W21 Anxiety and Anxiolytics (SM)

Question 1

What is anxiety?

Answer 1

• Anxiety is a feeling of unease, such as worry
  or fear, that can be mild or severe.
• Anxiety is a NORMAL stress/fear
  response to threatening situations - a protective function
• Becomes pathological when to non-threatening situations interpreted as threatening

Question 2

What is the limbic system comprised of?
What are the functions of these different regions of the brain?

Answer 2

• The limbic system, comprised of the hippocampus, amygdala, hypothalamus and thalamus, is mostly responsible for the emotional processing in the brain

Individuals with anxiety disorders have higher activity in the limbic system compared to normal.

• Cortex – negative cognition
• Hippocampus – memory
• Amygdala – fear perception
• Hypothalamus – stress responsiveness
• Basal ganglia/cerebellum – movement control

Question 3

What is happening in the anxious brain?
(pathways)

Answer 3

• Relative to the proximity and existence
  of the threat, the decision-making area
  in the brain triggers the response in the
  amygdala to initiate the ‘flight-fight’
  response
• Noradrenaline Pathways:
  = Alertness and attention are increased
• Serotonergic pathways:
  = Mood and well being may be depressed

Question 4

What is happening in the anxious brain & body? (physiological response)

Answer 4

• The HPA maintains stress responsiveness through release of ACTH and cortisol
• Hypothalamus responds to sensory amygdala and hippocampal inputs to adjust the balance of sympathetic/ parasympathetic output

Feel dizzy, dry mouth, pupils dilate, rush of information to the brain, temperature fluctuation, heartbeat increases, adrenaline races through the body, churning stomach, muscles feel weak/tense, inc sweating, digestive and urinary sysytem slows down, inc breathing expanding lungs,

Question 5

Pathophysiology of Anxiety

Answer 5

• Several neurotransmitters implicated
• ACh is the main neurotransmitter maintaining general arousal
• Heightened emotional arousal associated with noradrenergic and
  serotonergic activity
• GABA inhibits other neurotransmitter pathways
• increased GABA activity may have a protective effect against excessive stress
  reactions (potential target for pharmacological interventions)

Possible reduction in level of GABA inhibition
-reduced expression of GABAA-receptors
-reduced function/regulation of GABAA receptors by benzodiazepines
-reduced function/regulation of GABAA-receptors by neurosteroids

Question 6

Pathological Anxiety:
What are the different anxiety disorders?

Answer 6

• Generalised anxiety disorder (GAD):
  Motor tension, autonomic hyperactivity
• Phobic anxiety:
  -Simple phobias. (Agoraphobia, fear of animals and other social phobias).
• Panic disorders are characterised by acute attacks of fear.
• Obsessive-compulsive behaviours: repetitive ideas (obsessions) and behaviours (compulsions).

Question 7

What are the manifestations of anxiety?

Answer 7

1. Verbal complaints
   * anxious, nervous, edgy
2. Somatic and autonomic effects
   * restless and agitated, have tachycardia
   * increased sweating, weeping and often gastrointestinal disorders.
3. Social effects
   * interference with normal productive activities

Question 8

Causes of Anxiety?

Answer 8

1) Medical (Chronic metabolic and neurologic health, even general health
concerns)
2) Drug-Induced:
– CNS Stimulants
* Amphetamines, cocaine, TCAs, caffeine.
– Sympathomimetics
* Adrenaline/nor-adrenaline.
– Anticholinergics\Antihistaminergics
* Trihexyphenidyl, pethidine, diphenhydramine, oxybutynin.
– Dopaminergics
* Amantadine, bromocriptine, L-Dopa, carbi/levodopa.
3) Drug Withdrawal:
* Benzodiazepines, narcotics, barbiturates, opiates, alcohol and other addictive
drugs

Question 9

Pharmacotherapy: Anxiolytics
-adrenergic β-receptor blockers (manage sympathetic activity)

Answer 9

• Treat the symptoms of anxiety
• Reduce the sympathetic manifestations of stress/fear response
• No effect on affective components
• Useful in treating phobias
• Effects on memory consolidation – evidence for use in eliminating PTSD
  E.g. metoprolol, atenolol, bisoprolol

Question 10

Pharmacotherapy: Anxiolytics
Serotonergic pathways (to stabilize the mood and emotions)

Answer 10

• Buspirone
  -Partial agonist at 5-HT1A receptors
• Antidepressants
  -SSRIs - selective serotonin reuptake inhibitors (fluoxetine, citalopram)
  -Combined noradrenaline and 5HT uptake blockers (venlafaxine, duloxetine)
• Mood elevators
• Preferred choice for GAD and panic disorders
• Delayed clinical response (3-4 weeks)

Question 11

Pharmacotherapy: Anxiolytics
3. GABAergic pathways (to enable CNS depression)

Answer 11

• Glutamate (excitatory) is converted into GABA (inhibitory) by Glutamate decarboxylase (GAD)

Major inhibitory neurotransmitter in the brain
* Principally 2 GABA receptor subtypes
- GABAA (LGIC) & GABAB (GPCR)

- GABA-binding site &
affinities for allosteric
ligands
 - functional expression
 - BDZ binding/ efficacy

Question 12

Adverse (overdose) effects of benzodiazepines?

Answer 12

– significant respiratory depression and cardiovascular depression (cautioned in patients with pulmonary and cardiovascular disease)

Question 13

Antidote for BENZODIAZEPINE Overdose
BDZ ANTAGONIST: FLUMAZENIL

Answer 13

• Competitive antagonist
• Blocks many of the actions of
  – Benzodiazepines
  – Zolpidem
  – Zaleplon
  – eszopiclone
• Reversing the CNS depressant effects
• Hasten recovery
• Flumazenil acts rapidly but has a short half-life
• May cause a severe precipitated abstinence syndrome

Question 14

Benzodiazepines have varying half-life durations:
Which is preferred?

Answer 14

Longer half-life as the ones with a shorter half-life are more prone to addiction.