Gibbs: Benzos and sleep Flashcards
benzos are CNS _____
depressants
how are benzos different from other CNS depressants?
the CNS depression produced by benzos plateaus BEFORE achieving coma or lethal respiratory depression
different uses for benzos
sedation, acute anxiety, acute memory loss for surgery, hypnotic (sleep), anesthesia, anti-seizure, muscle relaxation
general characteristic structure of benzos
3 rings
ring A must be aromatic
(important for interaction with aromatic amino acids of the receptor protein)
increase activity if C7 substituent electronegative
substituents at C6,8,9 reduce activity
some structural characteristics of diazepam
ring A has electronegative Cl at C7
small alkyl group attached to N1 of ring B (increased agonist activity)
has a keto group at C2: this portion binds with the receptor histidine residue and acts as a proton acceptor
some structural characteristics of oxazepam
hydroxyl at C3 changes the elimination pattern (faster excretion)
some structural characteristics of midazolam
electron withdrawing halogen in position 2’ (ortho) of ring C: increases agonist activity
if substituent was in para position, would decrease agonist activity due to steric hindrance
key point of the general benzo structure & substitutents
the substituents are what affects potency & half life
short acting benzos
triazolam
midazolam
brotizolam
flurazepam
intermediate acting benzos
alprazolam
lorazepam
lormetazepam
oxazepam
temazepam
chlordiazepoxide
estazolam
long acting benzos
clobazam
clonazepam
clorazepate
diazepam
flunitrazepam
quazepam
what is the benzo target
GABAa receptor
general description of GABAa receptor
a macromolecular complex made up of 5 subunits forming a Cl- channel
20 diff subunits have been identified but primarily consist of alpha, beta, gamma
where does GABA bind on the receptor?
between the alpha and beta subunits
where do benzos bind on the receptor?
they bind between the alpha and gamma subunits– making them positive allosteric modulators (NOT receptor agonists as they don’t bind to GABA binding site)
how many molecules of GABA are required to activate the receptor
2
what happens upon activation of GABA receptor
increases Cl- conductance which increases the threshold to produce an action potential
benzos shift the GABA dose-response curve to the ___
left
which increases the frequency of channels opening
what accounts for the differences among benzo effects that are observed clinically
the existence of multiple receptor subtypes
BZ1 is responsible for?
sedation, amnesia, possibly antiseizure
BZ2 and BZ3 are responsible for?
anxiolytic and muscle relaxant properties
BZ5 is responsible for?
learning, memory effects
what are some other compounds that bind to the GABAa-chloride channel complex?
-endogenous compounds like allopregnanolone, DHEA
-BZ antagonist flumazenil
-selective BZ1 receptor agonists (Z drugs- selective sedative/hypnotic actions)
-general anesthetics etomidate and propofol
-ethanol and barbiturates
some characteristics to know for barbiturates
bind at a different site on the GABAa complex to facilitate GABA effect & increase chloride conductance: only alpha and beta subunits are required for action. can have effect on their own WITHOUT the presence of GABA. can lead to respiratory depression/death
increase duration of hyperpolarization as opposed to frequency
shift GABA dose response curve to the left and increase its maximum height
points to know for benzo kinetics
rapidly absorbed after PO admin; rapidly distributed to brain/spinal cord after IV admin
depending on lipophilicity, can also rapidly distribute to fat–> leads to rapid termination of CNS effect following acute IV dose (diazepam)
downside of diazepam
less than 30 minute duration, downside to use for seizures
key points for lorazepam kinetics
less lipophilic than diazepam, so slower onset & slower redistribution into fat= longer duration of effect. better for acute treatment of seizures
key points for clorazepate kinetics
prodrug for nordiazepam
hydrolyzed into stomach to active metabolite then rapidly & completely absorbed
used to treat anxiety, can combo w/ other medications to treat seizures
benzo metabolism key points
phase 1 N-dealkylation or hydroxylation (CYP), phase II glucuronidation
many have active metabolites which makes it hard to correlate therapeutic effects with blood levels
benzo adverse effects
respiratory depression (really bad when combined with other CNS depressants like opioids)
the elderly are more sensitive: better to use drugs with intermediate t1/2 and no active metabolites (lorazepam, oxazepam, temazepam)
TOLERANCE common with chronic use
unlike barbiturates, benzos do not ______
induce their own metabolism
benzo discontinuation syndrome
rebound symptoms within hours or days: anxiety, insomnia, muscle tension, seizures, suicidality
severity is proportional to magnitude of dose & duration of treatment
the onset depends on BZ half life (short like alprazolam is especially severe– whereas long half life like chlordiazepoxide is self tapering)
benzo drug interactions
other CNS depressants: alcohol, opioids, insomnia drugs, fluoroquinolones
CYP inhibitors like chlorpromazine, PPIs, specific antibiotics & antifungals
names of the z drugs
zolpidem, zaleplon, eszopiclone
definition of z drug and how do they act
a group of hypnotic drugs that bind to the BZ receptor, but are not benzos. they are used to facilitate onset & maintenance of sleep. they are selective BZ1 agonists
zolpidem & zaleplon pearls
selective BZ1 agonists: produce sedation
minimal muscle relaxation, antiepileptic, antianxiety.
indicated for sleep onset insomnia
eszopiclone pearls
active S(+) isomer of zopiclone, classified as BZ1 agonist though some claim it binds to a different site, used for treatment of insomnia
z drugs boxed warning
sleepwalking, sleep driving, and engaging in other activities while not fully awake: has resulted in death. z drugs are contraindicated in people who have previously experienced these behaviors after taking.
which drug is a BZ antagonist
flumazenil
what is flumazenil for
to hasten recovery postop or treat BZ overdoses
however it can cause withdrawal in BZ dependent patients
what is different about the metabolism of lorazepam
no active metabolites
active metabolites of alprazolam & triazolam
alpha hydroxy metabolies
active metabolites of diazepam, prazepam, and chlorazepate
desmethyldiazepam
oxazepam
what are the active metabolites of chlordiazepoxide
desmethylchlordiazepoxide
demoxepam
desmethyldiazepam
oxazepam
active metabolites of flurazepam
hydroxyethyl flurazepam
desalkyl flurazepam
which benzos are better for old people
LOT
lorazepam
oxazepam
temazepam
