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neurology/psychiatry > Gibbs: Benzos and sleep > Flashcards

Gibbs: Benzos and sleep Flashcards

1
Q

benzos are CNS _____

A

depressants

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2
Q

how are benzos different from other CNS depressants?

A

the CNS depression produced by benzos plateaus BEFORE achieving coma or lethal respiratory depression

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3
Q

different uses for benzos

A

sedation, acute anxiety, acute memory loss for surgery, hypnotic (sleep), anesthesia, anti-seizure, muscle relaxation

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4
Q

general characteristic structure of benzos

A

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

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5
Q

some structural characteristics of diazepam

A

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

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6
Q

some structural characteristics of oxazepam

A

hydroxyl at C3 changes the elimination pattern (faster excretion)

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7
Q

some structural characteristics of midazolam

A

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

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8
Q

key point of the general benzo structure & substitutents

A

the substituents are what affects potency & half life

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9
Q

short acting benzos

A

triazolam
midazolam
brotizolam
flurazepam

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10
Q

intermediate acting benzos

A

alprazolam
lorazepam
lormetazepam
oxazepam
temazepam
chlordiazepoxide
estazolam

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11
Q

long acting benzos

A

clobazam
clonazepam
clorazepate
diazepam
flunitrazepam
quazepam

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12
Q

what is the benzo target

A

GABAa receptor

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13
Q

general description of GABAa receptor

A

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

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14
Q

where does GABA bind on the receptor?

A

between the alpha and beta subunits

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15
Q

where do benzos bind on the receptor?

A

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)

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16
Q

how many molecules of GABA are required to activate the receptor

A

2

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17
Q

what happens upon activation of GABA receptor

A

increases Cl- conductance which increases the threshold to produce an action potential

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18
Q

benzos shift the GABA dose-response curve to the ___

A

left
which increases the frequency of channels opening

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19
Q

what accounts for the differences among benzo effects that are observed clinically

A

the existence of multiple receptor subtypes

20
Q

BZ1 is responsible for?

A

sedation, amnesia, possibly antiseizure

21
Q

BZ2 and BZ3 are responsible for?

A

anxiolytic and muscle relaxant properties

22
Q

BZ5 is responsible for?

A

learning, memory effects

23
Q

what are some other compounds that bind to the GABAa-chloride channel complex?

A

-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

24
Q

some characteristics to know for barbiturates

A

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

25
Q

points to know for benzo kinetics

A

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)

26
Q

downside of diazepam

A

less than 30 minute duration, downside to use for seizures

27
Q

key points for lorazepam kinetics

A

less lipophilic than diazepam, so slower onset & slower redistribution into fat= longer duration of effect. better for acute treatment of seizures

28
Q

key points for clorazepate kinetics

A

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

29
Q

benzo metabolism key points

A

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

30
Q

benzo adverse effects

A

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

31
Q

unlike barbiturates, benzos do not ______

A

induce their own metabolism

32
Q

benzo discontinuation syndrome

A

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)

33
Q

benzo drug interactions

A

other CNS depressants: alcohol, opioids, insomnia drugs, fluoroquinolones
CYP inhibitors like chlorpromazine, PPIs, specific antibiotics & antifungals

34
Q

names of the z drugs

A

zolpidem, zaleplon, eszopiclone

35
Q

definition of z drug and how do they act

A

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

36
Q

zolpidem & zaleplon pearls

A

selective BZ1 agonists: produce sedation
minimal muscle relaxation, antiepileptic, antianxiety.
indicated for sleep onset insomnia

37
Q

eszopiclone pearls

A

active S(+) isomer of zopiclone, classified as BZ1 agonist though some claim it binds to a different site, used for treatment of insomnia

38
Q

z drugs boxed warning

A

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.

39
Q

which drug is a BZ antagonist

A

flumazenil

40
Q

what is flumazenil for

A

to hasten recovery postop or treat BZ overdoses

however it can cause withdrawal in BZ dependent patients

41
Q

what is different about the metabolism of lorazepam

A

no active metabolites

42
Q

active metabolites of alprazolam & triazolam

A

alpha hydroxy metabolies

43
Q

active metabolites of diazepam, prazepam, and chlorazepate

A

desmethyldiazepam
oxazepam

44
Q

what are the active metabolites of chlordiazepoxide

A

desmethylchlordiazepoxide
demoxepam
desmethyldiazepam
oxazepam

45
Q

active metabolites of flurazepam

A

hydroxyethyl flurazepam
desalkyl flurazepam

46
Q

which benzos are better for old people

A

LOT
lorazepam
oxazepam
temazepam

neurology/psychiatry (22 decks)

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