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Anxiolytic drugs : important
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““A REVIEW ON PRECLINICALA REVIEW ON PRECLINICAL
EVALUATION OF ANXIOLYTICS”EVALUATION OF ANXIOLYTICS”
PRESENTING BY,PRESENTING BY,
Ms. SONALI B. DIWATEMs. SONALI B. DIWATE
GUIDED BY,GUIDED BY,
PROF. R. CHANSHETTIPROF. R. CHANSHETTI
MODERN C.O.P.,MOSHI, PUNE-412105MODERN C.O.P.,MOSHI, PUNE-412105
2. To Review and Study the Preclinical Evaluation of Anxiolytics.To Review and Study the Preclinical Evaluation of Anxiolytics.
OBJECTIVEOBJECTIVE
1.TO COLLECT THE INFORMATION ABOUT ANXIETY & ANXIOLYTICS. (LITERATURE1.TO COLLECT THE INFORMATION ABOUT ANXIETY & ANXIOLYTICS. (LITERATURE
SURVEY).SURVEY).
2.TO SURVEY THE STATUS AND STANDARD ANXIOLYTIC DRUGS AVAILABLE IN2.TO SURVEY THE STATUS AND STANDARD ANXIOLYTIC DRUGS AVAILABLE IN
MARKET.MARKET.
3. TO STUDY THE COMMON ADR & USES OF ANXIOLYTICS.3. TO STUDY THE COMMON ADR & USES OF ANXIOLYTICS.
4.TO STUDY THE PHRMACOKINETICS,PHARMACODYNAMICS OF ANXIOLYTICS.4.TO STUDY THE PHRMACOKINETICS,PHARMACODYNAMICS OF ANXIOLYTICS.
5.TO EXPLAIN INVIVO & INVTRO MODELS FOR PRECLINICAL EVALUATION OF5.TO EXPLAIN INVIVO & INVTRO MODELS FOR PRECLINICAL EVALUATION OF
ANXIOLYTICS.ANXIOLYTICS.
6.TO ANALYZE ALL THE PARAMETERS RELATED TO ANXIOLYTICS6.TO ANALYZE ALL THE PARAMETERS RELATED TO ANXIOLYTICS
7.SUMMERIZATION OF THE INFORMATION.7.SUMMERIZATION OF THE INFORMATION.
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3. CONTENTS…..CONTENTS…..
1. AIM AND OBJECTIVE1. AIM AND OBJECTIVE
2.INTRODUCTION TO ANXIETY & ANXIOLYTICS2.INTRODUCTION TO ANXIETY & ANXIOLYTICS
3.STANDARD ANXIOLYTICS AVAILABLE IN MARKET3.STANDARD ANXIOLYTICS AVAILABLE IN MARKET
4. COMMON ADR & USES OF ANXIOLYTICS4. COMMON ADR & USES OF ANXIOLYTICS
5. PHARMACOKINETICS & PHARMACODYNAMICS5. PHARMACOKINETICS & PHARMACODYNAMICS
6. PRECLINICAL SCREENING METHODS6. PRECLINICAL SCREENING METHODS
7. SUMMERY7. SUMMERY
8. CONCLUSION8. CONCLUSION
9. BIBLIOGRAPHY9. BIBLIOGRAPHY
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4. INTRODUCTION TO DEPRESSIONINTRODUCTION TO DEPRESSION
1. Anxiety is an emotional state commonly caused by the perception of real or danger
that threatens the security of an individual.
2.It allows a person to prepare for or react to environmental changes .
3.Anxiety can produce uncomfortable nature.
The Symptoms of Anxiety
1. Sweating
2. Shaking
3. Palpitation
4 .Blushing
5. GI Discomfort
6. Lack Of Sleep
7. Lack Of Concentration
8. Irritation
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TYPES OF ANXIETY
Panic Disorder-unreasonable fear spreading
for 10-20min
Generalized Anxiety Disorder-experienced
when person thinking about no. of events
Social Anxiety Disorder-means fear about
interaction with social programs.
Obsessive Compulsive Disorder-repeated
experience of specific image or thoughts.
5. HISTORY OF ANTIDEPRESSANTSHISTORY OF ANTIDEPRESSANTS
The drugs or agents which are used in treatment of anxiety is called as
Anxiolytics.
Anxiolytics acts by balancing brain neurotransmitters level to ease anxiety.
CLASSIFICATION OF ANXIOLYTICS
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INTRODUCTION TOINTRODUCTION TO ANXIOLYTICS
1. BENZODIAZEPINES-ALPRAZOLAM,CHLORDIAZEPOXIDE,DIAZEPAM,LORAZEPAM
2. AZAPIRONES-BUSPIRONE,TANDOSPIRONE,GEPIRONE
3. BETA BLOCKER-PROPRANOLOL
4. CARBAMATES-MEPROBAMATES
6. STANDARD DRUGS AVAILABLE IN MARKETSTANDARD DRUGS AVAILABLE IN MARKET
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SR.NO DRUG MARKETED PREPARATION DOSE
1 ALPRAZOLAM Xanax 0.25mg
2 DIAZEPAM Valium 5mg
3 BUSPIRONE Buspar 5mg
4 PROPRANOLOL Deralin 2.5mg
5 MEPROBAMATE Miltown 5mg
7. COMMON ADVERSE DRUG REACTIONCOMMON ADVERSE DRUG REACTION
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Very common (>10%
incidence) adverse effects
include:
Dizziness
Headache
Common (1-10%
incidence) adverse effects
include:
Nervousness
Insomnia
Disturbance in attention
Uncommon (0.1-1%)
adverse effects include:
Hypertension
Redness and itching of
the eyes
Altered taste
Conjunctivitis
Flatulence
Anorexia
Increased appetite
Salivation
8. DRUG INTERACTIONS
• Alprazolam is primarily metabolised via CYP3A4.Combining CYP3A4 inhibitors such
as cimetidine, erythromycin, fluoxetine, fluvoxamine,itraconazole, ketoconazole,
nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of
alprazolam, which may result in excessive accumulation of alprazolam. This may
result in exacerbation of its adverse effect profile.
• Imipramine and desipramine have been reported to be increased an average of
31% and 20%, respectively, by the concomitant administration of alprazolam
tablets in doses up to 4 mg/day .
• Combined oral contraceptive pills reduce the clearance of alprazolam, which may
lead to increased plasma levels of alprazolam and accumulation.
• Alcohol is one of the most important and common interactions. Alcohol and
benzodiazepines such as alprazolam taken in combination have a synergistic effect
on one another, which can cause severe sedation, behavioural changes, and
intoxication. The more alcohol and alprazolam taken the worse the interaction.
Combination of alprazolam with the herb kava can result in the development of a
semi-comatose state.Hypericum conversely can lower the plasma levels of
alprazolam and reduce its therapeutic effect.
10. The mechanism of action of BENZODIAZEPINES:
Benzodiazepines acts selectively on GABAA receptor which mediate fast inhibitory
synaptic transmission throughout the CNS. They enhance the response to GABA by
facilitating opening of GABA- activated chlorine channels & increases affinity of GABA
for the receptor.
The mechanism of action of BUSPIRONE:
It is a partial agonist at 5HT1A receptor. These are the auto receptor that reduces
release of 5HT & other mediators. They also inhibits the activity of noradrenergic
locus cerulus neurons & thus interferes with arousal reaction.
The mechanism of action of BETA BLOCKER:
Many symptoms of anxiety such as palpitation, rise in BP, tremor due to over
activation of sympathetic system. Beta blocker help anxious patient by cutting
vicious cycle & provides symptomatic relief. They do not affect psychological
symptoms.
The mechanism of action of CARBAMATES:
Acts on several levels of CNS,including limbic system, thalamus & spinal cord. It has
mild to moderate tranquilizing, anticonvulsant & skeletal muscle relaxing activity.
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PHARMACOKINETICS & PHARMACODYNAMICS OF ANTIDEPRESSANTSPHARMACOKINETICS & PHARMACODYNAMICS OF ANTIDEPRESSANTS
1) GIVEN BY ORAL ROUTE
2) METABOLISM BY LIVER
3) EXCREATION THROUGH URINE
12. CLASSIFICATION OF SCREENING METHODSCLASSIFICATION OF SCREENING METHODS
IN VIVOIN VIVO METHODSMETHODS
1.Foot shock induced aggression
2.Isolation induced aggression
3.Maternal induced aggression
4.Light & Dark model
5.Open field test
6.Elevated plus maze model
7.Anticipatory anxiety in mice
8.Marble burying behavior model
9.Staircase test
10.Marmoset test
11.Cork gnawing test in rats
IN VITROIN VITRO METHODSMETHODS
1.GABA receptor binding
2.GABA receptor binding
3.Benzodiazepine receptor binding
4.Serotonine receptor binding
[5HT1A, 5HT2A]
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13. FOOT SHOCK INDUCED AGGRESSION
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PURPOSE:
Induction of aggression in
pair of mice by giving shock
to feet of mice. Anxiolytics
reduces fighting behavior in
mice.
EVALUATION:
Record fighting behavior
before & after treatment.
Procedure:
1.Place pair of mice in a box
consisting of grid floor, which is
made up of steel rods kept at
distance 5-6 mm & constant
current(0.8mA) is allowed to
pass for 5sec & 5sec
intermission.
2.Record fighting behavior in pair
of mice for 5min before & after
treatment.
14. ISOLATION INDUCED AGGRESSION
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PURPOSE:
Keeping one of the mice
alone for prolonged period of
time, so that aggression
develops against same sex
animal. Anxiolytic agent
suppress isolation induced
aggression .
EVALUATION:
Record no. of attacks
before & after treatment.
Procedure:
1.Keep mouse or rat alone for long
period of time result into generation
of aggression. Place intruder into
cage of isolated mouse.
2.Isolated mouse attacks on intruder
within 10 sec & record no of attacks
for 3 min.
15. MATERNAL INDUCED AGGRESSION
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PURPOSE:
1.Induction of an intruder in
cage of parturient female rat,
induced high level aggression
against such intruder.
2. Maternal aggression is
characterized by high intensity
attacks on head or neck of
intruder. Anxiolytics reduces
the aggression.
EVALUATION:
Record fighting behavior
before & after treatment.
Procedure:
1.One male intruder is placed in
female’s home cage for 5 min.
2.The ongoing behavior is
videotaped & analyzed later.
3.Each intruder is used only once
& sacrificed immediately
afterwards with an i.p.
overdose
of pentobarbital, followed by
shaving & describing the
wounds on wound charts.
16. IN VITROIN VITRO METHODMETHOD
GABAGABAAA RECEPTOR BINDINGRECEPTOR BINDING
TISSUE PREPARATION :
MALE WISTAR RATS ARE DECAPITATED
THE BRAINS RAPIDLY REMOVED
THE HYPOTHALAMIC REGION IS PREPARED, WEIGHED AND HOMOGENIZED
[IN 9 VOLUMES OF ICE-COLD 0.32 M SUCROSE SOLUTION USING A
POTTER- ELVEJHEM HOMOGENIZER]
THE HOMOGENATE IS CENTRIFUGED AT 1000 G AT 0-4 oC
THE SUPERNATENT IS DECANTED &USED FOR EXPERIMENT
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PRINCIPLE :
1. THE BASIC BEHIND TO FOLLOW
INVITRO SCREENING METHOD IS
THAT TO FIND OUT BINDING
CHARACTERISTICS OF TEST DRUG
WITH SPECIFIC RECEPTOR.
2. FOR THIS WE ARE USING
RADIOLEGANG THAT MAY BE
AGONIST OR ANTAGONIST.
3. THEN THE REACTIVITY IS MEASURED
USING LIQUID SCINTILLATION
METHOD
4. CALCULATE TOTAL BINDING,NON-
SPECIFIC BINDING,SPECIFIC BINDING.
EVALUATION :
1.THE PERCENTAGE INHIBITION AT EACH DRUG CONCENTRATION IS THE MEAN OF 3 DETERMINATIONS.
2.IC50 VALUES ARE DERIVED FROM LOG-PROBIT ANALYSIS.
3.IC50 VALUES FOR THE STANDARD DRUGS.
17. ASSAY PROCEDURE
IN THIS WE DETERMINE WE DETERMINE TOTAL BINDING & NON-SPECIFIC BINDING.
1.TOTAL BINDING:
INTHIS PELLET SUSPENSION IS UTILIZED
INCUBATE THE TISSUE WITH RADIOLABELLED SUBSTANCE HAVING AFFINITY FOR SPECIFIC & NONSPECIFIC BINDING SITE.
MEMBRANE SOLUTION IS SUBJECTED TO CENTRIFUGATION FOR FAST REACTION OF BINDING
CARRY OUT FILTERATION & SEPARATED FRAGMENTS DISSOLVED IN SCINTILLATION FLUID
MEASURE RADIOACTIVITY USING LIQUID SCINTILLATION COUNTER
..
CONT…… IN VITROCONT…… IN VITRO METHODMETHOD
GABAA RECEPTOR BINDINGGABAA RECEPTOR BINDING
18. 2. NON SPECIFIC BINDING:
IN THIS SUCH DRUG IS USED WHICH WILL BIND TO SPECIFIC SITE AND WHICH IS NON
RADIOLABELED.SO THAT NON RADIOLABELED SUBSTANCE WILL REPLACE ONLY RADIOLABELED BINDED DRUG FROM
SPECIFIC BINDING SITE AND ONLY RADIOLABELED NON SPECIFIC BINDING REMAINS AS IT IS.
INCUBATE THE TISSUE WITH RADIOLABELLED SUBSTANCE+DRUG(STANDARD/TEST).
SELECT DRUG WITH BINDS ONLY TO SPECIFIC SITE.
NON RADIOLABELED DRUG WILL REPLACE RADIO SUBJECT FROM SPECIFIC BINDING SITE.
MEASURE RADIOACTIVITY USING LIQUID SCINTILLATION COUNTER.
THIS WILL GIVES RADIOACTIVITY OF NON SPECIFIC SITE.
2. SPECIFIC BINDING = TOTAL BINDING- NON-SPECIFIC BINDING
A
CONT…… IN VITROCONT…… IN VITRO METHODMETHOD
GABAA RECEPTOR BINDINGGABAA RECEPTOR BINDING
19. CONCLUSIONCONCLUSION
1. Anxiety is an emotional state commonly caused by the perception of real or danger that
threatens the security of an individual.
2.It allows a person to prepare for or react to environmental changes .
3.Anxiety can produce uncomfortable nature.
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