Sedative-Hypnotic Drugs Flashcards
What is a sedative vs a hypnotic drug? Shared characteristic?
Sedative - produces a calming or drowsiness (relief of anxiety)
Hypnotic - facilitates onset and maintenance of sleep
Shared characteristic: CNS depression
What are sedative-hypnotics with the highest lipid solubility often used for? Give two examples.
Rapid entrance into the CNS and thus induction agents in anesthesia
- Thiopental - rapid acting barbiturate
- Propofol - non-benzo, non-barb
What are some OTC sedative-hypnotics?
- 1st generation antihistamines
- L-tryptophan
- Melatonin, metabolite of serotonin
What terminates the action of thiopental and propofol?
Rapid redistribution of the drug from brain to peripheral tissues, and subsequent metabolism and secretion
Do sedative-hypnotics cross the placenta?
Yes! use with caution in pregnancy, as they depress neonatal vital functions
How are sedative-hypnotics typically grouped?
By duration of action, with rapid (few minutes), medium (hours), and long-acting (Days) in terms of halflife
How are benzodiazepines metabolized?
The major must first be oxidized in the liver by CYP450, and then ALL will be conjugated with glutathione and excreted in the urine
What benzos have the highest risk of excessive sedation and why?
Chlordiazepoxide, diazepam, and flurazepam
- > many active metabolites which still must be metabolized by the liver.
- > Even metabolites can bind plasma proteins, which correlates with lipid solubility and further reduces drug metabolism
What are two benzos which do not undergo liver microsomal oxidation and are directly conjugated? Why is this relevant?
- Oxazepam - think of the ox on the wall
- Lorazepam
-> safe to give in patients with impaired liver function
What are the three main hypnotics and why are they short-acting?
They are rapidly metabolized by the liver
- Zolpidem
- Zaleplon
- EsZopiclone
(3 Z’s for sleep)!
How do benzodiazepines work? How does this change GABA’s pharmacodynamic parameters?
Bind an allosteric site on GABA-A and increase the frequency / probability of GABA-mediated chloride channel opening (binding GABA does not always cause it to open)
Increases POTENCY of GABA (less GABA required to get the same response)
How do barbiturates work? How does this change GABA’s pharmacodynamic parameters? What other drug falls into this class?
Bind an allosteric site on GABA-A and increases the duration of GABA-mediated choride channel opening (higher efficacy, but no change in potency)
Propofol (similar in use to thiopental) has the same mechanism, but is a non-benzo, non-barb
How do we know that the “3 Z” hypnotics bind the same allosteric site as benzodiazepines, despite being non-benzodiazepines?
CNS depressant effects are antagonized by the benzodiazepine receptor antagonist “flumazenil” - fluffy the dog
What drug is a partial agonist of 5-HT1A receptors and what is its primary indication? How long is its effect?
Buspirone
Takes weeks to manifest the effects -> used for long-term anxiety treatment, especially generalized anxiety disorder of patients with substance abuse (not dangerous like benzos)
Does Buspirone interact with benzodiazepines?
No, it has no cross-reactivity with any GABA-mediated drugs. It is not even a CNS depressant, just an anxiolytic Therefore, if discontinuing a benzo for it, benzo should be tapered
What is the melatonin receptor agonist approved for sleep onset insomnia? Is it good for sleep maintenance? Does it or buspirone have abuse potential?
Ramelteon (“melt way” in Sketchy)
Only good for falling asleep
No abuse potential for either
What are the adverse effects of ramelteon?
Increased serum prolactin, decreased serum testosterone, and doing things while asleep
What is one drug which can be used for both sleep onset and sleep maintenance insomnia? Does it have abuse potential? What are its side effects?
Suvorexant -> orexin receptor antagonist
- > no abuse potential
- > daytime drowsiness and suicidal ideation
What is the first stage of CNS depression?
Sedation, with disinhibition of behavior and anxiolysis
What is the second stage of CNS depression? What happens to REM?
Hypnosis - sleep onset and increased duratino of sleep state
REM sleep is decreased with high dose benzos, so REM rebound will occur upon withdrawal of chronic use -> predisposes to falling asleep during the day
What benzo is used to cause and maintain anesthesia? Barbiturates?
3rd stage
Almost all barbiturates can do this
Only midazolam is a benzo used to maintain anesthesia
What occurs after anesthesia in CNS depression? Why is this important?
Medullary depression (reduced firing of medullary neurons)
- > Leads to respiratory arrest, hypotension, and cardiovascular collapse
- > cause of death in suicidal overdose
What is a “selective” anticonvulsant action? What drugs can do this?
Seizure suppression without marked sedation caused by CNS depression
Phenobarbital and clonazepam can do this
What drugs treat status epilepticus?
Diazepam, lorazepam, or phenobarbital (first two are likely to cause heavy sedation)
When is muscle relaxation incurred by sedative-hypnotics?
At higher doses, prior to the hypnotic phase (some sedation is likely)
What is psychological vs physiological dependence, and does this occur with benzos / barbs?
Psychological - compulsive use of drugs to reduce symptoms such as anxiety
Physiological - removal of drug will result in abstinence / withdrawal syndrome
Both of these classes cause dependence and induce tolerance
What drugs are more likely to induce withdrawal? What are not?
Short half-life drugs like triazolam and pentobarbital
Long half life i.e. phenobarbital and diazepam are self-tapering and less likely
Do buspirone and zolpidem and zaleplon and eszopiclone have dependence liability?
Much lower than benzos, with buspirone being the lowest (no CNS depressant effects)
What is the benzodiazepine / phenobarbital withdrawal symptoms?
Similar to alcohol withdrawal:
Anxiety, tremors, hyperreflexia, and even seizures
What benzos are best for treating phobia and panic disorders?
Alprazolam, clonazepam
What drugs are used in management of primary insomnia / sleep disorders?
Flurazepam and traizolam
Why are the 3 Z’s good as sleep AIDs?
Cause less daytime impairment due to short half lives, and have minimal effects on sleep patterns (no REM rebound)
What longer-acting drugs are good in ethanol withdrawal and why?
Chlordiazepoxide, diazepam - self-tapering effect since ethanol is also a GABA-A agonist
What drug is used in muscle spasticity?
Diazepam
What drug has awakened patients from a persistent vegetative state?
Zolpidem! one of the three Z’s
What is the most common side effect of benzos/barbs and who is at greatest risk? What should be done to mitigate risk?
Psychomotor dysfunction - including cognitive impairment, decreased psychomotor skills, and unwanted daytime sedation. Worse in drugs with long-lived active metabolites
Greatest risk: elderly patients, dose should be reduced by at least 50% since it increases the risk of falls and fractures. This is due to changes in brain function with aging (not liver)
How are sedatives useful for “date rape”? What drug is known for this?
High dose benzos can cause anterograde amnesia
Also chloral hydrate
What drugs, when added with benzos, can cause additive CNS depression?
Alcohol, antihistamines, antipsychotic drugs, opioid analgesics, and tricyclic antidepressants
What is a carbamate?
A group of miscellaneous sedative hypnotics with depressive effects of CNS, fallen out of usage
Who is most susceptible to sedative-hypnotic overdose? What is needed as supportive care?
Those with sleep apnea, cardiovascular disease, and respiratory depression. It is also less common with benzos than other CNS depressants (alcohols, barbs, carbamates)
-> Supportive care includes patent airway and ventilatory support
What is flumazenil used for and what should you watch out for?
Reverses CNS depressant effects of benzos as well as 3 Z’s (same GABA-A spot), as an antagonist
It has a short half-life, must be readminstered every 45 seconds, with care not to induce seizures (Too mush and u get seizure)
What sedative hypnotics induce microsomal CYPs?
Barbiturates and carbamates (think of the sketchy with car in the barber shop)
How can benzos have varying specificities, aside from their halflife?
Each has two alpha, two beta, and 1 gamma subunit, each with different isoforms -> different areas of the brain will have different receptor isoforms depending on gene expression
-> some alpha subunits of receptors are only expressed in the basal ganglia, for instance, and thus would be targeted in muscle relaxants
How does suvorexant work?
suvOREX-ANT -> dual orexin A/B peptide receptor antagonist. It is peptomimetic (mimcs a peptide, but is a small molecule), and blocks the orexin receptor.
Orexin is needed to keep you awake and cause you to eat.
What does orexin function loss result in? How does this happen in humans?
Narcolepsy, happens in humans due to autoimmune attack and destruction of orexin neurons in hypothalamus
Where do Orexin-A and Orexin-B interact?
At Orexin 1/2 and Orexin 2 receptors respectively.
They project all over the brain to cause arousal and wakefulness, including nucleus accumbens, locus ceruleus, PPN, ventral tegmental area, dorsal raphe, etc.
They all have different receptor type mixtures, so it’s good that suvorexant antagonizes both! (rational drug design, they chose this after they know what would work on both receptor subtypes)
