Benzodiazepines

Question 1

Leo H. Sternbach

Answer 1

• synthesized several compounds and initially, they didn’t produce any promising results
• 1957: they did a clean up of the Sternbach lab and the ones that were on the shelf were tested

Question 2

RO-5-0690

Answer 2

• one of the compounds that were tested and showed some interesting results in terms of the ability to calm or soothe animals
• the more sophisticated screening was done and it showed the potential to be an anxiolytic
• it became the first marketed benzodiazepine
• was given the generic name: chlordiazepoxide and the trade name was: Librium

Question 3

what was the second benzodiazepine to be created?

Answer 3

• diazepam

Question 4

what was benzodiazepine marketed name?

Answer 4

• the most well-known and was marketed as Valium

- benzodiazepines are minor tranquillizers (antipsychotics are major)

Question 5

Elevated Plus Maze

Answer 5

• screening apparatus that looks like a “+”
• it has legs that elevate it off the floor and it has 2 arms that have walls and 2 arms that don’t
• it’s expected for undrugged rats that they would spend most of the time in the walled arms bc it reflects the natural tendency to protect the rats
• drugs with anxiolytic effects alter the rat’s preference for the arms leading to a substantial increase in the amount of time that’s spent on the uncovered arms
• • if the drug doesn’t produce an increased amount of time in the uncovered area than the drug cannot be classified as an anxiolytic

Question 6

The Geller-Seifter Procedure

Answer 6

• multiple schedules of reinforcement - what an animal must do to
• there are 2 potential schedules: VI 2minute/FR1 with shock
• VI 2minute: dictates on average a reinforcer become available every 2 minutes and after if the animal presses the lever they will get the reinforcer - this type of schedule produces a very stable, moderate level of lever pressing
• FR1 with shock: dictates that with every lever press the animal will receive some food but they also receive a shock
• • undrugged animal will learn quickly to only press the lever when it is in the VI 2minute schedule and not press the lever in the FR1 with shock schedule
• • drugged animals (with anxiolytic) will press the lever during the FR1 with shock due to some sort of algesia (ie. the shock isn’t as painful) this is known as RELEASE FROM PUNISHMENT
• **no other class of drugs reliably produces release form punishment other than anxiolytics

Question 7

long-acting benzodiazepines

Answer 7

• most common: diazepam (Valium), chlordiazepoxide (Librium), flurazepam (Dalmane) and chlorazepate (Tranxene)

Question 8

intermediate-acting benzodiazepines

Answer 8

• most common: lorazepam (Antivan), clonazepam (Klonopin) - used by heroin users and flunitrazepam (Rohypnol - roofies/date rape drug)
• roofies are banned in Canada and the US but are smuggled in from Mexico

Question 9

short-acting benzodiazepines

Answer 9

• most common: midazolam (Versed), oxazepam (Serax) alprazolam (Xanax) and triazolam (Halcion - at one point was the most prescribed sleeping meds but had bad side effects so they took it off the market) - these drugs are sleep-inducing agents

Question 10

what group of users is most likely to abuse this drug

Answer 10

• middle-age women

- “Mother’s Little Helper”

Question 11

what would a benzodiazepine overdose consist of?

Answer 11

• opiate and a benzodiazepine (concurrent use) or concurrent use with alcohol
• its sometimes used to control the other withdrawal effects of some other drugs

Question 12

what effects do benzodiazepines produce?

Answer 12

• all produce relatively the same effects - reduce anxiety, sedation, muscle relaxation, an anticonvulsant action and sleep induction

Question 13

Benzodiazepines + sleep

Answer 13

• reduce the latency to fall asleep and reduce the amount of times one wakes up but they also reduce REM sleep
• tolerance develops to these sleeping effects and upon withdrawal REM goes fucking crazy
• benzodiazepines are not often used to treat insomnia anymore - Z Drugs: they have the same neurochemical effects of benzodiazepines

Question 14

Benzodiazepines + cognitive deficits

Answer 14

• deficits in working memory, processing speed, divided attention, visuoconstriction, recent memory and expressive language
• evidence that these effects will persist after a long period of abstinence

Question 15

Benzodiazepines + anteretrograde amnesia

Answer 15

• good at producing anteretrograde amnesia (failure of memory for events occurring from point of drug administration to when the blood level returns to near zero)
• sometimes beneficial in surgeries but this also forms the basis of using benzodiazepines as a “date rape” drug

Question 16

what are benzodiazepines useful in managing other than anxiety and sleep?

Answer 16

• withdrawal of alcohol and epilepsy

Question 17

are there any teratological effects?

Answer 17

• very few - if any - effects have teratological effects

Question 18

how do benzodiazepines work?

Answer 18

• they interact with GABA receptors but not directly on the GABA receptors - they exert their effects only in the presence of endogenous GABA
• they enhance the affinity of GABA for its receptors this is effected through the specific “satellite receptors” on GABA receptor itself
• when it occupies the satellite receptor, the GABA receptor switches to a high-affinity binding state and GABA is enhanced (ie. ion channels stay open longer)

Question 19

Benzodiazepines and reinforcing effects? Does it have an antagonist?

Answer 19

• evidence that there are some reinforcing effects since it has been shown to activate the dopaminergic VTA pathway (midazolam - short acting benzodiazepine to be the best)
• Flumazenil (Anexate, Romazicon) is the antagonist for benzodiazepine (which could be used if someone is going through an OD)
• it binds to the GABA receptor but doesn’t exert any action (primarily used as an IV injection)

Question 20

Benzodiazepines + tolerance and physical dependance

Answer 20

• tolerance develops fairly rapidly to the muscle relaxing, sedating, sleep-inducing and anticonvulsants effects of benzodiazepines
• less certainty for the amnesic or anxiolytics effects (if tolerance is shown its at a much slower rate and much less complete than seen with other effects
  Physical Dependance
• shown in both humans and animals (rats, dogs and monkeys)
• withdrawal symptoms have been observed in humans
• some uncertainty over how long and at what doses benzodiazepines have to be taken in order for dependance to develop but most studies suggests that a medical regime for less than 4 weeks is unlikely to produce dependance
• shorter-acting drugs are more likely to produce dependance and result in severe withdrawal

Question 21

Benzodiazepines + withdrawal

Answer 21

• increased neuronal excitation ranging from tremors to seizures, agitation and potential aggressive outbursts
• insomnia
• return of anxiety etc.
• gradually wane over the course of about 4 weeks