Anxiolytic Drugs and Hypnotics

Question 1

What is the stress response regulated by?

How do CRH levels affect the stress response?

What stimulates the HPA Axis? How is it linked with anxiety disorders?

What suppresses the HPA Axis? How is it linked with anxiety disorders?

How is Glutamate linked with Neuronal loss?

Answer 1

• Stress response regulated by HPA Axis; Cortisol released
• • Overexpressing CRH = ↑Anxiety-like behaviours
  • Underexpressing CRH = ↓Anxiety-like behaviours
• Amygdala; ↑Cortisol release
  o Amygdala Hyperactivity linked to Anxiety disorders
• Hippocampus; ↓ Cortisol release
  o Hippocampus Underactivity linked to Anxiety disorders
• Hyperactivity of Glutamate on NMDA receptors leads to Excitotoxicity = Neuronal loss

Question 2

What are Anxiolytics?

What are Hypnotics?

What triggers insomnia?

What are the 3 types of insomnia? What causes them?

Describe the therapeutic window of both these drugs?

Answer 2

• Drugs used to treat Anxiety Disorders
• Drugs used to treat Insomnia
• Anxiety
• Transient (Jet lag), Short-term (Illness, Stress), Chronic (Drug, Alcohol abuse)
• • Low dose; Anxiolytic effects
  • High dose; Sedation, Sleep
  • Toxic dose; Coma, Respiratory depression

Question 3

GABA:
What is it?

What are the 2 types of GABA receptors? What do they cause?

What is the common configuration of GABAa receptors? (LOOK AT PIC)

Where do agonists/antagonists (GABA) bind within the GABAa receptor?

Where do Benzodiazepines bind within the GABAa receptor?

Where do channel blockers and modulators (Picrotoxin, GA) bind within the GABAa receptor?

Where do allosteric modulators (Barbituates) bind within the GABAa receptor?

Answer 3

• Main inhibitory neurotransmitter in CNS
• • GABAa; Ligand-gated ion channels
  o Allows Cl- ions Influx = Hyperpolarisation, Inhibition of AP firing
  • GABAb; G-protein coupled receptors
• 2α, 2β, 1γ (α, β, α, γ, β)
• Between the α and β subunits
• Between the α and γ subunits
• Block the ion pore
• Bind to β subunits

Question 4

Serotonin (5-HT):
What is it? What’s it for?

What are the 2 types of 5-HT receptors?

What are these receptors a key drug target for?

Noradrenaline:
What is it? What’s it for?

What are the 2 types of NA receptors?

What are the receptors a key drug target for?

Answer 4

• Neurotransmitter in CNS and PNS; For Sleep, Wakefulness, Mood, Emotions
• • 5-HT3; Ligand-gated ion channel
  • 5-HT1 to 5-HT7; G-protein coupled receptors
• Depression and Anxiety Disorders
• Neurotransmitter in CNS and PNS; For Sympathetics, Attention, Sleep, Wakefulness
• α and β-noradrenergic receptors; G-protein coupled receptors
• Peripheral symptoms of Anxiety

Question 5

Benzodiazepines:
What are they? What are they used as?

How do they act?

How do they affect GABA affinity at its receptor?

Why are they preferred to Barbituates?

What is given to prevent Benzodiazepine overdose? Give an example

What are their different durations of action and the effects each has?

What are the side-effects?

How can they cause tolerance?

Answer 5

• GABAa receptor positive allosteric modulators; used as ANXIOLYTICS and HYPNOTICS
• Bind and stabilise GABAa binding site in the OPEN configuration (between α and γ subunits)
• ↑GABA Affinity at binding site = ↑Neuroinhibition
• They don’t activate any other receptors
• Competitive Antagonists; e.g. Flumazenil
• • Ultrashort acting; anaesthetic
  • Short-acting; hypnotic, anxiolytic, anti-convulsant
  • Medium acting; anxiolytic
  • Long-acting; anxiolytic, anti-convulsant, Treatment for Alcohol withdrawal
• Tolerance, Withdrawal symptoms, Amnesia
• With Anxiety, there’s an imbalance between Glutamate (Excitatory) and GABA (Inhibitory), so Benzodiazepines are given to increase GABA affinity; Over time, patient may develop Tolerance, where more of the drug is needed to produce the same effects

Question 6

Z-drugs:
Examples?

How do they act?

What is their duration of action? What does this make them suitable as?

Answer 6

• Zolpidem, Zopiclone
• Have a different structure to benzodiazepines, but still binds to the same site on GABAa receptors (between α and γ subunits)
• Ultrashort/Short-acting; Suitable as HYPNOTICS ONLY

Question 7

5-HT1A Receptor Agonists:
Example?

What is it used to treat?

How do they act? When are the effects seen?

What is the effect is taken long-term?

What are the side-effects?

Answer 7

• Buspirone
• GAD (Generalised Anxiety Disorder)
• Partial agonist of 5-HT1A auto-receptors = Inhibit Serotonin release; ANXIOLYTICS effects seen weeks later
• Induces Desensitisation of auto-inhibitory 5-HT1A receptors; leads to Downregulation of 5-HT1A receptors = Enhanced 5-HT release
• Dizziness, Nausea, Headache

Question 8

β-Noradrenergic Receptor Antagonists:
Example?

What are they?

What is their use?

Answer 8

• Propranolol
• Non-selective antagonist of β1 and β2 receptors; ANXIOLYTICS
• Reduces the peripheral anxiety symptoms of tachycardia, sweating, GI problems, tremor