Kruse DSA: Sedative Hypnotics Flashcards
What are the benzos that DONT end is pam or lam?
- Chlordiazepoxide
- Clorazepate
Benzo antagonist
-Flumazenil
Barbiturates
- end in “bital”
- except for Thiopental
What are the newer sedative-hypnotic drugs?
- Buspirone
- Exzopiclone
- Meprobamate
- Ramelteon
- Zaleplon
- Zolpidem
What is a sedative?
- a drug that decrases CNS activity, moderates excitement, and calms the recipient
- Anxiolytic because it reduces anxiety
What is a hypnotic?
- a drug that produces drowiness and facilitates the onset and maintenance ofa state of sleep
- recipient can be aroused easily from it
MOA of benzodiazepenes?
-promote the binding of major inhibitory NT GABA to the GABAa receptor and enhance the GABA induced ion currents
Do benzos have a low capacity to produce fatal CNS depression?
- yes
- so they are preferred over barbiturates
Barbiturates MOA:
-Bind to GABAa receptors and potentiate GABA induced chloride currents
=Can activate the cahnnel directly by acting as a GABA mimetic at high concentrations
=narrow therapeutic index and it is often not possible to achieve a desired effect without evidence of general depression of the CNS
What is absorption rate dependent on?
-the lipid solubility
What enzyme does the phase 1 rxn for benzos?
- CYP3A4
- then glucuronidation (phase 2)
Which benzos would be good to use in someone who has hepatic insufficiency?
-oxazepam and lorazepam
What is the result of GABAa receptor activation?
- increased Cl- influx
- reduced number of AP’s
What do benzodiazepines do to the GABA concentration-response curve?
- shift it to the left
- less GABA required to activate the receptor
- benzos just enhace the effect of GABA allosterically
Barbiturates MOA
- increase the duration of GABA-gated chloride channel openings
- less selective
Which drugs are agonists only when the alpha 1 subunit of the GABA receptor is included?
-Eszopiclone, zaleplon, and zopidem
the GABA antagonist
-flumazenil
inverse agonists
- negative allosteric modulators of GABA receptor
- ex: B-carboline class of compounds
Which drug will increase total sleep time?
-eszopiclone
what is the usual cause of death due to overdose of sedative hypnotics?
-depression of the medullary respiratory center
what is tolerance?
-decrease in responsiveness to a drug following repeated exposure and a common feature of sedative hypnotic use
what is dependence?
-the compulsive use of a substance despite significant problems resulting from such use
What doe Flumazenil do?
-binds to benzo binding sit eon GABAa receptors and acts as a competitive antagonist
what drugs does flumazenil block the action of?
-benzos, zolpidem, zaleplon, and eszopiclone
=does not block CNS effects of other sedative hypnotics, ethanol, opioids, or general anesthetics
adverse effects of flumazenil?
-agitation, confusion, dizziness, nausea
What are benzos widely used for
-the management of acute anxiety states (situational anxiety)
Benzodiazepine advantages in treating anxiety-
- high therapeutic index
- availability of flumazenil for overdose
- low risk of drug interactions based on liver enzyme induction
- minimal effects on cardiovascular or autonomic functions
which benzo is approved for tx of muscle spasticity?
-diazepam
What are the direct toxic actions of the sedative hypnotics?
- result from dose-related depression of the CNS
- Low doses may lead to drowsiness, impaired judgement, and diminished skills that can lead to impacts on driving ability job performance, and personal relationships
Which pts have more common increased sensitivity to sedative hypnotics?
-pts with CV disease, resp disease, or hepatic impairment
What condition makes barbiturates contraindicated?
-pts with hx of acute intermittent porphyria or other kinds of porphyria
what do we have to watch out for with drug interactions and sedative hypnotics?
-CYP 450 inhibitors
What is Ramelteon approved for?
-tx of insomnia characterized by difficulty with sleep onset
MOA for Ramelteon?
-agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brian
What pts do we have to be careful with when using ramelteon?
-pts with hepatic impairment
What is the parent drug of Ramelteon metabolized by?
-CYP1A2
What do we have do not coadminister with Ramelteon?
- Fluvxamine (SSRI)
- inhibitor of CYP1A2
Buspirone
approved for the tx of generalized anxiety disorder
- no sedation, hypnotic, euphoric, anticonvulsant, or muscle relaxant effects
- metabolized by CYP3A4, watch out for hepatic impairment
adverse effects of buspirone?
-tachycardia, palpitation, nervousness, GI distress, paresthesias, and dose-dependent papillary constriction
Meprobamate
- Approved for the short term relief of anxiety
- good preop agent used to releive anxiety and provide sedation
- Active metabolite of the drug carisoprodol
