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 ,
PATKI2
9. 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
10. 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
11. 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)
13. 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…
18. 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)
19. 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
21. 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
22. 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
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
27. 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
28. 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
29. 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).
30. Adverse effects of BZD
Blurred vision, nausea, dry mouth, urinary
incontinence.
irritability & sweating
Tolerance to sedative effects
Not teratogenic ; flaccidity & respiratory
depression in neonate
31. Drug interactions- BZD
Alcohol & CNS depressants-Potentiate depressant action
Enzyme inhibitors like Cimetidine, ketoconazole, erythromycin -
↓ metabolism
Caffeine inhibits anxiolytic effect of BZD
32. 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
33. Acute over dosage of BZD
Induces sleep; respiratory depression is
mild
Specific antagonist - flumazenil
34. 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. 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
38. 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
39. 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
51. 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
52. 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
53. 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
54. NMDA receptor BLOCKERS
Ketamine: IV general anesthetic
Phencyclidine: Psychedelic drugs
Memantine: Alzheimer's disease
Topiramate and Felbmate: Anti epileptic drugs
61. 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
62. 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