lec.7-426

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Transcript lec.7-426

ANTIANXIETY
Antianxiety agents, formerly called minor tranquilizers, and
known also as anxiolytic and tensiolytics, are used to control
neuroses and stress. Drowsiness is the most common untoward
effect of antianxiety agents.
Anxiety is an emotional state characterized by a disquietude of
mind and a fearful anticipation events which may be brought on by
stressful events in normal life.
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.
Classification
According to their chemical structure, antianxiety agents can be
divided into five classes:
1.
2.
3.
4.
5.
benzodiazepines- - GABA receptor modulators: Diazepam,
Alprazolam.
Non – benzodiazepines: Alpidem.
Propanediol carbamates: Meprobamate.
Antihistaminic: hydroxyzine.
Miscellaneous - 5HT agonists: Buspirone.
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) 3H-1,4-benzodiazepines
Chlordiazepoxide (librium)
• 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)
f)
g)
h)
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.
Diazepam (valium)
7- Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4benzodiazepin-2-one
Synthesis
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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.
Mode of action
2. Non-benzodiazepines
Alpidem (Ananxyl)
• It is an imidazopyridine antianxiety agent with anticonvulsant
properties.
• It is the first non-benzodiazepine anxiolytic to show selectivity for
omega-1 modulatory site of the GABA receptors.
• It is similar to benzodiazepines, but is significantly better tolerated
with lower abuse potential.
3. Propandiol Carbamates
• MOA: a carbamate derivative that
has multiple CNS sites of action by
inhibiting neurotransmission in the
thalamus and limbic system, inhibits
multi-neuronal spinal reflexes. Acts
like benzodiazepines, but less
selective and higher abuse potential.
• It is also used as a sedative and
hypnotic..
• 200, 400 and 600 mg tablets
CH3
O
H2N
O
O
H3C
NH2
O
Meprobamate - Equanil®,
Miltown®, Neuramate®
4. Antihistaminic
• Indications: Skin allergies (pruritis).
Also anxiety and tension, prior to
dental procedures, acute emotional
problems,
alcoholism,
anxiety
caused by heart disease, parenteral
antiemetic and analgesia
• MOA:
subcortical area CNSdepressant, a rapid-acting true
ataraxic
(calmative).
H1
Antagonist
• 10,25, 50, 100 mg tablets and
capsules, syrup, oral suspension
injection
N
O
OH
N
Cl
Hydroxyzine - Atarax®, Vistaril®
5. Miscellaneous
• Buspirone HCl - Buspar®
• 5-H Agonist
• Indications: management of anxiety
disorders.
• MOA: Unknown, has affinity for
serotonin 5-HT1A and D2-dopamine
receptors, but has NO anticonvulsant
activity nor muscle relaxant
properties
• No tolerance or withdrawal issues:
5, 10, 15 mg tablets
• Oxidative liver metabolism with
active metabolites.
• Often takes 3-4 weeks to see results