Kruse Sedative-Hypnotics Flashcards
Dose dependent depression of CNS function: What are the curves of barbituates and alcohol v. benzos and new hypnotics?
Which has steeper dose-response curve?
Barbituates/alcohol have a linear and **steeper increase making them more dangerous than curved plateau of benzos/newer hypnotics.
CNS effects with increasing dose: Sedation to hypnosis to anesthesia to coma.
MOA of ___:
Bind to specific allosteric GABA-A receptor subunits at CNS synapses enhancing increase in FREQUENCY of GABA-mediated ___ ion channel opening; enhance membrane hyperpolarization.
They increase frequency of channel openings by shifting the dose-response curve to the left. This means what?
Benzodiazepines
GABA mediated Chloride ion channel opening (increase FREQUENCY)
Shift dose response curve to the left means that less GABA required to activate the receptor
These clinical symptoms dictate use of what drug? Anxiety, hypnosis, night terrors and sleepwalking, spasticity, anticonvulsant for status epilepticus, alcohol detoxification (eg, DTs), general anesthesia
Benzos
MOA of___:
Facilitate GABA-A action by increasing the DURATION of __ channel opening
Barbituates - chloride
MOA of misc nonbenzo sedative-hypnotics:
- eszopiclone, zaleplon, and zolpidem
- ramelteon
- affect alpha1 subunit of GABA-A receptors (like benzos)
- activates MT1 and MT2 receptors
All sedative-hypnotics cross into three areas.
CNS (BBB), placental barrier, breast milk
Absorption of sedative-hypnotics depends on what solubility.
Metabolization of sedative-hypnotics (esp benzo and newer hypnotics) depends on what?
lipid solubility
metab depends on liver CYP3A4
Triazolam, thiopental, and newer hypnotics - relative lipid solubility and what this means for onset.
very soluble, so fast acting (good for anesthesia)
CYP__ for hepatic metabolism of benzos. Most undergo Phase __ reactions.
Are benzos with longer half lives or shorter half lives more likely to cause cumulative effects (drowsiness)?
CYP3A4
Phase 1 >Phase 2 (glucuronidation)
Longer 1/2 live has more cumulative dose (think postanesthetic respiratory depression).
Patient with a preexisting disease needs benzo for anxiety, so you give oxazepam and lorazepam? What condition are these indicated?
Because oxazepam and lorazepam only have to go through one hepatic metabolization step before being excreted.
The only barbituate excreted unchanged (not as a glucuronide conjugate). What pH can change its elimination rate?
Phenobarbital
Alkalinization of urine can increase elim rate.
Biotransformation of eszopiclone, zolpidem, zaleplon is through CYP___
CYP3A4
Phenobarbital (barbituate) and meprobamate (new sedative-hypnotic drug) have what special characteristic that affects bioavailability.
They can INDUCE hepatic CYP450 after long-term use, which can increase their/other drug metabolism.
Two fastest onset benzos.
Three int/longer onset benzos.
What does this mean for admin to patients with addiction problems?
Fast: Alprazolam and Diazepam (also, clorazepate and flurazepam) –> addictive
Slower: clonazepam, lorazepam, oxazepam –> not as addictive
GABA-A receptors are responsible for most ___ transmission in the CNS
inhibitory (CNS influx into neuron = polarization)
Benzos and Barbituates:
Cl influx –> _(hypo/hyper)__polarization of neurons —> _(increased/decreased)__ number of AP = ___ state of CNS
Cl influx –> HYPERpolarization of neurons —> DECREASED number of AP = DEPRESSED state of CNS
Flumazenil (antagonist) blocks the actions of benzos, eszopiclone, zaleplon, and zolpidem. But it does not block what three things with different binding sites?
Barbituates, meprobamate, ethanol, meprobamate, buspirone, ramelteon
Anxiety treated by S-H induced ___.
Hypnosis induces ___
sedation
sleep
persistent postanesthetic respiratory depression de to what drug class?
Benzos, which have long half lives
eszopiclone, zaleplon, and zolepidm have what anticonvulsant activity?
none
Drug that binds to benzo binding site on GABA-A receptors and acts as a competative antagonist
Flumazenil.
Drug used to treat benzo overdose and shorten recovery following benzo anesthetic
Flumazenil
Concomitant treatment of anxiety:
____ on short term relief (acute panic attacks)
____ for long term treatment
Short term - benzo
Long term - SSRI
Two risks of using benzos for sleep problems.
Can cause daytime sedation
Risk of developing tolerance and anterograde amnesia.
Most commonly used agents for sleep problems:
- which for helping fall asleep
- which for helping staying asleep
Help falling asleep - zaleplon and zolpidem OR ramelteon
Help staying asleep - eszopliclone
What class is contraindicated in porphyria?
barbitates
Ramelteon MOA
do not admin with what SSRI?
Agonist at MT1 and MT2 receptors in suprachiasmic nucleus of the brain.
Fluvoxamine inhibits CYP1A2
Drug used for generalized anxiety disorder that does not cause sedation, hypnotic, euphoric, anticonvulsant, or muscle relaxant effects (limited psychomotor impariment, making it less addictive).
What is the onset - fast or slow?
buspirone
Slow onset - 1 to 2 weeks
(AE=tachycardia, palpitations, nervousness, GI distress, paresthesias, dose dependent papillary construction)
Drug used for short term relief of anxiety and sedation. But has a high abuse and dependence potential.
Meprobamate
Toxicities/risk of ___:
extensions of CNS depressant effects. Dependence liability
benzos
Toxicities/risk of ___:
Toxicity shows agitation,
confusion. Possible withdrawal
symptoms in benzodiazepine dependence
flumazenil
Toxicities/risk of ___:
Toxicity shows extensions of
CNS depressant effects. Dependence liability greater than benzodiazepines
Interactions: additive CNS depression with ethanol and many other drugs Induction of hepatic drug metabolizing enzymes
barbituates
Toxicities/risk of \_\_\_: Toxicity shows extensions of CNS depressant effects Dependence liability Interactions: additive CNS depression with ethanol
eszopliclone, zaleplon, zolpidem
Toxicities/risk of ___:
Toxicity shows dizziness, fatigue, endocrine changes
Interactions: Fluvoxamine inhibits metabolism
ramelteon
Toxicities/risk of ___:
Toxicity shows tachycardia,
paresthesias, gastrointestinal distress
Interactions: CYP3A4 inducers and inhibitor
buspirone
