Gibbs: Benzos and sleep Flashcards
(46 cards)
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
