Anxiolytics

Question 1

What is an anxiolytic?

Answer 1

Reducing anxiety or tranquilizing

Question 2

What is a sedative?

Answer 2

Calming, relaxing, or sleep
inducing

Question 3

What is a hypnotic?

Answer 3

Sleep inducing or sopoforic

Question 4

What is anxiety?

Answer 4

Anxiety is the anticipation of potential danger

Question 4

Describe the physiological anxiety response

Answer 4

Physiological responses including sympathetic activation

Question 5

What is normal anxiety?

Answer 5

Normal anxiety is a survival response leading to activation of the sympathetic nervous system for fight-or-flight response to danger

Question 5

Describe sympathetic effects of chronic anxiety

Answer 5

Sympathetic effects e.g. increased muscle tension, digestive problems, sleep disturbance

Question 6

What leads to an escalated anxiety spiral?

Answer 6

Escalating anxiety cycle due to performance decrease and fear of failure (driving further
anxiety)

Question 7

What anxiety disorder has the highest comorbidity for alcohol abuse?

Answer 7

Social anxiety disorders

Question 8

Describe panic disorder

Answer 8

• Accompanied by strong sympathetic NS activation
• Panic attack in response to a cue can lead to phobia
• Susceptibility for un-cued panic attacks leads to panic disorder

Question 9

Name 2 early anxiolytics and sedative hypnotics

Answer 9

Alcohol was the first ‘drug’ in widespread
use to reduce anxiety and cause sedation –
still a common self-medication

• Bromides– 19th and 20th century (esp. KBr,
  NaBr)

Question 10

Describe contemporary sedative hypnotics

Answer 10

• Barbiturates
• Benzodiazepines

Question 11

Why is bromide toxicity a big concern?

Answer 11

• Bromide has a half-life of ~8-12 days making dosing
  difficult and intoxication problematic

Question 12

Describe barbital

Answer 12

• Barbital was the first psychoactive barbiturate synthesized in 1903 and marketed as
  Veronal (after the Italian town of Verona)
• Barbital found to have relaxing and sopoforic effects
• Long half-life meant drowsiness extended for days

Question 13

Describe phenobarbital

Answer 13

Phenobarbital was developed in 1912 and was noted to be faster acting, of shorter
duration, and having excellent anticonvulsant properties

Question 14

Describe barbiturate classification

Answer 14

Barbiturates can be classed
according to the relative
lipophilicity of the compound.

Increasing the lipophilicity of
barbiturates results in faster
uptake into the brain and more
rapid sedation.

Question 15

Give an example of an ultrashort barbiturate

Answer 15

• Thiopental
• Unconsciousness lasts 20-30 minutes and
  ends due to redistribution of lipophilic
  barbiturates into fatty tissues

Question 16

Give an example of an intermediate barbiturate

Answer 16

• Amobarbital (Amytal)
• Prescribed for insomnia, high abuse
  potential

Question 17

Give an example of a longer-acting barbiturate

Answer 17

Phenobarbital

Question 18

Describe adverse effects

Answer 18

• Intoxication (high doses) leads to
  staggering, jumbled speech, impaired
  thinking
• Coma and death due to respiratory
  depression

Question 19

Describe illicit use

Answer 19

• High abuse potential due to rapid tolerance
  and dependence
• Often used in conjunction with
  amphetamines
• Amphetamines during the day (uppers or
  pep-pills)
• Barbiturates at night (downers or goofballs)
• High potential for interactions with ethanol
• Decreasing safety margin with tolerance
  leads to high potential for overdose

Question 20

Describe synaptic effects of barbiturates

Answer 20

• Positive allosteric
  modulation at the
  barbiturate binding site
• Increases GABA affinity
• Prolongs open time
• High doses – GABA
  mimetic (opens GABAA in
  absence of GABA)

Question 21

Describe barbiturate drug effects

Answer 21

• Barbiturates are CNS depressants and cause
  broad increases in inhibitory neurotransmission
• Important effects in the reticular formation
• Pontine – normally activates cortical centres
• Medullary – normally supresses cortical centres
• Balance of barbiturate effect in the reticular
  formation
• Medullary first – euphoria resulting from cortical
  activation (disinhibitory)
• Pontine first – relaxation, drowsiness, sleep from
  cortical depression (inhibitory)

Question 22

Describe barbiturates & dopamine

Answer 22

Paradoxically, barbiturates decrease
mesolimbic DA release in the NAc
through effects on VTA GABA
interneurons.

Question 23

Describe barbiturate tolerance

Answer 23

• Metabolic tolerance:
• Barbiturates induce microsomal enzymes leading to greater liver metabolism
• Increased drug dose required to achieve same blood levels
• Leads to cross-tolerance among different barbiturates
• Pharmacodynamic tolerance:
• Cellular changes in GABAA receptor function and expression
• Greater barbiturate dose required to elicit inhibitory effect

Tolerance leads to decreased safety margin

Question 24

Describe barbiturate dependence study

Answer 24

• Drugs were abruptly withdrawn at end of trial and monitored

Question 25

Describe barbiturate withdrawal

Answer 25

• 24-36 hours: increasing anxiety and weakness developed
• At peak subjects could not stand unassisted
• Drop in blood pressure – fainting on standing
• Tremors, anorexia, vomiting, abdominal distress, insomnia, weight loss,
  increased startle response, hyperreflexia
• Significant appearance of convulsions and psychosis

Question 26

Describe rebound hyperactivity

Answer 26

• Since barbiturates enhance GABAA
  function, rebound results in
  hyperexcitability and convulsions

Psychosis developed 3-5 days after
withdrawal lasting as long as 9 days
* Delirium, agitation, insomnia,
confusion, disorientation, auditory
and visual hallucinations
* High BP, temperature, pulse