PHRM845 Exam 4 (Ott)

Question 1

Sleep-wake cycle

Answer 1

-Non‐rapid eye movement (NREM) ‐ ~ 75% of sleep time
* Stage N1 – transition between wakefulness and sleep
* Occurs over 15 – 30 minutes
* Stage N2 – lighter alpha‐wave sleep – about ½ of TST
* Stage N3 – delta or slow‐wave – most restorative sleep, appears to be protein synthesis, wound healing, restoration of immune function
* Heart rate and respiratory rate are generally slow and regular
-Rapid eye movement (REM) ‐ ~ 25% of sleep time
* May play a role in memory consolidation
* Lowest muscle tone of the night
* Associated with dreaming
* Happens about every 90 minutes and occurs 4 to 5 times per night
* Heart rate, respiratory rate, and blood pressure are irregular with rapid fluctuations
-Adults 18 – 64 years old should have at least 7 hours of sleep per night. Less than 6 hours of sleep is associated with obesity, diabetes, hypertension, heart disease, stroke, depression, impaired immune function, increased pain

Question 2

Disease states, medications and substances associated with insomnia

Answer 2

-Anxiety
-Caffeine
-Modafinil
-Amphetamines
-Beta-agonists
-Beta-blockers
-Nicotine
-Thyroid meds
-Mood disorders
-Bupropion
-Decongestants
-Methylphenidate

Question 3

DSM-5: Sleep-wake disorders

Answer 3

**NOT just about inability to sleep; sleep and wakefulness can be a problem
Includes:
*Insomnia Disorders
*Breathing‐Related Sleep Disorders
*Obstructive Sleep Apnea Hypopnea
*Central Sleep Apnea
*Narcolepsy
*Circadian Rhythm Sleep‐Wake Disorders
*Non‐24‐Hour Sleep‐Wake Type (blindness)
*Shift Work Type
*Sleep Related Movement Disorders
* Periodic Leg Movements in Sleep (PLMS)
*Restless Legs Syndrome (RLS)

Question 4

DSM-5: Insomnia disorders

Answer 4

*Difficult sleeping at night (wake up too early or trouble falling asleep)
**Meds are NOT first line
-Primary complaint of unsatisfying sleep quantity or quality
-Difficulties with sleep initiation (latency), sleep maintenance, and/or early‐morning awakening
-Takes place at least 3 nights per week
-Present for at least 3 months
-Not associated with another sleep‐wake disorder
-Duration
* Episodic – lasting 1 month to less than 3 months
* Persistent – Lasting > 3 months
* Recurrent – experiencing 2 or more episodes during 1 year
-Can also be classified as transient (jet lag), short‐term (up to 4 weeks),
long‐term (more than 4 weeks)

Question 5

Medications for sleep onset only

Answer 5

zaleplon, triazolam, eszopiclone,
zolpidem, ramelteon
*Z-hypnotics

Question 6

Medications for sleep maintenance only

Answer 6

suvorexant, doxepin, eszopiclone,
zolpidem

Question 7

Medications for sleep onset and sleep maintenance

Answer 7

eszopiclone, zolpidem, temazepam

Question 8

Treatment of insomnia disorders

Answer 8

First‐line treatment is non‐pharmacological
* Behavioral therapies, including stimulus control therapy, sleep restriction therapy,
relaxation training
* Sleep hygiene principles are necessary and should be counseled by the pharmacist – often need drug therapy
-The z‐hypnotics (zolpidem, eszopiclone, zaleplon) are the most commonly used sleep medications
* Interact with the alpha‐1 subunit of the GABA‐A receptor (benzodiazepines also
act at the GABA‐A receptor more globally)
* Zolpidem has several dosage forms, including a sublingual form (Intermezzo®) that
is FDA‐approved for use if the person wakes up in the middle of the night and has
at least 4 hours left to sleep
* Initial dose of zolpidem is lower in women and elderly – 5 mg
* Eszopiclone (Lunesta®) is FDA‐approved for long‐term (6 months) use – patients
complain of metallic taste (“chewing on quarters”)
* Zaleplon (Sonata®) – short‐acting, lower initial and max doses for elderly patients
* 3A4 substrates – metabolism is impacted by 3A4 inhibition and induction
* Somnolence, dizziness, ataxia, headaches
* Can cause parasomnias – unusual actions while a person is sleeping – is a
warning on all medications used for sleep (sleep behaviors–>with any FDA approved med for sleep disorder)
* Controlled substances – potential for misuse
*Additive effects with other CNS depressants (alcohol or benzos)

Question 9

Sleep hygiene

Answer 9

-The cooler, the better
-White noise
-Retrain bed to thinking bed is for sleep and sex
-Bedtime ritual
-Turning off screens/changing screen to bedtime lighting
-Black out curtains
**Bright screen tells body not to make melatonin

Question 10

Tx of insomnia disorders (with benzos)

Answer 10

The benzodiazepines can be used for insomnia
*Longer‐acting agents cause significant daytime hangover
*ANY benzodiazepine can be used for insomnia – even those we consider for anxiety
*MUST consider dose taper to discontinue to avoid life‐threatening withdrawal, including
seizures, can take up to 4 months to taper off
*Temazepam is the benzodiazepine used for sleep
*Drowsiness, dizziness, cognitive impairment, increased fall risk
-Melatonin agonists (ramelteon, tasimelteon) for sleep onset symptoms
-Orexin receptor antagonists (suvorexant, lemborexant) for sleep onset or
maintenance difficulties
-All medications FDA‐approved for insomnia have sleep behaviors warning

Question 11

Melatonin receptor agonists

Answer 11

Ramelteon
* Greater affinity for melatonin receptors than
melatonin
* Attentuates the alerting signal from the
suprachiasmatic nucleus to promote sleep
* Contraindicated with fluvoxamine (SSRI for OCD or depression) or
angioedema with past ramelteon use
* Sleep onset within 30 minutes; may require up to 3 weeks of use to see effect
* GI upset, next day somnolence, hyperprolactinemia, prolactinoma
* 8 mg 30 minutes before bed

Tasimelteon
* FDA‐approved for non‐24 sleep‐wake disorder in adults (ex: legally blind so don’t get sunlight through eyes to give sleep-wake signal) and nighttime sleep disturbances in Smith‐Magenis syndrome in
adults and children down to age 3
* Similar MOA, side effects, drug interactions as ramelteon
* Additional side effects
–increased ALT, nightmares, unusual dreams
* 20 mg prior to bedtime at the same time every night, on an empty stomach

Question 12

Melatonin receptor agonists are CYP ___ substrates

Answer 12

1A2
*Watch for 1A2 inhibitors and inducers

Question 13

Orexin receptor antagonists

Answer 13

Suvorexant
Lemborexant
Daridorexant

Question 14

Orexin receptor antagonists are associated with potential for ____

Answer 14

Worsening depression
Suicidal ideation
Complex sleep behaviors

Question 15

What is Suvorexant?

Answer 15

• 10 mg within 30 minutes of bedtime and at least 7 hours to sleep
• Daytime somnolence risk
• 10 mg: warning for impairment
• 20 mg: warn against daytime driving
• Contraindicated in narcolepsy – causes
  narcolepsy‐like side effects
• 3A4 substrate

Question 16

What is Lemborexant?

Answer 16

• 5 mg at bedtime with at least 7 hours to sleep
• Time to sleep onset may be delayed if taken with a meal
• Decrease dose with moderate hepatic impairment
• 10 mg dose: avoid next‐day driving
• Contraindicated in narcolepsy – causes
  narcolepsy‐like side effects
• 3A4 substrate

Question 17

What is daridorexant?

Answer 17

• 25 mg at bedtime with at least 7 hours to sleep
• Delayed absorption with a high‐fat, high‐calorie meal
• 50 mg dose: avoid next‐day driving
• Contraindicated in narcolepsy – causes
  narcolepsy‐like side effects
• 3A4 substrate

Question 18

What does Orexin do in the body?

Answer 18

Wakefulness neurotransmitter

Question 19

What are all the orexin receptor antagonists contraindicated with?

Answer 19

Narcolepsy

Question 20

With higher doses of Orexin, do NOT ___ the day after taking this medication.

Answer 20

Drive; less concern for this because as pts wake up, orexin receptors shut themselves off.

Question 21

What is Doxepin?

Answer 21

*FDA approved
* TCA – low doses exert effect through H1
receptor antagonism
* Useful for sleep onset and maintenance
difficulties
* Duration of action about 7 hours
* Anticholinergic side effects (not as much of an issue with lower doses)

Question 22

What is Trazodone?

Answer 22

Not FDA‐approved for insomnia
* Highly sedating antidepressant
* Commonly used in low doses for sleep (25 mg –100 mg)
* Long half‐life – may see daytime hangover
* AASM recommends against use, although will
clinically see use and there is an evidence base
for effectiveness

*Low-dose trazodone helps pts fall asleep, but may make it hard to wake up in the morning.

Question 23

What is mirtazapine?

Answer 23

• Not FDA‐approved for insomnia
• Sedation is a side effect of lower doses
• Clinically used as a sleep agent, especially in
  patients with depression who have difficulty
  sleeping
• Same side effects as seen for use in depression
  *Good adjunct to other meds
  *Weight gain is up to 30 lbs

Question 24

What is quetiapine?

Answer 24

• Atypical antipsychotic with sedation side effects
• Low dose quetiapine is not recommended for
  use in insomnia unless there is a co‐morbid
  psychiatric disorder (only has anti-histaminic effect & has street value)
• Would need other condition to justify using this medication

Question 25

OTC antihistamines for insomnia

Answer 25

-Diphenhydramine/Doxylamine
* Not recommended by AASM
* Avoid use for more than 10 days; tolerance to the hypnotic effect develops
* Anticholinergic side effects – avoid in
elderly patients
* Paradoxical reactions, especially in
children
* Avoid in narrow angle glaucoma and
acute asthma
* Avoid use in patients with benign prostatic hyperplasia due to urinary retention side effect

Question 26

What are natural products used for insomnia?

Answer 26

• Melatonin/Valerian/Chamomile
• Melatonin can be considered in jet lag
  and patients with low melatonin levels; 1A2 substrate
• Valerian may act on central GABA receptors, GI upset, headache, hepatotoxicity/pancreatitis (rare) reported; inhibits 2D6, 3A4, P‐gp
  transporters
• German chamomile contains a BZD‐like
  compound; allergic reactions in patients with daisy or ragweed allergies, inhibits 1A3, 2C9, 2D6, 3A4
• Kava may be used by patients but is not
  recommended due to hepatotoxicity

Question 27

CHOOSING TREATMENT – DRUGS OR NOT?

Answer 27

-The Academy of Sleep Medicine has stated that CBT and behavioral therapies are first‐line (ask what patient is doing around the time they go to bed)
-Sleep hygiene activities will help, but will need
concomitant drug therapy
-Availability of trained providers for CBT are limited
-Patients often want a “magic bullet” to treat insomnia
-Drug therapy is FDA‐approved for short‐term use (~ 10 days), but how long do you really see people taking these drugs?
-Misuse potential of the benzodiazepines and z‐hypnotics should be considered

Question 28

DSM-5 criteria: obstructive sleep apnea

Answer 28

-Breathing related sleep disorders are divided into obstructive sleep apnea, central sleep apnea, and sleep‐related hypoventilation
-Patient must have evidence of at least 5 obstructive apneas per hour of sleep confirmed by polysomnography (want pt to get sleep study done – don’t make assumptions)
* Nocturnal breathing disturbances
* Daytime sleepiness OR can have evidence of 15 or more obstructive apneas per hours
of sleep regardless of other symptoms, confirmed by polysomnography
-Symptoms include excessive daytime sleepiness, snoring, pauses
in breathing during sleep, headache, irritability, sore throat, erectile dysfunction, impaired memory, GERD, mood disturbance
-Clinically, there is greater recognition that many patients have both apnea and insomnia – both need to be treated with apnea treated first

Question 29

Guidelines for diagnostic testing for sleep apnea

Answer 29

1. Uncomplicated adults with signs of increased risk of moderate to severe OSA ‐
   polysomnography or home sleep apnea testing
2. Polysomnography only if there is significant cardiorespiratory disease, potential
   respiratory muscle weakness due to a neuro‐muscular condition, sleep‐related
   hypoventilation, chronic opioid medication use, history of stroke, or severe insomnia.
3. DO NOT recommend questionnaires or prediction algorithms be used without
   polysomnography or home sleep apnea testing.

Question 30

What is the biggest factor of obstructive sleep apnea?

Answer 30

Obesity/overweight

Question 31

Patient may have primary ___ and obstructive sleep apnea. Treat the OSA with ___ first.

Answer 31

insomnia
CPAP

Question 32

Tx of sleep apnea

Answer 32

-Weight loss (adjunctive rather than curative), smoking cessation, avoid alcohol and CNS depressants, sleep on side rather than back
-If a patient is overweight/obese and comes for evaluation for insomnia, consider assessment for sleep apnea prior to initiating medications
CPAP – continuous positive airway pressure (nasal preferred for tolerability); BiPAP
can be considered for those patients who don’t tolerate CPAP
-Oral mandibular devices may also be useful
-Excessive daytime sleepiness (EDS) can be treated with modafinil or armodafinil –need to review CPAP adherence first and possibility of RLS or PLMS
-Modafinil/armodafinil preferred over stimulants (improves wakefulness)
-Solriamfetol is FDA‐approved for EDS, does not treat airway obstruction
-Intranasal corticosteroids can be considered in patients with comorbid allergic rhinitis
-Surgery is an option
-When considering treating apnea and insomnia, ensure that the obstructive
apnea is addressed before recommending sedative/hypnotic drug therapy

Question 33

DSM-5 criteria: Narcolepsy

Answer 33

-Recurring episodes of irresistible need to sleep, fall asleep, or nap; three times per week over the past 3 months (excessive daytime sleepiness)
-At least one of the following:
*Cataplexy episodes (muscle response to strong emotion causes a loss of muscle tone (ex: laughing so hard you end up on the ground)
*Hypocretin deficiency
*REM sleep latency < 15 minutes on nighttime polysomnography or sleep latency test with a
mean sleep latency < 8 minutes and at least 2 sleep‐onset REM periods
-Mild – infrequent cataplexy attacks (< 1 per week)
-Moderate – cataplexy attacks daily or every few days; nocturnal sleep
disturbances
-Severe – cataplexy considered to be drug resistant with multiple attacks per
day; almost constant sleepiness; nocturnal sleep disturbances
-Sleep paralysis may also occur (Does NOT make narcolepsy; wake up in middle of dream/nightmare and can’t move)

Question 34

The narcolepsy tetrad

Answer 34

-EDS
-Cataplexy – sudden loss of muscle tone triggered by emotion
-Hallucinations (auditory/visual hallucinations when falling asleep or waking up)
-Sleep paralysis

Question 35

Tx of cataplexy

Answer 35

*Sodium oxybate (Xyrem®) – GHB – high sodium content
*Xywav® ‐ For adults and children aged 7 or older, also approved for idiopathic hypersomnia in adults – lower sodium content
*Dosed twice per night – first dose at bedtime, 2nd dose 2.5 – 4 hours later – must set alarm to wake up and take dose
*Lumryz® ‐ For adults only – ER dosage form, once nightly dosing, high sodium content
*Black box warning for respiratory depression and misuse risk
*Side Effects – N/V, paresthesias, disorientatin, irritability, sleepwalking, nocturnal enuresis, night cold sweats, weight loss/anorexia
*REMS – Schedule III for this use, Schedule I for all other uses
*TCAs (clomipramine), SSRIs, venlafaxine may provide some benefit

Question 36

Tx for excessive daytime sleepiness

Answer 36

*Modafinil/armodafinil: associated with possible life‐threatening rash
*Sodium oxybate (Xyrem)
*Methylphenidate, dextroamphetamine, mixed amphetamine salts
*Pitolisant and solriamfetol recently FDA‐approved for EDS
*Selegiline (not FDA‐approved, but may reduce EDS)

Question 37

What is Pitolisant?

Answer 37

-H3 receptor antagonist/inverse agonist
-Prolongs QT interval
-2D6/3A4 substrate
-Weak 3A4 inducer – may reduce
effectiveness of oral contraceptives
-Avoid use with centrally‐acting H1 receptor antagonists (OTC antihistamines)
-Contraindicated in severe hepatic
impairment

Question 38

What is solriamfetol?

Answer 38

-Dopamine norepinephrine reuptake inhibitor
(DNRI)
-Indicated for improvement in wakefulness in adults with excessive daytime sleepiness due to narcolepsy or obstructive sleep apnea
-Moderate renal impairment – start 37.5 mg, may increase to 75 mg after at least 7 days; severe renal impairment – starting and max dose= 37.5 mg
-Warnings: B/P and HR increases – avoid in unstable CV disease and arrhythmias; use caution in patients with a history of psychosis or bipolar disorder – decrease dose or discontinue if psychiatric symptoms develop; use with caution with dopaminergic drugs
**NOT absolute contraindications

Question 39

Shift work sleep disorder is a disorder of ____

Answer 39

Wakefulness
-Often a problem for people who work night shifts or those who have changing work shifts throughout the week or month
-Excessive “wake time” sleepiness is a result of poor sleep during the sleep period
-Sleep hygiene can be helpful, including black out curtains, noise makers (white noise, fans)
-Drug therapy of shift work sleep disorder focuses on improving wakefulness during the “wake time” versus improving sleep latency or maintenance during sleep time
-Modafinil and armodafinil are the drugs of choice, taken 1 hour before the work period starts during “wake time”
-Insomnia may also be a problem, can be addressed if improving
wakefulness doesn’t improve actual sleep

Question 40

What is restless legs syndrome?

Answer 40

An urge to move the legs in response to an uncomfortable or unpleasant sensation that (1) begins/worsens during periods of rest; (2) partially or completely relieved by movement; (3) worse in the evening/night or occurs exclusively at this time

Question 41

Drug therapy for restless legs syndrome

Answer 41

*Gabapentin enacarbil – prodrug of gabapentin, FDA‐approved for RLS, growing evidence base for effectiveness, may be considered first‐line
*Dopamine agonists (IR formulation) – pramipexole or ropinirole, orthostasis, somnolence side effect (can be used, but gabapentin works best)
* Levodopa/carbidopa can be considered
* Very little evidence for benefit > harm – opioids – do not recommend
* Iron supplementation may be considered
* Clonazepam may be considered

**May cause impulsive disorder
*Check iron and ferritin to ensure pt has good iron stores

Question 42

Generally restless legs syndrome starts ___ at lower legs and moves up ____

Answer 42

Unilaterally
Bilaterally

Question 43

Gabapentin enacarbil

Answer 43

Drug of choice for restless legs
-It is a prodrug, so take it a few hours before going to bed