia, Kleine-Levin syndrome, and sleep disorders affecting the ageing
population.
• The hypocretin system may be important in affective disorders such as major depression and
bipolar affective disorder.

18. SUVOREXANT (BELSOMRA)
• Suvorexant is an orexin receptor antagonist. The orexin neuropeptide
signaling system is a central promoter of wakefulness. Blocking the binding of
wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and
OX2R by Suvorexant is thought to suppress wake drive.
• Approved by the US FDA in 2014, as the first orexin-antagonist.
• It is indicated for the treatment of insomnia characterized by difficulties with
sleep onset and/or sleep maintenance.
• Available as film coated tablets containing 5 mg, 10 mg, 15 mg, and 20 mg.
• Recommended dose is 10 mg, taken no more than once per night and within
30 minutes of going to bed, with at least 7 hours remaining before the
planned time of awakening. The dose can be increased upto 20 mg once per
night daily.

19. LEMBOREXANT (DAYVIGO)
• Dual orexin antagonist (DORA), blocks OX1R and OX2R. Lemborexant has been reported to inhibit the
orexin signaling pathway and promote both REM and non-REM sleep.
• 5 and 10 mg Tablets.
• Indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
• Effective in primary insomnia and in insomnia associated with other diseases, such as depression.
• Most common adverse events reported in clinical trials was somnolence (10 mg, 10%; 5 mg, 7%;
placebo, 1.0%).
• The most common adverse events leading to discontinuation of lemborexant were somnolence (10
mg, 1.0%; 5 mg, 0.7%; placebo, 0.4%) and nightmares (10 mg, 0.3%; 5 mg, 0.3%; and placebo, 0%).

20. BENZODIAZEPINES USED AS HYPNOTICS
• Benzodiazepine receptor agonists approved by the US FDA for use as hypnotics include:
• Flurazepam (Dalmane),
• Temazepam (Restoril),
• Quazepam (Doral),
• Estazolam (ProSom), and
• Triazolam (Halcion).
• All have variable half-lives and different metabolites that affect their onset and duration of action.
• These drugs bind to a specific benzodiazepine site on the gamma-aminobutyric acid (GABA)
receptor complex, resulting in increased neuronal permeability to chloride ions. The shift in
chloride ions results in hyperpolarization and stabilization of the neuronal membrane leading to
inhibitory effects of this neurotransmitter.
• This class of drugs suppresses rapid eye movement (REM) sleep and reduces stages 3 and 4 sleep
while increasing stage 2 sleep.

21. BENZODIAZEPINES USED AS HYPNOTICS
Estazolam (ProSom) - Intermediate-acting drug for the short-term treatment of sleep disorders. Effective
in increasing the time spent asleep as well as reducing awakenings during the night. Half-life 10-24 Hrs.
Administered orally in a dose of 1-2 mg.
Temazepam (Restoril) – Intermediate-acting drug. Half-life 11 + 6 Hrs. Administered orally in a dose of 7.5-
30 mg.
Indicated for severe insomnia and other severe or disabling sleep disorders.
Acts in 1-hour and its effect lasts for 8-hours.
The United States Air Force uses temazepam as one of the hypnotics approved as a "no-go pill" to help
aviators and special-duty personnel sleep in support of mission readiness. "Ground tests" are necessary
prior to required authorization being issued to use the medication in an operational situation, and a 12-
hour restriction is imposed on subsequent flight operation.

22. BENZODIAZEPINES USED AS HYPNOTICS (CONTD.)
Triazolam (Halcion) - Half-life 2.9 + 1 Hrs. Administered orally in a dose of 0.125-0.250 mg. Triazolam was
the first short-acting benzodiazepine for promoting sleep but fell out of favour after reports of amnesia
with its use.
Flurazepam (Dalmane) – Long-acting; half-life 74-24 Hrs. Administered orally in a dose of 15-30 mg.
Officially indicated for mild to moderate insomnia with difficulty falling asleep, frequent awakening,
early awakenings or a combination of each.
Quazepam (Doral) – Long-acting agent with a half-life 39 Hrs. Administered orally in a dose of 7.5-15 mg.
Effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.
Has less overdose potential than other benzodiazepines (due to its novel receptor-subtype selectively).

23. SHORTCOMINGS OF BENZODIAZEPINES AS
HYPNOTICS
• Tolerance
• Dependence
• Psychomotor retardation
• Memory impairment
• Paradoxical inhibition (e.g., increased excitement, irritability, and impulsivity)
• depression,
• Teratogenic effects in pregnant women.
• Cognitive impairment, delirium, falls, and fractures in elderly.

24. NOVEL BENZODIAZEPINE RECEPTOR AGONISTS
• These drugs are collectively called “Z-Compounds” and include:
• Zaleplon
• Zolpidem
• S-Zopiclone
• Specifically act as agonists of GABAA receptors subunit ⍺1 and therefore
produce selective hypnotic effect without muscle relaxant, anticonvulsant
and other effects of other benzodiazepines which produce varying effects on
⍺2, ⍺3 and ⍺5 subunits.
• Produce a predominant hypnotic effect
• Exhibit weak anticonvulsant and skeletal muscle relaxant effects.
• Like benzodiazepines, intoxication caused by these drugs can be reversed by
Flumazenil (benzodiazepine receptor antagonist).Dr.Ashok Kumar Batham 24

25. ZOLPIDEM (AMBIEN)
• Shortens sleep latency and prolongs sleep duration.
• No effects on sleep stages.
• Beneficial effects found to be sustained upto 6-months in clinical trials.
• No development of Tolerance and Dependence.
• Beneficial effects on sleep persist upto 1-week after discontinuation.
• Has a short half-life ~ 2 hour.
• Does produce hang-over on waking up with sedation, delayed reaction time and anterograde amnesia.
• Approved for short-term treatment of insomnia.
• Available as immediate-release tablets of 5 and 10 mg; modified-release tablets of 6.25 and 12.5 mg
(Ambien and Ambien CR, respectively ); as sublingual tablets (Edluar and Intermezzo); and as an oral spray
(ZolpiMist, NovaDel Pharma).
• Immediate release and Modified-release tablets administered in doses of 5 or 10, and 6.25 or 12.5 mg,
respectively.
Dr.Ashok Kumar Batham 25

26. ZALEPLON (SONATA)
• A pyrazolopyrimidine derivative.
• Produces quick induction of sleep and has an an ultra-short duration of action.
• Absorption delayed by approximately two hours and is reduced by 35% if taken with high-fat or heavy
meals.
• Has a short half-life ~ 1 hour.
• Does not affect the duration of sleep and number of awakenings during sleep.
• Used for administration at bedtime for induction of sleep in patients having difficulty in falling asleep.
• Can be administered even in the later part of night (within 4-hours of anticipated waking time).
• Does not produce hang-over on waking up because of short half-life.
• Administered in doses of 5, 10 or 20 mg.
Dr.Ashok Kumar Batham 26

27. ESZOPICLONE (LUNESTA)
• S(+) enantiomer of Zopiclone which is used in many countries.
• Shortens sleep latency, prolongs sleep duration, improves sleep efficiency, and reduces sleep awakenings.
• Beneficial effects found to be sustained upto 12-months in clinical trials.
• No development of Tolerance and Dependence.
• Severe withdrawal reactions (rebound insomnia or seizures) not reported.
• Very mild withdrawal reaction in less than 2% patients in the form of abnormal dreams, anxiety, upset
stomach
• Has a short half-life ~ 6 hour.
• No observed psychomotor effects on the next day.
• Approved for long-term treatment of insomnia.
• Administered in doses of 1, 2 or 3 mg.
Dr.Ashok Kumar Batham 27

28. ANTIDEPRESSANTS USED FOR INSOMNIA
• Doxepin is approved by the US FDA or the treatment of insomnia with difficulty with sleep maintenance.
• Other tricyclic antidepressants (TCAs), such as amitriptyline, nortriptyline, trimipramine, and imipramine have
been used off-label to treat insomnia.
• Trazodone and Mirtazapine are also used ‘off-label’ for insomnia because of their sedative effects attributed to
5HT2 and H1-receptor blockades, respectively. Trazodone is administered at an initial dose of 25 to 50 mg at
bedtime, which is escalated up to 100 mg per night. Mirtazapine is used in a dose of 30 mg at bedtime for
insomnia.
• Nefazodone inhibits serotonin reuptake and is a potent antagonist at the 5-HT2 receptor. The US FDA has added a
Black Box warning regarding rare cases of liver failure associated with this drug.
• These drugs, cause an increased risk of atropine-like side effects, cardiac conduction abnormalities, orthostatic
hypotension, which, in turn, may increase the risk of falls and resulting injury. and slowed cardiac conduction.
• TCAs have been listed as potentially inappropriate for use in older adults.
• Safer treatment options have diminished the usefulness of these drugs.

29. ATYPICAL ANTIPSYCHOTICS
• Effects of antipsychotics on sleep have been studied in patients with comorbid conditions, such as depression and
psychosis.
• Not evaluated in subjects with primary insomnia.
• Not approved by FDA for the treatment of insomnia.
• Atypical antipsychotics, such as quetiapine, olanzapine, and risperidone, are commonly prescribed for sleep
disorders.
• The sedation associated with these drugs results from their antagonistic effects on multiple neurotransmitter
systems, particularly serotonin (5-HT2) and histamine (H1) receptors.
• Quetiapine is the most commonly prescribed antipsychotic for insomnia.
• Serious adverse events, such as metabolic syndrome and extrapyramidal effects, make these drugs less attractive
than agents approved by the FDA for this indication.

30. OTC ANTI-HISTAMINES
• Diphenhydramine and doxylamine are commonly used in over-the-counter insomnia
medications. They exert their effect by disrupting wake-promoting histaminergic
neurotransmission from the tuberomammillary nucleus by antagonism of the H1 receptor.
• These drugs are minimally effective in inducing sleep, may reduce sleep quality, and may
cause residual drowsiness. Therefore, the use of these drugs in insomnia patients is not
recommended.
• Moreover, antihistamines are associated with potent anticholinergic effects, such as dry
mouth, constipation, and confusion. Older individuals are particularly susceptible to these
effects.

31. Thank You