PHARMACOLOGY

2. Contents:
Definition of sedatives and hypnotics,
Insomnia and sleep,
Classification of hypnotic & sedatives,
Pharmacology of barbiturates ,
Pharmacology of benzodiazepines,
Pharmacology of non-benzodiazepine.

3. Sedatives:
A Drug that subdues excitement and calms the subject
without inducing sleep.
Drowsiness may be produced
Decreased responsiveness
Decrease in motor activity
Hypnotics:
A drug that induced sleep, similar to normal
arousable sleep .

4. The sedatives and hypnotics are more less general CNS
depressants which differ in ;
Dose action
Time action
The sedatives and hypnotics differ in;
Hypnotics sedatives
Quicker onset
Short duration
Steeper dose
response curve
Slower acting drug
Flatter dose response
curve

5. Insomnia & sleep. . .
Treatment of insomnia is most important for the use of
sedative and hypnotics.
REM Sleep: rapid eye movement
NON-REM sleep: non rapid eye movement
Sleep: It is an architectured cyclic process. The following are
stages of sleep.
Stage 0: (awake) 1-2%
Stage 1: (dosing) 3-6%
Stage 2: (un equivocal) 40-50%
Stage 3: (deep sleep transition) 5-8%
Stage 4: (cerebral sleep) 10-20%

6. Classification of drugs:
Barbiturates:
Long acting: Short acting Ultra short acting
Phenobarbitone Butobarbitone Thiopentone
Pentobarbitone Methohexitone

7. Benzodiazepine:
 Diazepam
 Flurazepam
 Nitrazepam
 Alprazolam
 Triazolam
Non benzodiazepine:
 Zopiclone
 Zolpidem
 zaleplon

8. These are prototype of CNS depressants.
Barbiturate are substituted derivatives of barbituric
acid(malonyl urea).
Barbituric acid as such is not a hypnotic but compounds
with alkyl or aryl substitution on C5.
Replacement of O with S at C2 yields thiobarbiturate
which are more lipid-soluble and more potent.
They are insoluble in water but their sodium salts dissolve
yielding highly alkaline solution.

9. Pharmacological actions:
Barbiturates are general depressants for all excitable cells.
CNS is more sensitive. Effect is more global but certain areas are
suseptible.
CNS: They show dose-dependent effect.
Hypnotic dose:(100-200mg of short acting barbiturate)
Shortens the time taken to fall asleep ,
• increases sleep duration ,
• Night awakenings are reduced,
• Hangover in the morning.

10. Sedative dose:
(Small dose of long acting barbiturate )
• Drowsiness
• Reduction in anxiety and excitability
• Impaired learning short term memory,
• Hyperalgesia and
• euphoria addicts.

11. Mechanism of action:
Barbiturates appear to act primarily at the GABA : BZD receptor –Cl
channel complex.
• Potentiate GABAergic inhibition by increasing the lifetime of Cl
channel opening induced by GABA.
•They do not bind to the BZD receptor, but bind to another site.
•The barbiturate site appears to be located on alpha &beta subunits.

13. Other systems:
Respiration:
It is depressed by relatively higher doses.
Neurogenic, hypoxic drives to respiratory centre are depressed in
succession.
Barbiturates do not have antitussive action.
•Effects of barbiturates:
At high concentration, barbiturates directly
Increase Cl conductance
Inhibit Ca2+ dependent release of neurotransmitters.
At very high concentrations, barbiturates
Depress voltage sensitive Na+ & k+ channels.

14. CVS:
Hypnotic doses of barbiturates produce a
• slight decrease in BP & Heart rate,
• Toxic doses produce marked fall in BP due to ganglionic
blocked,
•Vasomotor centre depression,
•Decrease in cardiac contractility.
•Reflex tachycardia can occur, though presser reflexes are
pressed
• The dose producing cardiac arrest is about 3 times larger
than that causing respiratory failure.

15. Pharmacokinetics:
Barbiturate are well absorbed from the G.I tract.
They are widely distributed in the body.
The rate of entry into CNS is dependent on lipid solubility.
a)Redistribution:
It important in case of highly lipid soluble thiophene & other.
After their .v. injection, consciousness is regained in 6-10 min due
to redistribution.
b)Metabolism:
Short acting barbiturates are primilarly metabolized in liver by
oxidation,dealkylation&conjugation.

16. c)Excretion :
Long acting agents are significantly excreted unchanged in
urine.
Uses:
Phenobarbitone used in epilepsy,
Thiopentone in anaesthesia,
The enzyme inducing property of phenobarbitone can be
utilized to hasten clearanceof congential nonhaemolytic
jaundice .
Adverse effects:
a. Idiosyncrasy.
b. Hypersensitivity.
c. Tolerance &dependence

17. Treatment:
1. Gastric lavage:
2. Supportive measures:
3. Alkaline diuresis:
4. Haemodialysis & haemofusion
 There is no specific anti dote for Barbiturates.
 In the past, analeptics like metrazole, bemegride, have been
used as an attempt to awaken the patient.
 This is dangerous, may precipitate convulsions while the patient
is still comatose- mortality may be increased.
 The emphasis is now keeping the patent alive till the poison is
eliminated.

18. USES:
Phenobarbitone in epilepsy.
 Thiopentone in anaesthesia.
Occasionally employed as adjuvants in psycosomatic disorders.
Enzyme inducing property of phenobarbitone is utilised to hasten
clearance of congenital non haemolytic jaundice and kernicturus.
ADVERSE EFFECTS:
Side effects
Idiosyncrasy
Hypersensitivity
•Tolerance and dependence
Acute barbiturate poisoning is mostly susidal , some times
accidental .
Lethal dose depends on lipid solubility. It is 2-3g for the more
lipid soluble agents and 5-10g for less lipid soluble.

19. Benzodiazepine:
•Chlorodiazepoxide & diazepam were introduced around 1960
as antianxiety drugs.
• Since this class has gained popularity over barbiturates as
hypnotic and sedative as well.
•BZDs have a high therapeutic index.
•Hypnotic doses do not affect respiration or cardiovascular
functions.

20. •High doses produce mild respiratory depression & hypotension.
•BZDs cause less distortion of sleep architecture.
•BDZs do not alter disposition of other drugs by microsomal enzyme
induction.
•They have lower abuse liability.

21. Why Do People Use
Benzodiazepines?
To get away from
this!
21

22. Mechanism of action:
BZDs act preferentially on mid brain ascending reticular
formation and a limbic system .
Muscle relaxation is produced by a primary medullary site of
action on cerebellum.
BZDs acts by enhancing pre/post synaptic inhibition through a
specific BZD receptor which is an integral part of the GABA –A
receptor
cl channel complex.

23. It has α and β sub units which are required for GABA
action and the binding site of GABA is present on β sub unit.
BZDs do not increase cl conductance they only have GABA
facilitatory action but not GABA mimetic action.
For example,
GABA antagonist bicuculline antagonizes BZD action in a
non-competitive manner.
The competitive BZD-antagonist flumazenil blocks the
sedative action of BZD as well as convulsant action of
DMCM.

25. Pharmacokinetics:
BZDs differ in lipid solubility by >54X .
Oral absorption of some drugs is rapid while others is slow
DRUG t1/2 (hr) redistribution Hypnotic dose
(mg)
Clinical indications
LONG ACTING:
Flurazepam 50-100 - 15-30 Chronic insomnia
diazepam 30-60 + 5-10 Short term insomnia
nitrazepam 30 +/- 5-10 Frequent nocturnal awakening
SHORT ACTING
alprazolam 12 + 0.25-0.5 Sleep onset difficulty
temazepam 8-12 + 10-20
triazolam 2-3 +/- 0.125-0.25

26. ADRs
Dizziness
Vertigo
Ataxia
Disorientation
Amnesia
Prolongation of reaction time
INTERACTIONS
BZDs
Synergize with alcohol and other CNS depressants.
Concurrent use with sodium valproate has provoked psychotic
symptoms .
Cimetidine , isoniazide and oral contraceptives also retard BZD
metabolism

27. Pharmacological actions:
ON CNS. . .
 The over all action of al BZDs is qualitatively similar to
barbiturates. But differ in time selectivity and course of action.
They significantly differ among different BZDs.
They hasten onset of sleep and reduce intermittent awakening
and increase total sleep time.
Night terrors and body movements during sleep are reduced
and subject wakes up with refreshing sleep.

28. Mild tolerance is seen.
They produce centrally mediated skeletal muscle relaxation
without impairing voluntary action.
Ex: clonazepam and diazepam's:
I.V diazepam causes analgesia.
Diazepam decreases nocturnal gastric secretions and prevent
stress ulcers.
Short lasting coronary dilatation is produced by I.V diazepam.

29. NON BZD –HYPNOTICS:
ZOPICLONE:
 This is newer cyclopyrolone hypnotic at sub type of BZD
receptor involved in hypnotic action .
It does not alter REM sleep and tends to prolong stagses 3&4
sleep.
T1/2 is 5-6 hrs .
It is indcated for short term treatment for insomnia.
SIDE EFFECTS:
Metalic taste
Impaired jurdgement
Dry mouth.

30. ZOLPIDEM:
An imidazopyridine acts on alpha -1 sub unit.
Sleep latency is shortened.
Sleep duration is prolonged.
Very less side effects.
Plasma t1/2 is 2 hrs.

31. ZALIPLON:
This is shortest acting newer non-BZD hypnotics that
selectively act on a subset of BZD R’s containing the alpha -1
subunit which appear to mediate the hypnotic action.
Effective only in sleep- onset insomnia, reduce the no’s
awakenings.
T1/2 is 1 hour.
Its efficacy is similar to zolpidem.

32. Summary:
Sedatives:
Benzodiazepines
Antipsychotics
Hypnotics: (Non-pharmacological 1st)
Antihistamines
Zolpidem
Benzodiazepines (rapid onset, short
t1/2)
Anxiolytics:
Benzodiazepines (acute)
Antidepressants (chronic)

33. REFERENCES:
K.D TRIPATHI
ROGER WALKER
DIPIRO

34. THANK
YOU