Sedatives and hypnotics are drugs that calm or induce sleep. Common classes include benzodiazepines (BZDs), barbiturates, and non-BZD hypnotics. BZDs are widely used and bind to GABA receptors to facilitate the effects of GABA, producing sedation, hypnosis, or anesthesia in a dose-dependent manner. They have a high safety profile but can cause dependence. Barbiturates also act at GABA receptors but have a lower safety margin and greater risk of overdose. Newer non-BZD drugs like zolpidem, zaleplon, and zopiclone have fewer side effects and lower abuse potential than B

1. SEDATIVES
&
HYPNOTICS
-By Dr. Jayesh Vaghela

2. Overview
 Sleep cycle
 Introduction about Drug groups
 Classification : - BZDs
- Barbiturates
- Non-BZD hypnotics
- Atypical Anxiolytics
 Recent advances
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3.  Sedative :
 A drug that ↓ excitement & calms the subject,
 Without Inducing sleep.
 ↓ responsiveness to any level of stimulation & ↓ motor activity
 Hypnotics :
 A drug that induces and/or maintains sleep
 Similar to normal arousable sleep
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4. History
 Alcohol, laudanum, herbals ⇒ sleep
 Bromide, Chloral hydrate, paraldehyde, urethane, sulfanol.
 1903 - Barbital
 1912 - Phenobarbital
 1960s - BZDs
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5. Dose Dependent Action
Sedation
(Sedative)
Sleep
(Hypnotic)
Anesthesia
(Anesthetic)
Coma Death
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6. Sleep Cycle
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• Eyes open – β, Eyes are closed - α wavesAwake
• Dozing, α + θ, disappearance of α – onset of sleepStage I
• θ + sleep spindles and K complex
• 40- 50% of total sleep time
Stage II
• Appearance of δ wavesStage III
• δ wave predominatesStage IV
• Reappearance of α, low voltage high frequency (Saw tooth waves)
• 20-30% of total sleep time
REM
N
R
E
M
70-
80%
Of
Total
sleep
time
Slow
wave
sleep

8. BENZODIAZEPINES ( BZDs )
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9. Benzodiazepines
a/c to Duration of Action
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Short acting
• Triazolam
• Oxazepam
• Midazolam
Intermediate acting Long acting
• Alprazolam
• Estazolam
• Temazepam
• Lorazepam
• Nitrazepam
• Diazepam
• Flurazepam
• Clonazepam
• Chlordiazepoxide

10. Benzodiazepines
a/c to Indications
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Hypnotic Antianxiety Anticonvulsant
• Diazepam
• Flurazepam
• Nitrazepam
• Alprazolam
• Temazepam
• Triazolam
• Diazepam
• Chlordiazepoxide
• Oxazepam
• Lorazepam
• Alprazolam
• Diazepam
• Lorazepam
• Clonazepam
• Clobazam

11. Site of Action
 Midbrain ( RAS ) - Wakefulness
 Limbic system - Thought & mental functions
 Medulla - Muscle relaxation
 Cerebellum - Ataxia
 Effect : Limbic system > Midbrain RAS
⇓
- Therapeutic dose ⇒ Anxiolytic > Sedative
- Higher dose ⇒ Depress RAS → Sedative & hypnotic effect
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Mechanism of Action

13. α γ
α
β
GABA
Bicuculline
Diazepam
Intra cellular side
Flumazenil
DMCM
Barbiturate
GABAA Receptor
Barbiturate receptor
BZD Receptor
Cl--
Picrotoxin
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β
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BZDs Barbiturates
o Less neuronal depression
o High therapeutic index
o More neuronal depression
o No effect on respiration or
cardiovascular functions at hypnotic
doses
o Only i.v. injection causes ↓ BP,
cardiac contractility
o Suppression is seen
o No effect on other body systems o Suppressive effects on other
systems,
- Skeletal & smooth muscles, kidney
o Specific antagonist – Flumazenil o No antagonist available

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BZDs Barbiturates
o No anaesthesia even at high doses,
o Patient can be aroused
o Loss of consciousness,
o Low margin of safety
o Not enzyme inducers –
- No metabolic tolerance
- Less drug interactions
o Potent enzyme inducers –
- Metabolic tolerance seen
- More drug interactions
o No effect on REM sleep
o Less distortion of normal hypnogram
o ++ suppression of REM sleep
o Withdrawal ⇒ rebound ↑ in sleep
o Hangover
o Abuse liability very low o Tolerance
o Dependence
o No hyperalgesia o Hyperalgesia
o ↑ Sensitivity to pain
o Amnesia without automatism o Amnesia with automatism
o Loss of short term memory

16. Pharmacokinetics
 Absorption : - All can be given orally ( Except, Midazolam )
 Distribution : - Wide volume of distribution
- PPB variable, flurazepam 10% to diazepam 90%
 Metabolism : - Phase 1 reactions ⇒ Phase 2 reactions
- Some phase 1 metabolites are active ⇒ ↑ T1/2 &
duration of action
- e.g. - Midazolam - Diazepam - Flurazepam
- Alprazolam - Chlordiazepoxide
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17. Categorization a/c to Pharmacokinetic Profile
1) Slow elimination of parent drug / active metabolite
 Flurazepam
2) Relatively slow elimination ; Marked Redistribution
 Diazepam, Nitrazepam
3) Relatively Rapid elimination ; Marked Redistribution
 Alprazolam, Temazepam
4) Ultra rapid elimination
 Triazolam, Midazolam
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18. Therapeutic uses
1) Anxiety Neuroses :
• Alprazolam : - Anxiety with Depression ( 0.25-0.5 mg BD/TDS )
- Anxiety with Panic disorder ( max 6 mg/day )
• Lorazepam : - Suitable for parenteral use
- Short lived anxiety states, Compulsive-Obsessive
neuroses, tension-induced psychosomatic symptoms
- Dose : 1 – 6 mg / day
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19. • Oxazepam : - Elderly or liver dysfunction with Short-lived anxiety
states
- Dose : 30 – 60 mg in 3 divided doses
• Diazepam : - Acute panic-anxiety with organic disease
- Where sedation is also required
- Dose : 2 – 10 mg BD / TDS
• Chlordiazepoxide:- Chronic Anxiety states
- Dose : 20 – 50 mg / day in 3 divided doses
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20. 2) Insomnia :
Type Duration Cause Drug Dose Remarks
Transient < 7 days Jet-lag
Shift work
Overnight journey
Triazolam 0.125 – 0.25
mg
Difficulty in
going to sleep
Temazepam 15 – 30 mg Inability to stay
asleep
Short
term
1 – 3 week Bereavement
Occupational
problems
Flurazepam 15 – 30 mg Frequent
nocturnal
awakenings
Temazepam 15 – 30 mg Inability to stay
asleep
Estazolam 1 – 2 mg --
Long term > 3 weeks Underlying disease
Personality disorders
Flurazepam 15 – 30 mg Intermittent use
( Break after
every 3rd day )
Nitrazepam 5 – 10 mg
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21. 3) Preanaesthetic medication & Induction of anaesthesia :
 Midazolam - i.v.
- More amnesia, rapid onset, shorter duration
 Others : Diazepam, Lorazepam
4) As skeletal muscle relaxant :
 Diazepam
 In muscle spasticity of central origin
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22. 5) As anticonvulsant :
 Status epilepticus - Diazepam & Clonazepam ( slow i.v. )
 Myoclonic / petit mal - Clonazepam
6) Treatment of alcohol withdrawal :
 Diazepam / Chlordiazepoxide
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23. Benzodiazepines as hypnotics
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Drug T1/2 ( hours ) Dose ( mg ) Indications
 Long Acting
Flurazepam 50 – 100 15 – 30 Chronic insomnia,
Short term insomnia with anxiety,
Frequent nocturnal awakening,
Night before operation
Diazepam 30 – 60 5 – 10
Nitrazepam 30 5 – 10
 Short Acting
Alprazolam 12 0.25 – 0.5 Sleep onset difficulties,
Patients who react unfavourably to
unfamiliar surroundings or unusual
timing of sleep
Temazepam 8 – 12 10 – 20
Triazolam 2 – 3 0.125 – 0.25

24. Adverse effects
 Higher safety margin ( 50 times dose )
 Tolerance to sedative effects – “ self inducers ”
 Dependence
 Down regulation ⇒ ↓ functional GABA activity
 ↑ Age ⇒ ↓ phase 1 metabolism ⇒ confusion, forgetfulness
 Paradoxical stimulation ( flurazepam )
 Flunitrazepam – sedative-amnesic effects – “ date rapes ”
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25. Drug Interactions
 CNS depressants - Potentiation (alcohol, hypnotics, neuroleptics)
 Smoking - ↓ Activity of BZDs
 Aminophylline - Antagonises sedative effects of BZDs
 Enzyme inhibitors - ↑ Activity
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26. NON – BZD HYPNOTICS
( THE “ Z ” COMPOUNDS )
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27. Zolpidem Zaleplon Zopiclone Eszopiclone
T1/2 2 hr 1 hr 5 – 6 hr
Use • Short term use in
• Sleep onset insomnia,
• Intermittent awakenings
Sleep onset
insomnia
Short term
insomnia
< 2 weeks
Short term &
chronic
insomnia
Advantage • No effect on sleep stages,
• Less day time sedation,
• No rebound insomnia,
• No tolerance,
• No abuse,
• Safety in overdose
• Late night,
• No day time
anxiety,
• No rebound
insomnia
-- --
Dose 5 – 10 mg HS 5 – 10 mg HS 7.5 mg HS --
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28. Flumazenil
 BZD analogue with little intrinsic activity
 Competes with BZD agonist & antagonist
 Uses :
 To reverse BZD anaesthesia :
- Dose : 0.3 – 1 mg i.v.
- Allows early discharge of patient after diagnostic procedures
- Facilitates postanaesthetic management
 BZD overdose :
- 0.2 mg / min i.v.
 ADRs : Agitation, discomfort, withdrawal seizures.
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29. BARBITURATES
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30. Barbiturates
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Long Acting Short Acting Ultra-short Acting
• Phenobarbitone • Butobarbitone
• Pentobarbitone
• Thiopentone
• Methohexitone
o Epilepsy
o Neonatal jaundice
Anaesthesia

31. Barbiturates
Binds to GABAA receptor (on α or β subunit)
Facilitates GABA action
Increase in duration of opening of Cl-
channel
Membrane hyperpolarization
CNS depression
At higher dose it can
act as GABA mimetics
Mechanism of Action
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32. Pharmacological Actions
 CNS - Generalized depression, Dose dependent action
 Sleep –
o ↓ Latency of sleep onset
o ↑ Total duration of sleep
o ↓ Night awakening
o Sleep cycle distortion - Hangover
o Rebound increase in REM sleep on discontinuation
 Anti - convulsant activity
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33.  RS :
 Depression of respiratory center
 CVS :
 Depression of VMC
 ↓ Myocardial contractility
 ↓ BP, HR
 Smooth muscles :
 ↓ tone & motility of bowel
 Kidney :
 ↓ Urine flow
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34. Adverse effects
 Hangover
 Hypersensitivity
 Tolerance & Dependence ( Abuse potential )
 Poisoning ⇒ No Antidote, Only Symptomatic Treatment
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35. Interactions
 Enzyme inducers - ↑ Metabolism, ↓ Effectiveness
- Steroids, Warfarin
 CNS depressants - Additive action
 Sod. Valproate - ↑ Concentration of phenobarbitone
 Phenytoin - Induction & Inhibition by phenobarbitone
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36. Atypical Anxiolytics
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37. Buspirone, Ipsapirone, Gepirone
 M/A - Partial agonist at 5-HT1A receptors
Activation of presynaptic inhibitory 5-HT1A receptor
↓ 5-HT neurotransmission
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 Use - Long term anxiety states ( effect take >2 weeks, not for acute )
 Advantages- minimal abuse potential
- No withdrawal reactions
- less impairment of psychomotor skills
 ADRs – Tachycardia, Nervousness, GI distress, Paresthesias

38. Beta Adrenoceptor Antagonist
 Worrying situations & Apprehensions ( job interview, exam, etc. )
Palpitation, tremors, GI upset.
Reinforce anxiety
 Propranolol 20 mg TDS breaks the vicious cycle
 CVS effects ⇒ Unlikely to be used as anxiolytic
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39. Melatonin
 Pineal gland hormone
 Affects sleep – wake cycle
 Darkness ⇒ Melatonin ⇒ MT1 MT2 receptors in SCN ⇒ Circadian
rhythm
 Use - Jet-lag insomnia
 Dose: 3 mg 2 hour before bed time
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40. Ramelteon
 MT1 & MT2 receptor agonist
 Use - Sleep onset insomnia
- Speeds sleep onset
- Longer duration of sleep
 Adv. - No dependence
- No rebound insomnia
 Dose- 8 mg ½ hour before going to sleep
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41. Tasimelteon
 MT 1 & MT 2 receptor agonist
 Recently approved by USFDA in Jan – 2014
 Use - Non 24-hour sleep wake disorder in totally blind
 ADR - Headache, Nightmares.
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42. References
 Catterall AW and Mackie K. Sedatives & Hypnotics. In : Bruton LL,
editor. Goodman & Gilman’s – The Pharmacological basis of
therapeutics. 12th edition. New York : Mc Graw Hill Publication; 2011.
p. 566-82.
 Schulman JM and Strichartz GR. Neurotransmission in central nervous
system. In: Golan DE, editor. Principles of Pharmacology – The
pathophysiological basis of drug therapy. 3rd edition. New Delhi:
Walters Kluwer Publication; 2012. p. 147-62.
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43.  Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi :
Jaypee brothers medical publishers; 2009. p. 360-71.
 Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New
Delhi: Paras publication; 2012. p. 212-22.
 Shrivastava SK. A complete textbook of medical pharmacology. 1st
ed. New Delhi: Avichal publication; 2012. p. 552-67.
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