HL PDA III Exam I - GABAergic Hypnotics LOs

True or False: an ideal hypnotic would change the normal sleep pattern, not cause side effects the next day, have no drug interactions, and be safe to use chronically

False

Explanation: we do not want to disrupt normal sleep patterns, but everything else is correct

What are the stages of sleep?

NREM-1, NREM-2, NREM-3, REM

What is NREM?

non rapid eye movement (has 3 stages)

What is stage 1 NREM?

between wakefulness and sleep,

some eye movement,

tonic muscle activity,

brief duration

What is stage 2 NREM?

little to no eye movement,

less tonic muscle activity,

brief duration

What is stage 3 NREM?

Delta sleep,

low tonic muscle actiity,

deepest stage of sleep,

restorative

What is delta sleep?

high amplitude slow activity delta waves are seen on an EEG

What is REM?

rapid eye movement sleep

What happens during REM?

brain becomes electrically and metabolically active,

increased cerebral blood flow,

muscle atonia,

dreaming,

increased internal temperature (poikilothermia)

True or False: 4-6 cycles of delta → REM sleep

True

Explanation: each lasts 70-120 minutes, but time in REM increases with each cycle to a max of 30-60 minutes

What is melatonin?

hormone that regulates sleep-wake cycle

True or False: melatonin is biosynthesized from 5-HT, released from pineal gland, and interacts with receptors in the suprachiasmatic nucleus (SCN)

True

Explanation: this is associated with our circadian clock and when increased melatonin is in the SCN we become sleepy

True or False: darkness promotes biosynthesis of melatonin so there is increased activation of melatonin receptors in the SCN

True

Explanation: on the other hand, light inhibits biosynthesis of melatonin signaling the body through SCN when to wake up

What is a diurnal cycle?

24 hour cycle

What is the diurnal cycle of sleep?

circadian rhythm for melatonin release → sleep regulation

What happens during evening hours in regards to melatonin?

Biosynthesis of melatonin rises in the evening and peaks during sleep,

Tissue levels of melatonin increase within the pineal gland and SCN,

Diurnal variation in melatonin levels can be measured via blood

What are the types of GABAergic hypnotics?

benzos and non-benzos

What drugs are melatonin congeners/agonists?

ramelteon and tasimelteon

What drugs are orexin inhibitors/antagonists?

daridorexant, lemborexant, suvorexant

Which benzos and non-benzos are short acting (t1/2 < 6 hours)?

Midazolam (Versed): IV

Triazolam (Halcion): PO

Eszopiclone (Lunesta): PO

Zaleplon (Sonata): PO

Zolpidem (Ambien): PO

Which benzos and non-benzos are intermediate acting (t1/2 6-24 hours)?

Alprazolam (Xanax): PO

Lorazepam (Ativan): IM, IV, PO

Temazepam (Restoril): PO

Which benzos and non-benzos are long acting (t1/2 > 24 hours)?

Clonazepam (Klonopin): PO

Diazepam (Valium): IM, IV, PO, PR

What is the MOA of BZRA (non-benzos)?

agonists at the benzodiazepine binding site on GABAA (same binding site as benzos)

True or False: non-benzos do NOT produce a GABAergic effect unless GABA is present

True

Explanation: they selectively bind to GABA-A receptors with an alpha-1 subunit

What is the physiological response of non-benzos?

sedative, hypnotic, amnesic, and motor impairing

Explanation: they do NOT produce anxiolytic, muscle relaxant, or alcohol potentiating effects

What is the MOA of melatonin congener/agonists?

agonists at MT1 and MT2 receptors

True or False: melatonin congeners/agonists lengthen sleep latency

False

Explanation: they shorten it!

True or False: melatonin agonists are well tolerated, have no dependency concerns, and low incidence of daytime adverse effects

True

Explanation: they are not controlled medications

What is the MOA of dual-orexin inhibitors?

competitive antagonist at OX1R and OX2R receptors (duality)

What is the physiological effect of dual-orexin inhibitors?

decreases sleep latency and increases sleep maintenance

True or False: OX-A and OX-B are inhibitory neuropeptides involving CNS signaling

False

Explanation: they are excitatory

What are DORAs?

dual-orexin receptor antagonists

True or False: eszopiclone is an R-enantiomer of racemic zopiclone

False

Explanation: it is an S-enantiomer

True or False: eszopiclone is enantiopure

True

True or False: food delays absorption for zolpidem

True

Explanation: take on an empty tummy

True or False: high-fat meals delay absorption for lunesta

True

Describe the excretion of nonbenzos

nearly the entire z-drug is excreted as urinary metabolites

Explanation: there is very little unchanged drug

How are nonbenzos metabolized?

CYP3A4 liver enzymes metabolize 50% or more of the dose and there are no relevant active metabolites

What is the half-life of zolpidem and lunesta?

2 - 2.5 hours

What is the half-life of zaleplon?

1 hour

Explanation: shorter duration of action and little-no daytime effects, but can wear off TOO soon

What are adverse effects of nonbenzos?

Complex sleep behaviors (sleep walking, driving, etc…),

Tolerance and dependence (use lowest dose),

CNS (dizziness, drowsiness, headache)

True or False: melatonin agonists have high oral bioavailability

False

Explanation: they have low oral bioavailability

How are melatonin agonists metabolized?

CYP3A4, CYP1A2, and CYP2C- extensively metabolize these drugs

True or False: dual orexin inhibitors have high oral bioavailability

True

Explanation: take on an empty stomach for rapid onset of action

How are dual orexin inhibitors metabolized?

CYP3A4/5 mostly

What are adverse effects of dual orexin inhibitors?

somnolence, fatigue, headache

True or False: orexin inhibitors are C-IV, but have low risk for dependency

True

True or False: benzos are mostly excreted in the urine and feces as unchanged drug

True

Which benzos avoid oxidative metabolism?

LOTs are directly glucuronidated which is good for patients with liver insufficiency

Explanation: loraze, oxaze, triaze