What are the parts of the brain and their respective symptoms that are activated from the Amygdala in response to fear?
1) Anterior Cingulate Cortex and Orbitofrontal Cortex = Fear affect and thoughts of fear
2) PAG = avoidance and motor responses - flight or flight or freeze
3) Hypothalamus = increased Cortisol, increased CAD, T2DM, Stroke
4) Respiratory Parabrachial Nucleus = increased RR, Dyspnesa, Asthma
5) Locus Coerulus and Cardiovascular = increased atherosclerosis, ischemia, BP, HR variability with chronic activation
6) Hippocampus -- remembering fear
What is Worry? What neironal circuits are involved with worry?
Worry = anxious misery, apprehensive expectation, obsessions
Cortico-Striato-Thalamo-Cortical Circuit that starts in Prefrontal Cortex
What are the classifications of Drugs used for Anxiety?
Antidepressants - SSRI/SNRI/Tricyclics/ Atypicals
Non-Benzodiazepine - Buspirone
What is firstline treatment for GAD?
Cognitive Therapy and then Antidepressants like SSRI/SNRI bc less side effects and administer 1x/day
What are some problems/side effects with SSRI?
Sexyal Dysfunction, Fatigue, Drowsiness
Slow Onset 2-6 weeks
What is Buspirone? How does it work? When is it used?
Buspirone - 5HT1A PArtial Agonist
good for use when SSRI not tolerated and good for anxiety with very little side effects
2Nd Choice for Tx for GAD behind SSRI
May be more effective on cognitive aspects of anxiety vs somatic (which BZD are better for)
What are the Pros and Cons of Busprione?
Pros - NO SYMPTOMS OF: Ataxia, confusion, memory problems, no abuse potential, no dependence, and not interactions w EtOH
Cons - Side effects: dizziness, HA, Nausea, Drowsiness
How do neurosteroids work? What are they?
Metabolites of Progesterone / Pregnenolone that form in glial cells in the brain and are released with stress and SSRIS
Positive Modulation of GABA-A receptors giving tonic inhibition in post-syn neuron
What is the GABA receptor's structure? What does it do?
GABA-gated Chloride Channel with 5 subunits that are 4 TMD each
Binding of GABA open channel and increase Chloride
What are the purposes/binding/effects of the different subunits of the GABA channel?
Alpha 1 subunit associated with sedation and binding of Ehtanol and volatile anasthetics
Alpha 2 subunit associated with anxiety and where Benzodiazepines bind
All these things bind to increase channel opening probabiliy
What can you give in the event of a BZD Overdose? How does it work?
Antagonists effects of Agonists but by itself does not affect the receptor
...Inverse Agonist reduce GABA stimulated Cl Flux
What are the BZD used for anxiety?
What are the BZD used for sedation/hypnosis?
Anxiety - Diazepam (long acting metabolites so dont have to taper), Oxazepam (elderly, conjugation only)
Sedation - Temazepam, Triazolam, Midazolam
How are BZD taken care of in the liver? Whichones have special reactions?
Most are oxidized in the liver and their products are still active (Nordiazepam) and then have Phase 2 Glucuronide conjugation reaction to Oxazepam leading to elimination
Oxazepam, Temazepam, and Lorazepam can be directly conjugated and eliminated
What are withdrawal symptoms of BZD?
Anxiety (vs reemergence)
essentially, accentuated symptoms from original anxious bout
What does Orexin/Hypocretin do?
Loss of Orexin B signaling leads to narcolepsy
What is narcolepsy? How do you treat it?
Sudden, irregular and uncontrollable tendency to fall asleep
can be accompanied by cataplexy
from loss of lateral hypothalamic neurons that produce Hypocretin
Treatment - Stimulants, Antidepressants, Modafinil
How are BZD used for sleep? What are some effects?
Used and are effective and safe but can get tolerance and some dependence
Side Effects: Ataxia, confusion, memory disturbances
*Hip fractures in elderly!
*Additive to other CNS depressants like EtOH which can be fatal
Generally do NOT depress HR and Respiration
What are the other drugs used for sleep that are the best? What do they do? Why are they so great?
PAMs = Positive Allosteric Modulators - Alpha 1 Subunit
Positive Allosteric Modulators for GABA channel at the Alpha 1 subunit!!!!!
NO REBOUND!!!!!!!!! Good for long term use
What does Melatonin do?
Good for resetting natural clock by acting on Suprachiasmatic nucleus
used for sleep induction or jetlag to reset clock
Again, what are the Z drugs? How do the work? What's up w/half-lives?
Eszopiclone, Zolpidem, Zaleplon
bind at GABA rec A1 site and are positive allosteric modulators
Half-life approximates duration of sleep
What are the benzos used for sleep?
Temazepam, Estazolam, Triazolam
How is Trazadone used for sleep and what does it do?
SEdating atypical antidepressant that's given for sleep in MUCH lower doses than depression
Depression dosin is 150-600 mg and Hypnotic dosing is 25-150 mg
Acts at H1, Alpha1 and 5HT2A
Little action at Serotonin transporters at the lower doses
Summary for Anxiolytic drugs: First and Second line usage? After that it's BZD and what are effects of BZD?
Other drugs you could use?
SSRI first line bc few Side effects and Buspirone second choice but both are slow
Then BZD act fast but large abuse potential, withdrawal symptoms, ETOH interactions, Ataxia, memory disturbances - ACT AT GABA ALPHA2
Gabapentin and Tiagibine alternatives