Barbiturates and Benzodiazepines Flashcards
What kind of drugs are they?
What other drugs have similar effects?
What 6 side effects do they cause?
With what do the side effects depend on?
What happens to the CNS effects when you increase the sedative-hypnotic dose of either drug?
What receptors do they bind to & what is the mechanism behind their action?
Dose-dependent sedative-hypnotic drugs - depression of the brain
Alcohol, general anaesthesia
- Sedation
- Anxiolysis (reducing anxiety)
- Hypnosis
- Anticonvulsant (prevent seizures)
- Anaesthesia
- Respiratory depression (fail exchange CO2)
Increasing dose & increasing depression of brain function
Benzodiazepines - central nervous effects will plateau after sedation/anxiolysis to hypnosis -> no further effects
Barbiturates - sedation/anxiolysis, hypnosis, anaesthesia, medullary depression, coma -> CNS system effects increases linearly with dose - doesn’t plateau
Bind to GABA-A at their respective binding sites - increasing their activity by increasing Cl- influx into the neurone
What are sedative-hypnotic drugs used for clinically? 5 uses
What was the first barbiturate?
What was the first barbiturate drug?
2nd drug?
What are the key characteristics of barbiturates required for clinical use?
What is the lipid solubility, duration & use for the following barbiturates:
1. Thiopental & methohexital
2. Amobarbital & secobarbital
3. Phenobarbital & mephobarbital
- Sedation with acute trauma/stress
- Anxiolysis with anxiety disorders (general, PTSD)
- Hypnosis - sleep problems
- Anticonvulsant - epilepsy
- Anaesthesia - surgery
Barbituric acid synthesised in 1864 Adolf von Baeyer - but pharmacologically inactive
Based off barbituric acid - barbital (veronal) in 1904 for insomnia
Phenobarbital 1912 - sedative/hypnotic & later recognised as anticonvulsant
Lipid solubility & action duration - higher lipid solubility = crosses BBB faster & rapid redistribution into fat stores & shorter action duration
- High, short, intravenous anaesthesia
- Moderate, intermediate, surgical anaesthesia & sleep induction/hypnosis
- Low, long, prolonged sedation & seizure control (anticonvulsant)
What were barbiturates initially used for on discovery?
What happened in the 1920s?
Late 1920s & 30s?
What is the problem with barbiturates & dosage?
What is the definition of tolerance?
What happens to the dose-response curve with barbiturates & tolerance for the desired effect?
What happens to the dose-response curve with barbiturates & tolerance for respiratory depression?
What does this show?
What is another problem with barbiturates?
Sedation & hypnosis - sleep cures of patients with psychotic disorders
Used as anticonvulsants - phenobarbital (still used now)
Intravenous anaesthetics - amobarbital, pentobarbital, hexobarbital
High doses lead to medulla depression (controls breathing/respiratory depression) - very narrow therapeutic range as it’s close to a dangerous dose
Adaptive response to prolonged drug use/exposure - means need larger dose to achieve a certain/same effect
Tolerance causes rightward shift - increasing dose required for certain response
Small rightward shift - low safety margin as not as much of a shift with effect
it’s much easier to get respiratory depression from a larger dose for the same desired effect
Drug dependence
what is the definition of drug dependence?
What kind of dependence do barbiturates cause & how?
What other dependence do they cause & what does this cause?
Why is there a potential for drug abuse?
What are barbiturates known as?
What happens when they are taken with psychostimulant?
What happens when they are taken with another depressant?
Physical/psychological state resulting from interaction between drug & organism - characterised by compulsion to take the drug on continuous basis to experience its psychic effects & avoid discomfort of its absence
Psychological dependence - effects on mesolimbic dopamine reward pathway - increased dopamine release from VTA through reward pathway leading to positive reinforcement
Physical - withdrawal symptoms are dangerous/fatal & can induce excitotoxicity (neuronal death due to too much excitation as opposite of Cl-), seizures and cardiac arrhythmias
Low dose has similar effects of alcohol - disinhibition, reduced anxiety, euphoria - desirable effects at low dose can lead to physical & psychological dependence - recreational use
Downers/depressants
Take edge off & prolong its effects
Potential overdose increased
What are the names of the barbiturates:
- Abbotts/blockbusters/nebbies/yellows
- Blue angels/bluebirds/blues
- F-40s/mexican reds/reds
- Christmas trees/trees/rainbows
What several things make barbiturates dangerous?
What are they used for now?
What is the general structural difference between barbiturates & benzodiazepines?
- Pentobarbital
- Amobarbital
- Secobarbital
- Secobarbital & amobarbital
Narrow therapeutic range/low safety margin, tolerance, dependence
Not for sedative-hypnotics - used more for anaesthesia (thiopental) in veterinary medicine & lethal injections in US (pentobarbital)
Barbiturates = 1 ring, benzodiazepines = 2 rings
When were benzodiazepines first developed?
What were the first drugs?
What is the core structure?
Why are BZDs better than barbiturates safety wise?
What are the effects of BZDs?
1950s - Leo Sternbach
Chlordiazeperoxide in 1961 & diazepam/valium 1963
Seven-membered diazepine ring fused to benzene ring
Has the same effects of low-dose barbiturates but diverge at high dose - can’t anaesthetise, less respiratory depression & difficult to overdose
Sedation, anxiolysis, anticonvulsant & Anterograde amnesia (memory loss - can’t form new memories)
What is the therapeutic index?
What is the therapeutic index for BDZ compared to barbiturates?
What are the duration/half-life, active metabolites & uses of the following BDZs:
- Midazolam
- Lorazepam
- Alprazolam
- Diazepam & chlordiazepoxide
- Flurazepam
LD50 (concentration that kills 50% people) / ED50 (potency)
BDZs higher (safer): higher LD50 (higher conc for death) vs potency, whereas barbiturates lower (more dangerous)
- Very short, hydroxylated derivative, hypnosis & intravenous anaesthesia
- Short, none, anxiolytic/hypnotic
- Medium, hydroxylated derivative, anxiolytic & antidepressant
- Long, nordazepam, anxiolytic, muscle relaxant, anticonvulsant
- Long, Desmethyl-flurazepam, anticonvulsant & anxiolytic
What are BDZs used to treat? 7
What is the problem with BDZs?
What is an example?
What are 2 other problems?
- Anxiety disorders
- Affective disorders - with antidepressants
- Insomnia
- Alcohol withdrawal - reducing symptoms
- Neuroleptic-induced movement disorders
- Delirium (worsening mental state)
- Aggressive behaviour with SCZ/psychotic disorders
Tolerance - need larger dose for same effects but more of an issue with anticonvulsant properties
Diazepam used to prevent pentylenetetrazol-induced seizures - requires increasing dose for anticonvulsant effect due to prolonged use
- Physical dependence - somatic withdrawal symptoms - less severe than barbiturates
- Physiological dependence - increased dopamine release from VTA neurones along mesolimbic reward pathway
How are BDZs subject to drug abuse?
How addictive is it?
Is it harmful?
What lead to a decline in BDZ use?
Are BDZs still prescribed?
Why are BDZs a problem in older people?
What kind of modulators are BDZ/barbiturates to GABA-A receptors?
Negative reinforcement of withdrawal symptoms & positive calming effect/increased dopamine release
Less than barbiturates (heroin) & cocaine
Less than barbiturates
NHS lawsuit against drug manufacturers La Roche in 1980s/90s due to high cost of people using chlordiazepoxide & diazepam - decreased use of hypnotics BDZs
Carefully against anxiety & epilepsy with guidelines to avoid dependency but mostly replaced e.g with SSRIs for anxiety treatment
Increase motor incoordination/balance problems
Positive allosteric modulators - bind on regulatory sites
What do BDZs/barbiturates do to neurone activity?
How does diazepam open GABA-A channels?
How does phenobarbital open GABA-A channels?
What happens to GABA-A receptors in presence of high [barbiturate]?
What happens at even higher concentrations?
Increase inhibition (action potential) & dampen activity
Increase frequency of open bursts - not duration
Increases duration of open bursts - not frequency
Open GABA-A receptors in absence of GABA by direct activation
Can inhibit the receptors completely
What is required on the GABA-A receptor for BDZs to bind?
What key residue is the determinant of BDZ binding?
Which subunits do not have this?
What does mutating the key residue do?
Therefore, what does this conclude about BDZs?
What did Tan et al 2011 do to identify the different physiological effects caused by BDZ modulation?
What were their conclusions?
How can you use these findings?
alpha & gamma subunit as binding site is at the interface between
H101 of a1,2,3,5
a4,6 as have arginine R instead R101
H101R of a1,2,3,5 removes sensitivity to modulation by BDZs (allosteric modulation)
Show GABA-A subunit selectivity
Mutated H101R in different a subunits in transgenic mice
a1 receptors important for sedation, a2 important for anxiolytic effects
Make BDZs that target specific receptor subunits for their desired effects e.g can mediate anxiolysis without sedation
What other drug binds to the BDZ binding site on GABA-A?
How do they act?
What are they used to treat?
Z drugs - Zopiclone, Zolpidem, Zaleplon
Sedatives/hypnotics - bind to increase inhibition too
Insomnia - marketed in 1990s
What other drug binds to the BDZ binding site on GABA-A?
How do they act?
What are they used to treat?
BZD antagonists - flumazenil/anexate
Binds to BZD site not no PAM effect (positive allosteric modulation) - acts as competitive antagonist so blocks effects of BZDs ligands
Reverse sedation after surgery & antidote in BZD overdose
What is pharmacodynamic tolerance?
What is the difference of barbiturates effects at high & low doses?
How is the amygdala important with BDZs?
How is this confirmed?
How did Paulus et al 2005 to test lorazepam dose-dependant amygdala activation?
What do patients with PTSD/social anxiety show in their amygdala activity?
What was the result of using lorazepam?
What do patients with panic disorder have less of?
CNS neurones adapt to presence of drug & become less responsive with chronic/prolonged drug use
High - global depression in activity
low - effects on specific brain areas/circuits
Animals with no amygdala function exhibited no anxiolytic effects from BZDs
fMRI studies - relating amygdala function with anxiety
used BOLD fMRI & modified emotion face assessment task to determine whether attenuation would occur with negative emotional faces (angry/fear) or positive emotion faces (happy)
Amygdala activity is hyperresponsive to fearful/angry faces
Decreased amygdala hyperresponsiveness to negative faces
BDZ receptor binding sites in left hippocampus & precuneus
What did lorazepam to do hippocampal activity?
What is linked with BZDs/barbiturates & the hippocampus?
What did Franks 2008 conclude?
How come?
What state does anaesthesia induce & how?
Reduces activity & performance in memory task
Inability to make memories, sedation/anaesthesia & loss of consciousness
The drugs might switch off hypothalamic arousal centres - which are inactive during sleep
Sleep initiation/maintenance is an active process - exerts inhibitory control over arousal nuclei through GABAergic inhibition from hypothalamus & basal forebrain - inhibition of arousal nuclei positive inhibitory feedback disinhibits sleep promoting centres - enhancing their firing & activating sleep
Reduced arousal & responsiveness - GABA-A receptor & 2PK channels in sleep/anasthesia
