Anxiolytic drugs : important

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Anxiolytic drugs : important

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    A REVIEW ON PRECLINICAL EVALUATION OF ANXIOLYTICS

    PRESENTING BY,Ms. SONALI B. DIWATE

    GUIDED BY,PROF. R. CHANSHETTI

    MODERN C.O.P.,MOSHI, PUNE-412105

  • To Review and Study the Preclinical Evaluation of Anxiolytics.

    OBJECTIVE

    1.TO COLLECT THE INFORMATION ABOUT ANXIETY & ANXIOLYTICS. (LITERATURE SURVEY).2.TO SURVEY THE STATUS AND STANDARD ANXIOLYTIC DRUGS AVAILABLE IN MARKET.3. TO STUDY THE COMMON ADR & USES OF ANXIOLYTICS.4.TO STUDY THE PHRMACOKINETICS,PHARMACODYNAMICS OF ANXIOLYTICS.5.TO EXPLAIN INVIVO & INVTRO MODELS FOR PRECLINICAL EVALUATION OF ANXIOLYTICS.6.TO ANALYZE ALL THE PARAMETERS RELATED TO ANXIOLYTICS7.SUMMERIZATION OF THE INFORMATION.

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    Sonali Diwate, RJSPM's COP, Pune.

  • CONTENTS..

    1. AIM AND OBJECTIVE2.INTRODUCTION TO ANXIETY & ANXIOLYTICS 3.STANDARD ANXIOLYTICS AVAILABLE IN MARKET4. COMMON ADR & USES OF ANXIOLYTICS5. PHARMACOKINETICS & PHARMACODYNAMICS6. PRECLINICAL SCREENING METHODS7. SUMMERY8. CONCLUSION9. BIBLIOGRAPHY

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    Sonali Diwate, RJSPM's COP, Pune.

  • INTRODUCTION TO DEPRESSIONAnxiety 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 Anxiety1. Sweating2. Shaking3. Palpitation4 .Blushing5. GI Discomfort6. Lack Of Sleep7. Lack Of Concentration8. Irritation5

    TYPES OF ANXIETY Panic Disorder-unreasonable fear spreading for 10-20minGeneralized 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.

    Sonali Diwate, RJSPM's COP, Pune.

  • HISTORY OF ANTIDEPRESSANTSThe 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 6INTRODUCTION TO ANXIOLYTICS

    BENZODIAZEPINES-ALPRAZOLAM,CHLORDIAZEPOXIDE,DIAZEPAM,LORAZEPAMAZAPIRONES-BUSPIRONE,TANDOSPIRONE,GEPIRONEBETA BLOCKER-PROPRANOLOLCARBAMATES-MEPROBAMATES

    Sonali Diwate, RJSPM's COP, Pune.

  • STANDARD DRUGS AVAILABLE IN MARKET7

    SR.NODRUGMARKETED PREPARATIONDOSE1ALPRAZOLAMXanax0.25mg2DIAZEPAMValium5mg3BUSPIRONEBuspar5mg4PROPRANOLOLDeralin2.5mg5MEPROBAMATEMiltown5mg

    Sonali Diwate, RJSPM's COP, Pune.

  • COMMON ADVERSE DRUG REACTION8

    Very common (>10% incidence) adverse effects include:

    DizzinessHeadache

    Common (1-10% incidence) adverse effects include:

    NervousnessInsomniaDisturbance in attentionUncommon (0.1-1%) adverse effects include:

    HypertensionRedness and itching of the eyesAltered tasteConjunctivitisFlatulenceAnorexiaIncreased appetiteSalivation

    Sonali Diwate, RJSPM's COP, Pune.

  • DRUG INTERACTIONS Alprazolam is primarily metabolised viaCYP3A4.CombiningCYP3A4inhibitors such ascimetidine,erythromycin,fluoxetine,fluvoxamine,itraconazole,ketoconazole, nefazodone,propoxyphene, andritonavirdelay the hepatic clearance of alprazolam, which may result in excessive accumulation of alprazolam. This may result in exacerbation of its adverse effect profile.Imipramineanddesipraminehave been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4mg/day . Combined oral contraceptive pillsreduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.Alcoholis 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 herbkavacan result in the development of a semi-comatose state.Hypericumconversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.

    Sonali Diwate, RJSPM's COP, Pune.

  • CONTRAINDICATIONS Myasthenia gravis.Severe respiratory impairment e.g sleep apnoea, COAD.Pregnancy Lactation

    Sonali Diwate, RJSPM's COP, Pune.

  • 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.

    10PHARMACOKINETICS & PHARMACODYNAMICS OF ANTIDEPRESSANTSGIVEN BY ORAL ROUTEMETABOLISM BY LIVEREXCREATION THROUGH URINE

    Sonali Diwate, RJSPM's COP, Pune.

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    Sonali Diwate, RJSPM's COP, Pune.

  • CLASSIFICATION OF SCREENING METHODS

    IN VIVO METHODS1.Foot shock induced aggression2.Isolation induced aggression3.Maternal induced aggression4.Light & Dark model5.Open field test6.Elevated plus maze model7.Anticipatory anxiety in mice8.Marble burying behavior model9.Staircase test10.Marmoset test11.Cork gnawing test in ratsIN VITRO METHODS1.GABA receptor binding2.GABA receptor binding3.Benzodiazepine receptor binding4.Serotonine receptor binding [5HT1A, 5HT2A]*

  • FOOT SHOCK INDUCED AGGRESSION11PURPOSE: Induction of aggression in pair of mice by giving shock to feet of mice. Anxiolyticsreduces 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.

    Sonali Diwate, RJSPM's COP, Pune.

  • ISOLATION INDUCED AGGRESSION11PURPOSE:Keeping one of the micealone for prolonged period oftime, so that aggressiondevelops against same sexanimal. Anxiolytic agentsuppress isolation inducedaggression . EVALUATION:Record no. of attacksbefore & 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.

    Sonali Diwate, RJSPM's COP, Pune.

  • MATERNAL INDUCED AGGRESSION11PURPOSE: 1.Induction of an intruder incage of parturient female rat,induced high level aggressionagainst such intruder.2. Maternal aggression ischaracterized by high intensityattacks on head or neck ofintruder. Anxiolytics reducesthe aggression. EVALUATION:Record fighting behavior before & after treatment.

    Procedure:1.One male intruder is placed in females 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.

    Sonali Diwate, RJSPM's COP, Pune.

  • IN VITRO METHODGABAA RECEPTOR BINDINGTISSUE 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

    16PRINCIPLE :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.THEN THE REACTIVITY IS MEASURED USING LIQUID SCINTILLATION METHOD 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.

    Sonali Diwate, RJSPM's COP, Pune.

  • 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

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