CNS Exam 3
Intrusive REM sleep episodes can occur during the day with fragmented sleep at night is referred to as what?
Narcolepsy
What are the 4 characteristic symptoms of Narcolepsy?
- Excessive daytime sleepiness
- Cataplexy
- Hypnagogic hallucinations that occur at sleep onset
- Sleep paralysis
Weakness or loss of muscle tone is known as what?
Cataplexy
Imagined sensations that occur while a person is falling asleep are known as what
Hypnagogic hallucinations
Muscle paralysis upon wakening is known as what?
Sleep paralysis
Narcolepsy's pathophysiology is still unclear, but appears to involve what system?
hypocretin-orexin system
Orexin peptides are released from where?
lateral hypothalamus
Orexin acts on what 2 receptors?
- OX1
- OX2
Orexin acts on its receptors to promote what?
wakefulness
Orexin is also involved in what other functions?
- eating
- reward
What is the pathophysiology of Narcolepsy?
- Loss of the hypocretin-orexin system in many narcoleptic
patients
- Decreased orexin neurons in lateral and posterior hypothalamus
- Reduced orexin levels in CSF and brain tissue
Pharmacological intervention of narcolepsy is what?
symptomatic
Is there a cure for narcolepsy?
No (treated pharmacologically)
What drugs help treat EDS?
Stimulants
What is the brand name of Modafinil?
Provigil
What is the R-isomer of modafinil?
Nuvigil
What is the brand name of Armodafinil?
Nuvigil
What is the MOA for Modafinil and Armodafinil?
- Unknown, possibly DAT inhibition
- In preclinical studies, increases in NE, DA, H neurotransmission have been observed
What are some other stimulants used to help treat EDS?
- Amphetamine
- Methylphenidate
What are the MOA of Amphetamine and Methylphenidate?
Increase catecholamine neurotransmission that leads to wakefulness and alertness
Between Modafinil and Armodafinil, which has the longer duration of action?
Armodafinil ( R-isomer)
Modafinil appears to be more selective in what area of the brain?
sleep/wake cycle of the hypothalamus
Which drug selectively binds to and inhibits DAT and NET?
Solriamfetol
What is the brand name of Solriamfetol?
Sunosi
What is the drug class of Sunosi?
Dopamine/Norepinephrine reuptake inhibitor
Sunosi improves what?
wakefulness
Sunosi reduces what?
- excessive daytime sleepiness (EDS)
What form of GHB is gamma-hydroxybutyric acid?
Endogenous
What form of GHB is gamma-hydroxybutyrate, sodium salt or sodium oxybate?
Therapeutic
What is the brand name of Sodium Oxypate?
Xyrem
What is the drug of abuse that is used as a date rape drug?
Illicit GHB
What is Xyrem used to treat?
- Cataplexy
- EDS
- in Narcolepsy patients
Pharmacological effects of sodium oxybate are due to weak agonist actions at which receptor?
GABAB
GABAB is what kind of receptor?
heterodimer (has R1 and R2 subunit)
GABAB is linked to which G protein?
Gi
Xyrem acts as an agonist at pre- and postsynaptic GABAB receptors and increases what?
inhibitory transmission
GABAB receptors are found in high concentrations of which parts of the brain?
- hippocampus
- cortex
- thalamus
Xyrem causes slow inhibitory postsynaptic potential by activating what channels?
K+
Xyrem causes inhibition of what?
voltage gated Calcium channels (decreasing the release of neurotransmitter)
Nightly doses of Sodium Oxybate (Xyrem) cause:
- Reduction of transitions between wakefulness and REM sleep during the day
- Reduction of cataplexy during the day
- Reduction of nocturnal awakenings
- Increase in slow wave sleep
List some clinical uses of sedative-hypnotics:
- Insomnia
- Anxiety
- Sedation and amnesia before and during medical procedures
- Epilepsy and seizures
These drugs decrease activity, calm, and reduce anxiety:
Sedatives
What is the MAIN indication of sedatives?
Anxiety
These drug produce drowsiness, facilitate onset and maintenance of sleep:
Hypnotics
What is the MAIN indication of hypnotics?
Insomnia
True or False: A drug with a narrow therapeutic index have a greater risk for unwanted SE.
True
List examples of wake-promoting neurotransmitters:
- Histamine
- NE
Wake-promoting transmitters are balanced by what?
sleep promoting transmitters (especially GABA)
What area of the hypothalamus is known as a "sleep-promoter" area?
VLPO (Ventrolateral preoptic area)
The VLPO projects inhibitory GABAergic neurons to the wake-promoting centers that include which parts of the brain?
- tuberomamillary nucleus
- locus coeruleus
What drives regulate the balance between sleep and wakefulness?
- Circadian
- homeostatic
The sleep-promoting areas and neurotransmitters predominate with GABA tone is known as what?
"off switch"
The wake-promoting histamine and other neurotransmitters predominate with activation of wake-promoting neurotransmitter centers and also the cortex is known as what?
"on-switch"
What is the brand name of alprazolam?
Xanax
What is the brand name of clonazepam?
Klonopin
What is the brand name of clorazepate?
Tranxene
What is the generic for Valium?
diazepam
What is the generic for ativan?
Lorazepam
What is the brand name of Quazepam?
Doral
What is the generic of temazepam?
Restoril
What is the brand name of Triazolam?
Halcion
What is the target receptor of benzodiazepines (BZD)?
GABAA receptor
What subunits are required for BZD activity?
- alpha
- beta
- gamma
BZDs bind to a specific recognition/receptor site located between which subunits?
alpha and gamma
Do BZD bind to the same site as GABA?
No (allosteric site between alpha and gamma subunit)
Positive allosteric modulation of GABAA receptors do what?
- Enhance GABA binding
- Increase in frequency of channel openings
Alpha-1 receptors associated with BZD are associated with what?
- somnolence/sleepiness
- amnesia
Alpha-2 receptors associated with BZD are associated with what?
- anxiolytic effects
- muscle relaxation
List some areas that BZD receptors are found in the CNS:
- amygdala
- brainstem
- hippocampus
- hypothalamus
- prefrontal cortex
- thalamus
- SC
The vast majority of BZD receptors are which type?
alpha-1
Which CNS effect is undetermined in regards to BZD receptors?
Anticonvulsant
BZD have what effects on sleep stages (sleeping state)?
- Decreased sleep latency
- Decreased number of awakenings
What is the time it takes to fall asleep known as?
Sleep latency
BZD have an increase in what stage of sleep?
stage 2
What sleep time is reduced with the use of a BZD?
- slow wave
- REM
True or False: The number of REM cycles increases with the use of a BZD.
True
The effects of sleep stages are reduced with the what of benzodiazepines?
chronic use
A BZD can have what organ system effects?
- Respiratory
- CV
What are the respiratory system effects of a BZD?
- Depression in patients with pulmonary disease
- worsen sleep-related breathing disorders
What are the CV system effects of a BZD?
- Minor in healthy subjects
- depression in patients with impaired CV function
A BZD can suppress what area of the brain?
hypothalamus
Which BZD is a prodrug that is converted to active metabolite in gastric juice?
Clorazepate
A BZD is highly what?
protein bound (70-99%)
Plasma free drug concentration of a BZD is equivalent to what?
CSF concentration
Why are benzodiazepines rapidly uptaken into the brain?
Their lipophilicity
Benzodiazepines are redistributed into what other tissues?
- Muscle
- fat
- bc of their lipophilicity
The metabolism of a BZD is associated with what CYP enzymes?
- CYP3A4 (mostly)
- CYP2C19
Which benzodiazepines are not hepatically metabolized?
- lorazepam
- oxazepam
- temazepam
What are the phase 1 reactions associated with a BZD?
- N-dealkylation (stage 1)- pretty quick rxn
- Hydroxylation (stage 2)- little slower rxn
Many phase 1 metabolites are what?
active
What are the phase 2 reactions of a BZD?
Glucuronide conjugation
Which benzodiazepines posses the major route of metabolism via glucuronidation (phase 2)?
- lorazepam
- oxazepam
Which BZD has a preferred pathway of glucuronidation?
Temazepam
Inactive metabolites are produced by which phase of metabolism in regards to a BZD?
Phase II
What kind of excretion is associated with phase 2 metabolism of a BZD?
Renal excretion
Temazepam is slowly converted into what by CYP (phase 1) metabolism?
Oxazepam
If temazepam undergoes CYP metabolism into Oxazepam, what is the next step of metabolism?
Glucuronidation
List examples of inhibitors of CYP3A4 that can influence concentration of BZDs:
- Macrolides
- Erythromycin
- Clarithromycin
- Ritonavir
- Antifungals
- Itraconazole
- Ketoconazole
- Nefazodone
- Grapefruit juice
A BZD with a shorter half-life may result in what SE?
Rebound insomnia
A BZD with a longer half-life may result in what SE?
Hang-over sleepiness
A BZD can be grouped by it's what?
half-life
Which drug is a competitive antagonist at BZ receptor binding site?
Flumazenil
Flumazenil is administered by which route only?
IV only (extensive first pass)
How long do the effects of Flumazenil last?
30-60 min
Flumazenil is used for which indications?
- Overdose of BZD
- Reversal of BZD agonist effects
Flumazenil may cause what?
seizures
Flumazenil is NOT intended for the overdose of which drugs?
- Barbiturates
- TCAs
Novel Benzodiazepine Receptor Agonists are known as what?
Z drugs
What are the 3 Z drugs?
- Zolpidem
- Zaleplon
- Eszopiclone
What is the brand name of Zolpidem?
Ambien
What is the brand name of Zaleplon?
Sonata
What is the brand name of Eszopliclone?
Lunesta
What are the indications of BZDAs (Z drugs)?
Short or long term relief of insomnia
BZDAs decrease what?
sleep latency
BZDAs have minimal effects on what?
sleep stages
Tolerance and dependence may occur with the long-term use of which drugs?
BZDAs (Z drugs)
Z drugs are agonists that have high affinity for which subunit GABA-A receptors and bind to the BZD recognition site?
α1 subunit
Which drug can be used to reverse the effects of Z drugs?
Flumazenil
The absorption of Zolpidem is slowed with what?
food
Ambien is extensively metabolized by which CYP?
3A4
Late night administration of Zolpidem may cause what?
- drowsiness
- delayed reaction time
- amnesia
Eszopliclone is the active enantiomer of what?
zopliclone (not used in U.S.)
Lunesta undergoes which metabolism?
- CYP3A4
- 2E1
Which drug requires IMMEDIATE use at bedtime?
Zaleplon (Sonata)
Sonata is mostly metabolized by what?
hepatic aldehyde oxidase (to a lesser extent by CYP3A4)
What is the brand name of Ramelteon?
Rozarem
What is the drug class of Rozarem?
Melatonin receptor agonist
Rozerem binds to which receptors?
- MT1
- MT2
MT1 and MT2 receptors are found where?
suprachiasmatic nucleus
The MT1 receptor promotes what?
sleep onset
The MT2 receptor does what?
regulates circadian rhythm
Ramelteon is more selective for which receptor?
MT1
Ramelteon has a what?
active metabolite
Ramelteon decreases what?
sleep latency
Ramelteon has no what?
- rebound insomnia
- withdrawal symptoms
Ramelteon has significant what metabolism?
first-pass
What is the main metabolism assoc. w/ Ramelteon?
CYP1A2
Which metabolism is also involved with Ramelteon?
CYP2C9
Ramelteon has potential drug-drug interactions when used with what of the CYP1A2 and CYP2C9 enzymes?
inhibitors
Which drug is used for Non-24-Hour Sleep-Wake Disorder?
Tasimelteon
What is the brand name of Tasimelteon?
Hetlioz
What is the drug class of Hetlioz?
Melatonin receptor agonist
Hetlioz activates the MT1 and MT2 receptors, however has higher affinity for which receptors?
MT2
What are the major metabolizers associated with Hetlioz?
- CYP1A2
- CYP3A4
Hetlioz has potential drug-drug interactions with which inhibitors?
CYP1A2
Hetlioz has potential drug-drug interactions with which inducers?
CYP3A4
What is the brand name of Suvorexant?
Belsomra
Which drugs are considered Novel hypnotic drugs?
- Tasimelteon (Hetlioz)
- Suvorexant (Belsomra)
What is the drug class of Belsomra?
Orexin receptor antagonist
Orexin 1 receptor is a GPCR coupled to which G protein?
Gq
Orexin 2 is GPCR coupled to which G protein?
Gq and/or Gi
- Suvorexant competes with WHAT and binds to orexin receptors
orexin
Orexin peptides are AKA what?
hypocretins
The metabolism of Belsomra is primarily by what?
CYP3A4 (excreted in feces)
What are the SE of Belsomra?
- somnolence
- signs of narcolepsy (RARE)
Orexin peptides are released from where?
lateral hypothalamus
Orexin peptides act on their receptors to promote what?
wakefulness
Orexin peptides are also involved in what other functions?
- eating
- reward
OX1 and OX2 are found in wake promoting areas such as the:
- locus coeruleus
- tuberomamillary nucleus
Which drugs reversibly depress the activity of excitable tissues?
Barbiturates
What is the brand name of Amobarbital?
Amytal
What is the brand name of Phenobarbital?
Luminal
What is the brand name of Butabarbital?
Butisol
What is the brand name of Pentobarbital?
Nembutal
What are the brand names of Secobarbital?
- Seconal
- Tuinal
What is the brand name of Methohexital?
Brevital
Barbiturates enhance what?
GABA binding
Which subunits are required for barbiturate binding?
- alpha
- beta
True or False: Barbiturates increase the duration of channel opening.
True
Barbiturates inhibit which receptors?
AMPA (Glutamate ionotropic receptors)
In the PNS, barbiturates depress what?
- ganglionic and neuromuscular transmission
- reduce activity of nicotinic receptors (found on NMJ and Ganglion)
What effects to barbiturates have on sleep stages?
- Decreased sleep latency
- Decreased number of awakenings
- Slow wave and REM sleep reduced
True or False: Barbiturates have significant CV system effects at therapeutic doses.
False; only at high doses
Barbiturates in high doses can have what effect on the CV system?
- Decreased HR and BP
- Depression of CV reflexes in CHF
In hypnotic doses, what are the effects of barbiturates on the respiratory system?
- Decrease respiratory drive
In high doses of barbiturates, what is the effect on the respiratory system?
Respiratory drive eliminated (drug suppresses medullary causing breathing to stop = fatal)
Chronic administration of barbiturates have what effects on the liver?
- Increase in CYP 450 oxidase activity
- Increase in glucuronyl transferase activity
- Increase in δ-aminolevulinic acid (ALA) synthetase
True or False: Chronic use of barbiturates can affect other drugs in the body by decreasing their strength/effectiveness.
True
Which miscellaneous agent is converted to the active compound: trichloroethanol, by alcohol dehydrogenase, and has similar actions to barbiturates?
Chloral hydrate
Which miscellaneous agent is approved only for anxiety (nighttime sedative) and has actions similar to BZDs?
Meprobamate
Chloral hydrate adverse GI effects on a what?
empty stomach (needs to be taken with food)
List some examples of OTC sleep meds:
- Diphenhydramine (Benadryl, Unisom SleepGels, SleepMelts)
- Doxylamine (Unisom SleepTabs)
What drug class are Diphenhydramine and Doxylamine?
H1 receptor antagonists
What SE do Diphenhydramine and Doxylamine produce?
anticholinergic
What are the 2 stages of the sleep cycle?
- NREM
- REM
NREM sleep occurs how long after falling asleep?
less than 45 min
When does REM sleep first occur?
70-90 min after falling asleep
How long does REM sleep last initially?
5-7 minutes (progressively becomes longer)
What is the average amount of sleep required for adults?
7-9 hours
Sleep facilitates what things?
- Hormone release
- Memory consolidation
- Tissue repair
Which gender predominates in having insomnia?
Women
Insomnia is characterized by what?
- Difficulty falling asleep
- Difficulty maintaining sleep
- Experiencing non-restorative sleep
- Causes
significant stress or
impairment in function
Insomnia that is less than 1 week and is self limiting is which class?
Transient
What are some causes of Transient insomnia?
- Acute life stress
- medical illness
- anxiety
- poor sleep habits or travel
Short-term Insomnia is considered how long?
1-3 weeks
Short-term insomnia is causes by what?
More severe stressors
Chronic insomnia is considered to last how long?
> 3 weeks/ 1 month to years
Chronic insomnia is frequently comorbid with what conditions?
psychiatric/medical conditions
List the stimulus control counseling points for non-pharm therapy for sleep disorders:
- Establish a regular sleep pattern: Go to bed and arise at about the same time daily, even on the weekends
- Sleep only as much as necessary, go to bed only when sleepy and use bed for sleeping or intimacy only
- If unable to fall asleep (within 20-30 minutes), do not continue to try to sleep; rather, perform a relaxing activity until you feel tired
- Avoid daytime napping
- Schedule “worry time” during the day
List the Good sleep hygiene counseling points for non-pharm therapy for sleep disorders:
- Exercise regularly (3-4x/week) but not within 2–4 hours of bedtime
- Make the bedroom comfortable for sleeping. Avoid temperature extremes, noise, and light
- Avoid using caffeine, alcohol, or nicotine for at least 4–6 hours before bedtime
- If hungry, eat a light snack, but avoid eating meals within 2 hours before bedtime and avoid drinking large quantities of liquid
- Engage in “relaxing and enjoyable activities” before bedtime
Are there guidelines for chronic insomnia?
No
What is the MOA for antihistamines used for sleep disorders?
Blocks histamine1 and muscarinic receptors
What are some OTC antihistamines indicated for sleep?
- Diphenhydramine (only FDA approved)
- Doxylamine
What is the dosing regimen for Diphenhydramine for sleep?
25-50 mg QHS
What is the dosing regimen for Doxylamine for sleep?
25-100 mg QHS
What is the maximum duration for antihistamines used for sleep?
14 consecutive nights
List some contraindications for antihistamines used for sleep:
- Angle closure glaucoma
- Male patients of advanced age
- CV disease
- Dementia
For special populations of patients (pregnancy, children, geriatrics, etc.) what should be recommended regarding oral antihistamines for sleep?
Refer them to healthcare provider
If a patient is recommended to take melatonin, when should they take the medicine?
1 hour prior to bedtime
If a patient is taking Valerian root for sleep, how long should they take it before bed?
1/2-2 hours
How long would it take for Valerian root to reach optimal effect?
2-4 weeks
Why should Valerian root NOT be recommended for sleep?
Teratogenic and hepatic toxicity
What is a central nervous system stimulant and depressant?
Alcohol
BZDRA bind to which receptors in the brain?
GABAA
Traditional BZDs increase what stage of sleep?
stage 2
Traditional BZDs decrease which sleep stages?
- REM
- Stage 3
- Stage 4
Traditional BZDs should be avoided in which patients?
- Pregnant
- History of substance abuse
Long term efficacy is not established for traditional BZDs, therefore should be used for how long?
14-28 days
List some adverse effects of traditional BZDs:
- Dose dependent
- Greatest potential for daytime sedation with high doses and long or intermediate half-lives and in elderly
- Anterograde amnesia
- Rebound insomnia
Which Z drug has rapid onset, and the shortest half life?
Zaleplon
Zaleplon selectively binds to which receptor?
BZ-1
Zaleplon is BEST used as a sleep aid for what?
middle-of-the-night awakenings
Plasma levels are increased with the use of Zaleplon and which drug?
Cimetidine (CYP inhibitor)
Plasma levels are decreased with the use of Zaleplon and which drug?
Rifampin (CYP inducer)
Zolpidem binds to receptor?
BZ-1
What is the maximum strength of Zalpleon or Zolpidem in elderly patients?
5 mg
Zolpidem has what kind of half-life?
Intermediate (6-8 hours)
What is the maximum initiation strength of Zolpidem for women?
5 mg (due to next morning impairment --> may titrate up to 10 mg PRN)
Which Z drug has a rapid onset, longer half-life, duration?
Eszopiclone
Lunesta is a better option for what?
- sleep maintenance insomnia
- early morning awakenings
Lunesta may be taken for up to how long?
6 months
What are the doses of Lunesta?
1, 2, or 3 mg
What is the max dose of Lunesta for elderly patients?
2 mg
What is the most unique SE of Lunesta?
Unpleasant taste (metallic taste)
Rozerem is selective for which receptors?
- MT1
- MT2
Rozerem regulates what?
- Circadian rhythm
- Sleep onset
How many active metabolites does Rozerem have?
1
How is Rozerem taken?
8 mg within 30 min of bedtime on empty stomach
Rozerem is viable option for what patients?
Those who have history of substance abuse
True or False: Rozerem has no next day somnolence or withdrawal effects.
True
Rozerem is metabolized primarily by which enzyme?
CYP1A2
Which patients would need a higher dose of Rozerem?
Smokers (smoking is CYP1A2 inducer)
What is the brand name of Suvorexant?
Belsomra
What is the drug class of Belsomra?
Orexin receptor antagonist
Orexin helps regulate what?
Wakefulness
What is the dosing of Belsomra?
10-20 mg 20 minutes before bed
Which drugs are alternatives for patients with nonrestorative sleep who should not receive benzodiazepines?
Antidepressants
Are lower or higher doses of antidepressants used for sleep?
Lower
List some TCAs used for sleep:
- Amitriptyline
- Nortriptyline
- Doxepin
What is the downfall of antidepressants used for sleep?
Significant daytime sedation and side effects
Which antidepressant results in daytime sedation and weight gain?
Mirtazepine
What is a 2nd line drug for transient/short-term insomnia?
Trazodone
What is the dosing for Trazodone for insomnia?
25-100 mg at bedtime
Trazodone may be used for insomnia that is induced with other drugs. What are other drugs that can induce this insomnia (antidepressants)?
- SSRI
- Bupropion
What are the SE associated with taking Trazodone for insomnia?
- Carry over sedation
- Orthostasis (dizziness, blood pressure bottoms)
- Priapism (erection lasting more than 4 hours)
Orthostasis is associated with which receptor?
alpha-1
What are the Guidelines for pharmacists related to BZDRAs for transient or short-term insomnia?
- BZDRAs 3-4 nights/week for 3-4 weeks (short term)
- Monitor
- Falling asleep (in < 2 hours), maintaining sleep, rest, daytime fatigue, and concentration
- Tolerance and dependence
- Rebound
insomnia or withdrawal effects
- Taper dose (slowly pull Pt. off)
- Consider special populations
- Ramelteon now alternative first line
What is defined as no air flow at the nose and mouth for at least 10 seconds?
Sleep Apnea
How many episodes/hour is mild sleep apnea?
5-15 episodes/hour
How many episodes/hour is severe sleep apnea?
> 30 episodes/hour
How many episodes/hour is moderate sleep apnea?
15-30 episodes/hour
What are the components of obstructive sleep apnea (OSA)?
- Caused by upper airway collapse and obstruction
- Loud snores or brief gasps that alternate with episodes of silence that lasts 20-30 second
- Disturbs partner; subject is often unaware
- Cessation of breathing 60-90 seconds with cyanosis
- Most subjects are overweight
What are the components of central sleep apnea (CSA)?
- Temporary loss of respiration during sleep- impaired respiratory drive
- Treatment is with PAP and ventilatory O2
What are some complications of OSA?
- Arrhythmias
- hypertension
- pulmonary heart disease
- sudden death
What are symptoms of OSA?
- Daytime headache
- poor memory
- irritability
What is the pathophysiology of OSA?
Airflow ceases --> episode stops by a reflex action from the decrease in O2 --> arousal --> breathing resumes
What is the treatment for OSA?
- Nonpharmacologic: Weight loss, removal of obstruction (e.g. tonsillectomy)
- No drug therapy
Which drug is used to promote wakefulness with OSA?
Modafinil
What are some stimulants that are used for Narcolepsy?
- Dextroamphetamine
- Methylphenidate
What is the standard treatment for EDS associated with Narcolepsy?
Modafinil
Modafinil is what enzyme inducer?
CYP3A4
Modafinil is what enzyme inhibitor?
CYP2C19
What are the most effective agents for cataplexy associated with narcolepsy?
- TCAs
- Venlafaxine
- Fluoxetine
True or False: The dosing of Fluoxetine for cataplexy associated with narcolepsy is the same dosing as depression.
True
Which drug is effective for hypersomnia and cataplexy?
Selegiline
What is the dosing of Sodium oxybate?
2.25 grams 2-4 hours before bedtime and 2.25 grams right at bedtime
What is the dosing of Sunosi for narcolepsy?
75 mg daily
What is the dosing of Sunosi for OSA?
37.5 mg daily
What is the max dose of Sunosi?
150 mg daily
Sunosi must be avoided how long before bedtime?
9 hours (TAKE IN THE MORNING)
The sleep-wake cycle is under what?
Circadian control
Circadian rhythm sleep disorders present with what 2 disorders (either/or)
insomnia or hypersomnia
What are 2 common examples of circadian sleep disorders?
- Jet lag
- Shirt work sleep disorder (SWSD)
What is the first drug to treat circadian rhythm sleep disorder in the blind?
Tasimelteon (Hetlioz)
Sleep disturbance assoc. w/ jet lag typically lasts how long?
2-3 days
Which travel is associated with a longer duration of jet lag?
Eastward
What treatments (short-term) are used for jet lag?
- Short-acting benzodiazepine receptor agonists
- Ramelteon
- Melatonin 0.5-5 mg at bedtime
Insomnia or excessive sleepiness that occurs because of working shifts during normal sleep time is known as what?
Shift work sleep disorder
What are the treatments for SWSD?
- Short-acting benzodiazepine receptor agonists
- Melatonin
- Ramelteon
- Modafinil FDA approved to improve wakefulness
Parethesias usually felt deep in calf muscles with urge to keep limbs in motion is known as what?
Ekbom syndrome
Ekbom syndrome is associated with what sleep disorder?
Restless leg syndrome (RLS)
What are the symptoms of RLS?
- Urge to move limbs usually associated with uncomfortable and unpleasant sensations
- Begin or worsen during rest/inactivity
- Exclusively present or worse in evening/night
- Temporarily relieved by movement
Which drugs are first line therapy for RLS?
Dopamine agonists
Which DA agonists are FDA approved for RLS?
- Ropinirole
- Pramipexole
- lower doses
Ropinirole and Pramipexole are indicated also for what?
Parkinson's disease
If frequent awakenings occur with RLS, what drugs are used?
Sedative hypnotics
What is the most frequently studied sedative hypnotic associated with RLS?
Clonazepam (0.5-2 mg)
What are other drugs used for RLS that have a shorter half-life and lack carry over sedation?
- Zolpidem
- Zaleplon
- Triazolam
What drug can be used for painful RLS?
Gabapentin (300-900 mg near bedtime)
Abnormal behavior or physiologic events that either occur during sleep or are exaggerated by sleep are known as what?
Parasomnias
List some examples of Parasomnias:
- Sleep walking and sleep terrors
- Sleep talking
- REM behavior disorders and nightmares
- Enuresis (urinating in sleep) and bruxism (grinding teeth)
Which drug is the treatment of choice for REM behavior disorder?
Clonazepam
Sleep walking and sleep terrors may be treated with what drugs?
- SSRIs
- BZDs
- TCAs
Alpha-2 on GABAA is responsible for what?
anxiolytic effects
Alpha-3 on GABAA is responsible for what?
muscle relaxant effects
Alpha-5 on GABAA is responsible for what?
anticonvulsant effects
Alpha-1 on GABAA is responsible for what?
Somnolence effects
Picotoxin is a toxin that derives from a plant or shrub that causes what?
Convulsions
Picotoxin inhibits what?
GABA function
Barbituate binding on AMPA receptors results in what?
Blocking the channel
Thiobarbituates are not useful for insomnia, but are useful for what?
Anesthesia (sulfur group present)
Which 2 BZDs have major metabolite half-lives and therefore would not be ideal for everyday use for someone who goes to work every day?
- Quazepam
- Flurazepam
BZDs that are metabolized at the top of their structures will have what?
Longer 1/2 lives
BZDs that have the 4th ring at the top causing metabolism to occur at the bottom of the structure will have what?
Shorter 1/2 lives
Which BZD possesses a Nitro group (N2O) and therefore is 7-10 times more potent than other BZDs?
Flunitrazepam
Flunitrazepam causes what?
Anterograde amnesia
Which Z drug has the greatest potency?
Zolpidem
Zolpidem is highly selective for which subunit?
alpha-1
The p-CH3 groups on FRAR and PAR of zolpidem are responsible for what?
alpha-1 selectivity
The removal of imidazole N of ERR of zolpidem leads to what?
complete loss of selectivity
The antiplanar (AP) region of zolpidem is responsible for what?
binding affinity and selectivity
Which enzyme is responsible for giving us the primary active metabolite in Zolpidem?
Alcohol dehydrogenase
What inhibits alcohol dehydrogenase?
Disulferism (Antabuse)
Which drug's binding site overlaps BZ site, but does not act like classical BZ's?
Eszipiclone (Lunesta)
Lunesta has a high affinity for which subunits?
- alpha-1
- alpha-3
Which Z drug is structurally unrelated to the others?
Zaleplon (Sonata)
Sonata has an affinity for which subunits?
- alpha 1 (high)
- alpha 5 (some)
Sonata has a weak SAR, but what distinct group on its structure seems to be important for binding?
CN
What is the major metabolism route for Sonata?
Aldehyde oxidase
Chloral hydrate is used for which patients?
Pediatrics
What is the prolonged active metabolite of Chloral hydrate?
trichloroethanol
What converts chloral into trichloroethanol?
alcohol dehydrogenase
H1 receptors are highly localized where?
- Hypothalamus
- Tuberomammillary nucleus
- suprachiasmatic nucleus
Do H1 receptor antagonists that don't penetrate the brain cause sleepiness?
NO
Suvorexant (Belsomra) is heavily oxidized by what?
CYP3A4