Sedatives- Austin

What are the 3 classifications of insomnia?

What disorders are each most frequently associated with?

• Onset Insomnia- difficulty falling asleep upon going to bed

  • frequently associated with ANXIETY

• Middle Insomnia- difficulty maintaining sleep, waking up during the night

  • frequently associated with PAIN disorders

• Late (terminal) Insomnia- early morning waking

  • frequently associated with DEPRESSION

What are the causes of insomnia?

• often multifactorial!!!!!!!!!!!!!!!!!!

• psychological

  • anxiety, depression, psychosis, behavioral patterns, substance use/abuse, stress

• physiological

  • CV, endocrine, and autonomic disorders

  • pain, fatigue, GERD, apnea

  • medications

NON-PHARM for Insomnia:

• reduce stress and anxiety

• improve sleep hygiene:

  • minimize daytime napping

  • eat meals on schedule

  • practice relaxing behaviors

  • go to bed around the same time at night

  • minimize use of electronic devices in bedroom

• substances: avoid caffeine, alcohol, and nicotine near bedtime

What classes can be used for pharm tx of insomnia?

• just recognize

sedative/hypnotics

• benzos

• benzo receptor agonists

• melatonin receptor agonist

• orexin antagonist

• barbiturates

• OTC/herbal therapies

Benzos should be avoided in what patients?

pregnancy

Should benzos be used long term for insomnia?

no—> long term use of benzos not recommended

MOA of benzodiazepines:

• results?

• bind to GABA_A receptor between a and y subunits—> act as weak positive allosteric agonists

• results: increase frequency of Cl- channel opening= hyperpolarization of neurons= reduced firing

What are the contraindications and cautions with Benzos?

• contraindications

  • risk from concomitant use with opioids

  • abuse misuse, and addiction

  • dependence and withdrawal reactions

  • closed-angle glaucoma

  • pregnancy/lactation

• caution

  • renal/hepatic disease

  • depressed/suicidal pts.

What are the drug interactions with Benzos?

• CNS depressants

  • opioids, alcohol, narcotics, antihistamines

What is the name of the drug that is a benzodiazepine antagonist/reversal drug and given IV for overdose/anasthesia reversal?

• MOA?

Flumazenil—> antagonizes GABA_A benzo site

Risk with Flumazenil?

may cause seizures/withdrawal

Ethanol also acts on the GABA_A receptor. Should flumazenil be considered for a pt. experiencing severe respiratory depression following excessive alcohol consumption?

NO!!!! won’t block the site ethanol binds to… flumazenil only blocks benzo binding site

List common benzodiazepines used in insomnia?

• temazepam

• triazolam

• flurazepam

MOA of benzodiazepine receptor agonists?

• binds selectively to GABA_A receptors with selectivity for a1 subunits

  • (also must be weak positive allosteric agonists that bind to GABA to exert effect)

The selectivity of benzodiazepine receptor agonists for a1 has what kind of INTRINSIC effects?

• what is reduced vs. what is conserved?

• reduced: anxiolytic, antiepileptic, muscle relaxant

• conserved: sedative and amnesic effect

ADRs of benzodiazepine receptor agonists:

• complex sleep behaviors- FDA warning 2007—> driving, eating, sex, destructive behavior while asleep

• rebound insomnia

• next-day drowsiness

• abuse

• tolerance/depedence

List the benzodiazepine receptor agonists:

• zolpidem (ambien)

  • multiple formulations (oral, SL, CR, spray)

• zaleplon (sonata)

• eszopiclone (lunesta)

benzodiazepine receptor agonists are what pregnancy category?

pregnancy cat C

Melatonin is an endogenous hormone that is produced by what gland? regulated by what gland? and act on what receptors?

• produced by pineal gland

• regulated by hypothalamus

• act on MT receptor

Is melatonin an acid or a base?

base

Function of melatonin in the body?

• idk how important

• synchronizes sleep-wake cycle

• influences circadian rhythm

What is the name of the melatonin receptor agonist used for insomnia?

Ramelteon

Answer the following about RAMELTEON:

• MOA

• pregnancy category

• metabolism

• ADRs

• MOA—> binds MT1 and MT2 receptors in suprachiasmatic nucleus (SCN) in hypothalamus

  • NO GABA effect

• pregnancy cat C

• metabolism: CYP1A2 (not rec in hepatic impairment)

• ADRs: dizzy, fatigue, depression

What is the name of the Orexin Receptor Antagonist used for insomnia?

Suvorexant

Answer the following about SUVOREXANT:

• MOA

• pregnancy category

• metabolism

• ADRs

• CONTRAINDICATION

• MOA: blocks wake-promoting neuropeptides orexin A and orexin B by binding OX₁ and OX₂

• pregnancy cat C

• metabolism: CYP3A4 (not rec in hepatic impairment)

• ADRs: dizzy, drowsy, HA, diarrhea

• C/I IN NARCOLEPSY

What class and drugs are used for occasional sleeplessness/insomnia and has a risk of anticholinergic side effects?

antihistamines—> doxylamine and diphenhydramine

PRACTICE:

Which statement correctly describes benzodiazepines?

a. structurally similar to GABA

b. structurally similar to glutamate

c. agonist at GABA binding site of GABA-A receptors

d. agonist at allosteric site of GABA-A receptors

d.

FYI Definitions

• limbic system: brain network for emotion, memory, and behavior—> inked to addiction (reward pathways) and mood disorders

• reticular activating system: A network of neurons in the brainstem that regulates wakefulness, attention, and sleep-wake transitions—> a target of sedatives

• abuse: Misuse of a substance despite harmful consequences, without physical dependence

• addiction: A chronic brain disease characterized by compulsive use, cravings, and continued use despite harm—> Involves changes to the limbic reward system.

• dependence: Physiological adaptation to a drug, leading to tolerance and withdrawal upon cessation—> can occur without addiction

• GABA_A receptor: NT receptor that inhibits neuronal activity when activated by GABA—> drug target of benzos and other insomnia meds

• Benzodiazepine intrinsic effects: Properties mediated via GABA receptors—> Sedation, anxiolysis, muscle relaxation, anterograde amnesia, anticonvulsant effects

• anterograde amnesia: Inability to form new memories after drug administration

• sleep hygiene: Behavioral practices to improve sleep quality (ex: Regular sleep schedule, dark/quiet bedroom, avoiding caffeine/alcohol before bed)

• orexin: neuropeptide drug target

• complex sleep-related behaviors: Unconscious actions during sleep (e.g., sleepwalking, eating, driving) triggered by sedatives

• narcolepsy: sleep disorder where you spontaneously fall asleep