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1. Sedative Hypnotics & Antianxiety
DR.K.UMA MAGESHWARI MBBS;MD
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACOLOGY

2. • Sedative and Hypnotics:
- Sedative is a drug that reduces excitement and calms the person.
- Hypnotic is a drug that produces sleep-resembling normal sleep
• Sleep :
- There are two phases of sleep
a. Nonrapid eye movement sleep (NREM)
b. Rapid eye movement sleep (REM)

3. • Classifications :
1. Benzodiazepines (BZDs) :
- Diazepam
- Lorazepam
- Clonazepam
- Clobazam
- Chlordiazepoxide
- Oxazepam
- Temazepam
- Midazolam
- Alprazolam
- Triazolam
- Flurazepam
- Nitrazepam

4. • Barbiturates :
- Long acting : Phenobarbitone
- Short acting : Pentobarbitone
- Ultrashort acting : Thiopentone, Methohexitone
• Nonbenzodiazepine hypnotics :
- Zolpidem, Zopiclone, Zaleplon, Eszopiclone
• Others :
- Melatonin
- Ramelteon
- Suvorexant

5. • BENZODIAZEPINES :
- BZDs have a benzene ring fused to a seven – membered diazepine ring
• Sites of Action :
- Midbrain –ascending reticular formation, limbic system, brain, stem.
• MOA :
- BZDs facilitate action GABA – they potentiate inhibitory effects of GABA

6. • MOA :
Benzodiazepines
Binds to specific site on GABAa receptor
(different from GABA – binding site)
Increase in frequency of opening of CLˉ channels
Increase in GABA – mediated chloride current
membrane hyperpolarization
CNS depression

7. • Pharmacological actions and Therapeutic uses :
1. Sedation & hypnotics: BZDs decrease time required to fall asleep. The total sleep time is
increased.
At present BZDs are preferred to barbiturates for treatment of short-term insomnia , like
- They have a wide therapeutic index
- They cause near-normal sleep; less rebound phenomena or withdrawal
- They produce minimal hangover effects
- They may cause minimal respiratory depression
- They are less likely to cause tolerance and dependence when used for short period
- They have no enzyme-inducing property; hence, drug interactions are less
- They have a specific BZD –receptor antagonist, flumazenil for the treatment of over dosage.

8. • Long term use of BZDs for insomnia is not recommended because of development of Tolerance,
dependence and hangover effects; these drugs occasional use by air travellers, shift workers.
2.Anticonvulsant like Diazepam, Lorazepam, Clonazepam, Clobazam.
- Intravenous diazepam /lorazepam is used to control life threatening seizures in status
epilepticus, tetanus, drug –induced convulsion, febrile convulsion, Clonazepam is used in the
treatment of Absence Seizures.
3. Diagnostic & minor operative procedures:
- BZDs i.v are used in endoscopies & minor procedures because of their sedative-amnesic-
analgesic and muscle relaxant properties.

9. 4. Pre-anaesthetic medication and general anaesthetic:
- These drugs are used as pre-anaesthetic medication because of their sedative and –amines and
anxiolytics effect
- Intravenous diazepam, lorazepam, midazolam are combined with other CNS depressants to
produce GA.
5. Antianxiety effect :
- Some of the BZDs are used for treatment of anxiety because they have selective anxiolytics
action at low dose, here the anxiolytics effect is due to their action on limbic system.
- Tolerance to anxiety action of BZDs develops only on prolonged use.

10. 6. Muscle relaxant which acts centrally :
- They reduce skeletal muscle tone by inhibiting polysynaptic reflex in the spinal cord.
- The relaxant effect of BZDs is useful in spinal injuries, tetanus and cerebral palsy and to reduce
spam due to joint injury or spam
7. To treat alcohol-withdrawal symptoms :
- Long acting BZDs such as chlordiazepoxide and diazepam are used for treatment of Alcohol-
withdrawal symptoms.

11. • PK :
- BZDs usually given orally or intravenously and occasionally by rectal route in children
- They have a large volume of distribution
- They have a short duration of action on occasional use because of rapid redistribution
- BZDs are metabolized in liver, some undergo enterohepatic recycling
- The metabolites are excreted in urine, it can cross placenta barriers.

12. • Adverse effects : BZDs have a wide range of safety, well tolerated, common side effects are
- Drowsiness
- Confusion
- Blurred vision
- Amnesia
- Disorientation
- Tolerance and withdrawal systems
• Withdrawal after chronic use causes – tremor, insomnia, restlessness, nervousness & loss of
appetite.
- During labour may cause respiratory depression and hypotonia in new born (Floppy baby
syndrome

13. • Inverse agonist(β-carboline) :
- Its interaction with BZD receptors will produce anxiety and convulsions.
• Flumazenil (BZD antagonist) :
- It is competitively reverses the effects of both BZD agonist (CNS depression) & BZD inverse
agonist
- It is given by i.v route and has rapid onset of action
- Flumazenil is used in the treatment of BZD overdosage and to reverse the sedative effects of
BZD during GA
- It can also be used to reverse the hypnotic effect of non –BZD hypnotics like Zolpidem,
Zaleplon and Eszopiclone.
• ADR:
- Confusion
- Dizziness
- Nausea

14. • BARBITURATES :
- All barbiturates are derivatives of barbituric acid.
- They are nonselective CNS depressants and act at many sites, ascending reticular activating
system (ARAS) being the main site
- At high concentration barbiturates have GABA- mimetic effect i.e. barbiturates can directly
increase CLˉ conductance into the neuron.

15. • MOA :
- Barbiturates have GABA facilitatory action – they potentiate inhibitory effects of GABA.
Barbiturates
Bind to GABAa receptor
( different from BZD-binding site)
The duration of CLˉ channel kept open is increased
Increase in GABA mediated chloride current
Membrane hyperpolarization
CNS depression

16. • Pharmacological action & Uses :
1. Sedation and Hypnosis- Barbiturates were used in the treatment of insomnia. They decrease
sleep latency, duration of REM sleep .
Barbiturates are not recommended because:
- They have a low therapeutic index
- They cause rebound increase in REM sleep on stoppage of therapy
- They cause marked respiratory depression
- They produce marked hang over effects
- They cause high degree of tolerance and drug dependence
- They are potent enzyme inducers and cause many drug interaction
- They have no specific antidote

17. • 2. GA – ultra short acting barbiturates (Thiopentone & Methohexitone) used for induction of
GA
• 3. Anti convulsant :
- Phenobarbitone has anticonvulsant effect and it is useful in the treatment of status epilepticus
and generalized tonic-clonic seizures
• 4. Neonatal jaundice of non haemolytic type :
- Phenobarbitone may be used to reduce serum bilirubin levels, induces glucuronyltransferase
enzyme and hastens the metabolism of bilirubin

18. • Adverse effects :
- Common side effects – drowsiness, confusion, headache, ataxia, hypotension, respiratory
depression
- Hypersensitivity reactions
- Tolerance develops to their sedative and hypnotic actions on repeated use
- Physical and psychological dependence on repeated use
- Prolonged use of phenobarbitone may cause – megaloblastic anaemia by interfering with
absorption of folic acid from gut
- Acute barbiturate poisoning – the signs and symptoms are drowsiness, restlessness ,
hallucination, hypotension, respiratory depression, convulsion, coma, death.

19. • Treatment of Acute barbiturates poisoning :
- Maintain airway, breathing, circulation
- Maintain electrolyte balance
- Gastric lavage – stomach wash with activated charcoal
- Alkaline diuresis – no specific antidote, main treatment is alkaline diuresis i.v NaHCO₃
alkalinizes urine
- Haemodialysis is used in severe cases

20. • NONBENZODIAZEPAM HYPNOTICS : they include
- Zolpidem, Zopiclone, Zaleplon, Eszopiclone and Etizolam.
- They have less antianxiety, anticonvulsant, and muscle relaxant effects than BZDs.
- Effect of REM sleep is less compared to BZDs
- They have less potential for abuse than BZDs
- Flumazenil can be used to treat their overdose.

21. • Zolpidem :
- Mainly produces hypnotic effect – decreases sleep latency and increases duration of sleep time
in insomnia
- It produces near-normal sleep like BZDs with minimal alteration in REM sleep; causes
minimal hangover effects and rebound insomnia
- Less likely to produce tolerance and drug dependence, lack of anticonvulsant, antianxiety and
muscle relaxant
- It is given orally, well absorbed, metabolized in liver and excreated in urine
- It has short duration of action and is used for short –term treatment of insomnia
- The action of zolpidem are antagonized by Flumazenil

22. MOA :
Zolpidem , Zopiclone , Zaleplon, Eszopiclone
(NBZDs hypnotics)
bind selectively to BZD binding site on GABAₐ receptor
facilitate GABA –mediated neuronal inhibition
CNS depression
• ADR :
- Headache
- Confusion
- Nausea
- vomiting

23. • Zopiclone :
- It is orally effective and is used for short –term treatment of insomnia.
- It produces near-normal sleep like BZDs
- Side effects are : headache, drowsiness, GI disturbance and metallic taste
• Zaleplon :
- It is useful in sleep onset insomnia
- It is shortest acting non-BZDs hypnotic
• Eszopiclone:
- It is used orally for short and long term treatment of insomnia
• Etizolam:
- BZD analogue with hypnotic , anticonvulsant, muscle relaxant and antianxiety effects, short
term treatment of insomnia

24. • ANTIANXIETY AGENTS :
1. Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Noradrenaline Reuptake
Inhibitors (SNRIs)
- These are preferred agents for most of the anxiety disorders, except acute anxiety.
- SSRIs are drugs of choice for generalized anxiety disorder, social anxiety and post-traumatic
stress disorder.
• Selective Serotonin reuptake inhibitors (SSRIs):
- Fluoxetin
- Fluvoxamine
- Citalopram
- Escitalopram
- Sertraline
- Paroxetine
- Dapoxetine

25. • MOA :
They inhibit Serotonin transporter (SERT)
block reuptake of 5-HT into the neurone
increases the availability of 5-HT at receptors
(in CNS and enhance serotoninergic activity)
- Orally effective
- Fluoxetine and sertraline produce active metabolites
- Fluoxetine is the longest acting SSRI, half life : 48-72 hours

26. • Adverse effects :
- GI symptoms like nausea, vomiting, diarrhoea
- Headache
- Insomnia
- Sexual dysfunction
- Impotence
- Loss of libido
- SSRIs inhibit drug metabolizing enzymes and cause interaction with other drugs, sertraline,
citalopram, escitalopram have less potential for interactions.

27. • Serotonin and Noradrenaline reuptake inhibitor (SNRIs) :
- Duloxetine
- Venlafaxine
• MOA :
- Inhibit the reuptake of serotonin and noradrenaline into the neuron
• Orally effective
• Adverse effect:
- Nausea
- Sweating
- Sexual dysfunction
- Anxiety
- Hypertension

28. 1. Melatonin :
- It is the hormone secreted by the pineal gland
- Involved in the maintenance of sleep-wake cycle and circadian rhythm
2. Ramelteon :
- It is a melatonin-receptor(MT₁ and MT₂) agonist, which can be used orally for the treatment of
sleep onset insomnia
- It reduces sleep latency and prolongs total duration of sleep
- It does not cause tolerance on chronic use
- Important ADR: Fatigue, dizziness
3. Suvorexant :
- It prevents Orexin( neuropeptide in hypothalamus) from maintaining akefulness by blocking
orexin receptors.
- It is useful in chronic insomnia

29. THANK YOU