Sedatives and Hypnotics Pharmacology Clinical uses Sedation Coping with stress and anxiety Smoothing effects of stimulants Potentiation of narcotics Treatment of serious mental disorders Pleasurable sensations, including intoxication Classifications Benzodiazepines Diazepam, Clonazepam, Oxazepam, Clobazam, Clordiazepoxide, Midazolam Barbiturates Phenobarbitone, Amobarbital, Thiopental-Na Newer drugs Zolpidem, Zaleplon, Buspirone Chloral hydrate Paraldehyde Diphenhydramine Benzodiazepines Properties High therapeutic index (high LD50) Relatively safe in overdose Develop tolerance slowly Less addiction liability Benzodiazepines Benzodiazepines Most commonly prescribed Benzodiazepines All Benzodiazepines are classified as Controlled Drugs in some countries. Most are CD Schedule 4 Diazepam (Valium,Anxicalm) Alprazolam (Xanax) Bromazepam (Lexotan) Clobazam (Frisium) Lormetazepam (Noctamid) Nitrazepam (Mogadon) Clonazepam Two are CD Schedule 3 Flurazepam (Rohypnol) Temazepam (Nortem) Structure Activity Relationship In ring A an electron – withdrawing group such as Cl, Br, NO2 or CN at position 7. A methyl Group is attached to the nitrogen atom in position 1 in ring B. However, substituents at position 1 that are metabolically are still clinically useful e.g. Flurazepam. Replacement of the carbonyl function with two hydrogens in position 2 gives medazepam, less potent than diazepam. Replacement of one of the hydrogen with a OH group on position 3 lower the activity on the one hand and aids elimination on the other. Introduction of a carbonyl function in the 3 position increases the duration of action and also favours formation of water soluble salts. e) α-pyridyl derivative and cycloalkyl substituent at 5 position give potent compounds. f) Electronegative substituents such as Cl or F at the ortho and disubstituted in both ortho positions in ring C. g) Derivatives with additional rings joining the diazepine nucleus at the 1 and 2 positions are generally more active than the corresponding 1-methylbenzodiazepines. h) Replacement of the benzene ring by heteroaromatic (e.g. pyrazole) resulted in compounds with interesting anxiolytic properties ( e.g. ripazepam). i) Saturation of the 4,5- double bond reduces potency, as does a shift of the unsaturation into the 3,4-position. Barbiturates Barbiturates Barbiturates Barbiturate poisoning Treatment of Barbiturate poisoning Buspirone

1. Sedatives and HypnoticsSedatives and Hypnotics
Sharmeen AsadSharmeen Asad
Lecturer, SUBLecturer, SUB

2. Pharmacology
Sedative:Sedative:
A drug that subdues excitement and calms the subject
Without Inducing sleep, though drowsiness may be
produced.
HypnoticHypnotic
A drug that induces and,/or maintains sleep, similar to
normal sleep.

3. Clinical uses
• Sedation
• Coping with stress and anxiety
• Smoothing effects of stimulants
• Potentiation of narcotics
• Treatment of serious mental disorders
• Pleasurable sensations, including intoxication
anxiety
relief
euphoria calmness sleep general
anesthesia
coma death

4. Classifications
• Benzodiazepines
Diazepam, Clonazepam, Oxazepam, Clobazam, Clordiazepoxide, Midazolam
• Barbiturates
Phenobarbitone, Amobarbital, Thiopental-Na
• Newer drugs
Zolpidem, Zaleplon, Buspirone
• Chloral hydrate
• Paraldehyde
• Diphenhydramine

5. Benzodiazepines
Properties
• High therapeutic index (high LD50)
• Relatively safe in overdose
• Develop tolerance slowly
• Less addiction liability
Mechanism of action:
• Binds with specific regulatory site on the
GABA receptor in the brain
• Enhance GABA activity
• Opening of Cl-
channels
• Hyperpolarization of cells
• Depression of CNS

6. Benzodiazepines
Classifications
i) Short acting :- Midazolam, Triazolam
ii) Intermediate acting:- Lorazepam, Oxazepam, Temazepam
iii) Long acting:- Diazepam, Nitrazepam, Clonazepam, Flurazepam
CNS effects:
• Anxiolytic
• Sedation and induction of sleep
• Anesthesia in combination with other drugs
• Muscle relaxation
• Anticonvulsant effects
• Anterograde amnesia

7. BenzodiazepinesIndications:
• Treatment of anxiety
• As sedative-hypnotic
• As muscle relaxant in Tetanus, Eclampsia, Epilepsy
• Anesthetic premedication
• Treatment of night terrors
• As anticonvulsant
Adverse Effects:
• Tolerance occur due to prolonged use
• Physiological dependency
• Sudden withdrawal may cause Restlessness, Anxiety, Weakness, Orthostatic
hypertension, Hyperactive reflexes, Generalized seizure
Benzodiazepine Antagonist:
• Flumazenil
• Competitively antagonize benzodiazepine site on GABA receptors
• Reverse the CNS depressive effect

8. Most commonly prescribedMost commonly prescribed
BenzodiazepinesBenzodiazepines
• All Benzodiazepines are classified as Controlled
Drugs in some countries.
• Most are CD Schedule 4
– Diazepam (Valium,Anxicalm)
– Alprazolam (Xanax)
– Bromazepam (Lexotan)
– Clobazam (Frisium)
– Lormetazepam (Noctamid)
– Nitrazepam (Mogadon)
– Clonazepam
• Two are CD Schedule 3
– Flurazepam (Rohypnol)
– Temazepam (Nortem)

9. - Acetylation of aminobenzophenone withchloroacetyl chloride to
give the chloromethyl amide.
- Heating this compound with ammonia or its latent equivalent,
hexamethylene tetramine (HMTA), can be envisaged to involve the
initial displacement of chlorine to give a glycineamide.
- Cyclization by imine formation then affords diazepam.
Synthesis of Diazepam

10. Structure Activity RelationshipStructure Activity Relationship
a) In ring A an electron – withdrawing group such as Cl, Br,
NO2 or CN at position 7.
b) A methyl Group is attached to the nitrogen atom in
position 1 in ring B. However, substituents at position 1
that are metabolically are still clinically useful e.g.
Flurazepam.
c) Replacement of the carbonyl function with two hydrogens
in position 2 gives medazepam, less potent than diazepam.

11. Replacement of one of the hydrogen with a OH
group on position 3 lower the activity on the one
hand and aids elimination on the other.
d) Introduction of a carbonyl function in the 3
position increases the duration of action and
also favours formation of water soluble salts.

12. e) α-pyridyl derivative and cycloalkyl substituent at 5
position give potent compounds.
f) Electronegative substituents such as Cl or F at the
ortho and disubstituted in both ortho positions in
ring C.
g) Derivatives with additional rings joining the diazepine
nucleus at the 1 and 2 positions are generally more
active than the corresponding 1-
methylbenzodiazepines.
h) Replacement of the benzene ring by heteroaromatic
(e.g. pyrazole) resulted in compounds with interesting
anxiolytic properties ( e.g. ripazepam).
i) Saturation of the 4,5- double bond reduces potency, as
does a shift of the unsaturation into the 3,4-position.

15. Barbiturates
Classifications
i) Ultra-Short acting :- Thiopental-Na
Duration of action: 30 minutes
As intravenous anesthetic
ii) Short acting:- Pentobarbital, Hexobarbital, Secobarbital
Duration of action: 2 hours
As sedative
iii) Intermediate acting:- Amobarbital, Butabarbital
Duration of action: 3-5 hours
As hypnotic
iv) Long acting:- Phenobarbitone, Barbital
Duration of action: > 6 hours
As anticonvulsant

16. Barbiturates
Pharmacological actions:
CNS:
Mild degree of sedation to general anesthesia
Anticonvulsant effect
Respiratory centre depression
Medullary vasomotor inhibition
CVS:
Hypotension
Decreased heart-rate
Circulatory collapse
Myocardial depression
Liver: Increase metabolism
Stimulate glucoronyl transferase
Eye: Miosis (high dose)
Kidney: Antidiuresis

17. Barbiturates
Indications:
• As therapeutic and diagnostic aid in psychiatry
• Reduce cerebral edema following surgery, head injury or cerebral ischemia
• As antiepileptic medications
• As anticonvulsant (Tetanus, Epilepsy and Eclamsia)
• Intravenous anesthesia
• Hyperbilirubinaemia
• Kernicterus (An abnormal accumulation of bile pigment in the brain and
other nerve tissue; causes yellow staining and tissue damage)
• Hemolytic jaundice
• Cholestasis (A condition in which little or no bile is secreted or the flow of
bile into the digestive tract is obstructed)
Adverse Effects:
• Automatism
• Hangover
• Physiological and psychological dependence
• Development of rapid tolerance

18. Barbiturate poisoning
Administration of 10-100 times of therapeutic dose
CNS:
Drowsiness
Respiratory depression
Slow and shallow breathing
Coma
CVS:
Hypotension
Shock
Cardiovascular collapse
Dehydration
Liver: Pulmonary oedema
Bronchopneumonia
Eye: Miosis followed by hypoxic paralytic dilatation
Kidney: Severe oliguria, Renal failure

19. Treatment of Barbiturate poisoning

20. Buspirone
A non-benzodiazepine anxiolytic drug
• Act on 5-HT1A receptor subtype in the brain and produce anxiolytic effect
• No influence on interaction of GABA with GABA receptor
• Relieves anxiety without causing marked sedation and euphoria
• Rapidly absorbed orally and metabolized extensively by first-pass effect
• Most effective in mild anxiety
• Not effective in panic disorder