M5 L3: Sedative-Hypnotics Agents Flashcards
what are sedatives
- reduce anxiety
- exert a calming effect w/o inducing sleep
what are hypnotics
- produce drowsiness
- encourage onset and maintenance of sleep
is CNS depression worse for hypnotics or sedatives
hypnotics > sedatives
indications of sedative-hypnotics
- anxiety
- insomnia
- amnesia + sedation
- epilepsy and seizure
- control of other drug withdrawal states
- muscle relaxation
- treatment in psychiatry
classes of sedative hypnotic drugs
- benzodiazepines (ex: diazepam)
- newer hypnotics: nonbenzodiazepines, z-drugs (ex: zolpidem)
- barbiturates (ex: phenobarbital)
others: (can look on slide for ex)
- melatonin receptor agonists
- orexin antagonist
- 5-HT receptor agonists
- antihistaminics
ion channels and NT receptors for sedative hypnotic drugs
**ligand-gated ion channel (ionotropic receptor)
- voltage gated ion channel
- G protein-coupled receptor
what is a GABAa receptor
ligand: GABA
- mediated inhibitory synaptic transmission in CNS
- target of barbiturates, benzodiazepines, and new hypnotics
Ionotropic receptor
what are benzodiazepines
- widely used sedative hypnotic drugs
- commonly used in 1990s
- heterocyclic 1,4-benzodiazepine ring sys
sedative hypnotic drugs mech of action
- act allosterically
- bind specific site on GABAa receptor, distinct from GABA binding site
- sedative hypnotics have a positive receptor affinity to GABA
- they facilitate GABA-mediated Cl-channel opening frequency
- this leads to an increase in membrane hyperpolarization
short acting ex of sedative hypnotic drugs
triazolam
intermediate acting ex of sedative hypnotic drugs
alprazolam
long acting ex of sedative hypnotic drugs
diazepam
what is the absorption through GIT of sedative hypnotic drugs
- variable rate - ex: triazolam is extremely rapid
- gastric HCL converts clorazepate (prodrug) -> active form
what is the metabolism of sedative hypnotic drugs
in the liver:
phase 1 - oxidation by P450 isozymes specially CYP3A4
phase 2 - conjugation results in glucuronides
how are sedative hypnotic drugs excreted
in urine
how is sedative hypnotic drugs administered
oral, IM, IV, rectal
how are sedative hypnotic drugs metabolized
done thru phase 1/2 reactions. use active metabolites, and go primarily thru conjugation
what are the effects of sedative hypnotic drugs
- sedation, hypnosis, anaesthesia (decline when taken after 1-2 weeks)
- anticonvulsant effect
- muscle relaxation
- respiratory depression, and cardiovascular depression (dangerous)
what are common adverse effects of sedative hypnotic drugs
- drowsiness, dizziness, deceased alertness and concentration
- impaired coordination
- decreased libido and ED
- impaired memory
- paradoxical reactions
- overdose and acute toxicity
- tolerance and dependence
sedative hypnotic drug tolerance
- develops w long-term use
- shown mainly w sedative-hypnotic muscle relaxant and anticonvulsant effects
- partial cross tolerance
- mech: not understood well but in animals its thru a downregulation of receptors
sedative hypnotic drug dependence
- arises from perceived relief of anxiety, euphoria, disinhibition, and promotion of sleep
what are ex of drug interactions that add to CNS depression with sedative hypnotic drugs
- additive CNS depression
- alcohol
- opioids
- anticonvulsants
- antidepressants
- antihistamines
what is flumazenil
1,4-benzodiazepine derivative
* Competitive antagonist with high affinity to
benzodiazepine binding site on GABAA receptor
* Blocks many actions of benzodiazepines & Z-
drugs
* Used in the treatment of overdose (antidote)
* Administration: IV – dose should be repeated
(short t1/2)
what are new hypnotic (Z-drugs)
Introduced in the late 80s / early 90s
* Strong hypnotics but weak sedatives
* Pharmacokinetics: refer to the table (look in slideshow)
* Less tolerance & dependence
* Administration: oral
ex of new hypnotic (Z-drugs)
- E.g., zolpidem, zaleplon, and eszopiclone
what are newer hypnotic (z-drugs) mech of action, and effect similar too
benzodiazepines
what have barbiturates mostly been replaced by
benzodiazepines
(bc of significant higher risk of overdose, lack of antidote)
what are barbiturates derived from
barbituric acid
barbiturates mech of action
- act allosterically
- bind to specific GABAa receptor
- barbiturates have a +’ve receptor affinity to GABA
- they increase the duration of GABA-mediated Cl- channel opening
- this leads to an increase in membrane hyperpolarization
- causes CNS depression associated w the effects of the drug
(take a look at slideshow)
medical uses of barbiturates
- general anesthetics ( thiopental-IV)
- anticonvulsants
- insomnia (replaced by benzodiazepines) [phenobarbital - oral]
adverse effects and drug interactions of barbiturates
- similar to benzodiazepines
- dependence > benzodiazepines
- hepatic microsomal enzymes induction leads to an increased metabolism
- more linear dose-response w barbiturates can increase toxicity
what kind of drugs are sedative-hypnotics
lipophilic drugs
sedative-hypnotics and pregnancy
avoid in:
- 1st trimester - teratogenic effect
- 3rd trimester - may induce premature labour
- Z-drugs are safer than benzodiazepines bc of lack of data
- antihistamines might b reasonable in early pregnancy
sedative-hyponotics and dependence/withdrawal sympt
- barbiturates > benzodiazepines > Z-drugs
- short acting > long-acting
- cross dependence can help prevent withdrawal sympt
ex: long-acting alleviate withdrawal sympt by shorter-acting drugs
