MBBS Sem IV lecture class

1. Sedative-Hypnotics-2
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College
19 August 2018 (3 Bhadra 2075), Sunday

2. At the end of the class, MBBS
Sem IV students will be able
to:
List the salient features of individual
benzodiazepines (BZDs)
Explain the pharmacology of non-BZDs
hypnotics
Understand the role of melatonin as hypnotic
Describe the pharmacological basis of
ramelteon as hypnotic agent

3. BZDs: Individual compounds
Diazepam
All purpose BZD
Produces active metabolite (desmethyl-
diazepam, oxazepam)
• Accumulation occurs on prolong use
Rebound insomnia on discontinuation: less
likely
Withdrawal reaction: mild

4. BZDs: Individual compounds
Flurazepam, Nitrazepam
Long acting BZDs
Accumulation and residual effects seen
• Day time sedation
Useful for patients with frequent night time
awakenings

5. BZDs: Individual compounds
Alprazolam
Intermediate acting
Few residual effects seen on next day
Discontinuation after regular use
• Marked withdrawal reactions
Used as anxiolytic, hypnotic
Temazepam: sleep onset difficulty

6. BZDs: Individual compounds
Midazolam
Extremely rapid elimination- peak effect in
20 mins
More liable for abuse
Available for premedication, intravenous
anaesthetic
• As hypnotic: NOT AVAILABLE

7. Non-BZDs Hypnotics
Zopiclone, Zaleplon, Zolpidem
Agonist of specific subset of BZD receptors(α1
subunit containing):
Hypnotic-amnestic action seen
Antianxiety, muscle relaxant, anticonvulsant
action- weak
Low abuse potential
Short duration of action

8. Individual compounds
Zopiclone
Prominent hypnotic action:
Acts on specific subtype of BZD receptor
Some degree of next morning impairment seen
Use:
Short term insomnia (<2 weeks)
Wean off patient on prolong BZD medication

9. Individual compounds
Zopiclone
Side effects:
Metallic/ bitter taste, impaired judgement
and alertness, psychological disturbances,
dry mouth
Dependence: milder form
• Eszopiclone- active enantiomer little
tolerance and dependence

10. Individual compounds
Zolpidem
Selective BZD receptor agonist: hypnotic
action
Advantages:
Sleep architecture minimally disturbed
Minimal day time sedation
Fading of hypnotic action on repeated use

11. Individual compounds
Zolpidem
Advantages:
Near absence of
tolerance
Low abuse potential
Use:
Sleep onset insomnia
Most
commonly
prescribed

12. Individual Compounds
Zaleplon
Shortest acting non-BZD hypnotic
Rapidly absorbed, high first pass metabolism,
rapidly metabolised, t½ 1 hour
No active metabolite
Use:
Sleep onset insomnia

13. Melatonin receptor agonists
Melatonin
Principle hormone of pineal gland
Synchronises sleep-wakefulness cycle to
circadian rhythm
Use:
Treatment of jet lag
Shift workers and elderly insomniacs

14. Melatonin receptor agonists
Ramelteon
Melatonin receptor agonist
Reduces sleep latency and increase sleep
duration
Next morning sedation, impairment not seen
Rebound phenomena, dependence not
reported
Use:

15. Flumazenil
BZD analogue
Competitive inhibitor of BZD receptors
Abolishes all activities of BZDs
Administered by intravenous injection
Onset of action: seconds
Duration of action: 1-2 hrs
Use: reverse BZD anaesthesia; BZD/non-BZD
overdose

16. Conclusion
Next day sedation is a common problem with
long acting BZDs
Midazolam is used as intravenous anaesthetic
and for premedication, but not as hypnotic
Non-BZD hypnotics act on specific subset of
BZD receptor that contains α1 subunits

17. Conclusion
Melatonin can be used to treat jet lag, shift
workers and elderly insomnia patients
Ramelteon is indicated for sleep onset
insomnia
Flumazenil:
BZD antagonist
Blocks effects of BZDs as well as non-BZDs

18. That’s all for today!
Next class: Antianxiety or anti-epileptics
Question???
Thank you!