Lecture 4: Sedative-Hypnotic and Anxiolytic Medications Flashcards
What are barbiturates, when were they introduced?
What are the mechanisms (effects) of the drug? Is it dose dependent?
Phenobarbital was introduced as sedative in 1912 (originally mechanism was unknown)
Classified by chemical structure
Mechanism: non-selective neuronal depression (reducing overall firing of neurons), depress polysynaptic diffuse brain-stem neuronal pathways (reduce activity between synapses) in the brain stem and cerebral cortex
Yes - dose dependent
From a metabolic standpoint what are the mechanisms of barbiturates? What can u do to measure sugar-use in brain?
Reduce electrical and metabolic activity (what you are doing, brain is running lower/using less energy)
Decreases in whole-brain glucose metabolism (cant break down or use sugars)
Reduction of excitatory activity or increased inhibitory
Give someone shot of radioactive traced glucose to see where it is being consumed in brain during tasks
What is the involvement of GABAa receptors in barbiturate interaction?
What can be a problematic result of interaction?
Hint: Cl-
Enhancement of GABA transmission - applying more breaks, depressing brain activity
Increased Cl- influx accounts for sedative-hypnotic actions, anesthetic properties
Can open Cl- channel in the absence of GABA - not good, GABA is key receptor is lock but barbituates push open the door without GABA
increases toxicity of B (inhibition without control)
High doses can produce amnesia and state of dementia
Therapeutic index is super skinny
What are the components present is demented states?
Sensorium - time and place Affect - expression of feelings Mental content - fund of knowledge Intellectual function - ability to reason Insight and judgement
What are the pharmacokinetics of barbiturates?
What are the differences between short-acting and long-acting barbiturates?
wide range of half-lives (3m - 120hr), after 6 half lives drug is removed
Rapidly and completely absorbed
Short-acting versions are very lipid soluble (BBB, induce sleep)
Long-lasting versions are more water soluble (blood/urine residues) - do not diffuse easily and last longer
What are the pharmacological effects of barbiturates?
Hint: unlike mechanism, think laymen effects or visible
Low degree of selectivity - acts like a big mallet, hits a ton of other receptors Suppression of REM sleep Cognitive inhibition (little dumb) Combination of barbiturates-alcohol can affect respiration, overdose
What are the psychological effects of barbiturates? What happens when combined with alc?
Similar to alc-induced inebriation
Low doses remove anxiety
High doses cause general behavioral depression and sleep
Affects respiration and can cause overdose
What are the principle properties of barbiturates?
Lethal in overdose
Narrow therapeutic range (v little doses allot)
Potential for tolerance, dependence and abuse
possible dangerous interactions
Teratogenic potential (unconfirmed)
“truth serum” - increases suggestibility
How can you distinguish a nonbarbiturate and what are some examples?
Different chemical structure but same effects
Soma, Quaalude (v popular in the 70-80), Paraldehyde
- used as date rape drug but is acc a anaphrodisiac
- banned in 1984 in the US
What are general anesthetics, how are they used? how are they administered? provide some examples
Potent CNS depressants, unconsciousness Low analgesic or euphoriant activity Used in medical settings Administered via inhalation or intravenous injection Nitrous oxide, isoflurane, halothane
Provide 4 examples of injectable anesthetics?
Pentothal, brevital, diprivan, amidate
What is Gamma Hydroxybutyrate (GHB)? what is a similarity? What are some characteristics/uses of the drug?
Is it found in the body?
W: Potent CNS depressant (inhibitory)
Structurally similar to GABA, derived from GABA
GHB increases DA levels in the brain, activates DA reward system
C: Easily crosses the BBB, high abuse potential, foreign availability
Synergistic effects with EtOh - two together are worse than both apart
U: Used as anesthetic, to treat sleep disorders, EtOH detox, also date rape drug
Used to treat narcolepsy (inappropriate levels of da in brain)
Normally found endogenously - body does produce it but not in dosage concentrations
How is GHB classified by the FDA?
both a schedule I and III drug - it is allowed for therapeutic uses but can be illegal if found outside of that context
What is the purpose of antiepileptic drugs? what is an important consideration pertinent to this drug?
Help deal with epileptic seizures
Treatment of bipolar disorders
Neuromodulators: wide array of applications
Chemically belongs to either - barbiturates (phenobarbital), hydantoins (phenytoin)
This drug has teratogenic effects, its important to weigh this against the pro of seizure control - a way to control for this is daily low doses
What is/what are the characteristics of a benzodiazepene? what is the mechanism of action?
next generation barbiturate, anxiolytic, sedative, anticonvulsant
Most widely used psychotherapeutic drug (valium, librium, xanax)
What are the mechanisms of action of a benzodiazepine? Where is the site of action? where are the side effects?
Potent GABA agonist - facilitate GABA binding
Causes influx of Cl- hyperpolarization
Site of action: limbic system
Side effects: ceberal cortex and brain stem
Where do the anxiety, panic, and behavioral responses to fear occur?
amygdala, orbitofrontal cortex and insula
experimented on via stimulation and lesions
In terms of benzos mechanism of A, where does a blockade occur? How does this potentially effect fear levels?
Blockade of GABAergic function in amygdala (blocks GABAs effect on amygdala) - increases amygdala functioning = anxiogenic responses to stimuli (overly scared)
BZ may increase threshold for responsiveness in amygdala - priming fear
How many kinds of bz are available and what are the primary differences between them?
Over 20
Rates of metabolism, active metabolites, plasma half-lives
Peak BAC occurs in 1hr
What is an active metabolite?
results when a drug is metabolized by the body into a modified form which continues to produce effects in the body. Usually these effects are similar to those of the parent drug but weaker, although they can still be significant
What benzos produce active metabolites? what is a metabolite of V?
Valium, librium, centrax
Nordiazepam - half life of 60hrs
What is significant about the use of benzos by the elderly?
Elderly have trouble metabolizing long-acting BZ and their metabolites (blood plasma concentration of the drug can persist)
Lower dosage required (50%) at shorter-acting BZ
Long term use can result in severe cognitive dysfunction
What are the pharmacological effects of benzos?
Mental confusion and amnesia - cerebral cortex and hippocampus
Muscle relaxant effect - spinal cord, cerebellum and brainstem
Antiepileptic actions - cerebellum and hippocampus
Behavioral rewarding effects - ventral tegmentum & nucleus accumbens
What are the clinical uses and issues associated with the use of benzos as treatment?
acts as cognitive inhibitor - may interfere with cognitive therapies
effective at producing anterograde amnesia - can be helpful for surgery sedation (lorazepam)
Typically used for short-term alleviation of anxiety or insomnia
What is rohypnol? uses/characteristics
used in 70s for deep sedation
up to 80% is absorbed by oral application
detectability lost after 72hrs
What are the overall advantages and disadvantages to benzos?
Good: rapid onset, anxiolysis, low-level side effects, good patient acceptance
Bad: impaired psychomotor performance, impaired learning and cognition, reduced alertness, paradoxical agitation, potential for dependence and abuse
What are the fetal effects of benzos?
infant dependence, floppy infant syndrome (low muscle tone)
What is the relevance of flumazenil to bzs?
Binds with high affinity to BZ site on GABAa receptor
Once bound it exhibits no intrinsic activity - once bound it stops doing things
Blocks BZ ability to interact with BZ site
Short half-life (1hr) - good for overdose situations
What are the characteristics of a 2nd generation anxiolytics? what are some examples?
Nonbenzobenzos (not classical structure)
Zolpidem (ambien) - partial agonist (not a tight fit) binds to GABA1a receptor
Used for insomnia, acts as sedative, not an anxiolytic (not for anxiety)
Fine tuned and rapidly absorbed by GI
Zaleplon (sonata) Hypnotic agent Bind to GABA1a receptor very short half-life (1hr) only 30% reaches blood plasma, sleep onset
What is a serotonergic anxiolytic? where is the second focus located?
Attention on presynaptic 5-HT transporter and postsynaptic 5-HT1a receptor
5-HT1a receptor: hippocampus, septum, amygdala, dorsal raphe nucleus
What is busporin? what does the activation of 5-HT1a do?
Anxiolytic with little hypnotic action
Low levels of amnesia
No additive effects with EtOH
Low dependence
Activation of 5-HT1a keeps anxiolytic balance
