Week 10- Drugs and Psychiatric Disease: Anxiety Flashcards
What are both anxiety and depression associated with in terms of neurotransmitter function?
-Genetic differences in 5-HT (serotonin function)
Anxiolytics and sedative hypnotics function
- Used to treat anxiety
Before barbiturates what were the options doctors had at their disposal for calming people or aiding sleep?
Alcohol – usually brandy
Bromides, chloral hydrate
Opium
These were not very effective and had major side effects
Barbiturates (history/discovery)
- Barbituric acid first synthesized in 1864 by Adolph von Baeyer -> Condensed animal waste (urea) with a derivative of apple acid.
-Origin of name is not clear
-No medical use was found until 1903 when it was found that barbital was effective in putting dogs to sleep
-Then used extensively for over 100 years as tranquilizers
What happened to barbiturate use in the 20th century
-Essentially the only drugs used as tranquilizers from 1920s to mid-1950s
-More than 2,500 barbiturates were synthesized: 50 marketed and used clinically
-Most prevalent illicit use in the 1960s, when barbiturates were sold as “downers”
-As medical use of barbiturates has declined, so has their availability and the prevalence of illicit use
What were barbiturates for the treatment of anxiety replaced with and why?
-By the mid 1990s, almost all barbiturates had been replaced by benzodiazepines as these Improved therapeutic index (i.e. greater range of effective doses)
Benzodiazepines (discovery + functions)
-First synthesized by Leo Sternbach in 1955. Thought to be inert ( have no use)
-Not tested until 1957. Found during spring cleaning and had “such pretty crystals” so people decided to run experiments on them.
-Found to be a potent sedative, anticonvulsant, and muscle relaxant
-Chlordiazepoxide (marketed as Librium) approved for use in 1960
Neurophysiology or barbiturates and benzodiazepines
-Barbiturates and benzodiazepines act principally through the GABAA receptor
-They increase the efficacy of GABA at its binding site but they themselves don’t bind to have an inhibitory effect.
-They are known as Positive allosteric modulators meaning they modulate the impact of an endogenous neurotransmitter
-They vary in their binding efficacy and therefore their overall strength
-Some modulators of the benzodiazepine binding site modulate GABA activity by more than 700%: which can be problematic!
GABAA receptors
-Composed of different subunits (alpha, beta, gamma)
-Binding efficacy (how well they bind) at these different sites (alpha sites for benzodiazepines) determines the drug’s effect.
What is the most prominent effect of a1 activation ? What is this also linked to in regards to benzos?
-The most prominent effect of α1 activation is sedation
-Activation of α1 is also linked to addictive effects of benzodiazepines
What is meant by this: the ability to modulate GABA function is self-limiting?
-It means there is an upper limit to the effect that benzos can have on GABA
-This is because benzos don’t modulate GABA activity by themselves they just impact how much of the already existing GABA will bind so in that way effect is limited/ constrained by how much ‘natural’ GABA there is
-High doses cause sedation, but are not life-threatening.
What about GABAergic drugs makes them difficult to use as anxiolytics?
-Sedative properties
-Causes people to sleep and so this although may reduce their anxiety symptoms it also comes with it’s own set of cognitive impairments.
Barbiturates (low versus high dose distinction)
-Low doses act like benzodiazepines: Modulate the efficacy of GABA at the receptor
-High doses directly modulate the receptor: no upper limit. They open chloride channels and can cause depression of breathing and the cardiovascular system -> cause of death via barbiturate overdose is a very real thing!
Why does the brain have benzodiazepine binding sites?
-Body likely has endogenous substances that use these binding sites
-These substances on not yet identified
but its proposed that they perhaps plays a role in modulating anxiety
-Evidence for this is that there is increased sensitivity to benzodiazepines following stress in lab animals
Abuse liability of benzos
-Benzodiazepines are not as abused as barbiturates, but still have abuse potential
-Abused by illicit use, combined with alcohol and other drug dependence
