Pharmacology of anxiety + sleep disorders

Question 1

what are the clinical uses of hypnotics and anxiolytics?

Answer 1

induction of sleep
relief of anxiety
sedation + amnesia (before medical procedure)
control of withdrawal states in addiction (e.g. delirium tremens)
muscle relaxation
severe behavioural disturbance

Question 2

describe the 2 process model of the sleep-wake cycle.

Answer 2

1. Circadian alerting signal - changes in hormones (cortisol + melatonin) either increase or decrease alertness
2. homeostatic sleep drive - increases throughout the day and reduces at night

Question 3

What is the role of the suprachiasmatic nucleus (SCN) in terms of the sleep-wake cycle?

Answer 3

This is found in the hypothalamus
It controls the 24-hour circadian rhythm
Neurones in the SCN increase activity in the light phase and reduce activity in the dark phase
*there is an increase in melatonin in the dark/sleep phase

Question 4

What neurotransmitter/chemical systems and which brain structures are involved in wakefulness?

Answer 4

Cholinergic system:
- pedunculo pontine + lateral dorsal tegmental nuclei

Monoaminergic projections:

• locus coeruleus
• raphe nuclei
• tuberomamillary nucleus

Question 5

What neurotransmitter/chemical systems and which brain structures are involved in sleep?

Answer 5

GABA + galanin neurones:

- ventrolateral preoptic nucleus

Question 6

Which neurotransmitters maintain wakefulness?

Answer 6

noradrenaline 
dopamine 
serotonin
histamine 
acetylcholine 
orexin

Question 7

Which neurotransmitters promote sleep?

Answer 7

GABA
melatonin
adenosine

Question 8

What do REM, NREM, and SWS stand for?

Answer 8

REM = rapid eye movement
NREM = non-rapid eye movement
SWS = slow wave sleep (NREM 3+4)

Question 9

How long does a sleep cycle last?

Answer 9

90 minutes

Question 10

What waves are associated with:

• Awake
• Stage 1 (awake + relaxed)
• Stage 2 (Stage 1 NREM)
• Stage 3 (Stage 2 NREM)
• Stage 4 (SWS)
• REM

And what are the frequencies of each wave?

Answer 10

• Awake:
  beta waves
  13-30 Hz
• Stage 1 (awake + relaxed)
  alpha waves
  8-12 Hz
• Stage 2 (Stage 1 NREM)
  theta waves
  3.5 - 7.5 Hz
• Stage 3 (Stage 2 NREM)
  theta waves with sleep spindles + k complexes
  12 - 14 Hz
• Stage 4 (SWS)
  delta waves
  <3.5 Hz
• REM
  random, fast with sawtooth waves
  low voltage

Question 11

Name the different types of insomnia.

Answer 11

transient (e.g. jet lag)
short-term ( associated with illness, bereavement and stress)
chronic - lasts >3 weeks

Question 12

What types of drugs are used to treat insomnia? Give examples of short-term and long-term use drugs?

Answer 12

benzodiazepines + Z-drugs
Short-term use: lorazepam + tenazepam
Long-term use: eszopiclone
+ extended release = zolpidem (for chronic insomnia)

Question 13

What are some of the unwanted effects of benzodiazepines?

Answer 13

• changes in sleep patterns (suppress deep sleep + REM sleep)
• daytime sedation
• rebound insomnia
• tolerance
• dependence

Question 14

What is the benefit of using pregabalin to treat insomnia?

Answer 14

No disruption of sleep patterns

No tolerance

Question 15

Where is orexin produced? What forms does it come in? What is its function?

Answer 15

Produced in the hypothalamus
Comes in two forms: orexin A + B
effects are mediated by OX1 and OX2 receptors –> allows regulation of arousal, appetite and wakefulness

Question 16

What is narcolepsy? What is it the result of?

Answer 16

Condition when a person falls asleep when in relaxing surroundings
Caused by a deficiency in orexin

Question 17

What is Suvorexant? What condition is it used in? What are the advantages of using this drug?

Answer 17

Dual orexin receptor (1+2) receptor antagonist
Used for insomnia
No amnesia, no dependence + abuse, no rebound insomnia, no resp, depression, no orthostasis or anticholinergic effects

Question 18

What brain structures and neurotransmitters are involved in anxiety?

Answer 18

Amygdala, insula, ACC, thalamus
Abnormalities in HPA axis
Monoaminergic systems
GABAergic systems

Question 19

what functional difference is commonly seen in people with anxiety?

Answer 19

hyperactivity of the limbic structures (i.e. amygdala) and the inability of higher cortical structures to control this

Question 20

Which genes have been associated with panic disorder?

Answer 20

COMT
CCK
CCKb receptor
Adenosine A2 receptor 
Monoamine oxidase A
5-HT2 receptor

Question 21

What gene is thought to be an anxiety suppressor?

Answer 21

KF-1 ubiquitin ligase

Question 22

Name the different classes of anxiolytics and give examples for each one.

Answer 22

Benzodiazepines:

• lorazepam
• alprazolam
• clonazepam
• diazepam

5-HT1a agonist/partial agonist:

• buspirone
• ipsapirone

SSRIs:

• fluoxetine
• escitalopram
• paroxetine

SNRIs:

• venlafaxine
• duloxetine

Beta-adrenoreceptor antagonist:
- propanolol

Question 23

What drug can be used on benzodiazepine overdose? What is the MOA of this drug?

Answer 23

Flumazenil

It competitively inhibits bezodiazepines/ acts as an antagonist at the benzodiazepine binding site

Question 24

What are the cellular targets for z-drugs?

Answer 24

alpha subunits of the GABAa receptors
alpha 1 subunit = hypnotic effect
alpha 3 subunit = anxiolytic effect