Topic 24: Benzodiazepines Flashcards
What is meprobamate (MPB)?
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eventually withdrawn due to abuse potential and narrow safety margin
What was the development of benzodiazepines?
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
What are the effects of benzodiazepines?
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
What is benzodiazepine use?
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
What is benzodiazepines pharmacology?
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
What is the metabolism of short-acting benzodiazepines?
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
What is the metabolism of long-acting benzodiazepines?
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
What is the benzodiazepine 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, partial agonist, antagonists, inverse agonists
How do benzodiazepines modulate GABAA sensitivity?
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
What is the interaction between endozepines and BZD receptors?
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
What are benzodiazepine agonists and inverse agonists?
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
What are the effects of BZD typical agonists?
classical BZD anxiolytics: diazepam, lorazepam, flunitrazepam
exert positive allosteric modulation on GABAA
anxiolytic, sedative-hypnotic, anti-convulsant
What are the effects of BZD competitive antagonists?
exert no effects at the BZD site but displace agonist binding
flumazenil - used to treat BZD overdose
What are the effects of BZD inverse agonists?
negative allosteric modulators of GABAA
anxiogenic effects
principally experimentally compounds, no therapeutic benefit
What is endozepine agonism?
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
What is benzodiazepine 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 as anxiolytics are transient and dissipate as the tolerance develops to the sedative effects
What is benzodiazepine dependence?
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
What is benzodiazepine abuse?
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
What is benzodiazepine withdrawal?
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
What are the adverse effects of benzodiazepines?
adverse intoxication can occur at higher doses: disorientation, cognitive impairments, amnesia, sedation
paradoxical effects at high doses: aggression, irritability, anxiety
What is benzodiazepine overdose?
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
What is flunitrazepam?
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
