Sedative-hypnotics Flashcards
Define sedative vs hypnotic
Sedative = anxiolytic; calms the patient
Hypnotic: promotes drowsiness and sleep
T/F: Sedative-hypnotics (SH) are lipid soluble
True. This allows them to cross BBB
Sedative-hypnotics are absorbed in ____
GIT
How are the CNS effects of sedative-hypnotics terminated?
by rapid REDISTRIBUTION of the drug from
brain to other highly perfused tissues
the higher rate of drug redistribution, the less its effect
All BDZs are absorbed completely, except
clorazepate
decarboxylated rapidly in gastric juice to N-desmethyldiazepam
nordiazepam
How are sedative-hypnotics metabolized?
via hepatic metabolism
Give examples of drugs that are converted initially to active metabolites with long half-lives
diazepam, flurazepam
Diazepam(28hrs) to Nordiazepam(60hrs) to Oxazepam(6hrs)
Flurazepam (2hrs) to N-desalkylflurazepam (50hours)
Undergo extrahepatic metabolism, and therefore do not form active metabolites
Lorazepam , tamezapam, and oxazepam
Main classes of drugs in sedative-hypnotics
Benzodiazepines
Barbiturates
Barbiturates are extensively metabolized Except
phenobarbital
Arrange the SH drugs in sequence based on increasing duration of action
zaleplon
It is a non-BDZ with biphasic release form
zolpidem
Examples of long-acting SH
chlordiazepoxide, clorazepate, diazepam, phenobarbital
Site of action of BDZ and barbiturates
GABA A receptor
Differentiate GABA A vs GABA B receptor
GABA A activation: ↑ Cl- influx; Ionotropic (fast)
GABA B activation: ↑ K+ efflux Metabotropic (slow)
Both mechanisms result in membrane hyperpolarization
GABA A receptor has how many subunits
5 subunits
o 4 transmembrane domains
o 2 α1, 2 β2, and 1 γ2 subunits
binding site for benzodiazepines is
between an α1 and the γ2
subunit
BDZ vs Barbiturates based on mechanism of action on GABA A receptor
BOTH increase the potency of GABA but by different mechanisms:
BDZ: increased FREQUENCY of opening of GABA receptor
Barb: increased DURATION of opening of GABA receptor
Is it okay to combine BDZ and Barbiturate?
No. they could have ADDITIVE effects. They can both stimulate the receptor. DO NOT MIX THESE DRUGS TOGETHER.
Antagonist of BDZ
Flumazenil
hence used as antidote for BDZ poisoning
Which has GABA-mimetic activity?
Barbiturates. They can mimic GABA esp at high doses
BDZ has NO GABA-mimetic activity.
Additional MOA of barbs
Inhibit complex I of the Electron Transport Chain
Give examples of SH that are neither BDZ or Barb
zolpidem, zaleplon, and esZopiclone
Z drugs
Adv of Z drugs
Less effect on cognitive function
Less tolerance and abuse liability
Give the dose-dependent effects of SH
Sedation (lowest dose)
Hypnosis
Anesthesia
Coma (highest dose)
What is paradoxical inhibtion?
Its a benzodiazepine induced hyper-reactive phenomenon. It takes the person to the extreme end of emotions, removes all inhibitory and suppressed signals resulting in extreme pychosis and agitation, paranoia and depression. Its a rare occurence in pts taking the drugs.
It is due to inhibition of inhibitory subcortical neurons during initial doses of BZ.
How does SH affect sleep?
Reduced REM duration
Increased of Non-REM (Stage II) duration (ex: Diazepam)
Used for anesthesia
Thiopental
Midazolam
Anesthesia can be produced by short acting barbiturates (eg,
thiopental) and certain benzodiazepines (eg,midazolam).
Can cause anterograde amnesia
benzodiazepines
Examples of SH with selective anticonvulsant action
Phenobarbital
Clonazepam
Used in status epilepticus
diazepam, lorazepam, or phenobarbital
Muscle Relaxation occurs only with high doses of most sedative-hypnotics Except
diazepam and Meprobamate (they can be used as muscle relaxant even at low doses)
Can cause medullary depression
Alcohols and barbiturates
BDZs are safe and rarely cause medullary depression
There is cross-tolerance between
BZ, barbituates, and ethanol
T/F Benzodiazepines are less toxic compared to all sedatives.
T
DOC for anxiety states
Alprazolam and clonazepam
DOC for sleep disorders
estazolam, flurazepam, and triazolam
T/F: Sedative hypnotic drugs recommended for breathing-related
sleep disorders
False. Sedative hypnotic drugs NOT recommended for breathing-related
sleep disorders
Used for induction of anesthesia
thiopental
components of anesthesia protocols
diazepam, midazolam
used for seizure disorders
clonazepam, phenobarbital
used for bipolar disorcer
clonazepam
used for muscle spasticity
Diazepam
used in management of withdrawal states
chlordiazepoxide, diazepam
benzodiazepines that have active metabolites
with long half-lives
DIAZEPAM, FLURAZEPAM
Barbiturates: Enzyme inducer or inhibitor?
Barbiturates are ENZYME INDUCERS
Mnemonic: PRC
Phenobarbital (barbiturates), phenytoin
Rifampicin
Carbamazepine, Chronic Alcohol use
Adverse effect associated with barbiturates
Acute intermittent porphyria
Mickey Finn is aka
Chloral hydrate
May displace coumarins from plasma protein
chloral hydrate
occasionally increases the incidence of nightmares
flurazepam
Examples of ATYPICAL sedative-hypnotics
Buspirone
Ramelteon
MOA of buspirone
Partial agonist of 5-HT1A serotonin receptors
T/F Buspirone affects GABA
False. It is partial agonist of 5-HT1A serotonin receptors
Use of buspirone
anxiolytic ONLY
it has NO anticonvulsant or muscle relaxant properties
Disadvantage of using buspirone
slow onset of action (>1 week) since it is only partial agonist
Advantage of using buspirone
Tolerance development is minimal with chronic use
little rebound anxiety or withdrawal symptoms on discontinuance
Minimal abuse
Metabolism of buspirone is Increased or decreased by erythromycin?
Decreased metabolism (leading to increased plasma levels)
Enzyme inhibitors: MEDVICK-A Metronidazole Erythromycin Valproic acid Isoniazid Cimetidine, ciprofloxacin Ketoconazole Acute Alcohol use
Novel hypnotic drug
Ramelteon
MOA Ramelteon
activates melatonin receptors in the suprachiasmatic nuclei
Effect of Rifampin on metabolism of Ramelteon
Increased metabolism
ENZYME INDUCERS
Mnemonic: PRC
Phenobarbital (barbiturates), phenytoin
Rifampicin
Carbamazepine, Chronic Alcohol use
Effect of fluconazole and fluvoxamine on ramelteon
Decreased metabolism
(azoles are enzyme inhibitors)
Enzyme inhibitors: MEDVICK-A Metronidazole Erythromycin Valproic acid Isoniazid Cimetidine, ciprofloxacin Ketoconazole Acute Alcohol use
Which one of the following statements is correct regarding
benzodiazepines?
A. Benzodiazepines directly open chloride
channels.
B. Benzodiazepines show analgesic actions.
C. Clinical improvement of anxiety requires 2 to 4
weeks of treatment with benzodiazepines.
D. All benzodiazepines have some sedative effects.
E. Benzodiazepines, like other CNS depressants,
readily produce general anesthesia.
Correct answer = D. Although all benzodiazepines can
cause sedation, the drugs labeled “benzodiazepines” in
Figure 9.1 are promoted for the treatment of sleep disorder.
Benzodiazepines enhance the binding of GABAA to its receptor,
which increases the permeability of chloride. The benzodiazepines
do not relieve pain but may reduce the anxiety
associated with pain. Unlike the tricyclic antidepressants and
the monoamine oxidase inhibitors, the benzodiazepines are
effective within hours of administration. Benzodiazepines do
not produce general anesthesia and, therefore, are relatively
safe drugs with a high therapeutic index.
Which one of the following is a short-acting hypnotic? A. Phenobarbital. B. Diazepam. C. Chlordiazepoxide. D. Triazolam. E. Flurazepam.
Correct answer = D. Triazolam is a short-acting drug. It has
little dayt
Which one of the following statements is correct regarding
the anxiolytic and hypnotic agents?
A. Phenobarbital shows analgesic properties.
B. Diazepam and phenobarbital induce the cytochrome
P450 enzyme system.
C. Phenobarbital is useful in the treatment of acute
intermittent porphyria.
D. Phenobarbital induces respiratory depression, which
is enhanced by the consumption of ethanol.
E. Buspirone has actions similar to those of the
benzodiazepines.
Correct answer = D. Barbiturates and ethanol are a potentially
lethal combination. Phenobarbital is unable to alter the
pain threshold. Only phenobarbital strongly induces the synthesis
of the hepatic cytochrome P450 drug-metabolizing
system. Phenobarbital is contraindicated in the treatment of
acute intermittent porphyria. Buspirone lacks the anticonvulsant
and muscle-relaxant properties of the benzodiazepines
and causes only minimal sedation.
A 45-year-old man who has been injured in a car accident
is brought into the emergency room. His blood alcohol
level on admission is 275 mg/dL. Hospital records show a
prior hospitalization for alcohol-related seizures. His wife
confirms that he has been drinking heavily for 3 weeks.
What treatment should be provided to the patient if he
goes into withdrawal?
A. None.
B. Lorazepam.
C. Pentobarbital.
D. Phenytoin.
E. Buspirone.
Correct answer = B. It is important to treat the seizures
associated with alcohol withdrawal. Benzodiazepines, such
as chlordiazepoxide, diazepam, or the shorter-acting lorazepam,
are effective in controlling this problem. They are less
sedating than pentobarbital or phenytoin.
Which one of the following is a short-acting hypnotic and better for sleep induction compared to sleep maintenance? A. Temazepam. B. Flurazepam. C. Zaleplon. D. Buspirone. E. Escitalopram.
Correct answer = C. Zaleplon has the shortest half-life and
duration of action. Buspirone and escitalopram are not
effective hypnotic agents. Temazepam and flurazepam have
longer durations of action and will reduce nighttime awakenings
but will have a greater risk of daytime sedation or
hangover effect compared to zaleplon.
Which of the following agents has a rapid anxiolytic effect
and would be best for the acute management of anxiety?
A. Buspirone.
B. Venlafaxine.
C. Lorazepam.
D. Escitalopram.
E. Duloxetine
Correct answer = C. The benzodiazepines have same-dose,
first-dose efficacy for anxiety, whereas the other agents
require 2 to 8 weeks for clinically significant improvement
in anxiety.
Which of the following sedative–hypnotic agents utilizes melatonin receptor agonism as the mechanism of action to induce sleep? A. Zolpidem. B. Eszopiclone. C. Estazolam. D. Ramelteon. E. Diphenhydramine.
Correct answer = D. Ramelteon is the only melatonin receptor
agonist to promote sleep, especially in sleep-phase
disrupted sleep. Zolpidem, eszopiclone, and estazolam all
utilize the benzodiazepine receptor, and diphenhydramine
is a histamine receptor antagonist.
All of the following agents for the management of insomnia are controlled substances and may have a risk for addiction or dependence except: A. Zaleplon. B. Flurazepam. C. Doxepin. D. Zolpidem. E. Triazolam.
Correct answer = C. Only doxepin, a tricyclic agent with
significant antihistaminergic properties, is considered to
have no risk of addiction or dependence, whereas the other
agents listed all have DEA schedule IV designations with
some risk for addiction or dependence, especially when
used for extended periods.
All of the following agents may cause cognitive impairment, including memory problems when used at recommended doses except: A. Diphenhydramine. B. Zolpidem. C. Alprazolam. D. Phenobarbital. E. Ramelteon.
Correct answer = E. All of the above listed agents, except
ramelteon, have been associated with cognitive impairments,
including memory impairment. Diphenhydramine
likely causes its cognitive problems from its anticholinergic
and antihistaminergic effects. Zolpidem, alprazolam, and
phenobarbital are well-known causes of cognitive impairment,
including anterograde amnesia. Ramelteon has
safety data extending to 6 months and is a noncontrolled
hypnotic agent acting as a melatonin receptor agonist. It is
not considered to have a risk for cognitive impairment as
compared to the other agents listed.
Which agent is best used in the Emergency Room
setting for patients who are believed to have received
too much of a benzodiazepine drug or taken an
overdose of benzodiazepines?
A. Diazepam.
B. Ramelteon.
C. Flumazenil.
D. Doxepin.
E. Naloxone.
Correct answer = C. Flumazenil is only indicated to reverse
the effects of benzodiazepines via antagonizing the benzodiazepine
receptor. It should be used with caution due to a
risk of seizures if the patient has been a long time recipient
of benzodiazepines or if the overdose attempt was with
mixed drugs. Naloxone is an opioid receptor antagonist.
The other agents are not efficacious in reversing effects of
benzodiazepines.
