-most commonly used to treat anxiety and sleep disorders
History of Compounds
● Self medication of drugs (ex: alcohol) were mainly for anxiety and sleep
○ So this is what made it easier to prescribe actual medications for
anx/sleep
● Barbiturates (popular in the 1960s, still used today)
○ Used in hospitals and very controlled environment
○ Used to put pets to sleep at the vet
● Miltown (meprobamate)
○ 1950s
○ best barbiturate at that time
○ Did not live up to reputation: people realized the bad side effects
(safety issues: easy to overdose- small therapeutic window)
● Librium (chlordiazepoxide)
○ started in 1961
● Benzodiazepines
Anxiety
● core idea:
○ involved unrealistic, irrational fears of anxiety of disabling
intensity
○ phobias
■ based on unrealistic irrational fear
■ persistent, disproportionate fear of some specific object/
situation with little actual danger to person
■ experience fight/flight response
● most frequently observed mental disorders
Phobias/ Panic Disorder
● Panic Disorder
○ recurrent panic attacks...sudden and unpredictable
● Agoraphobia
○ complication of panic attack
, ○ fear of places or situations from which escape is difficult or
embarrassing…
○ don’t leave home in severe cases
● PTSD
○ re-experiencing of prior traumatic events
○ intrusive thoughts, flashbacks, dreams
○ avoidance of situations, hyperarousal, sleep disturbance
○ have the inability to suppress the memory of the trauma
● OCD
○ unwanted, intrusive thoughts, distressing images
○ accompanied by compulsive behaviors
○ considered in spectrum of anxiety, but core symptoms are not
Barbiturates
● medical use has varied considerably
○ declined (toxicity, safety, dependence liability)
● differ from one another primarily due to their pharmacokinetics
○ how quickly? Intensity? Duration?
■ thiopental (15 mins)...anesthetic
■ secobarbital (~1.5 hrs)....sleep inducer
■ pentobarbital (4 hrs)...sedative and sleep inducer
■ phenobarbital (less than or equal to 6 hrs)....sedative or
anticonvulsant
Why need other anxiolytics?
● similarities between alcohol and barbiturates
● higher efficacy
● less abuse potential
● minimal potential for overdose (therapeutic window)
○ barbiturates are commonly used in putting animals down
(inducing death in organism)
Benzodiazepines
● ->3000 synthesized
● ~3 dozen used clinically
○ chlordiazepoxide (Librium)
○ Diazepam (Valium)-most popular
○ Oxazepam (Serax)
○ Clorazepate (Tranzene)
○ Loraxepam (Ativan)-second most commonly prescribed
○ Alprazolam (Xanax)-most commonly prescribed
■ growing fears of dependence on valium
, ■ limited evidence for better efficacy
■ people felt safer taking something not called Valium
● people were overdosing on Valium with some other
type of sedative
● similar to sedative-hypnotics
● effective anticonvulsants -muscle relaxants
● reduce aggressive tendencies
● decrease anxiety
● work in ~70-80% of patients
○ less likely in individuals with chronic dissatisfaction, insecurity,
and/or character disorders (antisocial personality)
● target the limbic system and areas that focus on motivation
● why?
○ more specific than barbiturates and similar compounds
■ also works on the limbic system
○ not effective as generals anesthetics
○ high therapeutic window!!!
● minimal drug-metabolizing enzyme effects
○ mostly pharmacodynamics, not pharmacokinetics
● complex array of pharmacology
○ differ in how they work pharmacodynamically
Mechanism of Action
● potentiates GABA at the GABAA receptor
● inhibitory effect also observed via oxygen consumption and glucose
metabolism -increases slow-wave EEG activity
○ not normal sleep!!!!
● highly effective at potentiating GABA at the GABA receptor
GABAA Receptors
● major inhibitory receptors in the brain
● are heteromeric ligand-gated ion channels
○ similar in structure to nicotinic acetylcholine receptors
○ permeable to chloride ions
● positive allosteric homogulators won’t work by themselves if not
opened up by the ligand…
● GABA has to open up the receptor
○ GABA causes conformational shift and makes binding site
available
Pharmacologically: why is benzodiazepine
● low doses... positive allosteric homogulators
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