Benzodiazepines Flashcards
Meprobamate (MPB)
MPB was an early non-barbiturate anxiolytic
MPB potentiates GABAA and acts as
a weak
partial agonist at the GABA site
Meprobamate (MPB) Eventually withdrawn due to
abuse potential and
narrow safety margin
Chlordiazepoxide found to have
sedative,
anxiolytic, and anticonvulsant effects
(Valium)
diazepam
BZD Effects
Anxiolytic and anticonvulsant
BZD Effects - sedation
less potent than barbiturates
BZD & muscles
Muscle relaxant
BZD Not effective as _____ but
anaesthetics BUT can be used as relaxants for pre-surgical anaesthesia
Midazolam
is a short-acting BZD used for brief
surgical procedures with local anaesthetic
Midazolam recovery
Recovery in a few hours with anterograde
amnesia – creates the illusion of anaesthesia
BZD Effects Lower incidence of (3)
tolerance,
less severe withdrawal,
greater safety margin than barbiturates
BZD use - like
Like barbiturates, the effects of BZDs 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
e metabolites
generated by type I metabolism
BZD Pharmacology
Some of the effects of BZDs relate to their slow metabolism and number of active metabolites
duration of effect of Benzos list
Oxazepam < Diazepam < Flurazepam
Diazepam half life
1-3 days but metabolites can be active and go on to have effects
Nordazepam results from _____ and has a half life of
Demethylation of Diazepam - half life of 2-7 days
Oxazepam results from _____ and has a half life of
oxidation and Demethylation of diazepam - half life of 4-15 days
temazepam results from _____ and has a half life of
oxidation of diazepam - half life of 4-18 days
prolonged action of metabolites
is beneficial for
anxiolytic and anticonvulsant use
Long elimination of metabolites reduces
reduces the
withdrawal syndrome
BZD metabolism - Short-acting BZDs
Enter the brain quickly due to high lipophilicity
Terminate quickly due to depot binding in fatty
tissues
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
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
