Topic 23: Barbiturates

Question 1

What are anxiolytic sedative hypnotics?

Answer 1

reducing anxiety or tranquilizing

calming, relaxing, or sleep inducing

sleep inducing or sopoforic

Question 2

What is anxiety?

Answer 2

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

Question 3

In what ways can anxiety be beneficial?

Answer 3

acute anxiety in response to stressors can be beneficial

moderate anxiety for exams drives studying

anxiety for public speaking prompts thorough preparation

Question 4

What is stress and anxiety?

Answer 4

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

Question 5

What is generalized anxiety disorder?

Answer 5

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

Question 6

What are panic attacks and panic disorder?

Answer 6

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

Question 7

What are contemporary anxiolytic and sedative hypnotics?

Answer 7

barbiturates
benzodiazepines

Question 8

What is bromide toxicity?

Answer 8

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

Question 9

What are barbiturates?

Answer 9

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

Question 10

What are the effects of barbiturates?

Answer 10

anxiolytic and tranquilizing at low doses

sedating and sopoforic at moderate doses

anesthetic at high doses

Question 11

What are ultrashort-acting barbiturates?

Answer 11

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

Question 12

What are short-intermediate-acting barbiturates?

Answer 12

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

Question 13

What are long-acting barbiturates?

Answer 13

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

Question 14

What are the side effects and safety margin of barbiturates?

Answer 14

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

Question 15

What are the sleep disturbance effects of barbiturates?

Answer 15

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

Question 16

What is the illicit use of barbiturates?

Answer 16

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

Question 17

What are the synaptic effects of barbiturates?

Answer 17

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)

Question 18

What are barbiturate drug effects?

Answer 18

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)

Question 19

What is the mechanism of barbiturate abuse?

Answer 19

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

Question 20

What is metabolic tolerance to barbiturates?

Answer 20

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

Question 21

What is pharmacodynamic tolerance to barbiturates?

Answer 21

cellular changes in GABAA receptor function and expression

greater barbiturate dose required to elicit inhibitory effect

Question 22

What is barbiturate dependence?

Answer 22

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

Question 23

What are the results of barbiturate dependence trials?

Answer 23

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

Question 24

What is barbiturate withdrawal?

Answer 24

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

Question 25

What is rebound hyperactivity in barbiturates?

Answer 25

pharmacological tolerance results in rebound hyperactivity on withdrawal

since barbiturates enhance GABAA function, rebound results in hyperexcitability and convulsions

psychosis developed 3-5 days after withdrawal lasting as long as 9 days: delirium, agitation, insomnia, confusion, disorientation, auditory, and visual hallucinations, high blood pressure, temperature, pulse

life-threatening aspects of withdrawal syndrome

Question 26

Why does barbiturate dependence need to be clinically managed?

Answer 26

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