Anxiolytics & Hypnotics

BZD vs. Barbiturate MOA

BZDs increase frequency of channel opening (need GABA); Barbs increase duration and can open channel WITHOUT GABA (lethal)

GABA-A Alpha-1 Subunit

Mediates sedation, amnesia, and ataxia; selective target for Z-hypnotics

GABA-A Alpha-2 & 3 Subunits

Mediates anxiolytic and muscle-relaxing effects; NOT targeted by Z-hypnotics

BZD REM Suppression

BZDs suppress REM more than Z-hypnotics; stopping BZDs causes REM rebound (nightmares/vivid dreams)

Metallic Taste (Dysgeusia)

Unique distinguishing side effect for Eszopiclone (Lunesta)

Z-Hypnotic BBW

All Z-drugs carry a Black Box Warning for complex sleep behaviors (sleep-walking, driving, or eating while not awake)

BZD Reversal Controversy

Flumazenil is a BZD antagonist but is controversial because it can precipitate seizures in chronic users

Orexin Antagonist Side Effects

Unique ADEs include sleep paralysis and cataplexy-like symptoms because they induce a temporary low-orexin state

Tasimelteon (Hetlioz)

Melatonin agonist FDA-approved specifically for Non-24-Hour Sleep-Wake Disorder (common in blind patients)

Buspirone Onset

Slow onset (3-4 weeks); NOT effective for acute anxiety or treating BZD withdrawal

What is GABA-A, and what type of receptor is it?

A ligand-gated chloride ion channel (fast, inhibitory); GABA-B is metabotropic (slow) by contrast

How do benzodiazepines and Z-hypnotics interact with the GABA-A receptor?

They bind the BZ site (alpha-gamma subunit interface) and INCREASE THE FREQUENCY of channel opening — GABA must already be present for them to work

How do barbiturates interact with the GABA-A receptor, and why does this make them more dangerous?

They bind a DIFFERENT site and INCREASE THE DURATION of channel opening; at high concentrations they can open the channel WITHOUT GABA present at all, removing any safety ceiling

Why do benzodiazepines have a wide therapeutic index while barbiturates have a narrow one?

Benzos need GABA present, creating a built-in ceiling on effect; barbiturates can act independently of GABA at high doses, allowing unlimited CNS depression as dose increases

Which GABA-A subunit is linked to sedation/amnesia/ataxia, and which drug class is selective for it?

Alpha-1 subunit; Z-hypnotics are alpha-1 selective (hypnotic effect only, no anxiolytic/muscle relaxant activity)

Which GABA-A subunits are linked to anxiolysis/muscle relaxation, and which to working memory impairment?

Alpha-2/alpha-3 = anxiolysis/muscle relaxation; alpha-5 = working memory impairment

What does the mnemonic ATOM stand for in the short-acting benzodiazepine group?

Alprazolam, Triazolam, Oxazepam, Midazolam

Which short-acting benzo is used for anxiety/panic disorder specifically?

Alprazolam

Which short-acting benzo has the shortest half-life (2-3 hrs) and is favored for insomnia (sleep onset) over anxiety use?

Triazolam

Which short-acting benzo has NO active metabolites, making it safer in hepatic/renal dysfunction?

Oxazepam

Which short-acting benzo is used for preanesthetic/procedural sedation?

Midazolam

What does "Could Take Longer" refer to, and which three benzos does it represent?

The intermediate-acting benzodiazepine group: Clonazepam, Temazepam, Lorazepam

Which intermediate-acting benzo is specifically used for sleep MAINTENANCE (staying asleep, not just falling asleep)?

Temazepam

Which intermediate-acting benzo is 1st-line for status epilepticus, alcohol withdrawal, and preanesthetic use (for amnesia)?

Lorazepam

Which THREE benzodiazepines (across all duration classes) share the trait of having NO active metabolites?

Oxazepam, lorazepam, and temazepam — all safer choices in hepatic/renal impairment

What does "Long name, long duration" refer to, and which two benzos does it represent?

The long-acting benzodiazepine group: Chlordiazepoxide and Diazepam

What is diazepam's active metabolite, and what is its half-life?

Desmethyldiazepam; half-life ~40 hours, causing cumulative dose-stacking risk with repeated dosing

What are diazepam's three main clinical uses?

Alcohol withdrawal, muscle spasticity (e.g. MS), and seizure termination (2nd-line, since lorazepam is 1st-line for status epilepticus)

Why would diazepam be a POOR choice in a patient with significant hepatic impairment?

Its long half-life and long-acting active metabolite could accumulate unpredictably if hepatic clearance is impaired, risking toxicity

How does half-life relate to withdrawal onset and severity for benzodiazepines?

Shorter half-life = more abrupt/severe withdrawal (e.g. alprazolam/lorazepam onset ~24 hrs); longer half-life = more gradual withdrawal onset (e.g. diazepam ~1 week)

Which two benzodiazepines are specifically flagged for the MOST severe withdrawal (delirium, psychosis)?

Alprazolam and triazolam (the "triazolobenzodiazepines")

Does tolerance develop equally to all benzodiazepine effects?

No — tolerance develops to drowsiness/sedation, but NOT to psychomotor impairment

Why are benzodiazepine overdoses rarely lethal alone, and what makes them dangerous?

Wide therapeutic index (lethal dose ~1000x therapeutic); danger comes from co-ingestion with other CNS depressants, especially opioids (respiratory depression risk)

Why are benzodiazepines not considered first-line for insomnia, despite being sedating?

They suppress REM sleep more than Z-hypnotics do, and cause REM rebound (increased dreaming/nightmares) upon discontinuation

What is flumazenil's mechanism, and what does it NOT reverse?

Competitive antagonist at the BZ (alpha-gamma) site; reverses BENZODIAZEPINE agonists ONLY — has no effect on GABA or barbiturate-site effects

What is a key pharmacokinetic limitation of flumazenil?

IV, rapid onset, but SHORT duration — may need redosing if a long-acting benzo or active metabolite is still present

What are the risks of using flumazenil in a chronic benzodiazepine user?

Can precipitate withdrawal and can lower seizure threshold

What do zolpidem, zaleplon, and eszopiclone (the "Z-drugs") have in common structurally and receptor-wise?

Structurally UNRELATED to benzodiazepines, but bind the SAME BZ site, selectively for the alpha-1 subunit (sedation/amnesia/ataxia only, no anxiolytic effect)

What Black Box Warning applies to ALL THREE Z-hypnotics?

Complex sleep behaviors (sleepwalking, driving, eating while not fully awake) — discontinue immediately if this occurs

Which Z-hypnotic has the shortest half-life (~1 hr) and fewest residual psychomotor/cognitive effects?

Zaleplon

Which Z-hypnotic has the longest half-life (~6 hrs, up to 9 hrs in elderly) and is used for sleep onset OR maintenance?

Eszopiclone

Which Z-hypnotic requires a lower dose (5mg) in women and the elderly due to increased half-life?

Zolpidem

Which Z-hypnotic causes a classic metallic taste (dysgeusia) as a distinguishing ADE?

Eszopiclone

Which agent should you choose for difficulty FALLING asleep vs. difficulty STAYING asleep?

Falling asleep: zaleplon or zolpidem (fast onset). Staying asleep: eszopiclone or zolpidem ER

Why do barbiturates cause more severe cardiovascular/respiratory depression than benzodiazepines?

They can open the GABA-A channel without GABA at high concentrations, removing any ceiling on CNS depression; respiratory depression can occur at only ~3x the normal hypnotic dose

Which barbiturate is used for barbiturate coma (severe brain injury/increased ICP) and status epilepticus, requiring ICU monitoring?

Pentobarbital

Which barbiturate has the longest half-life (~79 hours) and is used for refractory alcohol withdrawal and status epilepticus?

Phenobarbital

What is phenobarbital's major drug interaction, and why is it dangerous?

Strong CYP3A4 inducer, decreasing levels of apixaban/rivaroxaban with no way to monitor efficacy; effect can persist ~2 weeks after discontinuation

What is primidone metabolized to, and what is it used for?

Metabolized to phenobarbital; used for essential tremor

What is orexin, and what disease results from its deficiency?

A wakefulness-promoting neuropeptide from the lateral hypothalamus; narcolepsy results from orexin deficiency

What is the mechanism of orexin antagonists (suvorexant, lemborexant, daridorexant), and what condition do they treat?

Antagonize OX1R/OX2R receptors, reducing wakefulness signaling; used to treat INSOMNIA (not narcolepsy)

Why do orexin antagonist side effects (cataplexy, sleep paralysis, hallucinations) resemble narcolepsy symptoms?

Blocking orexin artificially induces a temporary low-orexin state, mimicking the natural orexin deficiency seen in narcolepsy

Which orexin antagonist's half-life is prolonged in hepatic disease (10-22 hrs normally, up to 49 hrs impaired)?

Suvorexant

Which orexin antagonist has the shortest half-life (8 hours), theoretically causing the least next-day sedation?

Daridorexant

What is a key safety advantage of orexin antagonists over BZD/Z-hypnotics?

No anterograde amnesia

What is ramelteon's mechanism — does it increase melatonin levels?

Direct agonist at MT1/MT2 receptors — it does NOT increase endogenous melatonin, it directly activates the receptor to mimic melatonin's effect

Why is ramelteon considered especially appealing for elderly patients or those with substance abuse history?

No rebound insomnia, withdrawal, or dependence, and it is NOT a controlled substance — avoiding the risks that make benzos/Z-hypnotics more dangerous in these populations

What is tasimelteon FDA-approved to treat specifically?

Non-24-Hour Sleep-Wake Disorder (a circadian rhythm disorder common in totally blind individuals)

Why does OTC melatonin's effect/content vary between products?

It is NOT FDA-regulated, so formulation and actual content can vary

What is buspirone's mechanism, and what is its major limitation?

Partial agonist at 5-HT1A (some D2 affinity); SLOW onset (3-4 weeks) means it is NOT useful for acute anxiety/panic — used for GAD only

Is buspirone effective for benzodiazepine withdrawal syndrome?

No — despite being an anxiolytic, it does NOT treat BZD/GABAergic withdrawal

Which classes covered in this chapter ARE controlled substances, and which are NOT?

Controlled: benzodiazepines, barbiturates, Z-hypnotics. NOT controlled: orexin antagonists, melatonin agonists, buspirone