Pharmacology PPT

1. SEDATIVES
&
HYPNOTICS
-By Chintan Doshi

2. Overview
 Sleep cycle
 Introduction about Drug groups
 Classification : - BZDs
- Barbiturates
- Non-BZD hypnotics
- Atypical Anxiolytics
 Recent advances
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3.  Sedative :
 A drug that ↓ excitement & calms the subject,
 Without Inducing sleep.
 ↓ responsiveness to any level of stimulation & ↓ motor activity
 Hypnotics :
 A drug that induces and/or maintains sleep
 Similar to normal arousable sleep
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4. Dose Dependent Action
Sedation
(Sedative)
Sleep
(Hypnotic)
Anesthesia
(Anesthetic)
Coma Death
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5. Sleep Cycle
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6. 6
• Eyes open – β, Eyes are closed - α waves
Awake
• Dozing, α + θ, disappearance of α – onset of sleep
Stage I
• θ + sleep spindles and K complex
• 40- 50% of total sleep time
Stage II
• Appearance of δ waves
Stage III
• δ wave predominates
Stage IV
• Reappearance of α, low voltage high frequency (Saw tooth waves)
• 20-30% of total sleep time
REM
N
R
E
M
70-
80%
Of
Total
sleep
time
Slow
wave
sleep

7. BENZODIAZEPINES ( BZDs )
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8. Benzodiazepines
a/c to Indications
8
Hypnotic Antianxiety Anticonvulsant
• Diazepam
• Flurazepam
• Nitrazepam
• Alprazolam
• Temazepam
• Triazolam
• Diazepam
• Chlordiazepoxide
• Oxazepam
• Lorazepam
• Alprazolam
• Diazepam
• Lorazepam
• Clonazepam
• Clobazam

9. Site of Action
 Midbrain ( RAS ) - ↓Wakefulness
 Limbic system - ↓ Thought & mental functions
 Medulla - Muscle relaxation
 Cerebellum - Ataxia
 Effect : Limbic system > Midbrain RAS
⇓
- Therapeutic dose ⇒ Anxiolytic > Sedative
- Higher dose ⇒ Depress RAS → Sedative & hypnotic effect
9

10. 10
Mechanism of Action

11. α γ
α
β
GABA
Bicuculline
Diazepam
Intra cellular side
Flumazenil
DMCM
Barbiturate
GABAA Receptor
Barbiturate receptor
BZD Receptor
Cl--
Picrotoxin
8/5/2021 11
β
11

12. 12
BZDs Barbiturates
o Less neuronal depression
o High therapeutic index
o More neuronal depression
o No effect on respiration or
cardiovascular functions at hypnotic
doses
o Only i.v. injection causes ↓ BP,
cardiac contractility
o Suppression is seen
o No effect on other body systems o Suppressive effects on other
systems,
- Skeletal & smooth muscles, kidney
o Specific antagonist – Flumazenil o No antagonist available

13. 13
BZDs Barbiturates
o No anaesthesia even at high doses,
o Patient can be aroused
o Loss of consciousness,
o Low margin of safety
o Not enzyme inducers –
- No metabolic tolerance
- Less drug interactions
o Potent enzyme inducers –
- Metabolic tolerance seen
- More drug interactions
o No effect on REM sleep
o Less distortion of normal hypnogram
o ++ suppression of REM sleep
o Withdrawal ⇒ rebound ↑ in sleep
o Hangover
o Abuse liability very low o Tolerance
o Dependence
o No hyperalgesia o Hyperalgesia
o ↑ Sensitivity to pain
o Amnesia without automatism o Amnesia with automatism
o Loss of short term memory

14. Pharmacokinetics
 Absorption : - All can be given orally ( Except, Midazolam )
 Distribution : - Wide volume of distribution
- PPB variable, flurazepam 10% to diazepam 90%
 Metabolism : - metabolized in liver mainly by CYP3A4
 Relatively slow elimination but marked redistribution: Diazepam
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15. Long Acting Shorter acting
Flurazepam Alprazolam
Diazepam Temazepam
Nitrazepam Trazolam

16. Therapeutic uses
1) Anxiety Neuroses :
• Alprazolam : - Anxiety with Depression ( 0.25-0.5 mg BD/TDS )
- Anxiety with Panic disorder ( max 6 mg/day )
• Lorazepam : - Suitable for parenteral use
- Short lived anxiety states, Compulsive-Obsessive
neuroses, tension-induced psychosomatic symptoms
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17. • Diazepam : - Acute panic-anxiety with organic disease
- Where sedation is also required
- Dose : 2 – 10 mg BD / TDS
• Chlordiazepoxide:- Chronic Anxiety states
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18. 2) Insomnia :
Type Duration Cause
Transient < 7 days Jet-lag
Shift work
Overnight journey
Short term 1 – 3 week Bereavement
Occupational problems
Long term > 3 weeks Underlying disease
Personality disorders
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19. 3) Preanaesthetic medication & Induction of anaesthesia :
 Midazolam - i.v.
- More amnesia, rapid onset, shorter duration
 Others : Diazepam, Lorazepam
4) As skeletal muscle relaxant :
 Diazepam
 In muscle spasticity of central origin
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20. 5) As anticonvulsant :
 Status epilepticus - Diazepam & Clonazepam ( slow i.v. )
 Myoclonic / petit mal - Clonazepam
6) Treatment of alcohol withdrawal :
 Diazepam / Chlordiazepoxide
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21.  Before ECT, electrical cardioversion of arrhythmias,
 cardiac catheterization,
 Endoscopies :Diazepam i.v
 in obstetrics and many minor procedures

22. Adverse effects
 Higher safety margin ( 50 times dose )
 Tolerance to sedative effects – Gradually
 Dependence
 Dependence producing liability of BZDs is low
Mild withdrawal symptoms:
 Anxiety
 Insomnia
 Restlessness
 Malaise
 Loss of appetite, bad dreams
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23. Contd.
 dizziness, vertigo, ataxia, disorientation, amnesia
 prolongation of reaction time
 Weakness, blurring of vision, dry mouth and urinary
incontinence are sometimes seen
 Given during labour:
 flaccidity and respiratory depression in the neonate

24. NON – BZD HYPNOTICS
( THE “ Z ” COMPOUNDS )
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25. Zolpidem Zaleplon Zopiclone Eszopiclone
T1/2 2 hr 1 hr 5 – 6 hr
Use • Short term use in
• Sleep onset insomnia,
• Intermittent awakenings
Sleep onset
insomnia
Short term
insomnia
< 2 weeks
Short term &
chronic
insomnia
Advantage • No effect on sleep stages,
• Less day time sedation,
• No rebound insomnia,
• No tolerance,
• No abuse,
• Safety in overdose
• No day time
anxiety,
• No rebound
insomnia
-- --
Dose 5 – 10 mg HS 5 – 10 mg HS 7.5 mg HS --
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26. Flumazenil
 BZD analogue with little intrinsic activity
 Competes with BZD agonist & antagonist
 Uses :
 To reverse BZD anaesthesia :
- Dose : 0.3 – 1 mg i.v.
- Allows early discharge of patient after diagnostic procedures
- Facilitates postanaesthetic management
 BZD overdose :
- 0.2 mg / min i.v.
 ADRs : Agitation, discomfort, withdrawal seizures.
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27. BARBITURATES
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28. Barbiturates
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Long Acting Short Acting Ultra-short Acting
• Phenobarbitone • Butobarbitone
• Pentobarbitone
• Thiopentone
• Methohexitone
o Epilepsy
o Neonatal jaundice
Anaesthesia

29. Barbiturates
Binds to GABAA receptor (on α or β subunit)
Facilitates GABA action
Increase in duration of opening of Cl-
channel
Membrane hyperpolarization
CNS depression
At higher dose it can
act as GABA mimetics
Mechanism of Action
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30. Pharmacological Actions
 CNS - Generalized depression, Dose dependent action
 Sleep –
o ↓ Latency of sleep onset
o ↑ Total duration of sleep
o ↓ Night awakening
o Sleep cycle distortion - Hangover
o Rebound increase in REM sleep on discontinuation
 Anti - convulsant activity
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31.  RS :
 Depression of respiratory center
 CVS :
 Depression of VMC
 ↓ Myocardial contractility
 ↓ BP, HR
 Smooth muscles :
 ↓ tone & motility of bowel
 Kidney :
 ↓ Urine flow
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32. Adverse effects
 Hangover
 Precipitation of acute intermittent porphyria
 Idiosyncrasy
 Hypersensitivity
 Tolerance & Dependence ( Abuse potential )
 Poisoning ⇒ No Antidote, Only Symptomatic Treatment
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33. Atypical Anxiolytics
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34. Buspirone, Ipsapirone, Gepirone
 M/A - Partial agonist at 5-HT1A receptors
Activation of presynaptic inhibitory 5-HT1A receptor
↓ 5-HT neurotransmission
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 Use - Long term anxiety states ( effect take >2 weeks, not for acute )
 Advantages- minimal abuse potential
- No withdrawal reactions
- less impairment of psychomotor skills
 ADRs – Tachycardia, Nervousness, GI distress, Paresthesias

35. Beta Adrenoceptor Antagonist
 Worrying situations & Apprehensions ( job interview, exam, etc. )
Palpitation, tremors, GI upset.
Reinforce anxiety
 Propranolol 20 mg TDS breaks the vicious cycle
 CVS effects ⇒ Unlikely to be used as anxiolytic
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36. Melatonin
 Pineal gland hormone
 Affects sleep – wake cycle
 Darkness ⇒ Melatonin ⇒ MT1 MT2 receptors in SCN ⇒ Circadian
rhythm
 Use - Jet-lag insomnia
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37. Ramelteon
 MT1 & MT2 receptor agonist
 Use - Sleep onset insomnia
- Speeds sleep onset
- Longer duration of sleep
 Adv. - No dependence
- No rebound insomnia
 Dose- 8 mg ½ hour before going to sleep
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38. Tasimelteon
 MT 1 & MT 2 receptor agonist
 Recently approved by USFDA in Jan – 2014
 Use - Non 24-hour sleep wake disorder in totally blind
 ADR - Headache, Nightmares.

39. Non pharmacological measures
 Psychotherapy
 Aerobics exercise
 Pranayama
 Meditation
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40.  In which of the following disorders, administration of barbiturates is
contraindicated?
 (a) Anxiety disorders
 (b) Acute intermittent porphyria
 (c) Kernicterus
 (d) Refractory status epilepticus

41.  Which of the following drugs is an antagonist to diazepam?
 (a) Phenargan
 (b) Flumazenil
 (c) Domperidone
 (d) Bromocriptine

42.  Inverse agonist of benzodiazepine receptor is:
 (a) Phenobarbitone
 (b) Flumazenil
 (c) Beta carboline
 (d) Gabapentin

43.  Fomepizole is a selective antidote for poisoning with:
 (a) MAO inhibitors
 (b) Ethyl alcohol
 (c) Methyl alcohol
 (d) Tricyclic antidepressants

44.  All of the following may be used for detoixification therapy of chronic
alcoholism except:
 (a) Naltrexone
 (b) Disulfiram
 (c) Flumazenil
 (d) Acamprostate

45.  The disulfiram alcohol reaction occurs due to inhibition of which
enzyme:
 (a) Alcohol reductase
 (b) Alcohol dehydrogenase
 (c) Aldehyde reductase
 (d) Aldehyde dehydrogenase

46.  Which of the following drug does not affect GABAA gated chloride
channel?
 (a) Muscimol
 (b) Alcohol
 (c) Picrotoxin
 (d) Buspirone

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