Benzodiazepines Flashcards by Cambell Meier

Meprobamate (MPB)

MPB was an early non-barbiturate anxiolytic

How well did you know this?

Not at all

Perfectly

MPB potentiates GABAA and acts as

a weak
partial agonist at the GABA site

How well did you know this?

Not at all

Perfectly

Meprobamate (MPB) Eventually withdrawn due to

abuse potential and
narrow safety margin

How well did you know this?

Not at all

Perfectly

Chlordiazepoxide found to have

sedative,
anxiolytic, and anticonvulsant effects

How well did you know this?

Not at all

Perfectly

(Valium)

diazepam

How well did you know this?

Not at all

Perfectly

BZD Effects

Anxiolytic and anticonvulsant

How well did you know this?

Not at all

Perfectly

BZD Effects - sedation

less potent than barbiturates

How well did you know this?

Not at all

Perfectly

BZD & muscles

Muscle relaxant

How well did you know this?

Not at all

Perfectly

BZD Not effective as _____ but

anaesthetics BUT can be used as relaxants for pre-surgical anaesthesia

How well did you know this?

Not at all

Perfectly

Midazolam

is a short-acting BZD used for brief
surgical procedures with local anaesthetic

How well did you know this?

Not at all

Perfectly

Midazolam recovery

Recovery in a few hours with anterograde
amnesia – creates the illusion of anaesthesia

How well did you know this?

Not at all

Perfectly

BZD Effects Lower incidence of (3)

tolerance,
less severe withdrawal,
greater safety margin than barbiturates

How well did you know this?

Not at all

Perfectly

BZD use - like

Like barbiturates, the effects of BZDs vary with their rate of onset and duration of effect in the body.

How well did you know this?

Not at all

Perfectly

BZDs have more rapid

onset and
termination of effect with increased
lipophilicity.

How well did you know this?

Not at all

Perfectly

BZDs often have active

e metabolites
generated by type I metabolism

How well did you know this?

Not at all

Perfectly

BZD Pharmacology

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

How well did you know this?

Not at all

Perfectly

duration of effect of Benzos list

Oxazepam < Diazepam < Flurazepam

How well did you know this?

Not at all

Perfectly

Diazepam half life

1-3 days but metabolites can be active and go on to have effects

How well did you know this?

Not at all

Perfectly

Nordazepam results from _____ and has a half life of

Demethylation of Diazepam - half life of 2-7 days

How well did you know this?

Not at all

Perfectly

Oxazepam results from _____ and has a half life of

oxidation and Demethylation of diazepam - half life of 4-15 days

How well did you know this?

Not at all

Perfectly

temazepam results from _____ and has a half life of

oxidation of diazepam - half life of 4-18 days

How well did you know this?

Not at all

Perfectly

prolonged action of metabolites

is beneficial for
anxiolytic and anticonvulsant use

How well did you know this?

Not at all

Perfectly

Long elimination of metabolites reduces

reduces the
withdrawal syndrome

How well did you know this?

Not at all

Perfectly

BZD metabolism - Short-acting BZDs

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

How well did you know this?

Not at all

Perfectly

BZD metabolism - Short-acting BZDs

- 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

BZD metabolism - Long-acting BZDs

* 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

BZD receptor - 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 (+ allosteric modulator of GABAA) * Partial agonists * Antagonists * Inverse agonists (- allosteric modulator of GABAA)

Classic benzodiazepines act as

positive allosteric modulators of GABA-A

BZD binding increases the

response of the channel to lower concentrations of GABA

BZD increase the frequency of

channel opening

Unlike barbiturates BZDs do not

have GABA mimetic activity

The BZD site has for many years been considered an ‘orphan receptor’

The existence of a natural ligand for the BZD site is proposed

Several compounds have been identified that bind the BZD site - termed

‘endozepines’

β-carbolines

Small molecule inverse agonists at the BZD site

β-carbolines list

* β-CCE * β-CCM * DMCM

Diazepam-binding inhibitor (DBI)

Protein inverse agonist at the BZD site

The BZD site of GABAA is able to elicit both

h 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

biological effect that is opposite that of agonists.

Effects of BZD classes - Typical agonists: Classical BZD anxiolytics

Diazepam, lorazepam, flunitrazepam

Typical agonists: Exert

positive allosteric modulation on GABAA

Typical agonists: effects

Anxiolytic, sedative-hypnotic, anti-convulsant

Competitive antagonists exert

Exert no effect at the BZD site but displace agonist binding

Competitive antagonists: Flumazenil

used to treat BZD overdose

Inverse agonists

Negative allosteric modulators of GABAA

Inverse agonists - effects

Anxiogenic

Inverse agonists - Principally experimental compounds, no

therapeutic benefit

To date most proposed endozepines function as

inverse agonists at the BZD site

Endozepines are

anxiogenic

In animal studies endozepines increase (3)

agitation, increase distress vocalizations, and increase aggressive behaviours

In human volunteers, endozepine administration increased (3)

muscle tension, autonomic hyperactivity, 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

BZD tolerance and dependence - tolerance

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 because

anxiolytics are transient and dissipate as the tolerance develops to the sedative effects

Animal models of dependence show BZDs to have

low risk of dependence

* Dependence seems to be problematic in

n human clinical use and abuse

Convergent site of action with

barbiturates and alcohol

Convergent site of action with barbiturates and alcohol

Cross-tolerance and potential for drug interactions

BZDs interact with alcohol and pose

e increased risk of toxicity and abuse when co-administered

, 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 _____ in elderly patients causing adverse events

bioaccumulate

Rebound effects

Rebound insomnia Anxiety

Withdrawal effects: (4)

* Fearfulness * Tremors * Agitation * Muscle spasms

Withdrawal easily managed with a

a long-acting BZD such as diazepam and slow weaning off the drug

Adverse intoxication can occur

at higher doses

Adverse intoxication can occur at higher doses (4)

* Disorientation * Cognitive impairments * Amnesia * Sedation

Paradoxical effects at high doses

* Aggression * Irritability * Anxiety

* 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

Overdose can present with unconsciousness but respiratory depression is only seen when another drug is present

Common with alcohol

Triazolam is a

short-acting BZD with rapid clearance used to treat insomnia (less hangover sedating effects)

Triazolam causes people

to do violent things