sedative-hypnotics Flashcards
sedative-hypnotic class use
-cause sedation or to encourage sleep
sedative (anxiolytic) drugs use
reduce anxiety and produce a calming effect
hypnotic drug use
cause drowsiness and promote the onset and maintenance of a state of sleep
Barbiturates
-much older and less commonly used
-pentobarbital
-secobarbital
-phenobarbital
Sedative hypnotics with distinct features
-Glutethimide
-Meprobamate(Miltown)
-chloral hydrate
-ethanol
Benzodiazepines
-widely used
-most contain carboxamide group
-a halogen OR nitro group is required of activity
Triazolam and alprazolam structure
include triazole ring
z drugs
-zolpidem(Ambien)
-zaleplon(Sonata)
-Eszopiclone(Lunesta)
Where does GABA interact?
- at two sites between alpha and beta subunits
-this triggers chloride channel to open and hyperpolarize
Where do benzodiazepines and z drugs bind at the receptor?
between alpha and gamma subunits, but z drugs only interact with a1 subunits
Flumazenil
-competitive benzodiazepine antagonist
-binds between alpha and gamma subunit
-reverse benzo and z drug effects
-short half life so require multiple doses
True or False: Benzodiazepines directly activate GABA receptors
False.
-enhances GABA’s effects allosterically
-increased frequency of channel opening event
Barbiturates action at GABA receptor
-increase duration of the opening of GABA gated chloride channels
-at high conc., may directly open channels
Sedation
-overall calming effects
-produced euphoria, impaired judgement
-AMNESIA (benzodiazepines)
Hypnosis
-all sedative-hypnotics will induce sleep if high enough dose
effects of benzodiazepines on sleeps:
1)time to fall asleep decreased
2) Stage 2 NREM increased
3) REM decreased
4) Stage 4 NREM decreased
effects of zolpidem on sleep
decrease REM
effect of zaleplon on sleep
decrease the latency of sleep onset with little effect on total sleep time, NREM, or REM
effect of eszopiclone on sleep
-increase total sleep time: increase stage 2
-decreases REM at highest dose
Significance of sedative-hypnotics on sleep
-REM rebound: crazy dreams in older drugs
-rebound insomnia in zolpidem and zalpelon
Anesthesia
-benzodiazepines such as diazepam, lorazepam, and midazolam may be used for anestesia
-suitability is determined by rapidity of onset and duration of effect
anticunvulsant
benzos: clonazepam, nitrazepam, lorazepam, diazepam
barbituates: phenobarbital(tonic-clonic)
Muscle relaxation
certain benzodiazepines and meprobamate may depress transmission at the neuromuscular junction
Respiration and cardiovascular function
-comparable to natural sleep
-significant effect in patients with pulmonary disease
Buspirone
-relieves anxiety without causing sedative, hypnotic, or euphoric effects
-no anticonvulsant or muscle relaxant properties, no effect on GABA
-5-HT1a receptor agonist
-risk of serotonin syndrome with 3A4 inhibitors
Ramelteon and tasimelteon
-melatonin receptor agonist
-no effect on GAM+BA
-Ramelteon reduces latency
-has longer half life than melatonin
Suvorexant
-first orexin receptor antagonist to treat insomnia
-orexin A and B peptides involved in wakefulness
Lemborexant (Dayvigo)
-Insomnia
-Orexin antagonist
Daridorexant(Quviviq)
-Insomnia
-orexin receptor antagonist
off label hypnotic drugs
-trazodone
-mirtazipine
-doxepin
-amitriptyline
OTC hypnotic
-diphenhydramine
-doxylamine
-melatonin
-CNM (Cannabinol)
PK of sedative-hypnotics
-all cross the placenta barrier
Desmethyldiazepam
-active metabolite for clorazepate, chlordiazepoxide, diazepam, and prazepam
-LONG half life
Triazolam
-short half life (2-5 hrs)
-favors use as hypnotic rater than sedative
Alprazolam an Triazolam metabolism
-same mechanism due to similar structure
-alpha-hydroxylation results in short half life due to inactive glucuronides
Metabolism of barbiturates
-oxidation via hepatic enzymes
-relatively slow
Z Drugs PK
-absorbed rapidly
-biphasic release-metabolized to inactive metabolite by 3A4
Phenobarbital PK
-long half life
-20-30% excreted unchanged in urine
Tolerance
decreased responsiveness following repeated exposure
-common in sedative-hypnotics
cross tolerance
can occur between sedative hypnotics and ethanol because of down regulation of GABA receptor?
Psychologic component of dependence
-behavioral patterns
-compulsive
Physiologic component of dependence
-altered state that requires continuous drug administration to prevent abstinence or withdrawal syndrome
-withdrawal symptoms are worse for meds with short half life
Clinical uses for sedative hypnotics
-anxiety
-insomnia
-sedation and amnesia
-epilepsy
-withdrawal
-muscle relaxation
secondary anxiety
-results from circumstances that are dealt with once or twice
-medical procedures
Alprazolam
-panic disorder and agoraphobia
-more selective than other benzos
-more toxic in overdose
choice of benzo for anxiety
1)onset of action
2) therapuetic index
3) risk for drug interactions
4) cardio or autonomic effects
Disadvantages of benzodiazepines
-dependence
-depression of CNS functions
-amnesia effects
-newer SSRI first choice
delirium tremens drug treatment
parenteral lorazepam
muscle relaxants
meprobamate
diazepam: skeletal muscle spascity
Toxic actions of sedative hypnotics
-low dose: drowsiness, impaired job perform and
-sleep walking with no memory
-amnesia
-hangover effects
-elderly more sensitive!
drug interactions
other CNS depressant drugs
