Transcript Sedative -Hypnotics

Sedative -Hypnotics
• 4th Year Pharmacy
• 2015- 2016
Major Uses
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A. Anxiety state
B. Insomnia
C. Epilepsy
D. Muscle spasticity
E. Induction of amnesia
F. Adjunct in alcohol withdrawal
G. For differential psychiatric diagnosis.
I-General Anesthesia
Classification
According to their chemical structure, Sedatives agents
can be divided into three classes:
1. benzodiazepines- - GABA
Diazepam, Alprazolam.
2. Barbiturates
3. Non- barbiturates
receptor
modulators:
1. Benzodiazepines
• In 1990 diazepam and lorazepam were in the top 20 most
frequently used generic drugs.
• Benzodiazepines are not general depressants of the CNS like
barbiturates and other sedatives and hypnotics.
• They don’t induce true anaesthetic effect, since awareness is still
present and total muscular relaxation is not obtained even in with
large doses.
• It is believed that they exert at least some of their action via
GABA- mediated inhibitory neurotransmission by binding to a
specific site on GABAA receptor.
• Benzodiazepines are orally absorbed.
1,4-benzodiazpine
7-chloro-1-methyl-5-phenyl-3H-1,4benzodiazepin-2-on
• 1960 by Hoffman –La Roche - which, since
1963, has also marketed the benzodiazepine
Diazepam (Valium). In 1977 benzodiazepines
were globally the most prescribed medications
1) 3H-1,4-benzodiazepines
Chlordiazepoxide (librium)
• The first drug discover
• Indications: anxiety, parenteral
for preanesthetic use, status
epilepticus, chemotherapy induced
N/V, acute alcohol withdrawl,
psychogenic catatonia, chronic
insomnia
• 0.5, 1.2 mg tablets, oral solution
concentrate, injection
7-Chloro-2-methylamino-5-phenyl-3H1,4-benzodiazepine-4-oxide
CH3
NH
N
Cl
N
O
Chlordiazepoxide HCl Librium®, Mitran®, Reposans®
Synthesis
Structure Activity Relationship
a)
b)
c)
In ring A an electron – withdrawing group such as Cl, Br, NO2,
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.
d)
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.
c)
d)
e)
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g)
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A phenyl substituent at the 5, position.
α-pyridyl derivative and cycloalkyl substituent at 5 position give
potent compounds.
Electronegative substituents such as Cl or F at the ortho and
disubstituted in both ortho positions in ring C.
Derivatives with additional rings joining the diazepine nucleus at
the 1 and 2 positions are generally more active than the
corresponding 1-methylbenzodiazepines.
Replacement of the benzene ring by heteroaromatic (e.g.
pyrazole) resulted in compounds with interesting anxiolytic
properties ( e.g. ripazepam).
Saturation of the 4,5- double bond reduces potency, as does a
shift of the unsaturation into the 3,4-position.
Benzodiazepines
3/2/11
CHEM E-120
12
Diazepam (valium)
7- Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4benzodiazepin-2-one
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Uses: It is used for the control of anxiety and tension state, the
relief of muscle spasm. It is also helpful in combating withdrawal
symptoms in chronic alcoholics.
It has shown effectiveness in certain types of epilepsy and in
labour it has many advantages over other drugs.
It is metabolized to nordiazepam which is also active with half –
life of 60 hrs.
Assay: A sample (0.5) is dissolved in glacial acetic acid (80ml).
The solution is titrated with 0.1 N perchloric acid and the
end point is determined potentiometrically.
Dose: 5 to 30mg daily in divided doses.
Metabolism
• Biotransformation of benzodiazepines takes place in the liver by
microsomal – metabolizing system. N-demethyation gives active
metabolite with longer life than the parent drug. Diazepam and
Chlorzepate to active metabolite such as N-desmethyl diazepam
(nordiazepam).
• Hydroxylation at position 3 followed by glucuronidation is the
main metabolic pathway.