Topic 24: Benzodiazepines

Question 1

What is meprobamate (MPB)?

Answer 1

MPB is an early non-barbiturate anxiolytic: less sedation than barbiturates, less cognitive side effects

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

eventually withdrawn due to abuse potential and narrow safety margin

Question 2

What was the development of benzodiazepines?

Answer 2

anxiolytic development was spurred by the commercial success of MPB

chlordiazepoxide found to have sedative, anxiolytic and anticonvulsant effects

brought to the market as Librium in 1960

followed shortly by diazepam (Valium) in 1961

Question 3

What are the effects of benzodiazepines?

Answer 3

anxiolytic and anticonvulsant

sedation: less potent than barbiturates

muscle relaxant

not effective as anesthetics but can be used as relaxants for pre-surgical anaesthetic

lower incidence of tolerance, less severe withdrawal, greater safety margin than barbiturates

Question 4

What is benzodiazepine use?

Answer 4

like barbiturates, the effects of benzos vary with their rate of onset and duration of effect in the body

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

BZDs often have active metabolites generated by type 1 metabolism

Question 5

What is benzodiazepines pharmacology?

Answer 5

some effects of BZDs relate to their slow metabolism and number of active metabolites

prolonged action is beneficial for anxiolytic and anticonvulsant use

long elimination reduces the withdrawal syndrome

Question 6

What is the metabolism of short-acting benzodiazepines?

Answer 6

enter the brain quickly due to high lipophilicity

terminate quickly due to depot binding in fatty tissues

tend to have “hangover” effects due to slow release from fatty tissues

Question 7

What is the metabolism of long-acting benzodiazepines?

Answer 7

slower onset due to lower lipophilicity

not readily taken up into fatty tissues

multiple active metabolites

long elimination half-lives

reduced withdrawal effects due to slow decline in systemic levels

Question 8

What is the benzodiazepine receptor?

Answer 8

BZD are positive allosteric modulators at the GABAA receptor

BZD site of GABAA is often referred to as the BZD receptor

many types of interactions at the BZD receptor

agonists, partial agonist, antagonists, inverse agonists

Question 9

How do benzodiazepines modulate GABAA sensitivity?

Answer 9

classic benzodiazepines act as positive allosteric modulators of GABAA

BZD binding increases the response of the channel to lower concentrations of GABA

BZD increase frequency of channel opening

unlike barbiturate BZDs do not have GABA mimetic activity

Question 10

What is the interaction between endozepines and BZD receptors?

Answer 10

the BZD site has for many years been considered an “orphan receptor”: the existence of a natural ligand for the BZD site is proposed, “Nature’s Valium” highly sought

several compounds have been identified that bind the BZD site: termed “endozepines”

beta-carbolines

diazepam-binding inhibitor (DBI): protein inverse agonist at the BZD site

Question 11

What are benzodiazepine agonists and inverse agonists?

Answer 11

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

inverse agonists bind and exert biological effect that is opposite that of agonists

Question 12

What are the effects of BZD typical agonists?

Answer 12

classical BZD anxiolytics: diazepam, lorazepam, flunitrazepam

exert positive allosteric modulation on GABAA

anxiolytic, sedative-hypnotic, anti-convulsant

Question 13

What are the effects of BZD competitive antagonists?

Answer 13

exert no effects at the BZD site but displace agonist binding

flumazenil - used to treat BZD overdose

Question 14

What are the effects of BZD inverse agonists?

Answer 14

negative allosteric modulators of GABAA

anxiogenic effects

principally experimentally compounds, no therapeutic benefit

Question 15

What is endozepine agonism?

Answer 15

to date most proposed endozepines function as inverse agonists at the BZD site: endozepines are anxiogenic

in animal studies endozepines increase agitation, increase distress vocalizations, and increase aggressive behaviors

in human volunteers, endozepines administration increased muscle tension, autonomic hyperactivity, and extreme apprehension

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 16

What is benzodiazepine tolerance?

Answer 16

no metabolic tolerance develops (no enzyme induction)

rapid tolerance develops to muscle relaxant and sedative effects (pharmacodynamic)

very little tolerance develops to anxiolytic effects

many adverse side effects of BZDs when used as anxiolytics are transient and dissipate as the tolerance develops to the sedative effects

Question 17

What is benzodiazepine dependence?

Answer 17

animal models of dependence show BZDs to have low risk of dependence: rats will not readily acquire self-administration of BZDs alone

dependence seems to be problematic in human clinical use and abuse

convergent site of action with barbiturates and alcohol: cross-tolerance and potential for drug interactions

Question 18

What is benzodiazepine abuse?

Answer 18

BZDs interact with alcohol and pose increased risk of toxicity and abuse when co-administered

however, BZDs are effective at treating alcohol withdrawal in chronic alcoholics

BZDs have increased risk of adverse events in elderly patients due to decreased liver function

BZDs tend to bioaccumulate in elderly patients causing adverse effects

Question 19

What is benzodiazepine withdrawal?

Answer 19

rebound effects: rebound insomnia, anxiety

withdrawal effects: fearfulness, tremors, agitation, muscle spasms

withdrawal easily managed with a long-acting BZD such as diazepam and slow weaning off the drug

Question 20

What are the adverse effects of benzodiazepines?

Answer 20

adverse intoxication can occur at higher doses: disorientation, cognitive impairments, amnesia, sedation

paradoxical effects at high doses: aggression, irritability, anxiety

Question 21

What is benzodiazepine overdose?

Answer 21

overdose can be managed by BZD competitive antagonist

Flumazenil displaces BZDs but has a short half-life

overdose can present with unconsciousness but respiratory depression is only seen when another drug is present: common with alcohol

Question 22

What is flunitrazepam?

Answer 22

high-potency short-acting BZD useful as a hypnotic

marked ability to induce anterograde amnesia, cause sedation and drowsiness

effects exacerbated by alcohol

one of the more widely reported “date-rape” drugs