Exam 4 Sleep Flashcards
What is a sedative?
-Calms anxiety
Decreases excitement and activity
-Does not cause drowsiness or impair performance
What is an anxiolytic?
Anti-anxiety
-Relieves anxiety without sedation
What is a hypnotic?
*Induces sleep
What is a narcotic?
“Sleep-inducing”
-now refers to opioids or illegal drugs
What brain region is involved in sleeping?
Reticular Formation
What are the 3 stages of sleep?
Wakefulness
Non-rapid eye movement (NREM)
Rapid eye movement (REM)
Waking up in the middle of which sleep stage makes you feel bad?
REM
What is REM sleep?
Similar to awake in EEG
*not sure why we have this or what benefit is
Which sleep stage is associated with dreaming?
REM
At what time does melatonin secretion stop?
7:30am
What time does high alertness begin?
10:00am
What are the biological regulators of sleep?
Neurotransmitters (GABA)
Neuromodulators
*What is the main target for current sleep medications?
GABA
Why do we target GABA for sleep?
Want to quiet down neurotransmitter activity
-GABA is inhibitory so we want to increase its effect
-GABA acts as a Cl channel, want to induce a Cl influx to hyperpolarize the cell membrane
What is the function of benzodiazepines?
Bind GABA receptors, make them function better
What type of ion channel is GABA?
Chloride
*What site on GABA do benzodiazepines target?
Benzodiazepine site (BZD): Allosteric a1 and y2
(allosteric means they do not bind at the active site)
*work at all a1-5
What affect do benzodiazepines have on GABA?
Facilitate GABA action
Increase frequency of channel opening*
*Work at a1-5 so they have many effects
What are the non-benzodiazepines that work at the benzodiazepine receptor?
Z-Hypnotics
-zolpidem
-zaleplon
-eszopiclone
*Where do the Z-hypnotics work on GABA?
BZ1 (benzodiazepine) receptors of a1
What is the benzodiazepine antagonist (used for overdose treatment)?
Flumazenil
*What affect do barbiturates have on the GABA channel and how does this compare to benzodiazepines?
Barbiturates: Increase duration of channel opening, have direct effects on GABA A
BZDs: Increase frequency of channel opening, have indirect effects on GABA
Which are more dangerous: benzodiazepines or barbiturates?
Barbiturates
-have a direct effect on GABA
**Benzodiazepines have a ceiling effect with how much they are able to increase the frequency of GABA channel opening
*Barbiturates do not show a ceiling effect with duration of channel opening and could theoretically keep the channels open forever
*If barbiturate dose gets too high patients can have seizures or go into a coma and die
*Positive alkylation of the benzodiazepine structure acts as what?
Source of active metabolites
*Annealating the 1-2 bond in the benzodiazepine structure with an “electron rich” ring causes what?
-High affinity
-Decreased half-life
*Does Diazepam have a short or long half-life?
LONG
Which benzodiazepine does not get metabolized into an active metabolite?
Lorazepam
Which benzodiazepines has a slow elimination rate (has an active metabolite)?
Diazepam
What are the active metabolites of diazepam?
-> Desmethyldiazepam -> Oxazepam
What two other indications is diazepam used for?
-Convulsive disorders (seizures)
-Accumulation of metabolites
Which benzodiazepine has an intermediate elimination rate?
Clonazepam
What other indication does clonazepam have?
Anticonvulsant
Which benzodiazepine has a rapid elimination rate?
Midazolam
Why do some benzodiazepines have slow elimination?
They have active metabolites that cause it
*What affect do benzodiazepines have on the sleep cycle?
Decrease REM
Decrease stage 3 and 4
-BAD, makes you not feel rested or recharged
***NOT AS COMMONLY USED AS A SLEEPING AID BECAUSE OF THIS
Besides sleep, what are benzodiazepines used for?
Anticonvulsants
What should benzodiazepines not be used with?
-Other sedatives
*Alcohol (also acts on GABA, could break ceiling effect and cause coma)
*Pregnancy and breastfeeding
What is Flumazenil used to treat?
Benzodiazepine overdose
Z-Hypnotic overdose
What drug do we use to treat a barbiturates overdose?
NONE
-cannot treat
*What Z-Hypnotics are used for SHORT-TERM treatment of insomnia? (7-10 days)
Zolpidem (Ambien)
Zaleplon (Sonata)
*What Z-Hypnotic is used for LONG-TERM treatment of insomnia?
Eszopiclone (Lunesta)
*What is a benefit of using Z-hypnotics over benzodiazepines?
Cause less negative effects on sleep patterns
*What are the side effects of Z-Hypnotics?
*PATIENTS MAY DO DAILY ACTIVITIES WHILE ASLEEP
-Sleep-driving, -cooking -eating, -sex
*WARN PATIENTS ABOUT THIS
True or False: Barbiturates are commonly used
False
-high abuse potential, less common now
What is the long-acting barbiturate?
Phenobarbital
What is the short to intermediate acting barbiturate?
Pentobarbital
Which barbiturate also acts as an anticonvulsant?
Phenobarbital
What side effect is the biggest concern with barbiturates?
Respiratory depression -> Death
(seizure, then coma, then death)
Top 3 most important facts about barbiturates:
-Bind to all GABA A “a1-5” receptors
-Increase duration of channel opening
-Direct effects on GABA
Top 2 most important facts about benzodiazepines:
-Bind all GABA A “a1-5” receptors
-Increase frequency of channel opening
Top 2 most important facts about Z-hypnotics:
-Bind GABA A “BZ1 receptors of a1”
-Increase frequency of channel opening
What is the difference between GABA A and GABA B?
GABA A= Cl ion channel
GABA B= GPCR
What type of receptor is the GABA B receptor?
Metabatropic (GPCR)
(initiates a number of metabolic steps to modulate cell activity)
What is the structure of the GABA B receptor?
Heterodimer
(made up of GABA B1 and GABA B2)
Which part of the GABA B Receptor heterodimer does GABA bind to?
(GABA B1 or GABA B2)
GABA B1
What is Xyrem?
-Sodium Oxybate, GHB*
-A strange drug that is not used often
-Sedative hypnotic
-Prescribers must be enrolled in a patient success program
*Huge abuse potential
What is Gamma-Hydroxybutyric Acid (GHB)?
-Sedative hypnotic
*High abuse potential
**Does not have an antagonist, cannot be reversed
Why is abuse of Gamma-Hydroxybutyric Acid (GHB) a concern?
It has no antagonist
*Cannot be reversed
When do melatonin levels peak?
The middle of the night
What are the melatonin AGONISTS?
-Ramelteon
-Tasimelteon
What is the nickname for Ramelteon and why is it called this?
“Master Clock”
-because it regulates circadian rhythms
(helps when melatonin is lost in aging and Alzheimer’s)
What makes Ramelteon a good drug of choice?
No abuse, withdrawal, or dependency
What disease state is Tasimelteon used to treat?
Non-24-hour sleep wake disorder
(in blind individuals)
What type of product is Tasimelteon registered as?
Orphan product
*this is an FDA approval of a drug for a rare disease that very few people face
(in this case, Non-24-hour sleep wake disorder)
What is orexin?
Neurotransmitter that works in the hypothalamus (sleep center) to promote wakefulness
*Want to reduce orexin to promote sleep
-Works on the reward pathway, some abuse potential
What drug is an orexin receptor antagonist?
Suvorexant
Where are receptors for Suvorexant located?
Hypothalamus
What affect does Suvorexant have on the reward pathway of Orexin?
Reduces rewarding stimuli (DA release)
–done through receptors that modulate the mesolimbic projections between the VTA and the nucleus accumbens
What was the label change made by the FDA for all sleep disorder drug products?
Label must include information about Sleep-Related behaviors
(sleep-driving, sleep-cooking/eating, sleep-phone calls)
What are other drugs that have sedative properties?
Trazodone
Antihistamines (OTC):
-Diphenhydramine
-Doxylamine
-Pyrilamine
What is the most commonly taken natural herbal/natural sedative?
Melatonin
True or False: Melatonin is FDA approved for sleep
False
Which herbal/natural sedative can cause hepatotoxicity?
Valerian
What is a big problem with herbal/natural products?
Many products do not actually contain the product/amount that they are advertising
What disease states are associated with insomnia?
Anxiety
Mood Disorders
What substances are associated with insomnia?
Caffeine
Nicotine
What drugs are associated with insomnia?
Modafinil
Amphetamines
Beta-agonists
Beta-blockers
Thyroid meds
Bupropion
Decongestants
Methylphenidate
What defines an “insomnia disorder”?
Difficulties with sleep initiation (latency), sleep maintenance, and/or early-morning awakening
**Taking place at least 3 nights per week
**Lasting at least 3 months
What is latency?
Sleep initiation
What is first-line treatment for insomnia disorders?
NOT MEDICATIONS
-setting up a sleep schedule, sleep hygiene*, avoiding screen time, etc
What are the most commonly used sleep medications?
Z-hypnotics
-Zolpidem
-Eszopiclone
-Zaleplon
How is dosing of zolpidem adjusted?
Initial dose is lower in women and the elderly
(5mg)
Which drug has metallic taste as a side effect?
Eszopiclone
What are the side effects of Z-hypnotics?
-Somnolence
-Dizziness
-Ataxia
-Headaches
*Parasomnias (unusual actions while sleeping)
What are Z-hypnotics a substrate of?
3A4
What is a barrier to receiving Z-hypnotics?
They are controlled substances
What is the preferred benzodiazepine for sleep?
Temazepam
What are the side effects Temazepam?
-Drowsiness
-Dizziness
-Cognitive impairment
-Increased fall risk
Which drug is contraindicated with Fluvoxamine?
Ramelteon
*concentration of this drug gets majorly increased by the other, cannot use together
What are the side effects of Ramelteon?
-GI upset
-Next day somnolence
-Hyperprolactinemia
-Prolactinemia
What is Ramelteon and Tasimelteon substrates of?
1A2
True or False: Melatonin only helps with falling asleep, not staying asleep
True
What are the orexin receptor antagonists?
Suvorexant
Lemborexant
Daridorexant
What is required when taking orexin receptor antagonists that may limit their use?
Need at least 7 hours of sleep
When are orexin receptor antagonists contraindicated?
With narcolepsy
What side effects do orexin receptor antagonists cause?
Narcolepsy-like SE
What are the orexin receptor antagonists substrates of?
3A4
How does Doxepin work?
Tricyclic antidepressant (TCA)
-low doses exert effect through H1 receptor antagonism
What are the side effects of Doxepin?
Anticholinergic
True or False: Trazodone is not approved for insomnia
True
What is a side effect of trazodone and why does it occur?
Daytime hangover
*because it has a long half-life
When would we use Mirtazapine for sleep?
-Clinically used as a sleep agent, but especially in patients with depression who have difficulty sleeping
When would we use Quetiapine for sleep?
Low doses are not recommended for insomnia use unless there is a co-morbid psychiatric disorder
When should we consider melatonin use?
Jet lag
Patients with low melatonin levels
What is melatonin a substrate of?
1A2
What side effects can be caused by German chamomile?
Allergic reaction in patients with ragweed or daisy allergies
In order to be diagnosed with obstructive sleep apnea, what must patients experience?
At least 5 obstructive apneas (with evidence) per hour of sleep confirmed by polysomnography
What are the symptoms of obstructive sleep apnea?
Excessive daytime sleepiness
Snoring
Pauses in breathing during sleep
Headache
Irritability
Sore throat
Erectile dysfunction
Impaired memory
GERD
Mood disturbance
If a patient has both insomnia and sleep apnea which is treated first?
Sleep apnea
-treating insomnia without having the patient on a sleeping mask could kill them
*recognized that these conditions often go together
What is the diagnostic test for sleep apnea and when do we use it?
Polysomnography
Only if:
-Significant cardiorespiratory disease
-Potential respiratory muscle weakness due to neuro-muscular condition
-Chronic opioid medication
-History of stroke
-Sever insomnia
What are the non-pharm treatments for sleep apnea?
-Weight loss (adjunct, not cure)
-Smoking cessation
-Avoid alcohol and CNS depressants
-Sleep on side, not back
What is the pharm cure for sleep apnea?
CPAP machine
-continuous positive airway pressure
How do we treat excessive daytime sleepiness (EDS)?
Modafinil
Armodafinil
**need to review CPAP adherence first and possibility of RLS or PLMS
What symptoms are considered “The Narcolepsy Tetrad”?
-Excessive Daytime Sleepiness (EDS)
-Cataplexy
-Hallucinations
Sleep Paralysis
*patients may experience all or some of the symptoms
What % of narcolepsy patients experience Excessive Daytime Drowsiness (EDS)?
100%
*generally more severe in Type 1 narcolepsy (with cataplexy or hypocretin deficiency syndrome)
What is cataplexy?
Sudden loss of muscle tone triggered by emotion
What percent of narcolepsy patients experience cataplexy?
75%
What % of narcolepsy patients experience hallucinations?
30-60%
What % of narcolepsy patients experience sleep paralysis?
25-50%
What % of narcolepsy patients experience all 4 symptoms in the narcoleptic triad?
10-33%
How do we treat cataplexy?
-Sodium oxybate
-Xywav
-Lumryz
Which cataplexy med has lower sodium content?
Xywav
Which cataplexy med is approved in children?
Xywav
*for adults + children 7 and older
Which cataplexy med is also approved for Idiopathic Hypersomnia in adults?
Xywav
Which cataplexy med is the original base med?
Sodium Oxybate (Xyrem)
Which cataplexy med is an ER dosage form that only requires once nightly dosing?
Lumryz
What is a side effect of Modafinil/Armodafinil?
Possible life-threatening rash
Which medications were recently FDA approved for excessive daytime sleepiness?
Pitolisant
Solraimfetol
What is the MOA of Pitolisant?
H3 receptor antagonist/inverse agonist
When is Pitolisant contraindicated?
Severe hepatic impairment
What are two negative affects that Pitolisant can have?
-Reduces effectiveness of contraception (3A4 inducer)
-Prolongs QT interval
What is Pitolisant a substrate of?
2D6/3A4
What drugs should we avoid using with Pitolisant?
Centrally-acting H1 receptor antagonists
(OTC antihistamine)
What is the MOA of Solriamfetol?
Dopamine norepinephrine reuptake inhibitor (DNRI)
What is Solriamfetol indicated for?
Improvement in wakefulness in adults with excessive daytime sleepiness due to narcolepsy or sleep apnea
What is the renal impairment dosing for Solriamfetol?
Moderate: Start 37.5mg, may increase to 75mg after 7 days
Severe: 37.5mg is starting and max dose
What are the warnings associated with Solriamfetol?
BP and HR increases
-Avoid in unstable CV disease and arrhythmias
-Caution in patients with history of psychosis or bipolar disorder
-Decrease or discontinue dose if psychiatric symptoms occur
-Caution with dopaminergic drugs
What drugs are used to treat shift work sleep disorder?
Modafinil and Armodafinil
*take 1 hour before work period starts
*WE WANT WAKEFULLNESS
What treatment do we use for Restless Legs Syndrome?
Gabapentin encarbile (preferred)
Dopamine agonists (IR pramipexole or IR ropinirole)
Iron supplementation is low iron is cause
What is Gabapentin encarbil?
Prodrug of Gabapentin
*FDA approved for RLS
*First-line
