For MBBS/BDS-Drugs Acting on CNS

1. Sedative Hypnotics

2. • Sedative:-Drug that reduces excitement and produces
calmness of the mind without inducing sleep.
• Hypnotic:-drug that produces sleep resembling normal
sleep.
• Sleep-A state of unconsciousness but still able to awaken
by normal sensory stimuli
• Type-NREM & REM sleep
• Sleeping between 7-9hr per night appears to be optimal for
health in adults aged ≥18 years

3. • Sleeping <7 h is associated with adverse outcomes,
• Obesity
• Diabetes,
• Elevated blood pressure,
• cardiovascular depression,
• All-cause mortality,
• Physiological disturbances such as impaired immune
function
• increased pain sensitivity
• impaired cognitive performance

4. Stages of Sleep
Non Rapid Eye Movement sleep
(NREM)
Rapid Eye
movement sleep
(REM)
Stage-0 Stage-1 Stage-2 Stage-3 Stage-4 Paradoxical
sleep
constitutes about
25% of the sleep
Time(Adult) and
50% in neonates
↑cerebral BF
Body relax
Penis-
erect(male)
Decrease with
Age advance
Stage of
wakefulness
1.Lying to bed
to falling
Asleep (close
eye)
2.Eye
movements are
irregular or
slowly rolling
Stage of
Drowsiness
1.Reduce eye
& muscle
activity
Light sleep
1.Subject
can be
aroused
easily
2.Slight
decrease
Body temp
Slow
breathing
pattern
Medium
sleep
1.Subject
can not be
aroused
easily
Deep cerebral sleep
1.Eye ball activity is
absent
2.Night terror may
occur
3.Growth Hormone
secretion is very high
4.Muscle-fully relaxed
5.If awakened-
disorientation for few
1-2 min
6.Count of 20
Approx. 1hr 20-25min

5. Sedatives & Hypnotics
Benzodiazepines Barbiturates Non-
Benzodiazepines
Miscellaneous
Hypnotic Antianxiety Anticonvuls
ant
Diazepam
Flurazepam
Nitrazepam
Alprazolam
Temazepam
Triazolam
Diazepam
Chlordiazepoxide
oxazepam,
Lorazepam,
Alprazolam
Diazepam,
Lorazepam,
Clonazepam
Clobazam
 Long Acting –Phenobarbitone
 Short Acting –Butobarbitone, Pentobarbitone
 Ultra short acting- Thiopentone Methohexitone
Zopiclone
Zolpidem
Zaleplon
Eszopiclone
•Triclofos
•Melatonin
•Ramelteon

6. Benzodiazepines
 All benzodiazepines (BZDs) have a benzene ring fused to a seven-
membered diazepine ring.
 Selective CNS depressants
 Sites of action:-
• BZDs act at
• Midbrain-ascending reticular activating system (ARAS)-A
wakefulness
• Limbic system- Thought, Emotion & mental function
• Medulla-Muscle relaxant action
• Brain stem,
• Cerebellum- Ataxia
 Sedatives-hypnotics produce their physiological effects by enhancing
the function of GABA-mediated chloride channels via agonism at
GABAA receptor

7. GABAA Receptor
Cl-
Cl
 GABA A receptor is a pentameric structure
 Compose of varying polypeptide subunit associated with a chloride
channel on the postsynaptic membrane

8. • Variation in the five subunits of GABA receptor confer
the potency of its sedatives, anxiolytic, hypnotic, Amnesic
and muscle relaxing properties
• It composed of 2α1 2β2 1γ2 subunit.
MOA:- Benzodiazepines facilitate action of gamma-aminobutyric
acid (GABA)—they potentiate inhibitory
effects of GABA
(Benzodiazepines
have no
GABA-mimetic
Action)

9. Advantages of Benzodiazepines over
barbiturates
1. Wide therapeutic index
2. Do not affect RS or CV function
3. Less distortion of sleep architecture & less rebound phenomena
upon withdrawal of Drug.
4. Produce minimal hangover effects & minimal respiratory
depression.
5. Do not alter disposition of other drugs by enzyme induction
6. Lower abuse liability
7. Specific BZD receptor antagonist→flumazenil, for the treatment of
overdosage
 At Present BZD’s preferred over Barbiturate because-

10. Margin of Safety

11. Pharmacokinetics
• Absorption:- Rapid & complete orally
• Administered-orally or intravenously occasionally by rectal route
(diazepam) in children
• IM absorption is irregular (except for lorazepam)
• Distribution-
Lipophilic, cross BBB
Large volume of distribution
Can cross placental barrier also
• Metabolism:- liver by hepatic microsomal enzymes(CYP3A4) except
lorazepam, oxazepam, temazepam so this can be given in hepatic
failure & elderly pt.
• Some of them produce active metabolites that have long half-life e.g.
flurazepam
• Excretion:- Urine

12. -:Pharmacological Action:-
1.CNS:- (Sedation & hypnosis)
 Low dose-Drowsiness ,sedation
 Dose increases-hypnotics
 Sleep induced-not natural (due to ↓REM sleep)
 Withdrawal drug-cause rebound ↑REM sleep
 ↓sleep latency-shorten the time to fall asleep
 ↑ total sleep time & ↓intermittent night awakening
 Long term use-develop tolerance (thus dose has to be ↑↑)
 Anterograde amnesia
 Anxiolytic action:- (due to action on limbic system)
 occurs in dose lower than hypnotics dose
 No development of tolerance-in anxiolytic dose

13.  Anticonvulsant action- (↑Seizure threshold)
 Potent Anticonvulsant-effective in all types of epilepsy but
tolerance develops upon chronic use.
 Central muscle relaxant action-
↓Muscle tone-
↓muscle spasm-
• Respiratory system:-
– at hypnotic and lower doses, no significant effect
– at higher doses, may promote apnea(Respiratory
depressant)
( ) polysynaptic reflex in spinal cord

14. • Cardiovascular system
– therapeutic doses-No significance change
– High dose/iv administration hypotension
• Gastrointestinal tract
– Prevent stress ulcers by ↓Nocturnal gastric secretion
– No significant effect-bowel movement

15. -:Therapeutic Uses:-
1.Insomnia:- As hypnotic
 It’s a symptom-if persistently for more than 3-4 night
Symptoms include-
(1.) Not able to fall asleep within-30-45min
(2.) more than 5-6 awakening/night
(3.) less than 6hr of sleep in normal adult
Cause:-
 Social/personal problems-illiness, unemployment, family problems
 Psychiatric disorder-Schizophrenia, depressant, Anxiety
 Other disease-Asthma,CHF,Migraine & pain,headache
 Drug & food-ephedrine,Amphetamine,coffee,tea,nicotine,
Types of insomnia:-
 Transient insomnia (less than 3 days)- cause –environmental or

16. • Also can occur due to Shift work, overnight work, change
in work pattern/new place, Jet lag
℞- Zolpidem (5/10mg HS), Zaleplon (Z-compound)/short
acting BZD’s like triazolam(0.5mg)
• Short term insomnia (3days-3 weeks)- cause due to
social/personal problem(unemployment, job problem,
family problem)
℞-Zopiclone, Eszopiclone (half an hour before going to bed in
lowest dose)
 Withdrawal of drug should be gradual to prevent rebound
insomnia
• Long term insomnia (more than 3 weeks):- Non-
pharmacological therapy like exercise, sleep hygiene

17. Non-Pharmacological Treatment
 Education about sleep hygiene
 Room ventilation
 Avoids-CNS stimulants like caffeine,tobacco
 Warm sweet Milk intake-d-tryptophan ↓time of onset of
sleep
 Elderly should restrict-fluid intake in the evening to
reduced nocturia
 Avoid day time napping
 Morning physical exercise-yoga, Meditation
 Sleep restriction therapy-sleep 30-60min less than usual
duration which help in onset of sleep

18. 2.Anxiety:- due to anxiolytic action.
 longer acting drug like Alprazolam, lorazepam, oxazepam,
diazepam preferred
 Clonazepam-panic disorder. The anxiolytic effect is due to their
action on limbic system
3. Epilepsy:- due to anti-convulsant action
 Absence seizure-clonazepam, clobazam
 Status epilepticus-lorazepam, diazepam(as they enter brain)
4.Skeletal Muscle spasm:- (Centrally acting)
 Acute muscle spasm
 Spinal injury-inhibit polysynaptic reflex
5. Preanesthetic medication:- (due to its sedative–amnesic and
anxiolytic effects) Hence, the patient cannot recall the perioperative
events later- lorazepam, midazolam
 GA- I.V. Diazepam, lorazepam, midazolam, + other central nervous
system (CNS) depressants

19. 6. Diagnostic and minor operative procedures:-
Before-ECT, electrical cardioversion, cardiac
catheterization, endoscopies-IV Diazepam
7. To treat alcohol-withdrawal symptoms-Chlordiazepoxide

20. Side Effects and Toxicities
Common side effects-
 Drowsiness, confusion, blurred vision, amnesia, disorientation
 Tolerance- to sedative-hypnotic effect(less than barbiturate)
 Dependence (physical& psychological)-least physical dependance
 More common with Diazepam, Alprazolam
 Withdrawal after chronic use:-
Tremor, insomnia, restlessness, nervousness and loss of
appetite.
 Use of BZDs during labour-
respiratory depression and hypotonia, hypothermia in the new-born

21. Interaction
1. BZD’s × Alcohol- potentiate CNS depressant
action
2. BZD’s × Anti-histaminics, opioids (other CNS
depressant) potentiate CNS depressant action of
BZD’s
3. BZD’s × CYP3A4 inhibitors (Erythromycin,
Ketoconazole)- inhibit metabolism of BZD’s leading to
prolong the action
4. BZD’s ×Valproate-psychotic attack

22. Benzodiazepine Antagonist- Flumazenil
• Competitively reverse-Action of BZD agonist & BZD
inverse agonist
• Administered-I.V. due to high fast pass metabolism
• Rapid onset of action
• Duration is shorter than with most benzodiazepines, so
monitoring is essential
Dose- 1-5mg i.v. for 2-10min
BZD
receptor
BZD agonist
β-carboline
Inverse agonist
Flumazenil

23. • Withdrawal (agitation, tremors seizures) may be
induced in patients who either abuse or chronically
take benzodiazepines for therapy
• Used:-
• overdose of benzodiazepines to reverse sedation &
respiratory depression
• To reverse Sedative effect of BZD’s(higher dose)
during general anesthesia
• Reverse the hypnotics effect of Z-compounds
SE:- confusion, dizziness and nausea.

24. Non-Benzodiazepine Hypnotics
 Also called as “Z” compounds-name started with Z
 Less abuse potential than BZD’s & short duration of action
 Less effect on REM sleep than BZD’s-negligible disruption
of sleep architecture
 Over dose can be antagonized by flumazenil
 They are preferred over BZD’s-
Sedative & hypnotic action equal with BZD’s
Wide margin of safety-safe long use (up to 12 month)
Week anxiolytic action
No anti-convulsant & central muscle relaxant action
No amnesia occurs

25. Zolpidem, zopiclone, zaleplon, eszopiclone
(Non-Benzodiazepine hypnotics)
Bind selectively to BZD binding site on GABAA receptor
Facilitate GABA-mediated neuronal inhibition
CNS depression
MOA:-

26. Zolpidem:-
• Chemically unrelated to benzodiazepines or barbiturates-
imidazopyridine group of drug
• Rapidly acting within 15 minutes of oral dose
• Mainly produce hypnosis, but no muscle relaxant or
anticonvulsant effects
• No effect on REM sleep
• T1/2-2hr
• ↓sleep latency ↑duration of sleep time
• Minimal hangover effect & rebound insomnia
• Less likely to cause tolerance & dependance
• Used for transient insomnia/short term insomnia
• SE- headache, confusion, Nausea, vomiting

27. Zopiclone-newer agent
• Effect on sleep resemble that of BZD
• Do not prolong REM sleep
• Prolongs Stage 3 & 4
• Does not disturb sleep architecture or hangover or
withdrawal
• T1/2-5hr
• Use:- Short term insomnia
• Side effects:-
• Metallic taste, impaired judgment (liable to road
traffic accident), dry mouth

28. Zaleplon
• Used in sleep onset insomnia
• Absorbed orally & rapidly-shortest acting “z”
compound
• Sustained efficacy on prolong use
• T1/2-1hr
• Preferred in bed time
• Bioavailability 30%-extensive first pass metabolism
• Safest among other drugs

29. Eszopiclone
• Enantiomer of zopiclone
• Reduced sleep latency
• No after use of drug on next day
• No tolerance reported
• Used in short insomnia
• Effect blocked by Flumazenil

30. Barbiturates
• Derivatives of barbituric acid-Acidic drug
• Used Earlier-upto 1960-not used now
• High incidence of
accidental,
suicidal, and
homicidal attempts and completions
• Non-selective CNS depressant
• Site of Action-ARAS main site of action
 Duration of action is very important clinically-
 Long acting barbiturate-used as anti-epileptics
 Short acting barbiturate-sedative-hypnotics & anxiolytics
 Ultra-shorting barbiturate-used for anesthetic induction

31. MOA:-
Barbiturate
↓
Bind to β-subunit of GABAA-Cl- channel complex
↓
↑duration of opening of Cl- channel
↓
↑GABA-mediated chloride current
↓
Membrane hyperpolarization
↓
CNS Depressant
•
Sub-anaesthetic dose-
Depress Glutamate induced neuronal depolarization
At Anaesthetic dose:-
Depress voltage sensitive Na + and K + channels to produced anesthetic
action
Other mechanism:-

32. Dose Dependent Action
Sedation
(Sedative)
Sleep
(Hypnotics)
Anesthesia
(Anesthetic) Coma
Death

33. -:Pharmacokinetics:-
Absorption- orally rapid, Food delay absorption
Distribution-widely in body
High lipid soluble-higher potency
Thiopentone sodium processed-redistribution
Barbiturate-acidic in nature
Metabolism:- liver by glucuronide conjugation &
oxidation
Excretion:- urine

34. Pharmacological Action
1.CNS:- CNS depressant
 Sedatives & hypnotics:-
 Low dose-sedation
 Hypnotic dose-↓sleep latency and night awakenings,
↑duration of sleep
 At present, barbiturates are not recommended because:
 They have a low therapeutic index.
 They cause rebound increase in REM sleep on stoppage of therapy(nightmares
).
 They cause marked respiratory depression.
 They produce marked hangover effects (headache and drowsiness on waking).
 They cause high degree of tolerance and drug dependence.
 They are potent enzyme inducers and cause many drug interactions.
 They have no specific antidote.

35. Anti-convulsant effect:- Phenobarbitone
Tolerance doesn’t develop to anti-convulsant dose
 General anaesthetic effect:- capable of producing surgical
anaesthesia
 Can impair learning, memory & judgment
 Depress all areas of CNS, Maximum-reticular activating
system
 Respiratory system-Dose dependent depression (hypnotic
dose/higher dose)
 CVS-Overdose produce marked hypotension(hypnotic dose
& anesthetic dose) due to ↓COP & Venous return
 Toxic dose-suppression to VMC-cardiac arrest
 Kidney:- ↓urine volume(oliguria)-poor urine formation

36. GIT:-
 ↓tone & amplitude of GIT Smooth muscle-at sedative &
hypnotic dose
 Hypnotics dose-delay gastric emptying
 Liver:- (liver microsomal enzyme inducer)
 Phenobarbitone-↑ glucuronyl transferase enzyme
 In neonatal jaundice-there is ↑unconjugated bilirubin level
unconjugated bilirubin -------------------→Conjugated bilirubin
glucuronyl transferase enzyme
Promote excretion
Phenobarbitone

37. Side Effects:-
1. Common Side Effect-
Drowsiness, confusion, headache, ataxia, hypotension and
Respiratory depression.
2. Hypersensitivity reactions like skin rashes, itching and
swelling of face may occur.
3. Tolerance develops to their sedative and hypnotic actions on
repeated use.
4. Physical and psychological dependence develops on
repeated use.
5. Phenobarbitone Prolonged use - megaloblastic anemia by
interfering with absorption of folic acid from the gut.

38. • 6. Precipitate attacks of acute intermittent porphyria-
barbiturate-increase δ-aminolevulenic acid
synthetase(D-ALA)-rate limiting enzyme in
Porphyrin synthesis- leading to accumulation of
toxic porphyrin precursors in the body
• 7. In case of acute barbiturate poisoning, the signs
and symptoms are drowsiness, restlessness,
hallucinations, hypotension, respiratory depression,
convulsions, coma and death.

39. Acute barbiturate poisoning
 Suicidal or rarely accidental
 Short-acting preparation are more lethal at lower dose
 Fatal dose-lipid soluble drug-2-3 gm , less lipid soluble
phenobarbitone- 6-10 gm
 Symptoms:-
o Metabolic coma
o Sever respiratory & cardiovascular depressant
o Acute renal failure
o Pulmonary edema
o Barbiturate blisters-due to deposition
Of porphyrin

40. Treatment-
Hospitalization
Maintain-ABC
No specific antidote
Gastric lavage
Artificial ventilation and O2 administration
General supportive measures
Alkalization of urine-Intravenous sodium bicarbonate
alkalinizes urine.
Hemodialysis-most effective treatment

41. Uses
A. For induction of anesthesia & short surgical
procedure:- Thiopentone sodium-i.v.
B. Antiepileptic- phenobarbitone
status epilepticus in children
Eclampsia
Young children with recurrent febrile seizures
C. Neonatal jaundice & kernicterus

42. -:Interaction:-
• Barbiturate
×warfarin,OCP,tolbutamides,griseofulvin,theophyll
ine-induced metabolism by glucuronyl
transferase.leading to therapeutic failure
• Barbiturate × CNS depressant
• Phenobarbitone ×sodium valproate-↑Cp of
phenobarbitone
• Phenobarbitone ×griseofulvin-↓absorption of
griseofulvin from git

43. Contraindication
Acute intermittent porphyria-barbiturate ↑ δ-
aminolevulenic acid synthetase-rate limiting
enzyme in porphyrin synthesis-leading to
accumulation of toxic porphyrin precursors in the
body
Liver & kidney disease
Sever pulmonary insufficiency

44. Melatonin
 Naturally occurring paracrine hormone of pineal glad in
brain
 “Hormone of darkness”-secrete at night & maintained
the body circadian rhythm
 Acts via Melatonin recptor-MT1 & MT2-(GPCR) found in
membranes of neurons of suprachiasmatic nucleus of
hypothalamus
 Melatonin process-
 Anti-oxidant,
 immunostimulant action,
 anti-cancer,
 maintained BP during sleep.

45. Ramelteon-Melatonin receptor Agonist
• Analogue of Melatonin
• MOA- Ramelteon
Binds
MT1 receptor MT2 receptor
Promote onset of sleep Shift the timing of circadian system
 No direct action on GABA-nergic transmission
 Absorption-orally & rapid
 Undergoes-extensive first pass metabolism
Use:-
 Sleep onset insomnia
 Chronic insomnia-no evidence of rebound insomnia, development of
tolerance upon chronic use

46. Questions
Q. Write short note on:
1.Non-Benzodiazepine hypnotics/Z compounds
2.Benzodiazepines
Q. Discuss the pharmacological basis for the use of
• Benzodiazepines are preferred over barbiturate in the
treatment of insomnia
• Barbiturates are contraindicated in Acute intermittent
porphyria
Q. Write mechanism of action, uses & adverse effect of
diazepam
Q. Pharmacotherapy of Insomnia