Sedatives Flashcards
What are three big types of sedative hypnotics? what are their properties?
they are depressant drugs that are also able to make you very sleepy
they include:
- benzodiazepines: libruim (the first one), Xanax, Valium, Ativan
- The benzodiazepine-like drugs: zopicione (lunesta), zolpidem (ambien), and zalepion
- Gamma-hydroxybuyrate (and its precursors): GHB
these all increase the effects of GABA in the CNS and depress neuronal excitability
all are used clinically to some degree, including GHB which is used to treat narcolepsy
where does BZD’s bind in GABA receptors? and what are their effects
BZD binding site is seperate from the GABA binding site
it is between the alpha (except 4 and 6) and gamma subunits
they work by increasing the affinity of the receptor for GABA and increase the frequency of channel opening
BDZ’s only exert effects if GABA binds and they cannot directly activate receptors or open the Chloride pore which makes it a property of BZD’s that makes it less dangerous
highest numbers of receptors in the cerebral cortex include in the striatum (where the NA is) and the cerebellum
What is an allosteric effect?
its when a compound binds to one side of a receptor and then increases its affinity for another Neurotransmitter
for example, BZD’s bind to GABA receptors on the alpha and gamma subunits and then once GABA binds to the alpha-beta subunits then it increases affinity for GABA in the entire receptor
what are 4 clinical uses of benzodiazepines?
- sedation/hypnosis (high dose) –> to sedate and induce sleep
- anxiolysis (low doses) –> to reduce anxiety
- muscle relaxant properties (low-medium doses)
- to treat seizures in emergency situations and short term
all doses differ in what kinds of effect it has on you
what was the peak BZD use in western europe and north america and who was it mainly used by?
in 1975, with 10-20% adults taking them on a daily basis mainly stay at home moms
What are the two long-acting benzodiazepines? what was a major issue with these?
chorodiazepoxide (librium) and diazepam (valium)
they have very long half lives about 100-200 hours because they make active metabolites that also have BZD properties
what are the two intermediate-acting benzodiazepines? what are their properties?
Oxazepam (serax) and Lorazepam (Ativan)
these are basically mimicing the metabolites of the long-acting BZD’s in order to reduce the half life. They did this by adding hydroxy groups which allowed the body to metabolize it quicker
but they still have fairly long half lives (about 10 hours)
what are the two short acting benzodiazepines? what are their properties?
Alprazolam (Xanax) and Triazolam (Halycon)
these have three nitrogen groups and have shortest half lives (about 2 - 10ish hours)
You take these to sleep or to prevent panic attacks etc..
Triazolam groups prevent metabolism into active metabolites and speeds up ability of body to get rid of the drug
what are some of the problems associated with the short acting benzodiazepine drugs?
they have a high affinity to gaba-a receptors which is good for sleeping and control anxiety but they have adverse CNS effect because of all of the drugs can cause some type of amnesia and cognitive impairement. these arent that bad when you’re asleep but the amnesia can carry on even after you wake up even after the BDZ has been completely metabolized out of the body
There is also research showing that triazolam and other short acting BDZ’s cause increase in murders and attempted murders by people taking them because it disconnects the pre-frontal cortex to other areas of the brain and results in poor judgement and decision making
What are some of the symptoms and use of BDZ?
besides clinical effects:
- euphoria
- studies show that most people prefer to take placebos over BZD’s and the people who take BZD’s over placebos have a history of drug abuse or opiod ise
- abusers take 40 times more than recommended dose because they build tolerance quickly
- it is linked to impaired driving, car accidents, accidents in general because of the sedative effects
What is the effects of BDZ on memory?
- can cause complete loss of recent events
- Short term memory is not transferred into long term
- memory issues can persists months after discontinuation
- mediated mostly through the alpha-1 subunits of gaba-a receptors
what is Rohypnol (flunitrazepam)? what is it used for typically
it is a date rape drug used to facilitate assult especially when mixed with ethanol and cause extreme sedation and very long term memory loss
What is Floppy Infant Syndrome?
it is the condition that a baby is in when they are born where they have no muscle tone, that can presist for months
this occurs when the mother is taking BZD’s while pregnant. BZD is very lipophilic so it can pass the lipid membrane of the placenta very easily and end up in the fetus. Because fetal liver is not properly formed, the baby ends up getting twice the level of drug than what was in the mother and the drug accumulates significantly
the only negative thing from this is that the baby will lose nutrition when its born because they have no muscle tone to eat and swallow. As long as the baby gets proper nutrition then they will be completely recovered after a month
how does benzodiazepines compare to other drugs of abuse in terms of the break points in experiments?
when using progressive ratios (increasing the number of times that the rat works for the drug) we can discover break points which are the points in which animal will no longer work for the reward
the sooner the break point the less rewarding the drug and the later the break point the more rewarding the drug
BZD’s were neither as strong as cocaine nor a drug that acts through same receptors as morphine (alfentanil)
cocaine had the highest breakpoint following an opiod
What effect does BZD’s have on the reward circuit and GABA-A receptors?
normally, theres gaba-a receptors that contian alpha-1 receptors that are connected to gaba releasing neurons that are not activated in tonic state because the gaba rreceptor is releasing neurons that act on VTA to slow down or shut off its activity and this is balanced with glutamate
when BZD binds on the gaba-a alpha-1 subunit receptors, then it potentiates the GABA binding on the gaba receptor and causes disinhibition of gaba release to the VTA
this causes an imbalance between glutamate and GABA firing on VTA and glutamate takes over the firing
when using an experiment of looking at the firing rate of the gaba releasing neuron when exposed to a BDZ called Midazolam, it was noticed that there was less firing of GABA onto the VTA
when flumazenil (a drug that prevents midazolam from binding to GABA-A receptors) binded to the receptors then GABA was release from VTA and there was no disinhibition showing that BZDs are the culprit in messing up the balance
