Topic 23: Barbiturates Flashcards
What are anxiolytic sedative hypnotics?
reducing anxiety or tranquilizing
calming, relaxing, or sleep inducing
sleep inducing or sopoforic
What is anxiety?
normal anxiety is a survival response leading to activation of the sympathetic nervous system for flight-or-fight response to danger
anxiety is the anticipation of potential danger
subjective unsettling feelings of concern or worry
physiological responses including sympathetic activation
ranges from vague discomfort to intense sense of terror
In what ways can anxiety be beneficial?
acute anxiety in response to stressors can be beneficial
moderate anxiety for exams drives studying
anxiety for public speaking prompts thorough preparation
What is stress and anxiety?
chronic or excessive anxiety can cause deterioration of performance and distracting preoccupation with the agitation associated with anxiety
sympathetic effects: muscle tension, digestive problems, sleep disturbances
escalating anxiety cycle due to performance decrease and fear of failure (driving further anxiety)
anxiety has high comorbidity with depressive disorders and substance abuse
What is generalized anxiety disorder?
symptoms of anxiety without identifiable cause
persistent anxiety most of each day for prolonged period (weeks-months)
constant worry, predicting, anticipating, or imagining failure or disastrous events
physical symptoms include muscle tension and agitation leading to poor concentration, irritability, and sleep disturbances
What are panic attacks and panic disorder?
experiencing physiological effects of fear reactions without threatening stimulus
accompanied by strong sympathetic NS activation: increased heart rate, chest pain, sweating, shortness of breath, faintness, choking, fear of losing control or dying
panic attack in response to a cue can lead to phobia
susceptibility for un-cued panic attacks leads to panic disorder
What are contemporary anxiolytic and sedative hypnotics?
barbiturates
benzodiazepines
What is bromide toxicity?
bromides are sedative possibly through effects on Cl- balance in the CNS
bromide has a half life of ~8-12 days making dosing difficult and intoxication problematic
bromism results from bromide toxicity: impaired though and memory, drowsiness, dizziness, irritability, emotional disturbances, repulsive skin eruption, psychosis
What are barbiturates?
barbiturates can be classed according to the relative lipophilicity of the compound
increasing the lipophilicity of barbiturates results in faster uptake into the brain and more rapid sedation
What are the effects of barbiturates?
anxiolytic and tranquilizing at low doses
sedating and sopoforic at moderate doses
anesthetic at high doses
What are ultrashort-acting barbiturates?
anesthetic
highly lipophilic
Thiopental, hexobarbital
IV administration results in rapid uptake and sleep in 10-20 seconds
unconsciousness lasts 20-30 minutes and ends due to redistribution of lipophilic barbiturates into fatty tissues
What are short-intermediate-acting barbiturates?
sedative
moderate lipid solubility
Amobarbital (Amytal) and pentobarbital (Nembutal)
sleep in 20-40 minutes lasting 5-8 hours
termination depends on liver metabolism
prescribed for insomnia, high abuse potential
What are long-acting barbiturates?
have low lipophilicity
Phenobarbital, mephobarbital
onset takes 1 or more hours
slow metabolism
effects last 10-12 hours
are effective for treating seizure disorders and anxiety
What are the side effects and safety margin of barbiturates?
anxiolytic effects are accompanied by cognitive side effects: mental clouding, loss of judgement, slowed reflexes
intoxication (high doses) leads to staggering, jumbled speech, impaired thinking: coma and death due to respiratory depression
alterations in REM sleep
produce tolerance and dependence: high abuse potential
What are the sleep disturbance effects of barbiturates?
despite their hypnotic effects, barbiturates do not induce restful sleep
short term use results in rapid sleep onset but decreased Stage 3 and 4 sleep
chronic use decreases REM sleep and stage 3 and 4 sleep and increases spontaneous awakenings
What is the illicit use of barbiturates?
high abuse potential due to rapid tolerance and dependence: increased abuse potential with faster onset
peaked in 60s and 70s
often used in conjunctions with amphetamines
high potential for interactions with ethanol
decreasing safety margin with tolerance leads to high potential for overdose
What are the synaptic effects of barbiturates?
barbiturates act at the GABAA receptor
positive allosteric modulation at the barbiturate binding site
increases GABA affinity
prolongs open time
high doses - GABA mimetic (opens GABAA in absence of GABA)
What are barbiturate drug effects?
barbiturates are CNS depressants and cause broad increases in in inhibitory neurotransmission
anticonvulsant by decreasing general excitatory
important effects in the reticular formation: pontine normally activates cortical centres, medullary normally suppresses cortical centres
balance of barbiturate effect in the reticular formation
medullary first: euphoria resulting from cortical activation (disinhibitory)
pontine first: relaxation, drowsiness, sleep from cortical depression (inhibitory)
What is the mechanism of barbiturate abuse?
paradoxically, barbiturates decrease mesolimbic DA release in the NAc through effects on VTA GABA interneurons
barbiturates can be demonstrated to reinforce through microinjection into the VTA (operant self-administration) suggesting the same neural substrates for addictions as other abused substances
What is metabolic tolerance to barbiturates?
barbiturates induce microsomal enzymes leading to greater liver metabolism
increased drug dose required to achieve same blood levels
leads to cross-tolerance among different barbiturates
What is pharmacodynamic tolerance to barbiturates?
cellular changes in GABAA receptor function and expression
greater barbiturate dose required to elicit inhibitory effect
What is barbiturate dependence?
intoxication induced with doses 4-12 times above therapeutic dose
peak sedative effect in 30-90 minutes
fully awake 4 hours after dose
period of cognitive impairment: inarticulate speech, clouded thought, coarse tremours of hand, depressed superficial reflexes, depression or mania
dependence induced by increasing doses every 12 hours for 92-140 days
What are the results of barbiturate dependence trials?
dependence trials resulted in continuous mild intoxication in most cases
confusion, inability to perform normal tasks
unkempt living quarters and decreased self-care
irritable, aggressive, and quarrelsome
staggering, frequent falls and injuries
drugs were abruptly withdrawn at end of trial and monitored
What is barbiturate withdrawal?
12-16 hours after last dose subjects appeared to sober: lack of sedative and cognitive effects
24-36 hours after last dose increasing anxiety and weakness developed
at peak subjects could not stand unassisted
drop in blood pressure, fainting
tremors, anorexia, vomiting, abdominal distress, insomnia, weight loss, increased startle response, hyperreflexia
significant appearance of convulsions and psychosis
