Pharmacology of Insomnia

2.  History
 Problem statement
 Physiology of sleep wake cycle
 Pathogenesis
 Pharmacological management
 Non Pharmacological approaches
 Newer targets

3. “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.”
Definition

4. History of Pharmacotherapy of Insomnia
Antiquity
1912
1959
19th century
• Alcoholic
beverages
• Lardanum
compound
• Herbal
formulations
COMPOUNDS
• Bromide
• Chloral hydrate
• Paraaldehyde
• Urethane
• Sulfonal
•1903- Barbital
1912- Phenobarbital
Chlordiazepoxide
Present
•Benzodiazepines
•1980 Non Benzodiazepines
•Melatonin and Analogues

5. 10- 50% of the
population are
affected.
20 % of adult
population
having chronic
insomnia
Increases with age
Twice as common in
females
• Up to 30 yrs [M/F 1:1]
• > 30 years females
• > 70 yrs M/F 1:2 ]
Lower
educational
attainment
Depression
Unemployment
Widowed,
divorced

6. Insomnia has a detrimental effect on health related quality of
life to the same degree as chronic disorders such as depression
and congestive heart failure (Katz & McHorney, 2002).
 economic costs that encompass
health care use,
absenteeism
accidents,
increased alcohol consumption
(Chilcott & Shapiro, 1996; Stoller, 1994)
annual cost was
estimated to be
between $35
to$107 billion a
year in the US

7. h
Adjustment insomnia
primary insomnia
Paradoxical insomnia
Insomnia due to medical
condition
Insomnia due to mental
disorder
•Inadequate sleep hygiene
•Insomnia due to drug or
substance abuse
•Idiopathic insomnia
•Behavioral insomnia of
childhood
•Primary sleep disorders
causing insomnia

8. The National Institute of Mental Health Consensus Development Conference
(1984)
1. Transient insomnia <3 days brief environmental stressor
• It may respond to attention to sleep hygiene rules.
• If hypnotics are prescribed ,lowest dose for 2-3 nights.
2 . Short-term insomnia lasts from 3 days to 3 weeks
personal stressor such as illness, grief, or job problems
• sleep hygiene education is the first step.
• Hypnotics may be used adjunctively for 7-10 nights.

9. 3.Long-term insomnia insomnia that has lasted for >3
weeks
No specific stressor may be identifiable.
A more complete medical evaluation is necessary in these
patients, but most do not need an all-night sleep study.

10. Promotion of wakefulness
Areas
Medullary reticular
formation
Thalamus
Basal forebrain
Neurotransmitters
Histamine (TMN) posterior hypothalamus
NA –(LC)
Serotonin – (DRN)
Dopamine –(VTA)
Acetylcholine – cholinergic neurons of the
basal forebrain

11. Promotion of wakefulness
•A novel neuropeptide, orexin (also known as hypocretin),
•localized to a cluster of neurons in the lateral hypothalamus
also appears to be involved in the control of wakefulness.

12. The anterior hypothalamus includes the ventrolateral preoptic nucleus
(VLPO), containing gamma-aminobutyric acid (GABA) and the peptide
galanin, which are inhibitory and promote sleep
These project to the TMN and the brainstem arousal regions to inhibit
wakefulness.
.

13. Melatonin synthesis is inhibited by light and stimulated by darkness
The nocturnal rise in melatonin begins between 8 and 10 pm and peaks
between 2 and 4 am, then declines gradually over the morning.
 Melatonin acts via 2 specific melatonin receptors:
 MT1 attenuates the alerting signal, and MT2 phase shifts the SCN clock.
The suprachiasmatic nucleus (SCN) is entrained to the external environment
by the cycle of light and darkness.
The retinal ganglion cells transmit light signals via the
retinohypothalamic tract to stimulate the SCN.
A multisynaptic pathway from the SCN projects to the pineal gland,
which produces melatonin.

14. 14

16.  Non-Rapid Eye Movement (NREM) sleep
◦ Stage I
◦ Stage II
◦ Stage III
◦ Stage IV
 Rapid Eye Movement (REM) sleep

18.  Normal sleep per day is between 6-8 hours,
although some people can maintain a 4-6 hour
cycle
 4-6 NREM/REM cycles per night
 Sleep structure changes throughout life
 Wakefulness after sleep
◦ Less than 30 minutes
 Sleep Onset Latency (SOL)
◦ Less than 30 minutes
 REM Sleep Latency
◦ 70-120 minutes

19. Predisposing
Anxiety,
depression
Precipitating
• Sudden change in life
• schedule changes,
• medications,
• medical conditions
Perpetuating
Poor sleep hygiene
over concern

20. Fatal familial insomnia
autosomal dominant human prion disease caused by changes in
the PRNP (prion protein) gene.
Disruption sleep pattern that progresses to hallucinations,
a rise in catecholamine levels,autonomic disturbances
significant cognitive and motor deficits. .
CLOCK and Per2.
A mutation or functional polymorphism in Per2 can lead to circadian rhythm
disorders
advanced sleep phase syndrome
delayed sleep phase syndrome
A mis sense mutation gene encoding the GABAA beta 3 subunit in a
patients with chronic insomnia.

21. Sleep Diary
A sleep diary is appropriate when a patient
reports an irregular sleep schedule.
Actigraphy
For actigraphy, a portable device is worn around the wrist to record gross motor
activity and light/darkness over extended periods.
Polysomnography
To distinguish between other sleep disorders
OSA
RESTLESS LEG SYNDROME

22. Benzodiazepines
Non-benzodiazepine hypnotics
Melatonin receptor agonists
Antidepressants
Antipsychotics
Antihistamines
Obsolete drugs

23. Sedative
hypnotic
property
7 membered Diazapene ringBenzene ring
5-aryl substituent
SAR OF Diazepam

24.  2-Keto Benzos
◦ Some administered as prodrug
◦ All have active metabolites
(commonly desmethyldiazepam)
◦ Long half-lives (most in excess
of 60 hours)
Diazepam
Chlordiazepoxide (Librium)
Flurazepam
Clonazepam Flunitrazepam

25. ◦ No active metabolites
◦ Not metabolized in the liver
◦ Intermediate half-lives (most ~ 8-20 hours)
Lorazepam Oxazepam

26.  Very rapid onset
 Very short half-life
Alprazolam Triazolam
Additional heterocyclic ring attached at the
1 and 2 positions
Some active metabolites
Short to intermediate half-lives (anywhere
from 3-14 hours)

27. Long acting
Diazepam , Flurazepam, Clonazepam, Chlordiazepoxide
Intermediate acting
Alprazolam, Estazolam, Temazepam , Lorazepam
Nitrazepam
Short acting
Triazolam , Oxazepam , Midazolam

28.  Site of action is the
GABAA receptor
 Structure of GABAA
receptor comprised of
5 subunits
 o 2 α subunits (to
which GABA binds)
 o 2 β subunits (to
which barbiturates
bind)
 1 γ subunit (to which
benzodiazepines bind)

29.  Thus far 16 different subunits have been identified
and classified into seven subunit families:
α,β,,,ε,θ,π.
 six α, three β , three  , and single  ε,θ,π. and
subunits
 Benzodiazepine-sensitive
 α1, α2, α3, α5
 Benzodiazepine-insensitive
 α4 and α6

30.  Myorelaxant, motor-impairing, and
anxiolytic-like properties thought to be
mediated by α2, α3, and/or α5 subunits
 Benzodiazepines acting on α2, α3, and/or
α5
nonsedative, nonamnesic anxiolytic
properties
 Sedative ,Anticonvulsant activity and
amnesic properties are thought to be
mediated by α1 receptors
Limbic system α2
Ascending
RAS

31.  The benzodiazepines do not substitute for GABA but
appear to enhance GABA's effects allosterically
without directly activating GABAA receptors or opening
the associated chloride channels.
 Benzodiazepines increase the affinity of the receptor
for GABA, and thus increase Cl- conductance and
hyperpolarizing current
 increase in the frequency of channel-opening events

32. Absorption
Except for Midazolam all can be
absorbed orally
Distribution
•90% Protien bound
• Cross the placental barrier
Metabolism
Phase 1 reactions ,
metabolites are
conjugated in phase 2
reactions
Phase 1 metabolites are
pharmacologically
active
Excretion
Water souluble
metabolites

34.  BZD are the choice of drugs for treatment of insomnia
 Drug with most suitable pharmacokinetic profile is chosen
Transient insomnia ( 3 DAYS )
Rapidly acting , rapidly eliminated BZD like
 Triazolam (0.125-0.25mg) HS
Effective in sleep initiation problems
 Temazepam 15-30mg at bed time
Effective in sleep maintenance
Used
intermittently

35. Long term insomnia > 3 weeks
Intermittent use of
Flurazepam (15-30mg) HS rebound insomnia and withdrawal effects are less
Nitrazepam (5-10mg) HS
Short Term insomnia 3days -3 weeks
Tremazepam (15-30mg)HS effective in sleep maintainence
Flurazepam(15-30mg)HS effective in early morning awakening
Estazolam(1-2mg) HS

36. Drug Peak Blood Level
(hours)
Elimination
Half-Life
1
(hours)
Comments
Alprazolam 1-2 12-15 Rapid oral absorption
Chlordiazepoxide 2-4 15-40 Active metabolites; erratic
bioavailability from IM injection
Clorazepate 1-2 (nordiazepam) 50-100 Prodrug; hydrolyzed to active form in
stomach
Diazepam 1-2 20-80 Active metabolites; erratic
bioavailability from IM injection
Eszopiclone 1 6 Minor active metabolites
Flurazepam 1-2 40-100 Active metabolites with long half-lives
Lorazepam 1-6 10-20 No active metabolites
Oxazepam 2-4 10-20 No active metabolites
Temazepam 2-3 10-40 Slow oral absorption
Triazolam 1 2-3 Rapid onset; short duration of action
Zaleplon <1 1-2 Metabolized via aldehyde
dehydrogenase
Zolpidem 1-3 1.5-3.5 No active metabolites
1
Includes half-lives of major metabolites.

37. DRUG EFFECT ON SLEEP
CYCLE
SYMPTOMS
Benzodiazepines Partial disruption of the
NREM/REM ratio
Slight decrease in REM
Decreased stage 1 and
stage 3 and 4
Increased duration of
stage 2
On withdrawal- vivid
dreams
Due to slight increase in
REM
Sleep latency shortened
Episodes of wakeing
between stage 4 and
REM decreased
Non Benzodiazepines Does not interfere with
sleep cycle
Decrease in stage 0 and
stage 1
Increased stage 3 and 4
No increase in REM on
withdrawal
Decreased sleep latency
And awakening
Refereshing sleep

38. Barbiturates Decreases the duration
of REM sleep
Alters the NREM/REM
RATIO
REM buildup
Severely alters the sleep
cycles
Decreased stage 0
Decreases the stage 1
And stage 4
On withdrawal
Nightmares
Decreased sleep
latency
Decreased night time
awakening

39. 1. Long-acting agents taken at bedtime
 daytime sedation the following day
 Cognitive impacts are considerable:
 Inhibition of learning behaviors, academic performance,
and psychomotor functioning common
2. Short-acting agents taken at bedtime
 early-morning wakening
 rebound insomnia the following night

40. 3. Advancing age retards Phase 1 metabolism of BZD
4. Respiration is not seriously depressed, unless benzo is
taken concurrently with another CNS depressant (i.e.,
alcohol)
5. Benzodiazepine Poisoning
Treated with the BZD receptor antagonist
iv. Flumazenil 0.2mg/min max 5mg till the symptoms of
respiratory depression , confusion lathargy , congnitive
symptoms disappear .

41. MECHANISM
Due to the gradual down regulation of the GABA receptors
Taken for prolonged periods of time
Drugs with Short to medium half life
WITHDRAWAL SYMPTOMS
anxiety state,
increases in rebound insomnia,
restlessness, agitation, irritability, etc

42.  Tolerence to the sedative effects
developes slowly mechaniasm is
unclear
 May be dude to self induction of
benzodiazepines
CYP3A4
CYP2C9
Potentiate the effects of other CNS depressants alcohol, hypnotics and
neuroleptics anticonvulsants
Enzyme inhibitors like cimitidine, ketoconazole enhance BZD action
Smoking and aminophylline antagonises the activity of BZD
DRUG INTERACTIONS

43. MOA – Benzodiazepine receptor 1 (BZ1) -- alfa 1 subunit
 Antianxiety , sedative in nature
 Do not alter REM Sleep Pattern
 Minimal day time residual sleepiness
 Risk of tolerance and dependence is much less than BZD
Drug t1/2 Action Use
Zolpidem(10-
20mg)
2-3 hrs Faster onset Transient insomnia
Zaleplon(10-20mg) 3-4 hrs Shorter duration of
hypnosis
Short term
insomnia
Zopiclone(7.5mg) 6-8 hrs Longer acting
Eszopiclone(1-
3mg)
6 hrs

44. Ramelteon
Melatonin levels in the suprachiastmatic nucleus rise and fall in a
circadian fashion,
Two GPCRs for melatonin, MT1 and MT2, are found in the
suprachiasmatic nucleus,
MT1 receptors promotes the onset of sleep
MT2 receptors shifts the timing of the circadian system
Ramelteon binds to both MT1 and MT2 receptors with high affinity
but, unlike melatonin, it does not bind appreciably to quinone
reductase 2, the structurally unrelated MT3 receptor

45. Pharmacokinetics of ramelteon
Absorption -rapidly GI tract ,peak serum concentration obtained in
1 hr
significant first-pass metabolism that occurs after oral administration,
ramelteon bioavailability is <2%
Distribution
In the bloodstream, ~80% of ramelteon is protein bound
Metabolism
hepatic CYPs 1A2, 2C9
t1/2 of ~2 hours in humans.
Of the four metabolites, one, M-II, acts as an agonist at MT1 and MT2
receptors
Inhibitors
CYP1A2- Ciprofloxacin Fluvoxamine
CYP2C9- Fluconazole
Inducer- refampin

46. Indications - transient and chronic insomnia
specifically sleep onset difficulties
Dosage 8-mg tablet be taken ~30 minutes before bedtime
ADVERSE REACTIONS
dizziness,
somnolence,
fatigue,
and endocrine changes as well as ↓ testosterone and
increases in prolactin.
Infertility

47. TCA
Amitriptyline doxepin
Side effects: dry mouth, urinary retention,
dizziness, daytime sedation
Used at much lower doses for insomnia
Mirtazapine
Associated with weight gain,
increased appetite, daytime
sedation and dizziness
Trazodone- off label use at
low doses
Major side effects: sedation,
dizziness, dry mouth, orthostatic
hypotension, priapism (rare)
No good research to support its
use

48.  Called the “atypical antipsychotics”
 Block dopamine from binding to receptors in the
brain
 Examples:
◦ risperidone (Risperdal)
◦ olanzapine (Zyprexa)
◦ quetiapine (Seroquel)
◦ ziprasidone (Geodon)

49.  Not FDA approved for insomnia
 Typically used at doses much lower than those for
treating psychosis
 Quite sedating but also associated with weight gain,
increased risk for diabetes, high blood pressure,
restless leg syndrome, muscle spasm or parkinson-
like symptoms
 Quetiapine and ziprasidone have been shown to
increase total sleep time as well as sleep efficiency

50.  Diphenhydramine
 Doxylamine
 Promethazine 25mg HS 10mg in children
 Commonly used in pediatric population as sedatives
 Little evidence to support their use
 Side effects:
 dry mouth, urinary retention, blurred vision, dizziness,
sedation, next day hangover

51.  Barbiturates
 Paraaldehyde

 Chloral hydrate

 Meprobamate

52. Classification
(1) Ultra-short-acting barbiturates: act within seconds, and their
duration of action is 30min. Therapeutic use of Thiopental:
anesthesia
(2) Short-acting barbiturates: have a duration of action of about 2h.
The principal use of Secobarbital, : sleep-inducing hypnotics.
(3)Intermediate-acting barbiturates: effect lasting 3-5h.eg
Amobarbital
(4)Long-acting barbiturates: >6h. Such as Barbital and
Phenobarbital. Therapeutic uses: hypnotics and sedative, and
antiepileptic agents at low doses.

53. Barbiturates depress the CNS at all level in a dose-
dependent fashion.
Now it mainly used in anaesthesia and treatment
of epilepsy; use as sedative-hypnotic agents is no
longer recommended.
Reasons:
(1) have a narrow therapeutic-to-toxic dosage range.
(2) suppress REM sleep.
(3) Tolerance develops relatively quickly.
(4) have a high potential for physical dependence and abuse.
(5) potent inducers of hepatic drug-metabolising enzymes

54. MOA
Barbiturates share with benzodiazepines the ability to
enhance the action of GABA, but they bind a different
site on the GABA-receptor/chloride channel, and their
action seems to prolong the duration of the opening of
GABA-activated chloride channels.
PK
High lipid solubility cross the blood-brain barrier and results in a short
onset.
redistribution to the other tissues results in short duration of action.
Metabolized by Phase 1 reaction in the liver
Barbiturates and their metabolites the excretion via the renal route.

55. Therapeutic uses
1. Sedative-hypnotic agents(obsolete )
2. convulsions as in status epilepticus.
3. Anesthetic (or be given before anesthetic)
4. Combination with antipyretic-analgesic
5. Treatment of hyperbilirubinemia and kernicterus
in the neonate.
Adverse effects
After effect: hangover, automatism, amnesia
Tolerance
Dependence: including psychologic and physiologic
dependence.
Depressant effect on respiration
Allergic Skin eruptions and porphyria

56. Mostly sucidal
Charaterised by respiratory failure ,
cardiovascular collapse
Coma
Renal failure
Treatment
1. Gastric lavage
2. Artificial respiration
3. Forced alkaline diuresis with mannitol and sodium
bicarbonate

57. Chloral hydrate (obsolete )
 Chloral hydrate was used for the short-term treatment of insomnia mid-20th century.
 It is also still used as a sedative prior to EEG procedures, few available sedatives that
does not suppress epileptiform discharges.
Paraaldehyde(obsolete )
 Paraldehyde is a polymer of acetaldehyde
 It was commonly used to induce sleep in sufferers from delirium
tremens
Meprobamate
 Was marketed as a anxiolytic and sedative
 MOA – Acts at the GABAA receptor in the limbic system

58. Cognitive Behavioral Therapy for Insomnia
(CBTi)
◦ Stimulus control therapy
◦ Sleep restriction therapy
◦ Relaxation training
◦ Cognitive therapy
◦ Sleep hygiene education

59.  Exercise earlier during the day, and no more than 4-6 hours
before sleep
 Keep bedroom dark and quiet, to be used only for sleep
 Curtail time in bed to only when sleepy
 Fixed sleep/wake times for 365 days
 Avoid naps
 Avoid stimulus or stimulating activities before sleep or in bed
 No alcohol at least 4 hours before sleep, no caffeine after
noon, and quit smoking!!
 Light snack before bedtime

60.  Use bedroom for sleep
 Go to bed only when tired and sleepy
 Remove clock from the bedroom to avoid
constantly watching it
 Regular sleep/wake times
 Light therapy if required
 No bright lights when you wake up at night

61.  An effective form of treatment
 Estimate the time actually asleep then limit
bedtime to that amount, but no less than 5 hours
 Add time in bed gradually once the patient sleeps
more than 85% of that time

62. The patient is educated to correct inaccurate beliefs about
sleep
•To reduce catastrophic thinking
•excessive worrying about the consequences of failing to
obtain adequate sleep.
Relaxation therapy
patient is taught to recognize and control tension through a
series of exercises
Biofeedback techniques can also be used. provide patients
with immediate feedback regarding their level of tension and
rapidly teaching them how to relax.

63. Valerian root Induction of sleep
Lavender Sleeping aids
Chamomile tea

64. Orexins
They excitatory neuropeptides that have a critical role in
maintaining wakefulness.
Orexin receptor antagonists promote sleep in animals and
humans
SB-649,868, 0rexin receptor antagonist in development
by GlaxoSmithKline.
Currently in Phase 2 development,
Bettica P, "Phase I studies on the safety, tolerability,
pharmacokinetics and pharmacodynamics of SB-649868, a novel
dual orexin receptor antagonist". J. Psychopharmacol. (Oxford)

65. Suvorexant (MK-4305) is a dual in development
by Merck & Co.
Suvorexant works by turning off wakefulness rather
than by inducing sleep.
It is not currently approved for commercial use, but it
has completed three Phase III trials
FDA Review
Increased somnolence the next day and users of higher
doses had an increased rate of suicidal ideation

66. •Treatment of insomnia requires a multimodal approach of cognitive and
behavioral therapy and pharmacotherapy
•Non Benzodiazepines are the most favored hypnotics , followed by
Benzodiazepines
•Looking into the future , Orexin antagonists could emerge as a new
treatment for insomnia

67. THANK YOUTHA