Download Sedative-hypnotics

Sedatives Hypnotics 9-10
Sedative-hypnotics
Objectives
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Identify the mechanism of action of sedatives and hypnotics and the underlying pathophysiology
as it relates to mechanism of action
Compare and contrast the different classes of sedative-hypnotics
Recall the indications, contraindications, adverse effects, and drug interactions for the drugs
discussed
Apply knowledge about these drug classes to therapeutic intervention, patient monitoring, and
patient prescribing
Insomnia
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Impairs daytime functioning
Worsens neurocognitive, behavioral, metabolic and autonomic parameters
Alters immune function
Chronic sleep deprivation is associated with an increased risk of:
o diabetes mellitus
o cardiovascular disease
o cancer
o mortality
Stages of sleep
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Non-REM (NREM) and REM
o 1 - 4 non-REM sleep
o 3 & 4 slow-wave (delta) sleep; metabolic activity and brain waves slow; no eye
movements, low tonic muscle activity
REM: rapid eye movement
o brain is electrically and metabolically activated
o 62 – 173% increase in cerebral blood flow
o paralysis of voluntary muscles
o fluctuation in cardiac and respiratory rate
o dreaming
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Sedatives Hypnotics 9-10
Normal sleep pattern
4-6 cycles of REM and NREM sleep each night, lasting 70 -120 minutes
Insomnia
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“Unsatisfactory sleep that impacts daytime functioning”
Difficulty falling asleep (sleep latency)
Difficulty staying asleep (wakefulness throughout the night)
Early morning awakening (terminal insomnia)
Non-restorative or unrefreshing sleep
Transient insomnia: 2-3 nights
Short-term insomnia: < 3 weeks
Chronic insomnia: > 30 days
Chronic insomnia
Associated with:
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Immune system dysregulation
Release of proinflammatory cytokines (IL-6 and TNF)
Disruption of the hypothalamic-pituitary-adrenal axis (HPA)
Depletion of brain serotonin and other NTs
10X more likely to be depressed
17X more likely to have anxiety
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Sedatives Hypnotics 9-10
Goals of treatment
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Address the underlying problem
Improve sleep quality and quantity
Improve daytime function
Minimal side effects
1st-line: non-pharmacologic therapy
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Cognitive behavioral therapy
Relaxation therapy
Exercise
Yoga/meditation
Non-pharmacologic recommendations
Stimulus control procedures
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Establish regular wake and sleep times
Sleep only as much as needed for feel rested
Go to bed only when sleepy
Bedroom is for two things only
Don’t force sleep; if not asleep within ~20 minutes, do something relaxing and try again
Avoid daytime naps
Schedule worry time during the day
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Sedatives Hypnotics 9-10
Sleep hygiene recommendations
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Exercise routinely, but not close to bedtime
Comfortable sleep environment – temperature, noise, lighting
Discontinue or reduce caffeine, nicotine, alcohol, other stimulants
Avoid excessive fullness or hunger at bedtime
Avoid large quantities of liquids in the evenings
No watching the bedroom clock
Do something relaxing and enjoyable before bedtime
Pharmacologic therapy
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Sedative: ability to calm or reduce anxiety – anxiolytic effect
o Minimal central nervous system depression
Hypnotic: ability to induce drowsiness and promote sleep
o More pronounced depression of the central nervous system
Benzodiazepine sedative-hypnotic drugs
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Benzene ring (benzo) joined to a 7-member ring with two nitrogen molecules (diazepine)
MOA: facilitate the activity of γ-aminobutyric acid (GABA), inhibitory neurotransmitter in the
CNS; bind to α1 (BZ1) and α2 (BZ2) subunits of the GABA ionophore
GABA regulates the excitability of neurons in almost every neuronal tract
Decrease sleep latency, increase Stages 1 & 2, decrease Stage 3 slow-wave sleep and REM
Receptor site for benzodiazepines
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The GABAA chloride ion channel is a protein complex pentameric form that has varying
combinations of α, β, and γ subunits. GABA binds to a site near the junction of α and β subunits;
this causes conformational changes that open the chloride ion channel leading to neuronal
membrane hyperpolarization.
Benzodiazepines bind to an allosteric site formed by the cleft between α and γ subunits; this
facilitates GABA binding & increases the frequency of chloride channel opening.
Benzodiazepine sedative-hypnotic drugs
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P’kinetics: well absorbed; distributed into the brain according to lipid solubility; extensively
metabolized in the liver (CYP450); urinary elimination
Chlordiazepoxide & diazepam are converted to long-acting active metabolites.
Alprazolam, midazolam, & triazolam are converted to a short-acting active metabolite.
All benzodiazepines, including those with no active metabolites, are eventually converted to
glucuronide compounds that are p’cologically inactive & are excreted in the urine.
The benzodiazepines that have no active metabolites include oxazepam, temazepam, and
lorazepam ("out the liver"); these may be the safest benzodiazepines to use in treating elderly
patients.
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Benzodiazepine sedative-hypnotic drugs
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Sedatives Hypnotics 9-10
Pharmacologic effects/Indications*
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Dose-dependent depression of the CNS: sedative (short-term), anxiolytic  hypnosis,
anesthesia
Given orally, low incidence of respiratory depression, coma or death unless administered
w/another CNS depressant
Anterograde amnesia – interfere w/formation of new memory
Anticonvulsant effects
Decrease muscle spasm
Also indicated for ETOH withdrawal
Drug interactions
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Alcohol/other CNS depressants potentiate effects
CYP450 inducers may decrease serum levels, e.g., rifampin
CYP450 inhibitors may increase serum levels, e.g., ketoconazole
Pregnancy category D
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Sedatives Hypnotics 9-10
Flunitrazepam
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Marketed as Rohypnol
Originally intended for deep sedation
10x more potent than diazepam
Illegal in the US
High induction of anterograde amnesia, “date-rape” drug
Roofie
Abuse potential
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FDA CIV
Benzos, Downers, Nerve Pills, Tranks
Selective benzodiazepine antagonist
Flumazenil
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MOA: Competitive receptor antagonist
Used to counteract adverse effects of benzodiazepines resulting from IV administration or
overdose
Given IV; rapid onset, short duration
AEs: seizures, arrhythmias, blurred vision, emotional lability & dizziness
Nonbenzodiazepine sedative-hypnotics
Chemically unrelated to the benzodiazepines
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MOA: act selectively at the BZ1 receptor in the CNS
P’kinetics: well absorbed; distributed to the CNS; metabolized in the liver via CYP3A4; excreted
in the urine
** zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta)
Nonbenzodiazepine sedative-hypnotics
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Pharmacologic effects: Reduce sleep latency, increase total sleep time; little effect on sleep
stages
Indication: insomnia
Nonbenzodiazepine sedative-hypnotics
Adverse effects
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Drowsiness, dizziness
Impaired memory
Psychomotor retardation
Bitter aftertaste (eszopiclone)
“Complex sleep-related behavior”: driving, talking on the phone, eating, etc., with no memory
of the event
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Sedatives Hypnotics 9-10
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Anaphylaxis & facial swelling as early as the first dose
Less potential for abuse than Benzos but still CIV
Drug interactions
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Avoid other CNS depressants, including EtOH
CYP 3A4 inhibitors such as azole antifungals & erythromycins inhibit eszopiclone metabolism
Safety
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ER visits due to zolpidem are up 220%...mostly with older patients
Both non-benzodiazepines and benzodiazepines work at GABA-A receptors for their hypnotic
effects
Both classes are on the Beers list of potentially inappropriate drugs in older patients
Insomnia benefit is only modest compared to their risk of delirium, falls, fractures, and car
accidents
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Sedatives Hypnotics 9-10
Other nonbenzodiazepine sedative-hypnotics
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Orexin receptor antagonist
o Suvorexant
Melatonin receptor agonists
o Ramelteon
o Tasimelteon
Antidepressants
o Amitriptyline
o Trazodone
o Mirtazapine
o Doxepin
Antihistamines
o Diphenhydramine
o Doxylamine
o Hydroxyzine
Herbs/supplements
o Melatonin
o Valerian root
Barbiturates
Chloral hydrate
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Sedatives Hypnotics 9-10
Suvorexant (Belsomra)
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MOA: an orexin receptor antagonist
o alters the signaling of orexins, neurotransmitters responsible for regulating the sleepwake cycle
o OX1R and OX2R are thought to suppress wake drive
o blocks the binding of wake-promoting neuropeptides orexin A and orexin B to receptors
Pharmacokinetics
o CYP3A is the major elimination pathway
o Concentrations are higher in obese patients
Suvorexant
Adverse effects
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Sleep paralysis; an inability to move or speak for up to several minutes during sleep-wake
transitions
Cataplexy-like symptoms
leg weakness lasting from seconds to a few minutes
Similar warnings as with non-benzodiazepines – daytime impairment, etc.
Drug Interactions
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Strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin, etc.) is not recommended
Strong CYP3A inducers (e.g., rifampin, carbamazepine and phenytoin) decrease suvorexant
exposure
Inhibits intestinal P-gp
Melatonin
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Hormone released by the pineal gland at night, reaching maximum blood levels between 2:004:00am
Release from the pineal gland is stimulated by darkness and inhibited by light
Available OTC either as a synthetic product or derived from animal pineal tissue
MOA: regulates the body’s circadian rhythm; appears to increase the binding of GABA to its
receptors
Decreases sleep latency, does not appear to suppress REM sleep
Meletonin
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P’kinetics: t ½ 20-30 min
AEs: daytime drowsiness (20%) headache (7.8%), dizziness (4%)
DIs: additive sedation with EtOH, BZDs, or other CNS depressants; case reports of minor
bleeding & decreased prothrombin activity with warfarin
Can worsen dysphoria in some people with depression
May increase the incidence of seizures
May decrease glucose utilization &  insulin resistance, theoretically  blood glucose
concentrations in people with diabetes
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Sedatives Hypnotics 9-10
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Can worsen blood pressure in patients on certain antihypertensive medications*
*Immediate-release melatonin 5 mg at night in combination with nifedipine GITS (Procardia XL)  SBP
an average of 6.5 mmHg, DBP by an average of 4.9 mmHg, &  HR by 3.9 bpm
Melatonin
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FDA orphan drug status for circadian rhythm sleep disorders in blind children and adults
Jet lag: majority of evidence shows that melatonin can modestly improve certain symptoms of
jet lag such as alertness & psychomotor performance, and, to a lesser extent, daytime
sleepiness & fatigue
Travelers traveling eastward through five or more time zones may find 2 - 3 mg of melatonin
useful when taken at local bedtime on the day of arrival & for 2 - 5 nights thereafter
Safety
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Unregulated and preparations vary in strength
Seems to be safe when used for up to two months
Pregnancy: POSSIBLY UNSAFE
High doses might inhibit ovulation, causing a contraceptive effect
Until more is known about the safety of melatonin, advise pregnant patients and patients
wishing to become pregnant to avoid using melatonin at any dose
Melatonin receptor agonist
Ramelteon (Rozerem)
http://www.youtube.com/watch?v=wdpOIaGnzvA
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MOA: high affinity for the MT1 and MT2 receptors, thought to be involved in the circadian
rhythm and normal sleep-wake cycle
No affinity for GABA or other neurotransmitters
Active metabolite: M-II
Decreases sleep latency - indicated to treat sleep-onset insomnia
Little to no residual effects the next morning
No evidence of rebound insomnia
Little potential for abuse – not a controlled substance
Melatonin receptor agonist: ramelteon
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P’kinetics: rapidly absorbed; extensive first pass metabolism (bioavailability of only 1.8%); high
fat food decreases the C max; hepatic metabolism via CYP1A2, 2C9 & 3A4; eliminated in the
urine; t 1/2 = 1 -2.6 h
AEs
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Somnolence, dizziness, nausea, fatigue, headache, insomnia
Increased serum prolactin levels – clinical significance remains unclear
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Sedatives Hypnotics 9-10
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Melatonin receptor agonist: ramelteon
DIs
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Strong CYP1A2, 2C9 and 3A4 inhibitors (e.g., fluvoxamine, fluconazole and ketoconazole)
increase concentrations significantly
Strong CYP enzyme inducers (e.g., rifampin) decrease concentrations
Patient information
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Take within 30 minutes of going to bed
Avoid hazardous machinery
Do not take after a high-fat meal
Pregnancy category C; avoid with lactation
Tasimelteon (Hetlioz)
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FDA-approved for the treatment of non-24 hour sleep-wake disorder in totally blind individuals
“non-24”
MOA: Melatonin receptor agonist
Pharmacokinetics: high-fat meal decreases absorption; extensively metabolized by CYP1A2 and
CYP3A4
AEs: headache, increased ALT, nightmares or unusual dreams, and upper respiratory or urinary
tract infection
DIs:
Strong CYP1A2 and 3A4 inhibitors (e.g., fluvoxamine, fluconazole and ketoconazole) increase
concentrations significantly
Strong CYP1A2 and 3A4 enzyme inducers (e.g., rifampin) decrease concentrations
Antidepressants
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MOA: block acetylcholine, norepinephrine and serotonin presynaptic receptors
Sedation is a side effect of these agents (H1 blockers)
Pharmacologic effects:
Decrease sleep latency
Decrease wakefulness after sleep onset
Increase total sleep time
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Suppress REM sleep
Antihistamines
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Common ingredient in OTC sleep aids
MOA: sedation is a side effect of H1 blockers
Anticholinergic effects may limit their use (delirium in elderly)
May reduce sleep quality
Residual drowsiness “hangover”
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Sedatives Hypnotics 9-10
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Nytol, Tylenol PM, Advil PM, Aleve PM
all contain diphenhydramine (Benadryl)
Unisom - doxylamine
Atarax, Vistaril – hydroxyzine - Rx
Valerian root
Valeriana officinalis
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Herbaceous perennials distributed in the temperate regions of North America, Europe and Asia
MOA: gamma-aminobutyric acid (GABA) agonist; inhibits GABA transaminase, increasing GABA
concentrations and decreasing CNS activity
May also bind directly to GABA-A receptors and stimulate the release and reuptake of GABA
Valerian
P’kinetics: metabolized in the liver, seems to inhibit CYP3A4; t ½ ~ 1.1 h
AEs: usually well-tolerated; headache, gastrointestinal upset, mental dullness, excitability,
uneasiness, cardiac disturbances, and insomnia.
Occasionally, dry mouth, vivid dreams, morning drowsiness
Several case reports of hepatotoxicity
DIs: EtOH, CNS depressants, CYP450 3A4 substrates
Valerian
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Modestly reduces sleep latency and improves subjective sleep quality
Continuous nightly use for several days to four weeks might be needed for significant effect
Unregulated by the FDA
No safety information in pregnancy
Barbiturates
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Seldom used for insomnia or anxiety since the development of benzodiazepines
Used for induction of anesthesia (thiopental) and some seizure disorders (phenobarbital)
Pharmacologic effects
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Sedation
Suppress slow wave and REM sleep
Effective for up to 2 weeks; lose the ability to induce and maintain sleep after this period
Receptor site for barbiturates
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The GABAA chloride ion channel is a protein complex pentameric form that has varying
combinations of α, β, and γ subunits. GABA binds to a site near the junction of α and β subunits;
this causes conformational changes that open the chloride ion channel leading to neuronal
membrane hyperpolarization.
Barbiturates bind adjacent to α and β subunits & increase the duration of chloride channel
opening, both in the presence & in the absence of GABA.
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Sedatives Hypnotics 9-10
Barbiturates
P’kinetics
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Well absorbed; distribute in to CNS; metabolized by the liver via CYP450 (strong inducers);
excreted in the urine; t ½ 15–80h
Adverse effects
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Respiratory depression, physical & psychological dependence; agitation, confusion, nightmares,
hallucinations, hangover
Drug interactions
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Contraindicated with CYP450 3A4 inhibitors: azole antifungals, protease inhibitors & other
antiretrovirals
Additive effects with other CNS depressants
Pregnancy category: D
Chloral hydrate
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Old hypnotic
Obsolete
Prodrug, metabolized by the liver to trichloroethanol
Effects are potentiated by alcohol combinations: “Mickey Finn”, “knock-out drops”
Treatment of insomnia in pregnancy
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Diphenhydramine - category B
Doxylamine – category A
Zolpidem – category B
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Sedatives Hypnotics 9-10
C.A. is a 66-year-old white female with a history of HF, COPD, HTN, and osteopenia. Her current
medications include lisinopril, carvedilol, furosemide, Oscal D, and Combivent. She complains of trouble
staying asleep several times per week for the past couple weeks, especially after she gets up to go to the
bathroom, and mentions that she has been drowsy during the day and is afraid to drive herself to
BINGO, an activity she enjoys. She denies having trouble falling asleep. She denies SOB, and her pain is
well controlled. After counseling her on sleep hygiene measures, you decide to prescribe:
a. melatonin
b. suvorexant (Belsmora)
c. temazepam (Restoril)
d. trazodone (Desyrel)
e. zaleplon (Sonata)
M.O. is a 29-year-old black female who frequently travels outside the U.S. on business. She has no
significant medical history and her only medication is Ortho Tri-Cyclen. She has been concerned about
jet lag, which she experiences frequently and she has been using Unisom (diphenhydramine) to help her
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Sedatives Hypnotics 9-10
sleep. She is concerned because she has had difficulty focusing at work during her business trips, even
when she gets a good night’s sleep.
What are your recommendations for this patient?
a. a glass of nice red wine
b. melatonin
c. temazepam (Restoril)
d. trazodone (Desyrel)
e. zolpidem (Ambien)
L.M. is a 65-year-old male s/p MI 5 days ago. He has a history of HTN and hypothyroidism. His
medications include ASA, levothyroxine, metoprolol, lisinopril & heparin SC. He complains of insomnia.
He has had difficulty falling asleep and early morning awakenings for 6 weeks prior to hospital
admission, which has worsened during hospitalization. He expresses fear about “life after a heart
attack”.
Which of the following hypnotics is best for LM?
a. lorazepam (Ativan)
b. diphenhydramine (Benadryl)
c. ramelteon (Rozerem)
d. zaleplon (Sonata)
e. zolpidem (Ambien)
J.A. is a 49-year-old male with HTN, hyperlipidemia and a history of alcohol abuse. He complains of
difficulty staying asleep leading to daytime sleepiness and irritability.
Which of the following hypnotics would you avoid in this patient?
a. amobarbital (Amytal)
b. diazepam (Valium)
c. diphenhydramine (Benadryl)
d. ramelteon (Rozerem)
e. zolpidem (Ambien)
Bottom line
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