PHARM - Anxiolytics

Question 1

discuss the role of the amygdala in anxiety

Answer 1

• thalamus → input to BLA (basolateral amygdala complex)
• BLA → CeA (central nucleus), also in the amygdala. input is either
  
  • excitatory, via direct projectections
  • inhibitory, via GABAnergic interneurons onto a2 - containing GABA_A receptors
• CeA → BNST (brainstem + hypothalamus)
• BNST → anxiety

Question 2

which two amygdala nuclei are involved in anxiety?

Answer 2

• basolateral amygdala complex (BLA)
• central nucleus (CeA)

Question 3

how does GABA serve as an inhibitory NT?

Answer 3

by inducing hyperpolarization of post-synaptic neurons such that any excitatory NTs from their pre-synaptic neuron cannot induce a potential high enough overcome threshold & initiate firing

Question 4

summarize the mechanism by which benzodiazepenes (BZs) serve as an anxiolytic

(i.e, BZ MOA)

Answer 4

• bind the benzodiazapene binding site of a2 - containing GABA_A receptors on the central nucleus (CeA) of the amygdala
• this increases GABAa receptor affinity for GABA
• binding of GABAa to these post-synaptic receptor i_nduces Cl- influx_
• Cl- influx hyperpolarizes the membrane
• hyperpolarization reduces any potential produced by exctitatory amino acids from the pre-synapse

Question 5

review - compare & contrast the major indications and MOAs of

• benzodiazapene - like drugs (BZLs)
• benzodiazapenes (BZs)

Answer 5

• MOAs: GABA_A receptor binding
  
  • BZL: a1 subunit - containing only (selective)
  • BZs a2 & a3 subunit - containing mostly (non-selective)
• indications:
  
  • BZL: hypnotic
  • BZs: ​anxiolytic > hyponotic, amnesia, muscle relaxing

Question 6

BZs

• includes which drugs?
• clinical uses
• MOA
• AE/CI
• drug-drug interactions

Answer 6

• drugs: -pams (diazepam, lorazepam), aprolezam, chlordiazepoxide
• clinical use: anxiety > hyponosis, muscle relaxation, AED
• MOA: enhance GABA affinity of a2 & a3 containing GABA_A receptors
• PK: metabolized by CYP-3A4
• AE:
  
  • CV / respiratory depression - usually mild
  • decreased motor skills
  • anterograde annesia
• CI: pregnancy, L & D, breast-feeding
• drug-drug interactions:
  
  • CNS depressants - inc risk of respiratory depression
  • CYP-3A4 inhibitors - inc plasma levels overall
  • flumazenil - antagonist

Question 7

BZs are what schedule drug?

Answer 7

schedule IV

Question 8

list which part of the CNS BZs interact with to

• reduce anxiety
• promote sleep (hypnosis)
• relax muscles

Answer 8

• anxiety - amygdala (limbic system)
• sleep - VLPO of hypothalamus
• muscle relaxation - supraspinal motor areas

Question 9

in what situations would a patient on BZs be at a risk for for respiratory depression?

Answer 9

• those with COPD and/or OSA
• those taking other CNS depressants

Question 10

BZs are in what pregnancy category?

what does this mean?

Answer 10

category D (warning)

are CI in pregnancy, L & D, breastfeeding

Question 11

tolerance develops to which therapeutic effects of BZs?

Answer 11

anti-convulsant

little or no tolerance to hypnotic or anxiolytic effects

Question 12

how do BZ withdrawal effects present?

Answer 12

• tachycardia
• systolic hypertension
• trembling
• GI distress
• sweating

Question 13

alprazolam what kind of drug?

Answer 13

BZ

Question 14

chlordiazepoxide - what kind of drug?

Answer 14

BZ

Question 15

diazepam - what kind of drug?

Answer 15

BZ

Question 16

lorazepam - what kind of drug?

Answer 16

BZ

Question 17

which BZs are best for treatment of generalized anxiety disorder (GAD)?

in which situations should they be used?

Answer 17

lorazepam & alprazolam

used when immediate stabiliziation is needed

Question 18

outline the treatment protocol for generalized anxiety disorder (GAD)

Answer 18

1. chronic treatment: SSRIs, SNRIs, buspirone - have delayed onset*
2. acute treatment (immediate stabilization): benzodiazapenes
   
   • alprazolam
   • lorazepam

Question 19

what processes define Phase I vs Phase II metabolism?

Answer 19

• Phase I: oxidation, reduction, hydrolysis
• Phase II: conjugation pathway

Question 20

a decrease in Phase I reactions can occur in which patient populations?

Answer 20

• those with liver disease
• geriatric patients

Question 21

categorize the BZs using the following

Answer 21

Question 22

which BZ is best for patients who are elderly and / or have impaired liver function?

why?

Answer 22

lorazepam (L for liver)

phase II metabolism only.

i.e, no Phase I metabolism, which can be impaired in both of these populations

Question 23

flumanezil

• clinical use
• MOA
• AE
• drug drug interactions

Answer 23

• clinical use: used to reverse
  
  • ​sedative affects of BZ post - anesthesia
  • BZ overdose
• MOA: is a competive antagonist of BZs
• AE: could precipitate BZ withdrawal
• drug-drug interactions: cancels BZ effects

Question 24

what are the effects of GABA in a patient taking BZs and flumazenil?

why?

Answer 24

same as the therapeutic effects of GABA alone

Question 25

how is BZ withdrawal treated?

Answer 25

1. switch to long acting BZ drug (diazepam, chlordiazepoxide) 2. then, gradually decrease the dose

Question 26

which BZ is FDA approved as a muscle relaxant? how does it work? why is this significant?

Answer 26

* diazapem * MOA: **hyperpolarization** **of the** **_pre-synaptic_ neuron in the spinal cord** → decreased release of excitatory NTs onto NNJ * different than **anxiolytic MOA**, in which post-synaptic GABAnergic tranmission in enahnced

Question 27

buspirone * clinical use * MOA * advantages

Answer 27

* clinical use: **GAD only** * MOA: partial agonist of _5-HT1A_ receptor * advantages: **less sedation (CNS depression)** * less likely to lead to _withdrawal_ sx * not C/I with other CNS depressants

Question 28

which drugs are used to treat a _fear of public performance?_

Answer 28

beta blockers 1. propanalol (non-selective) 2. metoprolol (B1 only) - if pt has COPD or asthma\*