Benzodiazepines

Question 1

Describe the first 2 benzos

Answer 1

Chlordiazepoxide found to have sedative,
anxiolytic, and anticonvulsant effects

Followed shortly by diazepam (Valium) in
1961

Question 1

Describe MPB

Answer 1

By 1957 MPB accounted for one third of all
prescriptions in the USA
* MPB potentiates GABAA and acts as a weak
partial agonist at the GABA site

Question 2

Describe benzo effects

Answer 2

• Anxiolytic and anticonvulsant
• Midazolam is a short-acting BZD used for brief
  surgical procedures with local anaesthetic
• Recovery in a few hours with anterograde
  amnesia – creates the illusion of anaesthesia

Question 3

Describe BZD characteristics

Answer 3

BZDs have more rapid onset and
termination of effect with increased
lipophilicity.

BZDs often have active metabolites
generated by type I metabolism.

Question 4

Describe BZD pharmacology

Answer 4

• Some of the effects of BZDs relate
  to their slow metabolism and
  number of active metabolites
• Long elimination reduces the
  withdrawal syndrome

Question 5

Describe short acting BZD metabolism

Answer 5

• Enter the brain quickly due to high lipophilicity
• Terminate quickly due to depot binding in fatty
  tissues

Question 6

Describe BZD receptor

Answer 6

• BZD are positive allosteric modulators at
  the GABAA receptor
• BZD site of GABAA is often referred to as
  the BZD receptor
• Agonists (+ allosteric modulator of GABAA)
• Inverse agonists (- allosteric modulator of
  GABAA)

Question 7

What does BZD do to GABA?

Answer 7

BZD increase the frequency of
channel opening

Question 8

What are endozepines?

Answer 8

• Several compounds have been
  identified that bind the BZD site

Question 9

Describe BZD agonists

Answer 9

The BZD site of GABAA is able to elicit
both positive and negative allosteric
modulation of GABA activity.

Negative allosteric modulators exert
biological effects as inverse agonists of
the BZD site.

Question 10

Give an example of a competitive antagonist

Answer 10

Flumazenil– used to treat BZD overdose

Question 11

Describe endozepine agonism

Answer 11

• To date most proposed endozepines function as inverse agonists at the BZD site
• Endozepines are anxiogenic
• The function of endozepines supports the model that the BZD receptor site plays
  a natural role in anxiogenesis
• BZD drugs may in fact antagonize endozepine-induced anxiety

Question 12

Describe BZD tolerance and dependence

Answer 12

• No metabolic tolerance develops (no enzyme
  induction)

Animal models of dependence show BZDs to
have low risk of dependence

• Dependence seems to be problematic in human
  clinical use and abuse

Cross-tolerance and potential for drug
interactions

Question 13

Describe BZD abuse and withdrawal

Answer 13

BZDs tend to bioaccumulate in elderly patients
causing adverse events

• Rebound effects:
• Rebound insomnia
• Anxiety

Question 14

Describe adverse effects of BZD and overdose

Answer 14

• Adverse intoxication can occur at
  higher doses
• Disorientation
• Cognitive impairments
• Amnesia
• Sedation
• Paradoxical effects at high doses:
• Aggression
• Irritability
• Anxiety
• Flumazenil displaces BZDs but has a
  short half-life

Question 15

Describe flunitrazepam

Answer 15

• Marked ability to induce
  anterograde amnesia, cause
  sedation and drowsiness