HUF 2-71 Hypnotics and anxiolytics

Question 1

Anxiety

Answer 1

• Uncertainty, apprehensiveness and unresolved fear
• Highly subjective
• Durations and extent of impact: individually different

Anxiety disorders: anxiety presented for a period of time
- Persistent, excessive and unrealistic worry about daily matters

Question 2

Drug classes for treating anxiety

Answer 2

1. Benzodiazepines
2. 5HT-1AR agonist - Buspirone
3. β blocker - Propranaol, Atenolol
   - Block effects of NA (stress hormone; fight or flight)
   - Don’t affect emotional symptoms of anxiety
4. Antidepressants (long term)
5. Antiepileptic drugs - Pregabalin
6. Atypical antipsychotic drugs (low dose for depression)

Question 3

Anxiety disorders and amygdala

Answer 3

• Amygdala, hippocampus, prefrontal cortex: pathophysiology of anxiety disorder
• Exaggerated output through amygdala
• BZD: ↑ GABA-A R
  => inhibition of amygdala

Question 4

Neural excitation / inhibition balance in brain

Answer 4

More inhibition: sleep, coma, death
- GABA-A (inhibit bran cells firing)

More stimulation: arousal, epilepsy, death
- NMDA (cause brain cells firing)

Question 5

Anxiolytic/hypnotics drugs

Answer 5

• Sedative-hypnotics e.g. Barbiturates, Benzodiazepine
• Treat anxiety, insomnia
• Low dose -> High dose:
  Anxiolysis, sedation, hypnosis, anesthesia, coma, death
• Allosteric modulators of GABA-A R

Question 6

GABA

Answer 6

• γ-aminobutyric acid
• Converted from GLU
• ↓ neuronal excitability
  ∴ inhibitory NT

GABA-A R: ligand-gated ion channel (ionotropic)

• Clockwise: α, β, α, β, γ2
• Binding site for BZD: between α and γ
• Biding site for GABA: between α and β

GABA-B R: GPCR (metabotropic)

Question 7

Benzodiazepine

Answer 7

• Act selectively on GABA-A R (allosteric modulation)
  => ↑ Receptor affinity to GABA
  => ↑ Open freq. of channel pore in presence of GABA
  => ↑ Cl- influx (hyperpolarisation)
  => ↑ inhibitory GABA transmission in CNS
• Bind to GABA-A R containing α1, α2, (α3) - subunits at BZD site
• Absence of GABA: agonist occupation of BZD has no effect

Question 8

Clinically useful effects of benzodiazepine

Answer 8

Diazepam, Lorazepam, Midazolam

• Sedation: tranquillising aggressive behaviours
• Anxiolysis: reduce anxiety
• Hynotic: high drug conc.
• Anterograde amnesia: loss of ability to create new memory
• Antiepileptic: intravenous diazepam for emergency treatment of status epilepticus
• Muscle relaxant: reduction of ms. tone (GABA-A R in spinal cord)

Question 9

Anxiolytic and hypnotic actions of BZS

Answer 9

1. Long t1/2; usually used for treating acute anxiety states
   - Diazepam: t1/2 = 2h, t1/2 of active metabolite = 36h
   - Lorazepam: t1/2 = 12h
   - Anxiolytic effect: binding to GABA-A R with α2/(α3) - subunits
2. Short t1/2: insomnia
   - Midazolam: t1/2 = 2h
   => ↓ hangover effect
   - Hypotic effect: binding to GABA-A R with α1/(α5) - subunits

Question 10

PK profile of BZD

Answer 10

• Lipophilicity => accumulated in adipose tissue
• Metabolised by CYP450; conjugated with glucuronate
  => Inactive polar metabolite
  => Excreted in urine
• Lorazepam: bypass phase I oxidation; metabolised only by phase II conjugation
• Long acting metabolites after liver metabolism
  => Hangover effect of diazepam (t1/2 of nordazepam = 100h)
• Midazolam: inactive metabolite with short t1/2 after phase I metabolism

DDI:
- Other drugs inhibiting CYP450 (e.g. SSRI)
=> ↑ blood [BZD]
- High dose
=> potentiate effect of other CNS depressants (e.g. alcohol, opioids)
=> CVS / Respiratory repression

Question 11

Drug addiction of BZD (Physical dependence)

Answer 11

Tolerance to BZD after long term use

• Gradual ↑ in doses required for desired effect
• Downregulation of GABA-A R

BZD withdrawal symptoms
- Insomnia, ANS hyperactivity (sweating, tachychardia), tremor, seizure, hallucination, delirium
- Can be mistaken for return of anxiety attacks
∴ Always Taper Sedative-Hypotics Doses

1. Limit duration of treatment
2. Long-term treatment of GAD: antidepressant or certain antiepileptics (↑ GABA transmissio) are more preferred

Question 12

Drug addiction of BZD (Psychological dependence)

Answer 12

• ↓ GABAergic inhibitory input to reward centre (VTA DA neurons)
  => ↑ DA release to nu. accumbens
  => Feel pleasure

Question 13

Acute toxicity of BZD with other CNS depressants

Answer 13

• Overdosing of BZD alone: not fatal acutely
• Combined with other sedatives (e.g. alcohol)
  => Synergistic fatal sedative effects on vital body functions

BZD antagonist: Flumazenil
=> Treat BZD overdosing

Question 14

Z-drugs (BZD receptor agonists)

Answer 14

• Short-acting hynotic drugs:
  Zolpidem (t1/2 = 2h)
  Zopiclone (t1/2 = 5h)
• Hypnotic action only; NO anxiolytic activity
• Seletively binding to GABA-A R with α1 subunit
• ↑ Cl- influx through GABA-A R via allosteric modulation
• ↓ Onset time for initiating sleep (sleep latency)
• ↑ Overall duration of sleep
• BZD may suppress length of REM sleep but Z-drugs do not alter sleep architecture

Question 15

5HT-1A R agonist - Buspirone as anxiolytic drug

Answer 15

• Not commonly used
• Help with anxiety produced by BZD abuse
• Treat GAD:
  NO sedation
  NO tolerance or withdrawal effects
• Partial agonist of 5HT-1A R (Gi)
• presynaptic autoreceptor 5HT-1A R activated => downregulate 5HT release
• Slow onset time
  1. Buspirone ↑ auto-inhibition of 5HT
  => ↓ neuronal firing
  => ↓ 5HT release and ↑ anxiety state

2. Auto-inhibitory receptors desensitised
   => ↑ neuronal firing
   => ↑ 5HT release (anxiolytic)