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5 principal categories of anxiety disorders
- Generalized anxiety disorder
- Panic disorder
What is acute anxiety?
Brief episodes of anxiety, in response to real-life stressors, symptoms occur only in response to these events
Generalized anxiety disorder (GAD)
Symptoms of anxiety have no real focus, are present for much of the day, and presist for months or years
Panic attacks and panic disorder
- Panic attack: sudden onset of intense fear without a threatening stimulus
- Panic disorder: chronic panic attacks
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...
Following a major stressor, mixed symptoms of anxiety and depression
- 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)
Key brain structure related to anxiety disorders
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
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
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
Chronic treatment vs. Acute treatment of anxiety
- Chronic treatment: BDZs or SSRIs
- Acute treatment: BDZs
What is used for acute treatment of anxiety?
GABA-A receptor is (ionotropic/metabotropic); GABA-B receptor is (ionotropic/metabotropic). Which do we focus more on in class?
Ionotropic; metabotropic; GABA-A
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
GABA-A receptors allow the flow of _______ ions
GABA-A receptor has ______ subunits. Name them.
- 5 subunits
- 2 alpha, 2 beta, 1 gamma or delta
BDZ binding site on GABA-A receptor when.....
Alpha subunit next to a gamma subunit
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)
Major actions of benzodiazepines
- Sleep (soporific effect)
- Muscle relaxant
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)
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
Inverse agonists of BDZs ________ the flow of chloride in the GABA receptor channel and lead to _________ anxiety.
Diazepam undergoes (phase I/phase II/both) reactions; oxazepam undergoes (phase I/phase II/both) reaction
Both; phase II
In older patients, which is better: diazepam or oxazepam? Why?
- 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
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
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
Advantages and disadvantages of BDZs with short half-life
- Advantages: no accumulation, less daytime drowsiness
- Disadvantages: more frequent dosing, rebound insomnia, rebound anxiety
Pharmacokinetics of BDZs: Absorption (acute vs. chronic use)
- Acute: faster absorption is important
- Chronic: doesn't matter
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)
Half-life of diazepam
30-60 hours (long)
Absorption of diazepam (rapid, intermediate, or slow?)
Chlordiazepoxide: half-life and absorption?
- Half-life: 15-20 hours
- Absorption: intermediate
Lorazepam: half-life and absorption?
- Half-life: 10-24 hours
- Absorption: intermediate
Long-acting BDZs and Short-acting BDZs: examples
- Long-acting: Chlordiazepoxide, flurazepam, diazepam, chlorazepate
- Short-acting: Lorazepam, temazepam
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
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
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
Age: Diazepam vs. Lorazepam
- Lorazepam: higher VOD, increased half-life, no change in clearance
- Diazepam: marked decrease in clearance, thus higher half-life
Buspirone: how does it work?
Agonist of the serotonin 1a receptor
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)