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Anxiolytics & Hypnotics (Anxiety and Stress disorders (Panic disorders…

- - - - noise related factors/ shift work patterns/ jet lag
    - - Emotional or illness related episode
    - - Psychiatric disorders: anxiety, depression, drugs, alcoho
- - - - treatment - increase inhibition
- - - - Benzodiazepines (BDZs)
        
        Positive allosteric modulators
        
        increase the inhibitory effects of GABA,
        by increasing the frequency of the Cl- channel opening
        
        cannot open the channel on their own
        
        bind to discrete binding site
        
        used clinically
        
        Negative allosteric modulators
        
        Inverse agonists
        
        used for research not for treatment
        
        close the Cl- channels, even in presence of GABA
        
        Benzodiazepine antagonist
        
        blocks the allosteric binding site of benzodiazepines, blockig the effects of both positive and negative modulators
        
        Clinical effects
        
        Sedation
        
        Hypnosis
        
        Muscle relaxation
        
        Anti-convulsion
        
        Amnesia
        
        side effects
        
        Confusion
        
        Drowsiness
        
        Forgetfulness
        
        Muscle incooridnation
        
        Day after impairment
        
        Driving, manual skill defects
        
        Toxic adverse effects
        
        prolonged sleep
        
        respiratory depression with Ethanol
        
        less dangerous than barbiturates
        
        overdose
        
        Dependence
        
        major problem in clinical use
        
        rebound anxiety
        
        tremor
        
        loss of apetite
        
        disrupted sleep
        
        lower onset, cravings and withdrawal than barbiturates
        
        Tolerance
        
        clinical uses
        
        Duration of action
        
        4h
        
        Midazolam
        
        T1/2 = ~3h
        
        active metabolite -OH
        
        uses
        
        1 more item...
        
        15h
        
        Lorazepam, Oxazepam, Temazepam
        
        uses
        
        1 more item...
        
        24h
        
        Alprazolam
        
        T1/2 = ~12h
        
        uses
        
        1 more item...
        
        active metabolite -OH
        
        Nitrazepam
        
        uses
        
        1 more item...
        
        ~48h
        
        Chlordiazepoxide (Librium)
        
        uses
        
        1 more item...
        
        Diazepam (Valium)
        
        active metabolite: Nordiazepam
        
        uses
        
        1 more item...
        
        T1/2 ~ 20h
        
        ~60h
        
        Clonazepam
        
        uses
        
        1 more item...
        
        Flurazepam
        
        active metabolite: Desmethyl
        
        uses
        
        1 more item...
        
        T1/2 ~1h
      - Non-Benzodiazepines
        
        Act at the same site as benzodiazepines,
        but are structurally different
        
        Zolpidem
        
        hypnotic
        
        Zopiclone
        
        hypnotic
        
        Zapeplone
        
        hypnotic
        
        all can be reversed by flumazenil
        
        all have short half lifes 2-7 h
      - Natural anxiolytics
        
        Neurosteroids
        
        Effects
        
        Anxiolytic
        
        sedative/hypnotic
        
        anticonvulsant
        
        motor incoordination
        
        Bind to a different allosteric site than
        Biodiazepines on GABA receptors
        
        Involved in
        
        stress responses
        
        premenstrual stress disorder
        
        sleep regulation
        
        neuronal development
        
        ethanol/drug intoxication
        
        catamenia epilepsy
        
        depression, pain
        
        naturally synthesised and released in the brain
        
        Diazepam binding inhibitor protein (DBI)
        
        binds the same binding
        site as Benzodiazepines
  - - - 5HT1AR - inhibitory autoreceptors
      - Buspirone - 5HT1AR partial agonist
        
        desensitises presynaptic 5HT1ARs
        
        very slow onset - weeks
        
        effective for generalised anxiety disorder, but not for phobias
        
        less problematic side effects than BDZs
        
        Dizziness
        
        Headache
        
        Nausea
        
        Initially, it causes more 5HT1AR activation, characterised by worsening of the symptoms. After a while, the receptors desensitise and there the anxiolytic effects are noticeable.
    - - B-adrenoceptor antagonists
        
        Propanolol
      - used for Anxiety with clear symptoms
        of peripheral autonomic effects
  - - - used for hypnotic only for elderly - no hangover effect
      - acts via GABA receptors
  - - - Act via GABAARs - differently to BDZs
      - used for
        
        Anaesthesia
        
        Sever intractable insomnia
        
        Epilepsy
      - side effects - respiratory depressionn
        
        not for elderly
        
        not for sedation
      - If GABA is present, they potentiate the GABA activity
      - If GABA is absent, they can stimulate
        Cl- channel opening on their own
    - - acts via GABAARs
      - less potent and more toxic than BDZs
  - - - sedation and Hypnosis
      - rapid tolerance
      - Diphenhydramine
      - Promethazine
    - - valerian acid
      - potentiates GABAR function
- - - - Major inhibitory NT, via GABAa and GABAb receptors
      - site of action of Barbiturates and Benzodiazepines
      - Increasing GABAergic activity reduces anxiety
      - Ubiquitous distribution throughout the brain
      - Most important drug target
      - GABA synapse pharmacology
        
        pentameric receptors
        
        GABA binding on both Alpha
        subunits needed to open the channel
        
        Benzodiazepine binding site,
        between Alpha and Gamma subunits
        
        Channels opening allows for Cl- influx
        
        Benzodiazep
    - - Major excitatory NT, via AMPAR, NMDAR and mGluRs
      - complex, both potentiation and inhibition of NMDARs confers anxiolysis
      - no approved drugs yet
  - - - Seratonergic projections from Raphe Nucleus to the forebrain
      - Increased seratonergic drive reduces anxiety
      - Large receptor family
        
        only agonists at 5HT1ARs are anxiolytic
      - Second most important drug targets
    - - noradrenergic projections from
        Locus Coeruleus (Pons) to the forebrain
      - Upregulated in anxiety - mediates physiology of anxiety
      - Antagonists of B-adrenoceptors are anxiolytic
      - Third most important drug targets