Pharmacology of Hypnotics - CROUSE

Learning Objectives

• Define sleep-related terminology

• Identify sleep-promoting and wake-promoting neurotransmitters

• Describe the MOA of sedative/hypnotics

• Compare and contrast the PK of BZD receptor agonists (BZDs and Z-drugs) including sex0related differences in PK

• List Contraindications for specific sedative/hypnotics

• Identify which sedative/hypnotics are controlled substances and carry a risk of misuse

• Describe adverse effects of sedative/hypnotics

Top 300 drugs

Doxepin

Temazepam

Eszopiclone

Zolpidem

off label for insomnia:

• Trazadone

• Mirtazapine

• Quetiapine

What does a sedative do?

• it is a CNS depressant

  • relieves anxiety

  • calming effect

what does a hypnotic do?

• it is a CNS depressant

  • Promote/maintain sleep

What is Soporific?

An adjective meaning to “cause sleep”

What NTs are sleep promoting in the body?

• Melatonin

• GABA

• Adenosine

What NTs are wake-promoting in the body?

• NE

• ACh

• Histamine

• Serotonin

  • 5HT2a stimulation = insomnia

• Dopamine

• Orexin (hypocretin)

Pathophysiology/Normal function of sleep cycles/Circadian rhythm

The Suprchiasmatic nucleus (SCN) - “master biological clock”

• Located in hypothalamus

• Controls circadian rhythm

  • Suppresses melatonin in light times

  • Pineal gland (PinG) releases/secretes melatonin in Darkness

HISTAMINE FOLLOWS CIRCADIAN PATTERN!

OREXIN is the OPPOSITE OF MELATONIN/HISTAMINE PATTERN

What drugs work on serotonin neural synapses and can cause drowsiness/sleep?

SSRIs AND SARI (serotonin 2A antagonist/reuptake inhibitor)

Insomnia-indicated drugs that are PAMs of GABAa receptor!!!

Traditional BZDs (EFQTT)

• Estazolam

• Flurazepam

• Quazepam

• Temazepam

• Triazolam

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Z-Drugs / “Z-Hypnotics”/ “non-benzodiazepine receptor agonists”

• Eszopiclone

• Zaleplon

• Zolpidem

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THEY have the same BINDING SITE!!

• TARGET alpha-1 subunit for sedation

Which 2 Benzodiazepines for Insomnia have the Longest half-lives? (Metabolites included)

Quazepam and Flurazepam

• (47-100 hrs in body for metabolite)

Which of the Z-drugs/Hypnotcs has the shortest half-life?

Zaleplon

What are unique AEs pertaining to insomnia BZDs?

Next-day sedation, anterograde amnesia

• do not combine with opioids

What are unique AEs pertaining to insomnia Z-drugs?

Sleep related behaviors

• Sleep dripping, sleep walking, etc

• Eszopicline = taste disturbances

Expected DDIs for Z-drugs and insomnia BZDs?

Pharmacodynamic

• Additive CNS drugs

  • that cause sedation, fatigue, etc

• Additive respiratory depression

Pharmacokinetic

• Depends on the agent

• example - diazepam (CYP3A4)

• May require higher doses for CYP3A4 inducer

Doses for each sex for Zolipidem (Ambien)?

• Ambien = M (10mg) // F (5mg)

• Ambien CR = M (12.5mg) // F (6.25mg)

• Edluar = M (10mg) // F (5mg)

• Intermezzo = M (3.5mg) // F (1.75mg) - dose Middle of night

• Zolpimist = M (10mg) // F (5mg)

Complex sleep-related behaviors for all BZDs and Z-drugs? (so ALL insomnia drugs)

• sleepiness during day

• not thinking clearly

• act strangely, confused, upset

• Sleep walking, sleep eating, talking, sexual activity, driving

What is the food effect with with DORAs? (orexin drugs used to treat insomnia)

Eating food DELAYS time to peak for drug activity (take on empty stomach)

Metabolism for DORAs?

CYP3A4 substrates!!!

Unique AE’s for DORAs (Orexiants)?

• Sleep paralysis

• Hypnagogic/hypnopompic hallucinations

• Cataplexy (sudden onset of involuntary muscle movements)

What comorbid disease state should DORAs really not be used in?

Patients with NARCOLEPSY!!!!

OTC antihistamines for insomnia?

Benadryl and Doxylamine!!

• DO NOT USE IN GERIATRIC PATIENTS OR NARROW-ANGLE-GLAUCOMA

What TCA is used for insomnia?

Doxepin!

• only used for sleep MAINTENANCE

• Food delays effect for insomnia meds

• Use low dose to prevent anticholinergic effect

• Remember to NOT USE WITHIN 14 days of MAOI

Which other off-label antidepressants/antipsychotics can be used (as second line) for insomnia?

1. Trazadone

2. Mirtazapine

3. Quetiapine

AE’s of off label antidepressants (trazodone/Mirtazapine)

Trazadone: Priapism, Orthostasis, falls

Mirtazapine: Weight gain

AE’s of off label antidepressants (Quetiapine)

Sedation, Weight gain, QTc prolongation

Trazadone is an antagonist for which receptors?

Histamine, Serotonin 5HT2A, and Alpha-1 adrenergic

Quetiapine is an antagonist for which receptors?

Histamine, Serotonin 5HT2A, Alpha-1 adrenergic, Dopamine D1, Dopamine D2

What prescription drug works on melatonin receptors to treat insomnia ?

Ramelteon!

• has risk of anaphylaxis including angioedema

• DO NOT USE WITH

  • Angioedema hx // CYP1A2 inhibitors

What OTC drug works on melatonin receptors to treat insomnia ?

Melatonin!!!

• BE CAREFUL because it is also a CYP1A2 substrate - causes lack of efficacy of melatonin

Counseling points for insomnia meds/Hypnotics?

• Do not take with food!

• Administer at bedtime (for most of them)

What is first-line treatment for insomnia?

CBT-I !!!!!!

• medications are second line/alternative