Anxiety

Anxiety

A normal & essential human response to impending or percieved danger. Response includes activation of the autonomic system (fight or flight). In contrast to fear which is a response to a known threat. It becomes a clinical issue when the anxiety has no reasonable cause & interferes with normal functioning
1. Serotonin
  1. ligands acting as antagonists at other 5-HT receptors (not 1A) eg ondansetron also have anxiolytic properties
  2. Activation of postmen serotonin receptors (5-HT2A, 2C, 3) increases anxiety. Activation of presyn serotonin receptors (5-HT 1A) reduces 5-HT release & therefore reduces anxiety
GAD- muscle tension, restlessness, autonomic effects: sweating, frequent urination, dizziness, difficulty in concentrating, insomnia, irritability
Post traumatic disorder-past events stop you from living your life
Panic disorder with or without agoraphobia-palpitations, nausea, fear of dying with no apparent cause
Sedatives- reduce alertness-can relieve anxiety & in higher doses, producing sleep
1. Hypnotics- induce sleep-triggers sleep response
  1. Anxiolytics- relieve anxiety & stress. Ideal anxiolytics have no sedative effect-sometimes referred to as 'minor tranquillisers'
    1. Treatment for anxiety includes not only anxiolytics but also psychological approaches & use of antidepressants
    2. Historical- Belladonna alkaloids-atropine, scopolamine & opiates- opium, morphine, diamorphine. Both still used as element of general anaesthesia and in eye drops
      1. Historical- early 20th century ones included bromide, chloral hydrate, urethane (still used for animal anaesthesia) & thalidomide (treats morning sickness during pregnancy) & barbiturates-seatives/hypnotics- eg amobarbital, phenobarbital-no longer used as sedatives because of harmful side effects (Phenobarbital is used as anti-convulsant & thiopental as iv anaesthetic)
    3. Current
      1. Benzodiazepines- anxiolytics, sedatives, hypnotics, anticonvulsants eg. diazepam, nitrazepam, flurazepam - now used as anxiolytics in acute cases only. Some compounds therapeutically selective-action at diff GABA A receptor subtypes may underlie this eg Zolpidem is a hypnotic, clonazepam is an anticonvulsant. Act at benzodiazepine (BDZ) site of GABA A receptors to increase the receptors affinity for GABA-
      2. Azapirones (anxiolytics)-none of the other side effects e.g..buspirone, ipsapirone-effectiveness develops over 1-3 weeks. Agonists/partial agonists at 5-HT1A receptors (which are presynaptic & thir activation by azapirones inhibits serotonin release via inhibition of adenylate cyclase)-their therapeutic effects are delayed (suggests complex mech of action). Buspirone also binds to DA receptors but anxiolytic effect due to action @ 5HT1A
      3. Barbiturates- their sedative & anxiolytic actions are thought to arise from their binding to GABA A receptors where they potentiate GABAergic signalling- dont bind where GABA binds, bind else where and increase GABA signalling
      4. Other anxiolytics
        The calcium channel blocker pregabalin has been recently approved to treat GAD (also an anticonvulsant & pain killer). Anti-depressants & anti-psychotics are also used to treat panic disorder. beta adrenoceptor antagonists eg propanolol are used in some cases to treat the symptoms of anxiety
      5. Other receptor systems
        In addition to GABA & 5-HT others are thought to be involved= NA & neuropeptides (CCK & substance P). There are currently no anxiolytic drugs acting at neuropeptide receptors
GABA A receptor
1. Ionotropic receptor permeable to chloride ions=hyperpolarises, action therefore inhibitory. Endogenous agonist is GABA. 5 subuunits
Side effects
1. Benzodiazepines & barbiturates- sedation, resp depression (particularly with alcohol)-can be treated with an antagonist eg flumazenil), tolerane & dependence (not addiction), increased anxiety, dizziness & nausea on cessation of treatment, paradoxical effects of benzodiazepines eg aggression, depression, confusion.
2. Azapirones- much less side effects- relatively minor: principally nausea, dizziness, headaches

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