The document provides an overview of sedative-hypnotics, including their definitions, types, mechanisms, and pharmacological effects, with a focus on barbiturates and benzodiazepines. It discusses the various stages of CNS depression, side effects, uses, and treatment of barbiturate poisoning, along with alternative hypnotics like non-benzodiazepine agents and melatonin. Additionally, it covers newer medications such as ramelteon and suvorexant, highlighting their roles in sleep regulation.

1. Sedative-Hypnotics
Dr. Arun Jakhar - MBBS,MD (KGMU)
Senior Resident
Department of Pharmacology
UPUMS, Saifai

2. Sedative:
subdues excitement
calms the subject without inducing sleep
drowsiness may be produced
decreased responsiveness to stimulation
decrease in alertness, ideation and motor activity

3. Hypnotic:
induces and/or maintains sleep
similar to normal arousable sleep
not to be confused with ‘hypnosis’
meaning a trans-like state
subject becomes passive and highly suggestible

4. Stages of CNS Depression

6. Stages Characteristics Duration Wave
0 (Awake) lying down to falling asleep 1-2% α - eyes closed
β - eyes open
1 (Dozing) neck muscles relax 3-6% α , θ
2 (unequivocal
sleep)
easily arousable 40-50% Sleep Spindles
K - complexes
3 (deep sleep
transition)
not easily arousable 5-8% θ
δ
4 (cerebral sleep) eyes are practically fixed
difficult to arouse
night terror
10-20% δ
REM (paradoxical
sleep)
Marked eye movements
dreams and nightmares
Irregular – BP, HR and Respiration
Muscles fully relaxed
Erection in males
20-30% All wave forms

9. BARBITURATES
• popular upto 1960s
• but are not used now to promote sleep or to calm patients
• are substituted derivatives of barbituric acid (malonyl urea)
• barbituric acid as such is not a hypnotic but compounds with alkyl or
aryl substitution on C5 have this property
• Replacement of O with S at C2 yields thiobarbiturates which are more
lipid-soluble and more potent

10. PHARMACOLOGICAL ACTIONS:
• depressants for all excitable cells
• more for the CNS
1. CNS:
Barbiturates produce dose-dependent effects:
sedation → sleep → anaesthesia → coma

11. Hypnotic dose:
• shortens the time taken to fall asleep
• increases sleep duration
• night awakenings are reduced
• REM and stage 3, 4 sleep are decreased
• REM-NREM sleep cycle is disrupted

12. • effects become progressively less if taken every night
• rebound increase in REM sleep and nightmares
• when drug discontinued after a few nights of use
• it takes several nights for normal pattern to be restored
• hang over (headache, dizziness, distortions of mood, irritability and
lethargy) may occur in the morning after a nightly dose

13. Sedative dose:
• smaller dose of a longer acting barbiturate
• given at daytime can produce drowsiness, reduction in anxiety and
excitability
• however, barbiturates do not have selective anti anxiety action
• they can impair learning, short-term memory and judgement
• euphoria may be experienced by addicts

14. 2. Other actions:
• at relatively higher doses
• depress respiration
• lower BP
• decrease cardiac contractility and heart rate
• but reflex tachycardia can occur due to fall in BP
• muscle tone, bowel motility and urine output are also reduced
• toxic does cause respiratory failure and cardiovascular collapse

15. MECHANISM OF ACTION:
• Increase duration of chloride channel opening
• At high concentrations:
directly increase Cl¯ conductance (GABA-mimetic action)
 inhibit Ca2+ dependent release of neurotransmitters
depress glutamate induced neuronal depolarization through AMPA
receptors (a type of excitatory amino acid receptors)
depress voltage sensitive Na+ and K+ channels

16. GABA(A)-benzodiazepine receptor-chloride channel complex

17. PHARMACOKINETICS:
• well absorbed from the g.i. tract
• widely distributed in the body
• rate of entry into CNS is dependent on lipid solubility
• Highly-lipid soluble thiopentone has practically instantaneous entry
while less lipid-soluble ones (pentobarbitone) take longer
• phenobarbitone enters very slowly
• cross placenta
• secreted in milk
• produce effects on the foetus and suckling infant

18. • termination of action of barbiturates:
redistribution, metabolism and excretion
• induce several hepatic microsomal enzymes (CYP3A4/5, CYP2D6,
CYP2C8/9, CYP2B6, UGTs)
• increase rate of their own metabolism as well as that of many other
drugs

19. USES:
1. phenobarbitone ----epilepsy
2. thiopentone/methohexitone ---anaesthesia
ADVERSE EFFECTS:
3. hangover
4. mental confusion
5. impaired performance and
6. traffic accidents
7. tolerance and dependence

20. Acute barbiturate poisoning:
• Mostly suicidal
• some times accidental
• infrequently encountered now
• Manifestations:
patient is flabby and comatose
shallow and failing respiration
fall in BP and cardiovascular collapse
renal shut down
pulmonary complications

21. Treatment of Acute barbiturate poisoning:
• Gastric lavage----activated
• Supportive measures:
patent airway, assisted respiration, oxygen, maintenance of blood
volume by fluid infusion and use of vasopressors—
dopamine may be preferred for its renal vasodilating action
• Alkaline diuresis
• Haemodialysis and haemoperfusion

22. BENZODIAZEPINES (BZDs)
• selective CNS depressants
• have a high therapeutic index
• hypnotic doses do not affect respiration or cardiovascular functions
• cause less distortion of sleep architec ture; rebound phenomena on
discontinuation
• do not alter disposition of other drugs by microsomal enzyme
induction
• have lower abuse liability than barbiturates
• specific BZD antagonist flumazenil is available

23. USES:
1. Antianxiety
2. Hypnotic
3. Muscle relaxant
4. Anticonvulsant
5. Alcohol withdrawal( Chlordiazepoxide)

24. MECHANISM OF ACTION:
• act preferentially on midbrain ascending reticular formation (which
maintains wakefulness)
• and on limbic system (thought and mental functions)
• Muscle relaxation----primary medullary site of action and ataxia is due
to action on cerebellum

25. GABA(A)-benzodiazepine receptor-chloride channel complex

26. ADVERSE EFFECTS:
hypnotic doses----dizziness, vertigo, ataxia, disorientation, amnesia,
prolongation of reaction time—impairment of psychomotor skills
(should not drive)
Sleep walking, sleep driving and other abnormal sleep behaviours with
no memory of these events has been recognized as a possible hazard
Hangover----less common
Weakness,
blurring of vision, dry mouth and urinary incontinence are sometimes
complained
Older individuals--more susceptible to psychomotor side effects
Like any hypnotic, BZDs can aggravate sleep apnoea

27. NON-BENZODIAZEPINE HYPNOTICS
• chemically different from BZDs
• but act as agonists on a specific subset of BZD receptors
• action is competitively antagonized by flumazenil
• which can be used to treat their overdose toxicity
• act selectively on α1 subunit containing BZD receptors
• produce hypnotic-amnesic action
• With weak antianxiety, muscle relaxant and anticonvulsant effects
• have lower abuse potential than hypnotic BZDs
• shorter duration of action----preferred over BZDs

28. • Zopiclone
• Eszopiclone
• Zolpidem
• Zaleplon

29. Types of Insomnia
• Chronic insomnia (> 3 weeks)
• Short-term insomnia (3–21 days)
• Transient insomnia (1–3 days)

30. BENZODIAZEPINE ANTAGONIST
FLUMAZENIL:
• competes with BZD agonists as well as inverse agonists
• reverses their depressant or stimulant effects respectively
• absorbed orally, but it is not used orally
• Injected i.v.-----action starts in seconds and lasts for 1–2 hours
• elimination t½ is 1 hr, due to rapid metabolism
Uses:
1. To reverse BZD anaesthesia
2. BZD overdose

31. Other Hypnotics
Triclofos:
• old CNS depressant
• fast-acting hypnotic
• acts in 30 min, action lasts 6–8 hours
• though obsolete
• some times used to sedate children in distress
• and rarely to induce sleep in adults

32. Melatonin:
• principal hormone of the pineal gland
• secreted at night
• important role in sleep-wakefulness cycle
• receptor MT1 and MT2 in the brain
• Both are GPCRs
• high doses (80 mg) of melatonin administered orally can induce sleep
low doses (2–10 mg) do not depress the CNS, but probably increase
the propensity of falling asleep
Uses: jet-lag, shift workers and elderly insomniacs

33. Ramelteon:
• MT1 , MT2 melatonin receptor agonist
• 8 mg ½ hour before going to bed
• hasten sleep onset as well as increase sleep duration
• without causing next morning sedation or impairment

34. Suvorexant:
• first member of a novel class of insomnia drugs—’dual orexin
receptor antagonists’ (DORAs)
• Orexins are neuropeptides found in lateral hypothalamus
• which promote wakefulness by acting on OX1R and OX2R
• orexin levels are high during day time and low at night,
• and that narcolepsy (episodes of sudden sleep) is associated with loss
of orexin neurones, support this role of orexin