DISCUSSES pharmacology of sedative hypnotics with their status, indications , adverse effects.

1. Sedative-Hypnotic Drugs
P S
PATKI
SCHOOL OF
MEDICINE.
BANGALORE.
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2. Objectives
 Define sedative and hypnotics.
 Different stages of CNS Depressants.
 Name benzodiazepines and pharmacological
actions.
 Name their adverse effects and indications.
 Name two barbiturates ,
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3. Dose-response curves for two
hypothetical sedative-hypnotics
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4. Sedative hypnotics

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7. Sedatives
Drugs that ↓ excitement, calm down
and cause drowsiness without
producing sleep.

8. HYPNOTICS
Drugs that induce and maintain sleep
similar to normal arousal sleep.

9. Tranquillizer
 Drugs that reduces tension and anxiety
without drowsiness or sleep

10. Sleep Pattern
NREM sleep
(slow wave EEG sleep)
REM sleep
(fast wave EEG sleep)

11. Different phases of sleep and their characteristics
NREM sleep
Stage 0 (awake)
From lying down to falling asleep and occasional nocturnal
awakenings – constitutes 1-2% of sleep time
eye movements are irregular or slowly rolling
Stage 1 (dozing)
Eye movements are reduced but there may be bursts of rolling
Neck muscles relax - occupies 3-6% of sleep time
Stage 2
Little eye movement, subjects are easily arousable
This comprises 40-50% of sleep time

12. Stage 3 (deep sleep transition)
Eye movements are few, subjects are not easily arousable
This comprises 5-8% of sleep time
Stage 4 (cerebral sleep)
Eyes are practically fixed, subjects are difficult to arouse.
Night terror may occur at this time
This comprises 10-20% of sleep time
slow wave sleep: physical restoration process
REM: consolidation of learning
During stage 2, 3 and 4 – HR, BP and respiration are steady and
muscles are relaxed

13. There are marked, irregular eye movements; dreams and night-
mares occur, which may be recalled if the subject is aroused
HR, BP – fluctuate, respiration irregular
Muscles are fully relaxed, DREAMS
Erection occurs in males
About 20-30% of sleep time is spent in REM
Normally stages 0-4 and REM occurs in succession over a
period of 80-100 min. Then stages 1-4-REM repeated cyclically
A normal 8 hrs sleep consists of 4 or 5 cycles of quite sleep
alternating with REM sleep
REM sleep (paradoxical sleep)

14. Stages of sleep

15. Insomnia
 It is defined as inadequate sleep and may be
manifested as difficulty in falling asleep or
difficulty in maintaining sleep with
intermittent wakening during sleep
 Exhaustion, tension, anxiety, depression,
caffeine, jet lag, etc…

16. Classification
1. Benzodiazepines:
Long acting (>24hrs):
Diazepam
Intermediate acting (6-24 hrs):
lorazepam, oxazepam, nitrazepam, alprazolam
short acting (< 6hrs):
triazolam, midazolam

17. Classification
1. Benzodiazepines:
 Hypnotic:
diazepam, alprazolam, triazolam, flurazepam
 Antianxiety:
diazepam, oxazepam, lorazepam, alprazolam
 Anticonvulsant:
diazepam, lorazepam, clonazepam, clobazam
 Muscle relaxant: Diazepam
 GA: midazolam
 Depression: Alprazolam

18. Classification
2. Barbiturates:
Long acting :
phenobarbitone, mephobarbitone
Short acting:
secobarbitone, pentobarbitone, butobarbitone
Ultra short acting :
thiopentone, methohexitone

19. Classification
3. Newer non-benzodiazepine hypnotics:
Zopiclone
Zolpidem
Zaleplon

20. Benzodiazepines (BZD)
Mechanism of action:
 BZD act on midbrain ascending reticular formation and
Limbic system
 Bind to BZD receptor (integral part of GABAA receptor –Clˉ channel
complex)

21. Mechanism of action:
Benzodiazepines
Increase in chloride conductance
No GABA mimetic action
Potentiates the inhibitory effects of GABA
Increase the frequency of opening of Cl- channel
Binds to specific site on GABA-A receptor
Membrane Hyperpolarization
CNS depression

22. GABAA- BZD receptor Cl- channel complex

23. Pharmacological actions of BZD
1. Sedation and hypnosis:
 Reduces sleep latency
 Reduces intermittent awakening
 Time spent in stage II ↑ and stage III & IV ↓
 Shortens REM phase
 Body movements during sleep ↓
 Sleep quality similar to natural sleep
 Tolerance develops gradually

24. Pharmacological actions of BZD
2. Anxiolytic - ↑ depressant effect
3. Muscle relaxant – medullary site action
4. Anticonvulsant – ↑ seizure threshold
5. Amnesia
6. Other actions – analgesia and ↓ nocturnal
gastric secretion

25. Pharmacokinetics
 Well absorbed orally
 IM – irregular
 Plasma protein binding varies : diazepam –
99% and flurazepam – 10%
 Widely distributed in the body

26. Diazepam
Desmethyldiazepam
Oxazepam
Medazepam
Chlorzepate
Alprazolam
Midazolam
TriazolamGlucuronide
conjugation
Temazepam
Lorazepam
Flurazepam
Desmethylflurazepam
elimination
Hydroxylated
metabolites
Chlordiazepoxide
Desmethylchlordia
zepoxide

27. Pharmacokinetics
 Highly lipid soluble – two phase plasma concentration
decay curve
 Metabolised in the liver – dealkylation and hydroxylation
 Excreted in urine
 Diazepam undergoes enterohepatic circulation
 Cross placenta and are secreted in milk

28. Effects of ligand BZD receptor
Agonist Antagonist Inverse
agonist
Ligand Benzodiazepines Flumazenil β- carboline
Effects Sedation, hypnosis,
antianxiety,
anticonvulsant,
muscle relaxation
Blocks &
reverses the
effect of BZD
Arousal, anxiety,
↑ muscle tone,
convulsions

29. D- Diagnostic and Minor operative procedures
I. Insomnia
A- Alchohol withdrawal syndrome
Z-
E- Epilepsy
P- Preanesthetic Medication
A- Anxiety
M- Muscle relaxation in tetanus,
cerebral palsy

30. Long term treatment with hypnotics:
 Rebound insomnia
 Change in sleep architecture
 Reduced effectiveness due to blockade of slow wave sleep
 Blocks the slow wave sleep – it is important for physical
restoration process
 Suppression of REM sleep

31. Adverse effects of BZD
 BZD – relatively safe drug with a wide margin of
safety
 Dizziness, vertigo, disorientation, muscle
weakness, impaired motor coordination,
prolongation of reaction time, hangover (less
common).
 Floppy baby syndrome.

32. Adverse effects of BZD
 Blurred vision, nausea, dry mouth, urinary
incontinence.
 irritability & sweating
 Tolerance to sedative effects
 Not teratogenic ; flaccidity & respiratory
depression in neonate

33. Drug interactions- BZD
 Alcohol & CNS depressants-Potentiate depressant action
 Enzyme inhibitors like Cimetidine, ketoconazole, erythromycin -
↓ metabolism
 Caffeine inhibits anxiolytic effect of BZD

34. Tolerance and dependence
 Less
 Tolerance to sedative effects develops slowly
 Withdrawal symptoms are mild and slow in onset
Symptoms include anxiety, nervousness, tremor, dizziness
and anorexia

35. Acute over dosage of BZD
 Induces sleep; respiratory depression is mild
 Specific antagonist - flumazenil

36. Flumazenil
 BZD analogue
 Compete with BZD agonist and inverse agonist
and reverses their effects
 I.V - action starts in seconds and lasts for 1-2 hours
 Elimination t1/2 is 1 hour
 Uses:
1. To reverse BZD anesthesia
2. BZD overdosage

37. Barbiturates
 Derivatives of barbituric acid

38. Barbiturates:
Long acting :
phenobarbitone, mephobarbitone
Short acting:
secobarbitone, pentobarbitone, butobarbitone
Ultra short acting :
thiopentone, methohexitone

39. Advantages of BZD over barbiturates
1. Induce sleep- natural
2. No hang over
3. High therapeutic index – 20 hypnotic doses x endanger life
4. Hypnotic dose – does not affect Resp / CV function
5. No action on other systems
6. No Microsomal enzyme induction
7. withdrawl syndrome are less marked

40. Advantages of BZD over barbiturates
8. Less dependence
9. Lower abuse liability
10. Do not produce hyperalgesia
11. Amnesia without automatism
12. Do not produce generalized CNS depression
13. Less distortion of sleep and rebound phenomena
14. Specific BZD antagonist available

41. Mechanism of action:
Barbiturates
Increase in chloride conductance
Potentiates the inhibitory effects of GABA
Increase the DURATION of opening of Cl- channel
Binds to specific site on GABA-A receptor
Membrane Hyperpolarization
CNS depression

42. GABAA- BZD receptor Cl- channel complex

43.  GABA mimetic action (high conc.)
 ↓ glutamate induced neuronal transmission

44. Pharmacological actions - barbiturates
 CNS:
 Sedation & hypnosis
 Anesthesia (higher doses)
 Anticonvulsant effect (sub hypnotic doses)
Hyperalgesia
 Respiratory system
Respiratory depression

45. SLEEP
NREM
(1,2,3,4)
REM
NREM
(1,2,3,4)REM
NREM
(1,2,3,4)
REM
Natural
sleep
BZD
induced
Barbiturate
induced
Sudden
discontinuation
Increased
REM
Nightmares
Night terror

46. Uses- Barbiturates
1. Epilepsy: Phenobarbitone
2. Anaesthesia: Thiopentol sodium
3. Kernicterus
4. Narcoanalysis
5. Sedation & hypnosis
6. Pre-anesthetic medication

47. Adverse effects - barbiturates
 Hangover
 Mental confusion, impaired
performance and judgement
 Idiosyncrasy
 Hypersensitivity

48. Tolerance & dependence - Barbiturates
 Develops on repeated administration
 Psychological & physical dependence – abuse
 Withdrawal symptoms
Anxiety, restlessness, abdominal cramps,
Hallucination, delirium & convulsions

49. Acute barbiturate poisoning
 Drug automatism
 Manifestation- CNS depression, shallow resp., CV
collapse, renal failure, pulmonary complications, bullous
eruptions
 Treatment:
Gastric lavage - activated charcoal
General supportive measures – A B C
Forced alkaline diuresis (Na bicarbonate1meq/kg IV +- mannitol)
Haemodialysis

50. Contraindications- Barbiturates
1. Acute intermittent porphyria
2. Liver and kidney disease
3. Severe pulmonary insufficiency

51. Drug interactions - Barbiturates
1) Enzyme induction ↓ effectiveness– warfarin, tolbutamide, OCP,
2) CNS depressants- opioids, alcohol– additive action
3) Sodium Valproate – ↑ plasma conc. of phenobarbitone

52. NON- BENZODIAZEPINE HYPNOTICS:
Zolipidem, Zopiclone, Zoleplon
Binds selectively to Benzodiazepine receptors
Facilitates GABA mediated neuronal inhibition
CNS depression

53.  Produces Hypnotic effect with minimal
anticonvulsant and muscle relaxant properties
 It produces natural sleep without alteration of REM
sleep.
 Minimal hangover effects
 Short duration of action
 Less likely to produce Tolerance and dependence

54. Short acting agents Long acting agents
Preferred in patients with sleep
onset insomnia
No REM suppression
Less hangover
Less tolerance and dependence
Less respiratory depression
Preferred in patients with daytime
anxiety, who can tolerate sedation
on next day and with depression.
Disadvantages:
Early morning awakening
Rebound anxiety
Amnesic episodes
Disadvantages:
Next day confusion
Cognitive impairment on next day
Delayed cognitive impairment

55. NMDA receptor
(N-methyl-D-aspartate)
 Mediate slow excitatory responses
 Long term adaptive changes in the brain
Normal stimulation – learning and memory(synaptic
plasticity)
Over stimulation – excitotoxicity in brain
(neurodegenaration and apoptosis

56. NMDA receptor BLOCKERS
 Ketamine: IV general anesthetic- dissociative
 Phencyclidine: Psychedelic drugs
 Memantine: Alzheimer's disease
 Topiramate and Felbmate: Anti epileptic drugs

57. Sedation Hypnosis
Drug Dosage Drug Dosage (at Bedtime)
Alprazolam (Xanax) 0.25-0.5 mg 2-3 times
daily
Chloral hydrate 500-1000 mg
Buspirone (BuSpar) 5-10 mg 2-3 times daily Estazolam (ProSom) 0.5-2 mg
Chlordiazepoxide
(Librium)
10-20 mg 2-3 times daily Eszopiclone
(Lunesta)
1-3 mg
Clorazepate
(Tranxene)
5-7.5 mg twice daily Lorazepam (Ativan) 2-4 mg
Diazepam (Valium) 5 mg twice daily Quazepam (Doral) 7.5-15 mg
Halazepam
(Paxipam)
20-40 mg 3-4 times daily Secobarbital 100-200 mg
Lorazepam (Ativan) 1-2 mg once or twice
daily
Temazepam (Restoril) 7.5-30 mg
Oxazepam 15-30 mg 3-4 times daily Triazolam (Halcion) 0.125-0.5 mg
Phenobarbital 15-30 mg 2-3 times daily Zaleplon (Sonata) 5-20 mg
Zolpidem (Ambien) 5-10 mg
Dosages of drugs used commonly for sedation and hypnosis
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58. 5-HT RECEPTORS
5-HT
5-HT1 5-HT2 5-HT3
5-HT4 5-HT5-7
1a
1b
1d
2a
2b
2c

59. 1 Selective Serotonin uptake inhibitors
Citalopram
Escitalopram
Fluoxetine
Fluoxamine
Sertraline
SSRIs
antidepressants

60. 5-HT 1A Partial agonists
Buspirone
Gepirone
Ipsapirone
Anxiolytic drugs
5-HT 1D Partial agonists
Sumatriptan
Naratriptan
Zolmitriptan
Rinzatriptan
Migraine drugs
3
4

61. 5-HT 2A, 2C antagonists
CLOZAPINE
OLANZAPINE
RESERPIDONE
ARIPIPRAZOLE
ZIPRASIDONE
NEWER
ANTIPSYCHOTIC
DRUGS
METHYSERGIDE
CYPROHEPTADINE
PROPHYLAXIS OF
MIGRAINE
5

62. 5-HT 3 antagonists
ONDANSETRON
GRANISETRON
DOLOSETRON
ANTIEMETIC DRUGS
6

63. 5-HT 4 agonists
CISAPRIDE
MOSAPRIDE
METOCLOPRAMIDE
PROKINETIC AGENTS
7

64. Melatonin
 It is a mediator that is synthesized from 5-HT in the pineal
gland.
 Melatonin receptors are mainly found in the retina
and brain.
 Melatonin secretion is high at night and low by day, therefore it
is important in the regulation of circadian rhythm
 Melatonin is medicinally used to control “jet-lag”
 Ramelteon

65. Melatonin
 Hormone of the pineal gland secreted at night
 Synchronizing action – sleep-wakefulness cycle with circadian
rhythm
 Treatment of jet-lag, elderly hypnotic dependent insomniacs and
shift workers
RAMELTEON
 It is a selective agonist at the MT1 and MT2 R of melatonin
 Used in insomnia – difficulty in falling asleep

66. TERIMA KASIH