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5 principal categories of anxiety disorders
- Generalized anxiety disorder
- Panic disorder
- Phobias
- PTSD
- OCD
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What is acute anxiety?
Brief episodes of anxiety, in response to real-life stressors, symptoms occur only in response to these events
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Generalized anxiety disorder (GAD)
Symptoms of anxiety have no real focus, are present for much of the day, and presist for months or years
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Panic attacks and panic disorder
- Panic attack: sudden onset of intense fear without a threatening stimulus
- Panic disorder: chronic panic attacks
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Three-component model of anxiety
- Stressors are perceived as threats, which initiates three components of anxiety
- Bodily effects: e.g. heart pounding, shallow breathing, etc...
- Upsetting thoughts: Anger, fear, doubt, etc...
- Ineffective behavior: escape, avoidance, indecision, etc...
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PTSD
Following a major stressor, mixed symptoms of anxiety and depression
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OCD
- Obsessive thoughts, compulsive behaviors
- Egodystonic: thoughts/behaviors in conflict with the ego (people with OCD know obsessions/compulsions are irrational but they do it anyway)
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Key brain structure related to anxiety disorders
Amygdala
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Amygdala and the HPA axis
- Amygdala activates the hypothalamus, releases CRF to initiate HPA stress response (stimulates pituitary, releases ACTH, stimulates adrenal gland to release cortisol), increasing plasma cortisol
- Cortisol stimulates hippocampus, which has inhibitory effect on HPA axis to prevent excessive cortisol release
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Dual role of CRF
- CRF released by hypothalamus to act on pituitary gland to control release of glucocorticoids from adrenal cortex in response to stress (HPA axis)
- CRF also acts as a neurotransmitter in brain areas associated with anxiety and is released following threatening stimuli, causing behavioral signs of anxiety and altered autonomic nervous system function
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Drug effects on locus coeruleus cell firing (BDZs, SSRIs, TCAs, MAO-Is)
- CRF increases anxiety and has an excitatory effect on LC neurons
- BDZs: enhance inhibitory function of GABA on LC neurons
- SSRIs: reuptake blockate of 5-HT enhances 5-HT inhibition of LC neurons
- TCAs and MAO-Is: enhance NE action at inhibitory autoreceptors to reduce LC firing
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Chronic treatment vs. Acute treatment of anxiety
- Chronic treatment: BDZs or SSRIs
- Acute treatment: BDZs
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What is used for acute treatment of anxiety?
BDZs
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GABA-A receptor is (ionotropic/metabotropic); GABA-B receptor is (ionotropic/metabotropic). Which do we focus more on in class?
Ionotropic; metabotropic; GABA-A
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Cycling of GABA between glutamatergic neurons and astrocytes
- After release of GABA, transport into astrocytes
- GABA --> glutamate --> glutamine (metabolized by GABA-T)
- Glutamine transported to neuron
- Glutamine --> glutamate --> GABA
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GABA-A receptors allow the flow of _______ ions
Chloride
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GABA-A receptor has ______ subunits. Name them.
- 5 subunits
- 2 alpha, 2 beta, 1 gamma or delta
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BDZ binding site on GABA-A receptor when.....
Alpha subunit next to a gamma subunit
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BDZ binding on GABA-A receptors: What's going on?
- Nothing happens in absence of GABA
- When BDZ is bound, GABA becomes more potent (more chloride allowed in)
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Major actions of benzodiazepines
- Sleep (soporific effect)
- Antianxiety
- Anticonvulsant
- Muscle relaxant
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Seizure treatment with valium
Treat seizure with valium to break the seizure, then a longer-lasting anticonvulsant to keep the patient seizure-free (this is because valium will get to work quickly)
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Subtypes of the alpha subunits on the GABA-A receptor and what they're associated with
- Alpha-1: Sedation
- Alpha-2: Anxiolytic and muscle-relaxant
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Inverse agonists of BDZs ________ the flow of chloride in the GABA receptor channel and lead to _________ anxiety.
Decrease; increased
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Diazepam undergoes (phase I/phase II/both) reactions; oxazepam undergoes (phase I/phase II/both) reaction
Both; phase II
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In older patients, which is better: diazepam or oxazepam? Why?
- Oxazepam
- P450 activity lower in older people, so phase I reactions are less effective; oxazepam can get cleared more efficiently since it only undergoes phase II reactions
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Importance of absorption and half-life in BDZs for soporific effect
- Faster absorption = faster initiation of sleep
- Longer half-life = helps you stay asleep longer
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Advantages and disadvantages of BDZs with long half-life
- Advantages: less frequent dosing, lack of rebound anxiety/insomnia, withdrawal effects less severe
- Disadvantages: accumulation, greater risk of next-day sedation when used for insomnia treatment
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Advantages and disadvantages of BDZs with short half-life
- Advantages: no accumulation, less daytime drowsiness
- Disadvantages: more frequent dosing, rebound insomnia, rebound anxiety
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Pharmacokinetics of BDZs: Absorption (acute vs. chronic use)
- Acute: faster absorption is important
- Chronic: doesn't matter
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Pharmacokinetics of BDZs: Half-life (acute vs. chronic)
- Acute: short half-life (don't want accumulation)
- Chronic: long half-life (want it to last longer)
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Half-life of diazepam
30-60 hours (long)
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Absorption of diazepam (rapid, intermediate, or slow?)
Rapid
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Chlordiazepoxide: half-life and absorption?
- Half-life: 15-20 hours
- Absorption: intermediate
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Lorazepam: half-life and absorption?
- Half-life: 10-24 hours
- Absorption: intermediate
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Long-acting BDZs and Short-acting BDZs: examples
- Long-acting: Chlordiazepoxide, flurazepam, diazepam, chlorazepate
- Short-acting: Lorazepam, temazepam
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Zolpidem (Ambien): How does it work? What is its half-life?
- Binds to a subset of BDZ receptors --> alpha-1 specific (thus more soporific effect)
- Half life = 2.5 hours
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Zolpidem and Zolpidem CR: concept of controlled release
- Two layers of the drug; one absorbed rapidly to quickly induce sleep, the other absorbed slowly to help stay asleep
- Advantageous due to short half-life of zolpidem
- Basically like two doses of the drug without having to wake up to take second dose
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Eszopiclone (Lunesta): How does it work, absorption rate, how is it metabolized, half-life?
- How it works: Not alpha-1 specific
- Absorption: rapid
- Metabolized: by liver
- Half-life: 6 hours
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Age: Diazepam vs. Lorazepam
- Lorazepam: higher VOD, increased half-life, no change in clearance
- Diazepam: marked decrease in clearance, thus higher half-life
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Buspirone: how does it work?
Agonist of the serotonin 1a receptor
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Concept of non-cross reactivity between buspirone/SSRIs and BDZs?
Bad to suddenly stop BDZs and start on buspirone or SSRI, because you will have withdrawal from BDZs (they don't cross react)
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