Chapter 12: CNS Depressant Drugs Flashcards
what type of receptors are GABA a receptors?
ligand ion channels
when GABA binds to GABA A receptors it causes an opening of the channels and ___ions enter, resulting in membrane ___
Cl-; hyperpolarization
when cl hyper polarizes the cell after GABA a activation, does this make the cell more or less excitable?
less
when GABA binds to GABA A receptors, the opening of the channel is ___ and will close once __
transient; GABA dissociates
when GABA A channels are exposed to GABA for a prolonged period of time, what happens to them?
they inactivate
there are ___ known allosteric binding sites on GABA A receptors
several
benzodiazepines, zolpidem and barbiturates are all __ modulators of GABA
positive allosteric
flumazenil is a ____ that competes with benzodiazepines at the GABA A receptor
allosteric antagonist
allosteric modulators act in a ____ way with the endogenous agonist
non-competitiive
when GABA A receptors become inactivated, it requires ____ before it can be reactivated
removal of GABA
most drugs acting on GABA A receptor are ____ modulators of GABA actions
positive allosteric
barbiturates such as phenobarbital bind GABA A and increase ___
duration of channel opening
when benzodiazepines and Z-hypnotics bind to the GABA A, they influence the ___ of the channel
frequency of opening
compare the Cl influx into GABA A when bound to barbiturates and benzos/Z-hypnotics
benz/Z: burst-like entrance of Cl
barb: more prolonged entrance of Cl
what is propofol?
anesthetic with similar activity to barbiturates
do benzo’s/Z-hpnotics, barbiturates, and propofol all bind to the same allosteric site on the GABA A receptor?
no, all different
the effects of GABA A modulators are ___ dependent
dose
at low to moderate doses, the effects of GABA A modulators are similar: ___ and ___
sedation and hypnosis (Sleep)
at higher doses, GABA A modulators induce ____ and many are used in combinations for ___
anesthesia; surgery
at high doses, barbiturates can open GABA A w/o GABA present, which has a higher risk of ___
over-activation of GABA A, leading to coma or death
increasing amounts of GABA, increases the amount of ___ ion entering the neuron
Cl
at high doses, can barbiturates still open GABA A channels even if no GABA is present? Can benzodiazepines?
yes; no
what are 2 examples of barbiturates?
pentobarbital and phenobarbital
why are barbiturates not used very often today?
largely replaced by Benzodiapenes which have better safety
give 2 examples of where barbiturates are still used today
anti seizure and surgical anesthesia
barbitaues are typically very ___ (hydrophilic / lipophilic) and have ___(high/low) distribution through the CNS
lipophilic; high
prolonged duration of action for barbiturates may be observed in patients with ___
poor organ function (renal / hepatic) and old age
barbiturates are known to induce ___ enzymes, including those involved in ____ metabolism
CYP450 enzymes; their own
t/f there are MANY drug-drug interactions with barbiturates
true
barbiturates are primarily metabolized by the ___
liver
barbiturates are primarily excreted by the __
renal system
barbiturates are absorbed ___ (slowly/rapidly)
rapidly
give 4 examples of benzodiazepines
diazepam, alprazolam, oxazepam, lorazepam
the differences among benzodiazepines stems from differences in the ways they are ____
metabolized
t/f all benzodiazepines have the same MOA
true
lorazepam has ___ (#) active metabolites, undergoes phase __ metabolism and is excreted by the __
0; 2; urine/kidneys
alprazolam has ____(#) active metabolites formed by phase 1 metabolism, which means each dose lasts as long as __
some; the active metabolites are present
diazepam has ___(#) active metabolites, including ___which can also be given on its own
several; oxazepam
diazepam has a very ____duration of action. Why?
long; has many active metabolites that all need to be cleared before effect wears off
___ is an example of a benzodiazepine pro-drug
clorazepate
on its own, clorazepate is not active @ GABA, but when hydrolysed in the stomach, it become the active ___
desmethyldiazepam
what type of benzodiazepines have active metabolites?
long-acting
how many active metabolites does oxazepam have?
none
clorazepate is activated in the stomach and has been seen to be activated less when the patient is also taking __
antacids
Z-hypnotics are a ___ class of agents that were designed specifically to act as __
newer; sleep aides
in patients with insomnia or disrupted sleep, sleep cycles can be __ and can result in the patient feeling ___ and may result in __ issues
irregular; unrested; cognitive
how do Z-hypnotics work?
act to speed up onset of sleep to reestablish sleep cycles
Z-hypnotics bind to similar but different sites on the GABA as ___
benzodiazepines
z-hypnotics increase the ___ of GABA channels
opening frequency
Z-hypnotics are similar to many benzodiazepines in theta they have ___ onsets of action and ___ duration of action
fast; short
why do z-hypnotics and many benzodiazepines have rapid onset and short duration?
no active metabolites
the onset and duration of z-hypnotics compared to benzo
faster and shorter
what is the onset time for z-hypnotic?
1-3 hours
what is the duration for z-hypnotics?
1.5-3 hours
z-hypnotocs are metabolized by ___ enzymes
CYP3A4
the presence of ____ can prolong the duration of action for z-hypnotocs
inhibitors
theoretically, benzodiazepines, z-hypnotics, and barbiturates can all cause sedation, hypnosis ad anesthesia, however in most practical cases, the therapeutic indications between them are delineated based on ___ properties of the agents
kinetic
at low doses, benzodiazepines have ___ and ___ effect
sedative and anxiolytic
whether z-hypnotics, benzodiazepines, and barbiturates have a sedative, hypnotic, or anesthetic outcome is based on the ___ given
dose
in anesthesia, we want rapid onset and predictable duration, meaning the drug used should g=have no ___
active metabolites
give 2 examples of drugs used as anesthetics
midazolam and propofol
t/f the retrograde amnesia effects of anesthesia are often beneficial
true
what are the 4 stages of CNS depression and anesthesia?
- analgesia
- excitement/delirum
- surgical anesthesia
- medullary depression and death
surgical anesthesia occurs when the CNS is suppressed to the point where a patient is ___ and ___
non-responsive to verbal commands (unconscious) and feeling is lost
if CNS depression goes beyond the level of surgical anesthesia, ___ and ___ become impaired and ___ will happen if intervention is not made
respiration and brain function; death
why are surgical anethtics typically given by continuous IV
want rapid onset and predictable duration
midazolam and propofol are typically used in surgical anesthesia bc they have ___
short duration of action
general anesthetics act to dress the CNS by either ___ or __
increasing inhibitory input or decreasing excitatory input
what are 2 ways gaseous anesthetics such as NO and desflurane are believed to work
- interact w/ membrane proteins to influence neuron excitability
- interact w/ ion channels such as nicotinic Ach receptors to reduce excitably of neuron
the precise MOA and interactions of gaseous anesthetics is ___
unclear
give 3 examples of IV anesthesia cocktails
- propofol
- benzodiazepines
- opioids
the effects of inhaled anesthetics are ___ dependent
dose
at moderate doses, nitrous oxide causes __
delirium effects (laughing gas)
nitrous oxide is useful in what type of procedures?
minor; such as dentistry, where full anesthesia is not needed, but is beneficial to have patient less aware
in most cases during surgery, both ___ and ___ types of anesthesia and used and are monitored closely by the anesthesiologist
inhaled and IV
most ADR of sedatives are related to extensions of their ____
pharmacologic effects
moderate CNS depression can cause __ and higher doses can cause
amnesia; cognitive and respiratory impairment
benzodiazepine OD can be reversed by __
flumazenil
flumazenil is a ___ of the benzodiazepine GABA A receptor
competitive antagonist
flumazenil cannot reverse the OD of __ or ___
barbiturates or other binding site of the GABA A
additive sedative effects can occur when patients take multiple drug with this type of action and this can be hard for HCW to control bc ___
many don’t require an Rx (such as alcohol)
ethanol is ___ in size and has ___ CNS actions
small; many
ethanol has ___ (high/low) penetrance of th eCNS
high
ethanol is known to CNS suppressive effects similar to __ and __
sedatives and general anesthesia
ethanol interacts with many ___ pathways and ___ processes
NT; cellular
ethanol has particularly high effects on __ and __
GABA and NMDA
ethanol ___ the effects of GABA A
enhances
ethanol ___the effects of glutamate s
reduces
what general inhibitory effects are associated with ethanol use?
slowed reaction time, poor coordination, acute cognitive impairment and memory loss
ethanol follows ___ order elimination kinetics, meaning there is a ___ amount of alcohol lost over time
0th; constant
is ethanol elimination concentration dependent?
no
the linear elimination of ethanol is the basis for ___testing and allows extrapolation back to a certain time to see how much alcohol would have been in their blood then
blood-alcohol
ethanol metabolism occurs primarily in the ___
liver
what are the 3 ways alcohol can be metabolized in the liver?
- alcohol dehydrogenase
- aldehyde dehydrogenase
- CYPP450 metabolism by the microsomal ethanol oxidizing system (MEOS)
___ is the primary enzyme responsible for metabolizing ethanol into acetaldehyde
alcohol dehydrogenase
the CYP MEOS pathway for metabolizing alcohol is minor unless
alcohol levels are high
the CYP MEOS pathway is seen more in cases of ___alcoholism and contributes to ___
chronic, tolerance
t/f induction of the CYP enzymes in the MEOS pathways can influence the metabolism of other drugs
treu
once acetlyadehyde is produced, ____ oxidizes it into acetate
aldehyde dehydrogenase
the accumulation of acetaldehyde metabolite causes systemic effects such as :
nausea, facial flushing, headaches and tachycardia
a polymorphism in ___ can cause some people/certain ethnicities to accumulate more acetaldehyde and have more adverse effects of alcohol
aldehyde dehydrogenase
what patient population is most at risk of adverse effects of sedatives? why?
elderly, have impaired clearance and more likely to be taking multiple medications that may result in additive effects
can tolerance to benzodiazepines and z-hypnotics happen?
yes, if used over long period of time
what is one of the possible reasons for tolerance to benzodiazepines / z-hypnotics relating to the GABA receptor?
GABA A receptors can become down regulated
if tolerance is caused by a down regulation of the GABA A can it be fixed by increasing the dose?
no, there are fewer receptors available no matter the dose
what is a non-receptor way that patients can become tolerant to benzodiazepines / z-hypnotics?
increased metabolism to more rapidly clear the drug
if tolerance is caused by increased metabolism, would increasing the dose help?
yes bc more drug would be at the action site and nothing is wrong with the receptor
what is the best practice for avoiding benzodiazepine / z-hypnotic tolerance?
starting at the lowest possible therapeutic dosing (start low, go slow)
what is psychologic dependence?
the patient shows drug-seekiing behaviour, once effect wears off they want more, can lead to misuse or overuse
what type of drugs often are associated with psychologic dependence>
addictive
what is physiological dependence?
involves withdrawal symptoms such as anxiety and agitation that is often worse than original symptoms
physiological dependence is more common when drugs are used for ____ amount of time and drugs with ___ half lives
extended; shorter
why do drugs with shorter half-lives have a higher incidence of physiological dependence?
the drop in effect is more pronounced
