Sedative-Hypnotics - Kinder Flashcards
benzo antagonist
flumazenil
sedative
reduce anxiety
-calming effect
hypnotic
drowsiness - facilitate onset of sleep
more pronounced depression of CNS
older sedative-hypnotics
alcohol and barbituates
increased dose - more anesthesia and coma
newer sedative-hypnotics
benzos and other newer drugs
greater dose required for anesthesia and coma
MOA of benzodiazepends
promote GAVA binding - at GABA-A
increased frequency of GABA channel openings
benzos
increased duration of GABA channel opening
barbituate
MOA barbituate
bind GABA-A potentiate GABA Cl current
lower capacity for CNS depression fatality
benzos - have displaced barbituates
can activate GABA channels directly at high dose
barbituate
require presence of GABA
benzos
activation of melatonin receptors MT1 and MT2
ramelteon
all sedative-hypnotics
cross CNS, placental barrier, and breast milk
metabolism of benzos
hepatic
-phase 1 and 2
phase 1 metabolites - active
desmethyldiazepam
active metabolite of chlordiazepoxide, diazepam, and clorazepatate
with t-1/2 of 40 hours
triazolam
short elimination t-1/2
favors use as hypnotic rather than sedative
cummulative toxicity
benzos with long t-1/2 - additive toxicity with multi doses
benzos for pt with liver issues
triazolam
lorazepam
oxazepam
bc not extensive metabolism in liver
hepatic metabolism and unrine glucuronide conjugate excretion
barbituates - except phenobarbitol (20-30% excreted unchanged)
short t-1/2
eszopiclone, zolpidem, zaleplon
alkanized urine
can increase elimination of phenobarbitol
MOA eszopiclone, zaleplon, zolpidem
GABA-A receptor agonists
CYP3A4
phase 1
glucuronidation
phase 2
metabolism of lorazepam, oxazepam, tamazepam
conjugation
good for hepatic impaired pt
metabolism of alphazolam and diazepam
oxiation
fast onset of action
diazepam and alprazolam
GABA-A receptor
two alpha 1, two beta 2, and one gamma 2 subunits
activation - chloride ion to center cell - hyperpolarization
GABA binding receptor
two sites between alpha and beta subunits
binding of benzos and newer hypnotics on GABA
between alpha and gamma
flumazenil binding
between alpha and gamma subunits
-reverse hypnotic effect of zolpidem and benzos
MOA benzos
enhance effect of GABA allosterically
-increased frequency of channel opening
barbituate MOA
increased duration of GABA channel opening
high concentration - directly activate receptor
eszopiclone, zaleplon, zolpidema
agonist at GABA-A receptor - only when alpha 1 subunit is included in receptor
flumazenil
block action of benzos, eszopiclone, zaleplon, and zolpidem
beta-carboline class
negative allosteric modulator of GABA receptor
dose dependent anterograde amnesia effect
benzos
increased total sleep time
eszopiclone
increased total sleep time
eszopiclone
stage 3 general anesthesia
high dose of barbs and older sedative-hypnotics
thiopental and methohexital
lipid soluble - to CNS rapidly - good for anesthesia
IV benzos
for anesthesia
postanesthetic resp depression
long use high dose benzos- long half life and active metabolites that are active
muscle relaxation
diazepam and meprobamate
cause of death with OD of sedative-hypnotics
resp depression
resp and cardiovasular depression of sedative-hypnotics
when given IV
tolerance
decreased responsive to drug after repeated exposure
feature of sedative hypnotics
cross tolerance
tolerance to drugs in same structural or mechanistic class
benzo tolerance
down regulation of GABA-A receptors
- hyperexcitability during withdrawal
- sx of withdrawal
barbituates
stimulate production of hepatic CYPs - rapid removal and breakdown of barbituates
schedule III drug
meducal use allowed - limited potential for dependence
schedule IV drug
medical use accepted - limited dependence possible
physiologic dependence
altered physios tate requires drug admin
anxiety, insomnia, CNS excitabilty
psychologic component of dependence
dependency of mind
-craving, irritable, insomnia, depression, anorexia
to avoid withdrawal symptoms
taper dose gradually over time
drugs with short half lives
sign of withdrawal between doses
ex - triazolam - half life 4 hours - daytime anxiety - when used to treat sleep disorder
MOA flumazenil
competitive antagonist GABA-A receptor
flumazenil t-1/2
short - requires repeated admin of flumazenil
to reverse CNS depression of benzos
adverse of flumazenil
agitation, confusion, dizzy, nausea
can precipitate abstinence syndrome in those physiologically dependent
tx acute anxiety and long term GAD
benzos
tx panic disorders and agoraphobia
alprazolam
more selective in these condictions
tx of GAD and phobias
SSRI and SNRI preferred
acute anxiety state
benzos
benzo pro and con of anxiety tx
pro - high therapeutic index
- have flumazenil fro OD
- low risk DDI
con - risk dependence
- depression CNS function
- amnestic effect
- with ethanol - additional CNS depression
tx sleep problem
zolpidem, zaleplon, eszopiclone - rapid onset of action, short t-1/2 (little hangover)
zolpidem - biphasic - sustained over entire night
trouble falling asleep
zaleplon and zolpidem rapid t-1/2
awaken early and difficulty sleeping through night
eszopiclone - t-1/2 6 hours
failure to remit insomnia after 7-10 days
indicate primary psych or meical illness
muscle spasticity tx
diazepam
withdrawal of ethanol
use drug with longer t-1/2
chlordiazepoxide, diazepam, phenobarb
drug interaction sedative-hypnotic
CNS depressant additive effect
induce P450
phenobarbital and meprobamate
ramelteon
for tx of insomnia due to difficulty with sleep onset
MOA ramelteon
agonist at MT1 and MT2 melatonin receptors
suprachiasmatic nuclei
avoid with ramelteon
coadmin of fluvoxamine (SSRI)
-bc inhibitors of CYP 1A2
endocrine changes
with ramelteon
decreased cortisol
decreased testosterone
increased PRL
buspirone
tx of GAD
take 3-4 week before effective
MOA - unknown
ADR buspirone
tachy, palps, nervous, GI distress, paresthesia, papillary constriction
flumazenil
blocks benzos and zolpidem, zaleplon, eszopiclone
MOA buspirone
unknown
partial agonist at 5-HT receptor and affinity at D2 receptors
ramelteon
extensive first pass