Pharm III: L5 Sedative and Hypnotics

4 Major groups of Sedatives

1. Barbiturates

2. Benzodiazepines

3. Z-hypnotics

4. DORAs

Benzodiazepines MOA

- GABA-A receptor positive allosteric modulator

- enhances GABA's inhibitory effect

Inpatient Benzodiazepines ID (5)

- alcohol withdrawal

- status epilepticus/seizures

- procedural sedation

- acute severe agitation

- catatonia

Outpatient Benzodiazepines ID (4)

- short-term/acute anxiety

- panic

- situational insomnia

- muscle spasm

Benzodiazepines: alcohol withdrawal preferred drug selection

Long acting diazepam or chlordiazepoxide

Benzodiazepines: Insomnia preferred drug selection

Short/intermediate-acting agents preferred

Benzodiazepines: best choice for liver impairment (3)

Lorazepam

Oxazepam

Temazepam

What should Benzodiazepines not be used with?

Opioids and alcohol

Benzodiazepines: if used with opioids and alcohol, what could it cause

Respiratory depression

Are Benzodiazepines susceptible for misuse?

Yes and can lead to death

Benzodiazepines: profiles at high risk of abuse (3)

- substance abuse hx

- moderate alcohol use

- aged 18-25yo

Benzodiazepines Boxed warning

Don't mix with opioids, abuse, misuse, addiction, physical dependance, and withdrawal

Chronic use of Benzodiazepines discontinuation

Gradual taper - can cause withdrawal syndrome

Benzodiazepines: when should you plan an exit/taper strategy with the patient?

At time of initiation

Benzodiazepine Withdrawal Syndrome onset

2-10 days after stopping

Benzodiazepine Withdrawal Syndrome severe reactions (4)

- seizures

- delirium

- psychosis

- life-threatening

Benzodiazepine Withdrawal Syndrome mild tx

prescribe long-acting benzodiazepine, or restart prior BZD at prior dose (unless short-acting)

Benzodiazepine Withdrawal Syndrome Mod-Severe tx

IV diazepam

Benzodiazepine Withdrawal Syndrome Acute tx goal

eliminate withdrawal sx without causing sedation/respiratory depression

Benzodiazepine Withdrawal Syndrome Long term goal

Once sx are controlled, taper long acting or intermediate acting BZD gradually over a few months or longer

Benzodiazepines: patient education

avoid combining with opioids or alcohol; driving risk; secure storage

Benzodiazepine Overdose: reversal agent

Flumazenil

Flumazenil MOA

Benzodiazepine receptor antagonist

Flumazenil warning

Can precipitate seizures in dependent patients

Barbiturates

- sedative-hypnotics capable of severe CNS depression

- high abuse/dependence

- very easy to die from overdose

Barbiturates MOA

- enhances GABA-A by increasing duration of Cl- channel open

- at high doses: directly opens Cl- channel, even in absence of GABA

- CNS depression

Barbiturates CNS depression cause

Respiratory depression + suppresses hypoxic drive

Barbiturates Short Acting (4)

- Thiopental

- Pentobarbital

- Secobarbital

- Methohexital

Thiopental abd Methohexital ID

Induction of anesthesia and procedural sedation

Barbiturates Intermediate acting (2)

- Butalbital

- Amobarbital

Butalbital ID

Tension/migraine combination products

Barbiturates Long acting

Phenobarbital

Phenobarbital ID (2)

- seizures/status epilepticus

- lethal injection

Barbiturates Acute Intoxication sx (4)

- sedation/confusion/stupor/coma

- respiratory depression

- decreased HR, BP, RR, and temp

- skin bullae (Barb blisters)

Barbiturates Acute Withdrawal Syndrome sx (6)

- anxiety/agitation

- insomnia

- tremors

- increased HR, RR, temp

- delirium/hallucinations/psychosis

- seizures

Insomnia 1st line

CBT-I

Insomnia FDR Approved Pharmacologic Options (5)

- benzodiazepines

- Z hypnotics

- ramelteon

- low dose docepin

- orexin antagonists (DORAs)

Insomnia off label pharmacologic options (2)

- trazodone

- mirtazapine

Z-Hypnotics (3)

- Zolpidem

- Zaleplon

- Eszopiclone

Z-Hypnotics MOA

act at the GABA-A benzodiazepine receptor

Z-Hypnotics key risks (6)

- complex sleep behaviors (sleep-driving)

- next-day impairment

- amnesia

- falls

- dependence

- tolerance risk

Z-Hypnotics ADRs (7)

- daytime drowsiness/somnolence

- dizziness

- complex sleep behaviors

- dry mouth

- N/HA

- hallucinations

- rebound insomnia w/ discontinuation

Dual Orexin Receptor Antagonists (DORAs) (3)

- Suvorexant

- Lemborexant

- Daridorexant

DORAs MOA

block wake-promoting orexin signaling

DORAs risk for tolerance/abuse?

Low risk

DORAs key risks (7)

- complex sleep behaviors

- next morning somnolence

- HA

- dizziness

- dry mouth

- hallucinations

- sleep paralysis

Ramelteon MOA

Melatonin receptor agonist

Ramelteon ADR (4)

- somnolence

- dizziness

- fatigue

- N/HA

Ramelteon rare ADRs (2)

- increased prolactin

- reduced testosterone

Low-dose Doxepin MOA

- TCA

- Primarily H1 antagonist

- minimal anticholinergic/5-HT/NE effect at insomnia dose

Low-dose Doxepin dose

6mg or less

Low-dose Doxepin ADR (2)

- somnolence/daytime grogginess

- postural hypotension

Trazodone ADR (3)

- somnolence/daytime grogginess

- postural hypotension

- alpha blockade (priapism)

Trazodone: avoid in

Sickle cell or multiple myeloma

Mirtazapine Insomnia dose

7.5mg or 15mg

Antihistamines as Sleep Aids for sleep onset insomnia (3)

- Diphenhydramine

- Hydroxyzine

- Doxylamine

Antihistamines: mild situation insomnia

Doxylamine

Antihistamines: when does tolerance usually develop?

1-2wks

Antihistamines ADR (2)

- daytime drowsiness

- anticholinergic effects

Insomnia Drugs: which to use to limit next morning sedations

Choose agents with shorter half-life (ramelteon, zaleplon, zolpidem)

Insomnia Drugs: If pt is older age, has cognitive dysfunction or opioid use, what should you avoid

BZDs and Z-hypnotics

Chronic Insomnia Tx Foundation

CBT-I + short term hypnotic prn

Acute Insomnia Tx Foundation

Sleep hygiene +/- trazodone, antihistamine, z-hypnotic, or DORA

Iatrogenic Insomnia tx

add a sedating agent, such as trazodone or mirtazapine to offset SSRI-induced infomnia

Treating Insomnia, what to avoid

Avoid stacking multiple CNS depressants and reassess regularly

Insomnia in older Adults: Beers Criteria

Avoid

benzodiazepine

Z-drugs

1st generation antihistamines

TCAs

Barbiturates (everyone, every age)

Insomnia in older Adults: safer options (3)

- low dose doxepin ≤6mg

- orexin antagonists (DORAs)

- ramelteon