Sleep and Sleep Disorders + Drugs

Question 1

Which neurotransmitter drives REM sleep?

Answer 1

acetylcholine from the brainstem to the thalamus and cortex

Question 2

describe the electrical activity of the various stages of sleep

Answer 2

Wake = alpha rhythm (eyes closed)

N1 = loss of alpha rhythm, decrease in frequency
N2 = spindles, K complexes
N3 = slow waves

REM = low amplitude, mixed frequency, theta, rapid eye movements

Question 3

Which structure in the brain controls the circadian rhythm?

Answer 3

Suprachiasmatic nucleus of the hypothalamus - has an endogenous oscillation of around 24 hours

Question 4

What does the Borbély 2 process model of sleep say?

Answer 4

There is a homeostatic drive to sleep (Process S)

There is a circadian rhythm which regulates sleep and many
physiologic processes (Process C)

Disruption of either of these components can cause sleep problems

Question 5

What occurs in central sleep apnea?

Answer 5

Brain does not send a signal to the phrenic nerve to breathe

May be associated with congestive heart failure, medications – treat underlying cause

Does not present with snoring (obstructive sleep apnea)

Question 6

type 1 versus type 2 narcolepsy

Answer 6

Type 1: with cataplexy, associated with loss of orexin/hypocretin neurons in the hypothalamus - occurs when REM related muscle atonia occurs during wake

Type 2: without cataplexy

Question 7

Why do hallucinations and sleep paralysis occur with narcolepsy?

Answer 7

hypnogogic/hypnopompic hallucinations occur because REM intrusion into wake-sleep transition

sleep paralysis occurs because of REM related muscle atonia persisting into wake (usually briefly)

cataplexy occurs when REM related muscle atonia occurs during wake

Question 8

what is the mainstay of therapy for insomnia?

Answer 8

Cognitive behavioral therapy for insomnia (CBT-I): treat underlying maladaptive thoughts which makes sleep difficult + work on proper sleep hygiene

Question 9

parasomnias

Answer 9

sleep walking/talking, night terrors, may involve complex behaviors like driving a car

very common in children, usually grow out of them, if tx is needed give clonazepam

involve “partial” sleep of the brain - some areas remain active during sleep

Question 10

with what diseases are REM Behavior Disorders associated?

Answer 10

fighting/punching/kicking in sleep, generally involving dream of being attacked - do NOT involve complex movements (driving a car, etc)

associated with synucleionpathies such as Parkinson’s Disease - may precede disease by many years

may be caused by SSRIs, can be treated with clonazepam or melatonin

Question 11

How can restless leg syndrome be treated?

Answer 11

may be underlying iron deficiency

if not, Gabapentin is first-line therapy

Question 12

what is the MOA of hypnotic benzodiazepines such as triazolam, temazepam, estazolam, flurazepam, and quazepam?

Answer 12

bind GABA(A) receptors and increase frequency of GABA-mediated chloride channel opening

rapid onset of action - used to treat insomnia; also have muscle relaxant and anticonvulsant properties

Question 13

why are hypnotic benzodiazepines such as triazolam, temazepam, estazolam, flurazepam, and quazepam now considered alternative agents?

Answer 13

bind GABA(A) receptors and increase frequency of GABA-mediated chloride channel opening

now considered alternative due to long half-lives + high potential for tolerance/dependence

Question 14

what are the adverse reactions of hypnotic benzodiazepines such as triazolam, temazepam, estazolam, flurazepam, and quazepam?

Answer 14

bind GABA(A) receptors and increase frequency of GABA-mediated chloride channel opening

adverse rxns: CNS depression, respiratory depression, high tolerance/decadence risk (schedule IV), withdrawal after abrupt cessation

Question 15

group the following hypnotic benzodiazepines as short, intermediate, or long-acting:
a. temazepam
b. quazepam
c. triazolam
d. estazolam
e. flurazepam

Answer 15

short acting: triazolam

intermediate acting: temazepam, estazolam

long acting: flurazepam, quazepam

bind GABA(A) receptors and increase frequency of GABA-mediated chloride channel opening

Question 16

what kind of drugs are triazolam, temazepam, estazolam, flurazepam, and quazepam? what is their MOA?

Answer 16

hypnotic benzodiazepines - treat insomnia (also have muscle relaxant and anticonvulsant properties)

bind GABA(A) receptors and increase frequency of GABA-mediated chloride channel opening

Question 17

what kind of drugs are zolpidem, eszopiclone, and zaleplon? what is their clinical use?

Answer 17

non-benzodiazepines hypnotics - bind same site on GABA(A) to increase frequency of chloride channel opening

used to treat insomnia by decreasing sleep latency (time to sleep), rapid onset and short half-lives

help you get your Zzzzzzz’s

Question 18

name 2 first-line options for sleep-onset insomnia and sleep maintenance / mixed insomnia

Answer 18

1. zolpidem
2. eszopiclone

non-benzodiazepines hypnotics - bind same site on GABA(A) to increase frequency of chloride channel opening

help you get your Zzzzzzz’s

Question 19

what black box warning is mandated on zolpidem, eszopiclone, and zaleplon? what kind of drug are these?

Answer 19

non-benzodiazepines hypnotics - bind same site on GABA(A) to increase frequency of chloride channel opening —> treat insomnia

schedule IV controlled substances, but not common choices for abuse

FDA mandated black box warning for rare but serious complex sleep behaviors - sleep walking/eating/driving

Question 20

what kind of drugs are ramelteon and tasimelteon, and what is their clinical use?

Answer 20

melatonin receptor agonists (MT1 and MT2) in suprachiasmatic nucleus of hypothalamus, >15x more potent than melatonin

used to treat sleep-onset insomnia (NOT used for sleep maintenance)

Question 21

for what is ramelteon a first line option?

Answer 21

melatonin receptor agonist (MT1 and MT2) in suprachiasmatic nucleus of hypothalamus, >15x more potent than melatonin

first-line for sleep-onset insomnia (NOT used for sleep maintenance), but reduced efficacy compared to GABAergic non-benzodiazepine hypnotics (zolpidem, eszopiclone)

Question 22

what side effects are associated with ramelteon?

Answer 22

melatonin receptor agonist used to treat sleep-onset insomnia

side effects: somnolence, nausea, dizziness, fatigue, endocrine changes (low testosterone, high prolactin)

no risk of dependence/abuse (not classified as controlled substance)

Question 23

name a melatonin receptor agonist that is a first-line option for sleep-onset insomnia

Answer 23

ramelteon: agonist at MT1 and MT2 in suprachiasmatic nucleus of hypothalamus, >15x more potent than melatonin

used to treat sleep-onset insomnia (NOT used for sleep maintenance)

Question 24

what kind of drugs are suvorexant, lemborexant, and daridorexant, and what is their clinical use?

Answer 24

dual orexin receptor antagonists (DORAs): antagonize orexin (OX) neurotransmitter at both OX1 and OX2 receptors in brain

orexin is a central promoter of wakefulness

DORAs are first line options for sleep maintenance or mixed insomnia, also second-line for sleep-onset insomnia

Question 25

what is the function of the neurotransmitter orexin? how is this targeted in drug therapy?

Answer 25

orexin = central promoter of wakefulness

dual orexin receptor antagonists (DORAs): first line options for sleep maintenance or mixed insomnia, also second-line for sleep-onset insomnia

ex: suvorexant, lemborexant, daridorexant

Question 26

for what condition are DORAs first-line options for? what about second-line?

Answer 26

DORAs = dual orexin receptor antagonists: block OX1 and OX2 receptors

orexin = NT which promotes wakefulness

first line for sleep maintenance or mixed insomnia; second line for sleep-onset insomnia

ex: suvOREXant, lembOREXant, daridOREXant

Question 27

how can doxepin be used to treat insomnia? what kind of drug is this?

Answer 27

tricyclic antidepressant (TCA) with high selectivity to antagonize post-synaptic H1 receptors

used at doses much lower than those to treat depression, antihistaminic activity enhances sleep time and maintenance (long half life = long acting)

low dose is first-line for sleep maintenance or mixed insomnia (NOT indicated for sleep-onset insomnia)

Question 28

name a TCA that is a first-line option for sleep maintenance or mixed insomnia

Answer 28

doxepin: has high selectivity to antagonize post-synaptic H1 receptors

used at doses much lower than those to treat depression, antihistaminic activity enhances sleep time and maintenance (long half life = long acting)

(NOT indicated for sleep-onset insomnia)

Question 29

what are the side effects of doxepin when used at low enough doses to treat insomnia?

Answer 29

doxepin = TCA with high selectivity to antagonize H1 receptors —> enhanced sleep

side effects: somnolence, nausea, upper respiratory tract infections

Question 30

which of the following is NOT a schedule IV controlled substance?
a. triazolam
b. doxepin
c. suvorexant
d. eszopiclone
e. flurazepam

Answer 30

b. doxepin = TCA selective for H1 (antagonize)

these are all used to treat insomnia

a. triazolam = short acting benzodiazepine
c. suvorexant = dual orexin receptor antagonist (DORA)
d. eszopiclone = non-benzodiazepine hypnotic
e. flurazepam = long acting benzodiazepine

note while the rest are schedule IV, only benzodiazepines pose a real dependence risk

also note ramelteon and tasimelteon (melatonin receptor agonists) are also not controlled substances