Detail about Sedatives and hypnotics drugs by kashikant yadav

1. Sedatives and hypnotics
PRESENTED BY : Kashikant Yadav
M pharm (Pharmacology )

2. Sleep
 Absence of wakefulness and markedly
reduced responsiveness to environment
stimuli
 Why we sleep?

3.  Not yet fully understood
 Restoration of natural balance among the
neuronal centre in the brain
 Association between the sleep and growth in
the early years of life
 Normal person spend 1/3 of his/her life

4. Sleep cycle
 Based on electrophysiological studies sleep
has been classified into two type:
 Non Rapid Eye Movement sleep (NREM)
(Quite or Deep sleep)
– Consist of four or five alternative cycle
 Rapid Eye Movement sleep (REM)
(Paradoxical)

5. Non Rapid Eye Movement sleep
(NREM)
 Deep sleep or quite sleep
 Progression from 1 to 4 stages
 Characterized by deeper level of sleep
 Takes 90 to 120 minutes

6. Type of sleep disorder
 Insomnia:
– Not enough sleep or sleep of poor quality
 Hypersomnia
– Excessive daytime sleepiness
 Parasomnia
– Unusual happening in the night
– Nightmares
– Night terror
– Sleepwalking (somnambulism)

7. SEDATIVE:
 A drug that subdues excitement and calms
the patients without inducing sleep.
 Sedation refers to decrease responsiveness
to any level of stimulation.
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8. HYPNOTICS:
 A drug that induces sleep similar to normal
arousal sleep.
 Both sedative and hypnotics are more or less
general CNS depressant
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9. Classifcation:
1. Barbiturates:
 Long acting – Phenobarbitone
 Short acting - Pentobarbitone
 Ultrashort acting – Thiopentone, Methohexitone
2. Benzodiazepines:
 Hypnotics – Diazepam, Alprazolam, Triazolam,
Nitrazepam
 Anti-anxiety – Diazepam, Lorazepam, Alprazolam,
Chlordiazepoxide
 Anti-convulsant – Diazepam, Lorazepam,
Clonazepam, Clobazam
3. Newer non-benzodiazepine hypnotics: Zopiclone,
zolpiden, Zaleplon.
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10. Introduction (Barbiturates)
 Oldest among sedative and hypnotic class
 Due to no. of disadvantages
 Low therapeutic index
 Cause dependence
 high abuse potential
 Repeated use leads to the development of tolerance
 Acute barbiturate withdrawal in drug abusers can cause
a fatal withdrawal syndrome
 Drug has been largely replaced by newer drugs

11. 1. BARBITURATES
 They are the CNS depressant used to sedate
the patients or to induce and maintain sleep.
These drugs produce dose-dependent effect.
 Sedatives → Hypnotics → Anaesthesia →
Coma.
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12. Mechanism of action:
 These drugs increased the life time of Cl –
channel opening induced by GABA.
 At very high concentration barbiturates
depress voltage sensitive sodium and
potassium channel as well.
 They also block excitatory glutamate
receptor.
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16. Classification: (as per duration of action)
Ultra-short acting : Thiopental
 It acts within second.
 Duration of action is about 30mins.
 Used in intravenous induction of anaesthesia.
Short acting : Pentobarbitol, amobarbitol
 It has duration of action 3-8hrs.
 It is effective as antianxiety and sedative and
hypnotics.
Long acting: Phenobarbitone
 1-2 days of duration of action
 Used in the treatment of seizures.16 sedatives and hypnotics

17. Action:
1. CNS:
 At low dose it produces sedation.
 At higher dose the drug causes hypnosis
followed by anaesthesia and finally coma
and death.
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18. Action
 The drugs do not have selective antianxiety
action.
 It can impair learning, short term memory
loss and judgment.
 They have no analgesic action.
 Euphoric may be seen in addicts.
 They may have anti-convulsant property.
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19. Action
2. Respiratory: Barbiturates suppress hypoxic
and chemoreceptors response to co2 and
over dose is followed by respiratory
depression and death.
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20. 3. Skeletal muscles: Anaesthetic dose reduce
muscle contraction by depressing excitability
of neuromuscular junction.
4. CVS: Hypnotic dose produce slight decrease
in BP and heart rate. It decreases cardiac
contractility
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21. Action
5. Kidney: It reduces urine flow by decreasing
BP and increasing ADH release.
6. Enzyme induction: It induces cytochrome
P450 microsomal enzymes in the liver.
Chronic administration reduces the action of
drugs that are dependent on P450
metabolism.
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22. Therapeutic uses:
 Now, they are not used as hypnotics
and anxiolytics .
 They are replaced by benzodiazepines.
 Only ultra-short acting Thiopental are
used intravenously to induce
anaesthesia.
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23. Therapeutic uses:
 Long acting phenobarbitone is used in
epilepsy.
 They are used in long term management
of tonic-clonic seizure
 They are sometimes used as adjuvant in
psychosomatic disorder.
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24. Pharmacokinetics:
 They are absorbed orally
 Distributed widely throughout the body.
 They cross the placenta and secreted in the milk.
 Low lipid solubility are excreted in the unchanged form by
the kidneys. i,e phenobarbital.
 High lipid solubility are metabolized to more polar
compounds in the liver before being excreted via the
kidneys. i,e thiopental.
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25. Adverse effects:
 Drug hangover
 Nausea
 dizziness.
 CNS – causes drowsiness
 impaired concentration
 mental and physical sluggishness.
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26. Adverse effects:
 Withdrawl symptoms cause tremor,
anxiety, weakness, restlessness, nausea and
vomiting and cardiac arrest due to tolerance
and dependence.
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27. Interaction:
 Additive action with other CNS
depressant and alcohol.
 Sodium valproate increases plasma
concentration of phenobarbitone.
 They induce metabolism of many drugs
and reduce their effectiveness.eg.
warfarin, griseofulvin and OCP.
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28. Benzodiazepines

29. Introduction
 Chlordiazepoxide
 Many other drug was evolved
 Largely replaced the barbiturates in clinical
practice

30. Classification
 Short acting with t ½ less then 5 hours
– Alprazolam, Triazolam
 Intermediate acting t ½ 5-24 hours
– Nitrazepam, Lorazepam, Oxazepam, Temazepam
 Long acting with t ½ longer then 24 hours
– Flurazepam, Daizepam, Chlordiazepoxide,
Chlorazepate

31. Site of action
 Four main site where it exert their depressant
effects
 Limbic system
– Regulation of emotional and behavioral responses
– GABA normally functions to inhibit excess stimulation
of limbic system.

32.  Reticular formation system
– Regulates the degree of wakefulness and
alertness
– GABA normally functions to decrease the activity
of reticular formation.
– BZD which increases the inhibitory action of GABA
there by producing sleep

33.  Cerebral cortex
– Excessive stimulation of cerebral cortex can
cause convulsion
 Spinal cord
Helps regulate the degree of skeletal muscle tone
and responsiveness of spinal reflexes that also
maintain skeletal muscle activity

34. Mechanism of action:
 They act on mid brain (wakefulness) and on
limbic system (thought and mental function).
 Muscle relaxation is produced by a primary
medullary site of action and
 Ataxia is due to action on cerebellum.
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35. Mechanism of action:
 They act on the GABA receptor which is the
major inhibitory neurotransmitter.
 Binding of GABA to its receptor triggers an
opening of a chloride channel, which leads to
a increase in chloride conductance.
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36. Mechanism of action:
 The influx of chloride ion causes a small
hyperpolarization that moves the
postsynaptic potential away from its firing
threshold and thus inhibits the formation of
action potentials.
 It enhances the frequency of cl- channel
opening.
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39. Action
 CNS action: They increase onset of sleep
• reduce intermittent awakening
• increased total sleep time
• skeletal muscle relaxation
• decreases nocturnal gastric secretion and
prevents stress ulcers.
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40. Therapeutic uses:
 Anxiety disorder: they are useful in treating
the anxiety. These drugs can produce
addiction, so should be used for severe
anxiety and only for short period of time.
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41. Therapeutic uses:
 Muscular disorder: Useful in the treatment of
muscle spasms such as occurring in muscle
strain, in treating spasticity from multiple
sclerosis and cerebral palsy.
 Amnesia: In premedication for endoscopic,
bronchoscopic and angioplasty.
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42. Therapeutic uses:
 Seizure: In the treatment of epilepsy BZD are
used.
 Sleep disorder: All BZD have sedative effect
on low dose and hypnotic effect on large
dose.
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43. Pharmacokinetics:
 The drugs are lipophilic, they are rapidly and
completely absorbed after oral administration
and distribute throughout the body.
 Most BZD are metabolized by the hepatic
microsomal system to compounds that are
also active.
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44. Pharmacokinetics:
 All BZD cross the placental barrier and may
pass in the breast milk.
 The drugs’ effects are terminated by
excretion and also by redistribution.
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45. Adverse effects:
 Dizziness, vertigo, ataxia, disorientation,
amnesia,impairment of psychomotor skills.
 Hangover may be seen on large dose.
 Weakness, blurring of vision, dry mouth and
urinary incontinence.
 Paradoxical stimulation, irritability and
sweating (Flurazepam).
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46. Interaction:
 Alcohol enhance the effects of CNS
depressant.
 CNS depressants enhance the sedative,
hypnotic effects of BZD.
 Cimetidine, isoniazides and OCP retards the
BZD metabolism.
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47. BZD in pregnancy
 Not certainly known to be use
 Should be avoided
 as animal study has shown Diazepam has
teratogenic effect on mice
 Drug should be avoid in early pregnancy as
far as possible

48. BENZODIAZEPINE ANTAGONIST:
FLUMAZENIL:
 It is a BZD analogue which competes with
BZD agonists for the BZD receptor and
reverses their depressant effects.
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49. BENZODIAZEPINE ANTAGONIST:
 Flumazenil abolishes the hypnogenic,
psychomotor and cognitive effects of BZDs.
 Flumazenil is absorbed orally; oral
bioavailability is -16%, but it is not used
orally.
 On i.v. injection, action of flumazenil starts in
seconds and lasts for 1-2 hr; elimination tl/2
is 1 hr, due to rapid metabolism.
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50. Uses:
1. To reverse BZD anaesthesia: An i.v.
injection of 0.3-1 mg of flumazenil.
2. BZD overdose: 0.2 mg/min may be injected
i.v. till the patient regains consciousness.
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51. Adverse effects:
 Flumazenil is safe and well tolerated.
 Agitation, discomfort, tearfulness, anxiety,
coldness and withdrawal seizures are the
occasional.
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52. Comparison
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54.  Thank you.
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