Barbiturates Flashcards
Anxiolytic
Reducing anxiety or tranquilizing
Sedative
Calming, relaxing, or sleep inducing
Hypnotic
Sleep inducing or sopoforic
soporific
tending to induce drowsiness or sleep
Normal anxiety is a
survival response leading to activation of the
sympathetic nervous system for fight-or-flight response to danger
Anxiety is the
anticipation of potential danger
anxiety is the Subjective unsettling feelings of
concern or worry
Physiological responses of anxiety including
sympathetic activation
anxiety range
Ranges from vague discomfort to intense sense of terror
Acute anxiety in response to stressors can be
beneficial
Moderate anxiety for exams drives
studying
Anxiety for public speaking prompts
thorough preparation
Chronic or excessive anxiety can cause
deterioration of performance and
distracting preoccupation with the agitation associated with anxiety
Sympathetic effects of stress and anxiety
increased muscle tension, digestive problems, sleep disturbance
Escalating anxiety
cycle due to performance decrease and fear of failure (driving further
anxiety)
Anxiety has high comorbidity with depressive disorders and substance abuse 59%
of patients with major depressive disorder have a co-morbid anxiety disorder
Anxiety has high comorbidity with depressive disorders and substance abuse 20%
of patients anxiety/mood disorder patients have a comorbid substance abuse
disorder (esp. alcohol)
Rates of alcohol abuse highest with
social anxiety disorders
GENERALIZED ANXIETY
DISORDER (GAD)
Symptoms of anxiety without identifiable cause
GAD Persistent anxiety most of
each day for prolonged periods (weeks/months)
GAD Constant
worry, predicting, anticipating, or imagining failure or
disastrous events
physical symptoms of GAD (5)
muscle tension and agitation leading to
poor concentration, irritability, and sleep disturbances
PANIC ATTACKS / PANIC
DISORDER
Experiencing physiological effects of fear reactions without
threatening stimulus
PANIC ATTACKS / PANIC
DISORDER Accompanied by strong
sympathetic NS activation
PANIC ATTACKS / PANIC
DISORDER 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
Early anxiolytic and sedative hypnotic
drugs
alcohol & Bromides
Contemporary anxiolytic and sedative
hypnotics
- Barbiturates
- Benzodiazepines
Bromide toxicity
Bromides are sedative possibly through effects on Clbalance in the CNS
Bromides were the first effective
anticonvulsant
Bromides have the side effect of
decreased libido which coincidentally supported the prevailing notion (at the time) that epilepsy was caused by masturbation
- Bromide has a half-life of
~8-12 days making dosing
difficult and intoxication problematic
Bromism results from
bromide toxicity
Bromism results from bromide toxicity (5)
- Impaired thought and memory
- Drowsiness, dizziness
- Irritability, emotional disturbances
- Repulsive skin eruption (rash)
- Bromide psychosis (delirium, delusions, vivid
hallucinations, mania, lethargy, and coma)
Barbital was the first
psychoactive barbiturate synthesized in 1903 and marketed as
Veronal
Barbital found to have
relaxing and sopoforic effects
Barbital Long half-life meant
drowsiness extended for days
Phenobarbital was developed in 1912 and was noted to be
faster acting, of shorter duration, and having excellent anticonvulsant properties
Barbiturates can be classed
according to the
relative
lipophilicity of the compound.
Increasing the lipophilicity of
barbiturates results in
n faster
uptake into the brain and more
rapid sedation
Effects of barbiturates low doses
Anxiolytic and
tranquilizing at low
doses
Effects of barbiturates moderate doses
Sedating and sopoforic
effects of barbiturate’s at high doses
Anesthetic at high doses
Ultrashort-acting barbiturates are
anaesthetic
Ultrashort-acting barbiturates are
anaesthetic - Highly
lipophilic
Ultrashort-acting barbiturates are
anaesthetic - names
Thiopental, hexobarbital
Ultrashort-acting barbiturates are
anaesthetic - IV administration results in
rapid uptake and sleep in 10-20 seconds
Ultrashort-acting barbiturates are
anaesthetic - Unconsciousness lasts ____ and
ends due to
20-30 minutes and
ends due to redistribution of lipophilic
barbiturates into fatty tissues
Short/intermediate-acting barbiturates
are
sedative
Short/intermediate-acting barbiturates
are sedative - Moderate
lipid solubility
Short/intermediate-acting barbiturates
are sedative - names
Amobarbital (Amytal) and pentobarbital
(Nembutal)
Short/intermediate-acting barbiturates
are sedative - Sleep in
20-40 minutes lasting 5-8 hours
Short/intermediate-acting barbiturates
are sedative - termination
depends on liver metabolism
Short/intermediate-acting barbiturates
are sedative - prescribed
for insomnia, high abuse
potential
Long-acting barbiturates are effective at
are effective for treating seizure
disorders and anxiety
Long acting barbiturates have low
lipophilicity
Long-acting barbiturates - names
Phenobarbital, mephobarbital
Long-acting barbiturates - onset
takes 1 or more hours
Long-acting barbiturates - metabolism
slow
Long-acting barbiturates lasting effects
10-12 hours
Side effects and safety margin of barbiturate’s
Anxiolytic effects are accompanied by
cognitive side effects
- Anxiolytic effects of barbiturate’s are accompanied by
cognitive side effects (3)
- Mental clouding
- Loss of judgement
- Slowed reflexes
barbituate Intoxication (high doses) leads to (3)
staggering, jumbled speech, impaired
thinking
barbituates cause
Coma and death due to respiratory
depression
REM and barbiturates
Alterations in REM sleep
barbiturate’s and tolerance
Produce tolerance and dependence resulting in high abuse potential
Safety margin of barbiturate’s
narrows due to
tolerance mechanisms
Despite their hypnotic effects,
barbiturates do not
induce restful
sleep.
sleep - Short term use results in
rapid sleep
onset but decreased Stage 3 & 4 sleep.
Chronic use decreases
REM sleep and
stage 3 & 4 sleep and increases
spontaneous awakenings.
Illicit use
High abuse potential due to rapid tolerance
and dependence
Illicit use * Often used in conjunction with
amphetamines
Often used in conjunction with
amphetamines
Amphetamines during the day (uppers or
pep-pills)
Barbiturates at night (downers or goofballs)
High potential for interactions with
ethanol
Decreasing safety margin with tolerance
leads to
high potential for overdose
Synaptic effects of barbiturates - Barbiturates act at the
GABA-A receptor
at the
barbiturate binding site
Positive allosteric
modulation
barbiturate’s and GABA affinity
Increases GABA affinity
channel open time and barbituates
Prolongs open time
High doses -Synaptic effects of barbiturates
– GABA mimetic (opens GABAA in absence of GABA)
Barbiturate drug effects
Barbiturates are CNS depressants and cause
broad increases in inhibitory neurotransmission
Barbiturate drug effects - Anticonvulsant by
decreasing general
excitability
Barbiturate drug effects - Important effects in the
reticular formation
Pontine
normally activates cortical centres
Medullary
– normally supresses cortical centres
Balance of barbiturate effect in the reticular
formation - Medullary first
euphoria resulting from cortical activation (disinhibitory)
Balance of barbiturate effect in the reticular
formation - pontine first
relaxation, drowsiness, sleep from
cortical depression (inhibitory)
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.
Pentobarbital administration inhibits
NAc dopamine release and can inhibit ketamine induced dopamine release.
Barbiturate tolerance
Tolerance develops through metabolic and pharmacodynamics mechanisms
Metabolic tolerance - enzymes
Barbiturates induce microsomal enzymes leading to greater liver metabolism
Metabolic tolerance: drug dose
Increased drug dose required to achieve same blood levels
Metabolic tolerance - cross tolerance
Leads to cross-tolerance among different barbiturates
Barbiturate tolerance Pharmacodynamic tolerance - cellular
Cellular changes in GABAA receptor function and expression
Pharmacodynamic tolerance - dosage
Greater barbiturate dose required to elicit inhibitory effect
Tolerance to sedative, anxiolytic and hypnotic effects are more
pronounced than tolerance to respiratory
depression
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 tremors of hand, depressed superficial reflexes, depression or mania
Dependence induced by
increasing doses every 12 hours for 92-140 days
Dependence trials resulted in
continuous mild intoxication in
most cases
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
Barbiturate withdrawal - 12-16 hours
12-16 hours after last dose subjects appeared to sober
Barbiturate withdrawal - 24-36 hours
24-36 hours after last dose increasing anxiety and weakness developed
24-36 hours after last dose increasing anxiety and weakness developed
- At peak subjects could not stand unassisted
- Drop in blood pressure – fainting on standing
- Tremors, anorexia, vomiting, abdominal distress, insomnia, weight loss,
increased startle response, hyperreflexia
withdrawal - Significant appearance of
convulsions and psychosis
Rebound hyperactivity
Since barbiturates enhance GABAA
function, rebound results in
hyperexcitability and convulsions
Psychosis developed 3-5 days after
withdrawal lasting as long as
9 days
Psychosis developed 3-5 days after
withdrawal lasting as long as 9 days
- Delirium, agitation, insomnia,
confusion, disorientation, auditory
and visual hallucinations - High BP, temperature, pulse
Withdrawal is typically managed
clinically
Intermediate acting barbiturates replaced with
long acting drug (typically phenobarbital)
Phenobarbital weaned
over a long period to
minimize severity of withdrawal
