Anxyolytics/Sleeping Drugs

Question 1

What are the parts of the brain and their respective symptoms that are activated from the Amygdala in response to fear?

Answer 1

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

Question 2

What is Worry? What neironal circuits are involved with worry?

Answer 2

Worry = anxious misery, apprehensive expectation, obsessions

Cortico-Striato-Thalamo-Cortical Circuit that starts in Prefrontal Cortex

Question 3

What are the classifications of Drugs used for Anxiety?

Answer 3

Antidepressants - SSRI/SNRI/Tricyclics/ Atypicals

Benzodiazepines

Non-Benzodiazepine - Buspirone

Anticonvulsants

Question 4

What is firstline treatment for GAD?

Answer 4

Cognitive Therapy and then Antidepressants like SSRI/SNRI bc less side effects and administer 1x/day

Question 5

What are some problems/side effects with SSRI?

Answer 5

Sexyal Dysfunction, Fatigue, Drowsiness

Slow Onset 2-6 weeks

Question 6

What is Buspirone? How does it work? When is it used?

Answer 6

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)

Question 7

What are the Pros and Cons of Busprione?

Answer 7

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

Question 8

How do neurosteroids work? What are they?

Answer 8

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

Question 9

What is the GABA receptor’s structure? What does it do?

Answer 9

GABA-gated Chloride Channel with 5 subunits that are 4 TMD each

Binding of GABA open channel and increase Chloride

Question 10

What are the purposes/binding/effects of the different subunits of the GABA channel?

Answer 10

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

Question 11

What can you give in the event of a BZD Overdose? How does it work?

Answer 11

Flumenazil!!!

Antagonists effects of Agonists but by itself does not affect the receptor

…Inverse Agonist reduce GABA stimulated Cl Flux

Question 12

What are the BZD used for anxiety?

What are the BZD used for sedation/hypnosis?

Answer 12

Anxiety - Diazepam (long acting metabolites so dont have to taper), Oxazepam (elderly, conjugation only)

Sedation - Temazepam, Triazolam, Midazolam

Question 13

How are BZD taken care of in the liver? Whichones have special reactions?

Answer 13

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

Question 14

What are withdrawal symptoms of BZD?

Answer 14

Tachycardia

STartle Response

GI discomfort

Rebound insomnia

Anxiety (vs reemergence)

seizures

essentially, accentuated symptoms from original anxious bout

Question 15

What does Orexin/Hypocretin do?

Answer 15

Loss of Orexin B signaling leads to narcolepsy

Question 16

What is narcolepsy? How do you treat it?

Answer 16

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

Question 17

How are BZD used for sleep? What are some effects?

Answer 17

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

Question 18

What are the other drugs used for sleep that are the best? What do they do? Why are they so great?

Answer 18

PAMs = Positive Allosteric Modulators - Alpha 1 Subunit

Positive Allosteric Modulators for GABA channel at the Alpha 1 subunit!!!!!

Zolpidem

Zaleplin

exZoplicone

NO REBOUND!!!!!!!!! Good for long term use

Question 19

What does Melatonin do?

Answer 19

Good for resetting natural clock by acting on Suprachiasmatic nucleus

used for sleep induction or jetlag to reset clock

Question 20

Again, what are the Z drugs? How do the work? What’s up w/half-lives?

Answer 20

Eszopiclone, Zolpidem, Zaleplon

bind at GABA rec A1 site and are positive allosteric modulators

Half-life approximates duration of sleep

Question 21

What are the benzos used for sleep?

Answer 21

Temazepam, Estazolam, Triazolam

Question 22

How is Trazadone used for sleep and what does it do?

Answer 22

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

Question 23

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?

Answer 23

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