This document defines sedatives and hypnotics, and classifies common drugs used as such. It describes the mechanisms, pharmacokinetics, uses and side effects of barbiturates, benzodiazepines, zolpidem, and zaleplon. Barbiturates act by facilitating GABA activity and directly activating chloride channels, while benzodiazepines facilitate GABA activity at receptor sites. Both are metabolized in the liver and have risks of tolerance, dependence and withdrawal. Benzodiazepines generally have fewer side effects and less abuse potential than barbiturates. Zolpidem and zaleplon are shorter acting hypnotics that also facilitate G

1. L.Nagakrishna.
Pharmacology.

2. DEFINITION
SEDATIVE : Drugs that clam the patient and reduce anxiety
without inducing normal sleep.
 Site of action is on the limbic system which regulates thought
and mental function.
HYPNOTICS : Drugs that initiate
sleep.
and maintain the normal
 Site of action is on the midbrain and ascending RAS which
maintain wakefulness.

3. CLASSIFICATION OF DRUGS

Barbiturates.

Benzodiazepines ( BDZ ).

Non BDZ drugs

Zolpidem

Zaleplon

zopiclon

4. BARBITURATES
Classification:
Long acting( 24-28 h): Phenobarbitone
Intermediate (8-24h): Amylobarbitone
Bayere dicoverer
of barbiturates.
Short-acting(3-8h):
•
•
•
Pentobarbitone
Secobarbitone
Amobarbital
Ultrashort acting (25 minutes): Thiopentone, Methohexitone.

5. 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.

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

7. 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).

8. 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).

9. 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.

10. 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

11. USES
 ANTICONVULSANT: Phenobarbitone.
 INDUCTION OF ANESTHESIA: thiopentone and
methohexitone.
HYPNOTIC: pentobarbital
HYPERBILIRUBINEMIA AND KERNICTERUS :
pentobarbital

12. ADVERSE EFFECTS
 Respiratory depression.
 Hangover: residual sedation after awakening.
 Tolerance
 Withdrawal symptoms
 Precipitation of acute attack of porphyria.
 Many drug interactions.
 Allergic reaction: urticaria and skin rash.
Toxicity : Respiratory depression, Cardiovascular collapse, coma
and death.

13. BENZODIZEPINES

Sedative (Anxiolytics) :
Alprazolam Chlordiazepoxide oxazepam
Diazepam
lorazepam

Hypnotics :
Triazolam Diazepam Alprazolam
Lorazepam Estazolam Temazepam
Flurazepam Nitrazepam Quazepam

Preanesthetics :
Diazepam
- Midazolam
Leo sternback

14. MECHANISM OF ACTION
Bzs bind to the α subunit of the GABA receptor.
Bzs
facilitation of GABA action on GABA receptors
chloride channels opening
membrane hyperpolarization
action potential
chloride influx to the cell
cell
inhibition of propagation of
inhibitory effect on different sites of the brain
especially motor cortex, and limbic system.

15. PHARMACOKINETICS
 most of them are well absorbed orally.
 Bzs are lipid soluble and widely distributed
 Redistribution from CNS to skeletal muscles, adipose tissue.
 Cross placental
barrier during pregnancy and are excreted
in milk (Fetal & neonatal depression).
 Highly bound to plasma protein.

16. PHARMACOKINETICS
 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 active : Incresae
elimination half life of the parent compound , cumulative
effect with multiple doses.
EXCEPT No active metabolites are formed for (LEO)
Lorazepam, Estazolam, Oxazepam.

17. Therapeutic uses
ANXIETY DISORDERS :
alprazolam, lorazepam, oxazepam, diazepam and
chlordiazepoxide.
 Alprazolam has anxiolytic-antidepressant effect.
 Diazepam is preferred in acute panic-anxiety.
 Chlordiazepoxide is preferred in chronic anxiety states.

18. Therapeutic uses
INSOMNIA : in ability to sleep.
 Triazolam, lorazepam is effective in treating individuals who
have difficulty in going sleep.
 Flurazepam, temazepam & nitrazepam is useful for insonia
caused by inability to stay asleep.
 Normal sleep consists of distinct stages,based on three
physiologic measures: the electroencephalogram, the
electromyogram, and the electronystagmogram.
 Non-rapid eye movement(NREM) sleep: 70%-75%.
 Rapid eye movement(REM) sleep.

19. Therapeutic uses
 To control withdrawal symptoms of alcohols
diazepam- chlordiazepoxide.
 Treatment of epilepsy
 Diazepam – Lorazepam: Status epilepticus
 Clonazepam-Clorazepate: absence , myoclonic seizures.
 Muscle relaxation: in spastic states (Diazepam) .

20. Therapeutic uses
 In anesthesia :
Preanesthetic medication diazepam
Induction of balanced anesthesia (Midazolam)

22. ADVERSE EFFECTS
 Ataxia (motor incoordination), cognitive impairment.
 Hangover Sleep tendency, drowsiness, confusion especially in
long acting drugs.
 Tolerance
 Physical and Psychological dependence
 withdrawal symptoms
 Rebound Insomnia, anorexia, anxiety, agitation, tremors and
convulsion.

23. FLUMAZENIL
 A selective competitive antagonist of BZD receptors (Bz1).
 Blocks action of benzodiazepines, zaleplon and zolpidem but
not other sedative /hypnotics.
 Blocks psychomotor, cognitive and memory impairment of
BZs.

24. PHARMACOKINETICS
 Has short duration of action T 1 /2 = 1 hour.
 Absorbed orally .
 Undergoes extensive first pass metabolism.
 NO active metabolites.
 Should be used IV .
 Repeated doses are necessary.

25. THERAPEUTIC USES
 Acute BZD toxicity (comatose patients).
 Reversal of BZD sedation after endoscopy, dentistry.
SIDE EFFECTS
 Nausea
 Dizziness
 Precipitate withdrawal symptoms.

26. DOSE RESPONSE CURVE OF DRUGS
Drug-A = Barbiturates , Drug-B = Benzodizepaines.

27. WHY BENZODIZEPINES HAS
SUPRESSED BARBITURATES ?
BZS
BARBITURATES
 They do not produce anesthesia in
 Produce loss of consciousness and







high doses & patient can be
aroused.
These are not enzyme inducers,
Very low abuse liability.
Lesser distortion of normal
hypnogram.
Bzs have no hyperalgesia.
Bzs can be used as day time
anxiolytic.
Do not effect respiratory or cvs
function.
There is a specific antagonistFlumazenil.







have low margin of safety
enzyme inducers.
High abuse liability.
Marked suppression of REM
sleep.
Hyperalgesic action.
Unacceptable drowsiness is seen.
Causes respiratory and depression
& hypotension.
No specific antagonist.

28. ZOLPIDEM
 acts on benzodiazepine receptors (BZ 1) & facilitate GABA
mediated neuronal inhibition.
 Its action is antagonized by flumazenil.
 rapidly absorbed from GIT and metabolized to
metabolites via liver CYT P450.
 Short duration of action ( 2- 4 h).
inactive

29. 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.

30.  has no muscle relaxant effect.
 has no anticonvulsant effect.
 Minimal psychomotor dysfunction
 Minimal tolerance & dependence.
 Minimal rebound insomnia.

31. THERAPEUTIC USES AND
ADVERSE EFFECTS
 a hypnotic drug for short term treatment of insomnia
 Dose should be reduced in hepatic or old patients.
Adverse Effects
GIT upset
Drowsiness
Dizziness

32. ZALEPLON
 Rapid absorption
 rapid onset of action
 Short duration of action (1 hr)
 Metabolized by liver microsomal enzymes
 metabolism is inhibited by cimetidine.

33.  Only hypnotic effect
 decreases sleep latency
 Little effect on sleep pattern
 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.