Anxiolytics and Hypnotics Flashcards
GABA channels let
Chloride anions in
Mechanism of action for pharmacological agents treating acute anxiety and insomnia
For a majority of these drugs, action is to increase GABAergic energy
GABA agonists uses
Act to hyperpolarize cells (Cl- in)
- anxiolytics
- hypnotic (sleep)
- surgical anesthesia
GABA A vs GABA B receptor
- GABA A is an ion channel
- GABA B is a metabotropic receptor
What happens when you block GABA A
no medicine blocks GABA A, experiments have shown blocking this channel to cause seizures
What happens with increased GABAergic transmission between normal transmission and death
normal GABAergic transmission
> then relief from anxiety (anxiolytic)
> then sedation (sedatives): drowsiness, increase in reaction time
> then hypnosis (sleep)
> then confusion, delirium, ataxia (stumbling gait)
> then surgical anesthesia
> then depression of respiratory and vasomotor center
> then coma
> death
Why are depressants addictive?
- depressants at high doses will reduce activity of all neurons, but depressants at low doses will disinhibit dopamine neurons
- so, normally DA neurons are inhibited by inhib. interneurons. Removing the inhibition allows the DA-ergic neurons to burst fire
- burst-fire DA mimics natural reward
How to learn and survive (DA mechanism)
When something new happens, dopamine neurons fire
- if that new thing has a good outcome, they fire more
- if that new thing has a bad outcome, they fire less
(more firing = more DA)
next time we encounter that cue, we remember what happened last time and can predict whether it will be pleasurable or painful based on what happened last time
Eventually, with a conditioned stimulus and expectation of a reward, dopamine firing…
shifts to occur at the CS and not at the actual reward itself
It is very difficult to unlearn a behaviour that consistently…
causes a dopamine surge. Drugs of abuse take advantage of this and hijack the ‘reward’ system
Addiction
compulsive (drug use) despite adverse consequences (expanded to include gambling, sex, eating, shopping)
Ethanol action on reward system
disinhibits dopamine neurons by inhibiting inhibitory interneurons (more DA released)
Barbiturates
- increase the length of time that the channel stays open, which increases the efficacy of GABA (positive modulators of GABA) so that more Cl- comes in every time the channel opens
- Used for rapid sedation and anesthesia
- used in assisted-suicide and capital punishment
why aren’t barbiturates used for anxiety anymore
- can cause lethal overdose
- chronic use can cause tolerance (GABA related), physical dependence, and addiction (DA related)
Barbiturates and: babies, alcohol, BZDs
- barbiturates can cross the placenta and cause baby to be born sluggish and with respiratory depression (can also cross breastmilk)
- additive effects with alcohol
- superadditive effects with BZDs because BZDs increases affinity of GABA to GABA A
examples of barbiturates
phenobarbital, pentobarbital, thiopental
Actions at the Benzodiazepine Modulatory Site
(and examples of drugs)
- agonism (partial and full) - anxiolytic and sedative hypnotic agents are agonists
- inverse agonism - will cause anxiety and seizures but also counteract ethanol intoxication. ex. Ro15-143
- Antagonism - counteract OD of BZDs. ex. flumazenil (will compete with BZDs for binding site)
Ro15-143
was a drug that never left clinical trials
- on its own it produces anxiety and seizures
- can be used to counteract drunkenness but problem is people would drink more after waking up and then Ro15-143 would wear off and they would have even more alcohol in their system than before
Tolerance: good and bad scenarios
good: you adjust to SSRIs (no more gut probz, headaches, insomnia, etc)
bad: you adjust to barbituates and alcohol so with repeated use, efficacy goes down
tolerance is good when it gets rid of negative effects but bad when it reduces efficacy