Sedatives are drugs that reduce excitement and calm a person, while hypnotics produce sleep resembling normal sleep. The document discusses several classes of sedatives and hypnotics including barbiturates, benzodiazepines, and newer nonbenzodiazepine hypnotics like zolpidem and zaleplon. It provides details on their mechanisms of action, pharmacokinetics, therapeutic uses, and adverse effects.

1. Sedatives and Hypnotics
Madan Sigdel (M. Pharm.)
Department of Pharmacology
Gandaki Medical College

2.  Sedatives: it is a drug that reduces excitement and
calms the person
 Hypnotics is the drug that produces sleep
resembling the normal sleep
 The sedatives and hypnotics are more or less
general CNS depressants with some what differing
time- action and dose-action relationships. Those
with quicker onset, shorter duration and steeper
dose response curve are preferred as hypnotics
while more slowly acting drugs with flatter dose
response curves are employed as sedatives

3. classification
1. Barbiturates
Long acting Short acting Ultra short acting
Phenobarbitone Butobarbitone Thiopentone
Pentobarbitone Methohexitone
2. Benzodiazepines
Hypnotic Antianxiety Anticonvulsant
Diazepam Diazepam Diazepam
Flurazepam Chlordiazepoxide Lorazepam
Nitrazepam Oxazepam Clonazepam
Alprazolam Lorazepam Clobazam
Temazepam Alprazolam
Triazolam
3. Newer nonbenzodiazepine hypnotics
Zopiclone, Zolpidem, Zaleplon

4. Drug-A = Barbiturates , Drug-B = Benzodizepaines

5. BARBITURATES

6. MECHANISM OF ACTION
 Facilitation of GABA action on the brain: Barbiturates bind
at the β sub unit of GABA-A receptor and increase the
duration of the GABA gated channel opening but in large
dose, they can directly activating chloride channels.

7. SUB-ANAESTHETIC DOSES:
depress excitatory neurotransmitter actions
ANAESTHETIC DOSES:
 Interfere with Na+
& K+
transport across cell membranes
(reticular activating system inhibition).

8. PHARMACOKINETICS
 All barbiturates are weak acids
 lipid soluble
 absorbed orally.
 distribute throughout the body
 Thiopentone is highly lipid soluble (high rate of entry into
CNS- quick onset of action).

9. PHARMACOKINETICS
 Redistribute in the body from the brain to skeletal muscles-
adipose tissues.
 Metabolized in the liver to inactive metabolites
 Excreted in the urine.
 Alkalinization increases excretion (NaHCO3)
 Cross the placenta ( pregnancy).

10. PHARMACOLOGICAL
ACTIONS
CENTRAL NERVOUS SYSTEM: In a dose-dependent fashion.
 Sedative
 Hypnotic
 Anesthesia in large dose
 Anticonvulsant action
 Coma and death.
RESPIRATORY SYSTEM:
 suppress hypoxic and chemoreceptor response to CO2
 Large doses leads to respiratory depression & death.

11. PHARMACOLOGICAL
ACTIONS
CVS:
 Healthy patient: at low doses, they have insignificant
effects.
 Hypovolemicstates, CHF: normal doses may cause
cardiovascular collapse.
 Large dose → circulatory collapse due to medullary
vasomotor depression.
SKELETAL MUSCLE:
 Anesthetic dose reduce muscle contraction by depressing
excitability of neuromuscular junction

12. Barbiturates poisoning
 Maintain ABC
 Maintain electrolyte balance
 Gastric lavage- after stomach wash, administered activated
charchoal it may enhance the elimination of phenobarbitone.
Endotracheal intubation is performed before gastric lavage to
protect the airway in uncouncious patient.
 Alkaline diuresis: i.v. NaHCO3
 Haemodialysis is employed in severe cases.
 Drug interactions: Barbiturates are potent microsomnal
enzymes and reduces the effectiveness of oral drugs ( e.g.
OCP, oral anticoagulants, oral hypoglycemics etc.)

13. Therapeutic uses
1. Sedation and hypnosis : barbiturates were used in the treatment
of insomnia. At present barbiturates are not recommended.
2. General anesthesia (GA) ultra short acting barbiturates
( thiopentone and methohexitone ) are used in induction of GA.
3. Anticonvulsant: Phenobarbitone has anticonvulsant effect and
used in treatment of status epilepticus and generalized tonic-
clonic seizures ( GTCS , grand mal epilepsy )
4. Neonatal jaundice and non-haemolytic type: phenobarbitone
may be used to reduce serum bilurubin levels. It induces
glucuronyl transferase enzyme and hastens the metabolism of
bilurubin.
5. Diagnostic aid and Psychiatry: i.v. thiopentone in subanesthetic
dose produces a state of deep sedation. The patient becomes
more communative, which helps in diagnostic of psychiatric
disorders like histeria

14. ADVERSE EFFECTS
 Common side effects are drowsiness, confusion, headache,
ataxia, hypotension and respiratory depression
 Hangover: residual sedation after awakening.
 Tolerance
 Withdrawal symptoms
 Precipitation of acute attack of porphyria.
 Allergic reaction: urticaria and skin rash.
Toxicity: drowsiness, Restlessness, hallucinations, hypotension
Respiratory depression, convulsion, Cardiovascular collapse,
coma and death.

15. MECHANISM OF ACTION
 Benzodiazepines act very selectively on GABAA-receptors, which
mediate the fast inhibitory synaptic response produced by activity
in GABA-ergic neurons.
 The effect of benzodiazepines is to enhance the response to
GABA, by facilitating the opening of GABA-activated chloride
channels (an increase in the frequency of channel opening, but no
change in the conductance or mean open time).
BENZODIAZEPINES

16. MECHANISM OF ACTION
 Benzodiazepines bind specifically to a regulatory site on the
receptor, distinct from the GABA binding site, and enhanced
receptor affinity for GABA.
 The GABAA-receptors is a ligand-gated ion channel consisting of a
pentameric assembly of subunits.

17. PHARMACOKINETICS
1. most of them are well absorbed orally,
Rapid absorption
e.g. triazolam & Alprazolam diazepam & chlorazepate
Slow absorption e.g. lorazepam & oxazepam, temazepam (LOT)
2. Chlorazepate is a prodrug converted by acid hydrolysis in
stomach to form nordiazepam (desmethyldiazepam).
3, Can be given parenterally
Diazepam-Chlordiazepoxide (IV only NOT IM)
Midazolam – Lorazepam (IV or IM)

18. 4. Bzs are lipid soluble and widely distributed
5. Redistribution from CNS to skeletal muscles, adipose tissue)
(termination of action).
6. Cross placental barrier during pregnancy and are excreted in
milk (Fetal & neonatal depression).
7. Highly bound to plasma protein.
8. ALL Bzs are metabolized in the liver
Phase I: ( liver microsomal system)
Phase II: glucouronide conjugation and excreted in the urine.
Many of Phase I metabolites are activePhase I metabolites are active→
↑ elimination half life of the parent comp. → cumulative effect
with multiple doses
 EXCEPT No active metabolites are formed for (LEO) Lorazepam,
Estazolam, Oxazepam

19. Pharmacological action
1. Sedation and hypnosis- All BZDs are preferred drug for short term
insomina, because they:
 have wide therapeutic index
 cause near normal sleep with minimal REM suppression and
less REM rebound on withdrawal
 Produce minimal hangover effects ( headache and residual
drowsiness on walking)
 Cause minimal respiratory depression
 Are less likely to cause tolerance and dependence when used
for short period
 Have no enzyme inducing property hence less drug interaction
 Have a specific BZD receptor antagonist flumazenil which
can be used for the treatment of overdosage.

20. 2. Anticonvulsant: Diazepam, Lorazepam, Clonazepam,
etc. have selective anticonvulsant effect (i.v.) diazepam/
Lorazepam is used to control life threatning seizures in
status epilepticus, tetanus, drug induced convulsion,
febrile convulsions etc. clonazepam is used in the
treatment of absence seizures.
3. Diagnostic endoscopies: i.v. BZDs are used because of
their sedatives-amnesic and muscle relaxing properties.
4. Pre-anesthetic medication: these are the drugs used in
pre-anesthetic medication because of their sedatives-
amnesic and anxiolytic effects. Hence the patients
cannot recall the perioperative events later

21.  Antianxiety (anxiolytic effect) Some of the BZDs
( daizepam, Chordiazepoxide, etc. ) have selective action at
low doses. The anxiolytic effect is due to their action on
limbic system.
 Muscle relaxant: (centrally acting): BZDs reduce skeletal
muscle tone by inhibiting polysynaptic reflexes in the spinal
cord. The relaxant effects of BZDs are particularly useful in
spinal injuries, tetanus, cerebral palsy and to reduce spasm
due to joint injury or sprain.
 To treat alcohol withdrawal symptoms.

22. Individual agents
1. Diazepam: it is used to control convuslion but not for long
term therapy of epilepsy because of sedative effect and rapid
development of tolerance to the anti convulsant effect
2. Flurazepam: it produces active metabolites that have long
plasma half lives, hence cummulative effects may be seen
with repeated doses.
3. Alprazolam: it is short acting BZD. In addition to
antianxiety action, it also have antidepressant effect.
4. Midazolam: it is short acting benzodiazepam with potent
amnesic effect. It is mainly used i.v. anesthetics in minor
surgical procedures.
5. Lorazepam: it is short acting BZD with antianxiety,
anticonvulsant, sedative and amnesic effects.

23. Adverse effect
 BZDs have a wide margin of safety. They are generally well
tolerated. The common side effects are drowsiness, confusion,
blurred vision and amnesia, disorientation, tolerance and
dependence.
 Withdrawal after chronic use cause symptoms like tremors,
insomnia, restlessness, nervousness and loss of appetite. Use
of BZDs during labor may cause respiratory depression and
hyptonia in newborn ( Floppy baby syndrome)
 In some patients these drugs may produce paradoxical effects ,
i.e. convulsions and anxiety.

24. Inverse agonist and antagonist
 Inverse agonist- their interaction with BZDs receptor will
produce anxiety and convulsions
 Benzodiazepines antagonist (Flumazenil)
Flumazenil competitively reverses the effect of both BZD
agonist (CNS depression ) and BZD inverse agonists (CNS
stimulation)
Flumazenil is not used orally because of first pass
metabolism. It is given by i.v. route and has rapid onset of
action.
Advese effects: confusion, dizziness and nausea

25. ZOLPIDEM
 Acts on benzodiazepine receptors & facilitate GABA mediated
neuronal inhibition.
 Its action is antagonized by flumazenil.
 rapidly absorbed from GIT and metabolized to inactive
metabolites via liver CYT P450.
 Short duration of action ( 2- 4 h).
 Only hypnotic effect
 Its efficacy is similar to benzodiazepines.
 Minor effect on sleep pattern, but high doses suppress REM.
 Respiratory depression occur at high doses in combination
with other CNS depressant as ethanol.

26.  Has no muscle relaxant effect.
 Has no anticonvulsant effect.
 Minimal psychomotor dysfunction
 Minimal tolerance & dependence.
 Minimal rebound insomnia.
Uses
 a hypnotic drug for short term treatment of insomnia
Dose should be reduced in hepatic or old patients.
Adverse Effects: GIT upset, Drowsiness Dizziness

27. Zaleplon
Binds to BZs receptors and facilitate GABA actions.
 Rapid absorption
 rapid onset of action
 Short duration of action (1 hr)
 Metabolized by liver microsomal enzymes
Only hypnotic effect
Decreases sleep latency
Little effect on sleep pattern

28.  Potentiates action of other CNS depressants (alcohol).
 Dose reduction as before.
 Used as hypnotic drug
 Advantages
Less impairment of pyschomotor performance than BZs or
zolpidem.

29. Enumerate BZDs. Explain the mechanism of
action, therapeutic use and adverse effect of
them.
Define sedatives and hypnotics. Classify
sedatives and hypnotics drugs.
Why BZDs are preferred to barbiturates as
sedatives and hypnotics ?
Write short notes on : Flumazenil
: Zolpidem