Benzodiazepines and Non-Benzodiazepine Sedatives. Sleep aids.

Benzodiazepines and Non-Benzodiazepine Sedatives

Mechanism of Action - Benzodiazepines

Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.

alprazolam (Xanax ®)	buspirone (BuSpar ® )
chlordiazepoxide (Librium ®)	clorazepate (Tranxene ®)
clonazepam (Klonopin ®)	diazepam (Valium ®)
estazolam (ProSom ®)	eszopiclone (Lunesta ® )
flurazepam (Dalmane ®)	lorazepam (Ativan ®)
midazolam (Versed ®)	Oxazepam (Serax ®)
ramelteon (Rozerem ® )	temazepam (Restoril ®)
triazolam (Halcion ®)	zaleplon (Sonata ® )
zolpidem (Ambien ®)

alprazolam (Xanax ®):

Short half-life

Dosing (Adults):
Anxiety: Immediate release: Effective doses are 0.5-4 mg/day in divided doses; the manufacturer recommends starting at 0.25-0.5 mg 3 times/day; titrate dose upward; maximum: 4 mg/day

Anxiety associated with depression: Immediate release: Average dose required: 2.5-3 mg/day in divided doses

Panic disorder:
Immediate release: Initial: 0.5 mg 3 times/day; dose may be increased every 3-4 days in increments </= 1 mg/day; many patients obtain relief at 2 mg/day, as much as 10 mg/day may be required

Extended release: 0.5-1 mg once daily; may increase dose every 3-4 days in increments </= 1 mg/day (range: 3-6 mg/day)

Switching from immediate release to extended release: Patients may be switched to extended release tablets by taking the total daily dose of the immediate release tablets and giving it once daily using the extended release preparation.

Dose reduction: Abrupt discontinuation should be avoided. Daily dose may be decreased by 0.5 mg every 3 days, however, some patients may require a slower reduction. If withdrawal symptoms occur, resume previous dose and discontinue on a less rapid schedule.

SUPPLIED:
Solution, oral (Alprazolam Intensol®): 1 mg/mL (30 mL)
Tablet (Xanax®): 0.25 mg, 0.5 mg, 1 mg, 2 mg
Tablet, extended release (Xanax XR®): 0.5 mg, 1 mg, 2 mg, 3 mg

buspirone (BuSpar ® ):

Non-Benzodiazepine (Anxiolytic)

Mechanism of Action
The mechanism of action of buspirone is unknown. Buspirone has a high affinity for serotonin 5-HT1A and 5-HT2 receptors, without affecting benzodiazepine-GABA receptors; buspirone has moderate affinity for dopamine D2 receptors

Dosing (Adults):
Generalized anxiety disorder:
Adults: 15 mg/day (7.5 mg twice daily); may increase in increments of 5 mg/day every 2-4 days to a maximum of 60 mg/day; target dose for most people is 30 mg/day (15 mg twice daily)

May take 2-3 weeks to see full effect. Avoid abrupt discontinuation - requires gradual reduction in dose.

Dosing adjustment in renal or hepatic impairment: Buspirone is metabolized by the liver and excreted by the kidneys. Patients with impaired hepatic or renal function demonstrated increased plasma levels and a prolonged half-life of buspirone. Therefore, use in patients with severe hepatic or renal impairment cannot be recommended.

SUPPLIED:
Tablet, as hydrochloride: 5 mg, 7.5 mg, 10 mg, 15 mg, 30 mg

chlordiazepoxide (Librium ®):

Long half-life

Dosing (Adults):
Anxiety:
Oral: 15-100 mg divided 3-4 times/day.
I.M., I.V.: Initial: 50-100 mg followed by 25-50 mg 3-4 times/day as needed.

Preoperative anxiety: I.M.: 50-100 mg prior to surgery

Ethanol withdrawal symptoms: Oral, I.V.: 50-100 mg to start, dose may be repeated in 2-4 hours as necessary to a maximum of 300 mg/24 hours

Note: Up to 300 mg may be given I.M. or I.V. during a 6-hour period, but not more than this in any 24-hour period.

Dosing adjustment in renal impairment: Clcr<10 mL/minute: Administer 50% of dose
Dosing adjustment/comments in hepatic impairment: Avoid use

SUPPLIED:
Capsule, as hydrochloride: 5 mg, 10 mg, 25 mg

Injection, powder for reconstitution, as hydrochloride: 100 mg [diluent contains benzyl alcohol, polysorbate 80, and propylene glycol]

clorazepate (Tranxene ®):

Long half-life

Dosing (Adults):
Anxiety:
Regular release tablets (Tranxene® T-Tab®): 7.5-15 mg 2-4 times/day .
Sustained release (Tranxene®-SD): 11.25 or 22.5 mg once daily at bedtime.

Ethanol withdrawal: Initial: 30 mg, then 15 mg 2-4 times/day on first day; maximum daily dose: 90 mg; gradually decrease dose over subsequent days

SUPPLIED:
Tablet, as dipotassium: 3.75 mg, 7.5 mg, 15 mg
Tranxene®-SD™: 22.5 mg [once daily]
Tranxene®-SD™ Half Strength: 11.25 mg [once daily]
Tranxene® T-Tab®: 3.75 mg, 7.5 mg, 15 mg

clonazepam (Klonopin ®):

Long half-life

Dosing (Adults):
Seizure disorders:
Initial daily dose not to exceed 1.5 mg given in 3 divided doses; may increase by 0.5-1 mg every third day until seizures are controlled or adverse effects seen (maximum: 20 mg/day)

Usual maintenance dose: 0.05-0.2 mg/kg; do not exceed 20 mg/day

Panic disorder: 0.25 mg twice daily; increase in increments of 0.125-0.25 mg twice daily every 3 days; target dose: 1 mg/day (maximum: 4 mg/day)

Discontinuation of treatment: To discontinue, treatment should be withdrawn gradually. Decrease dose by 0.125 mg twice daily every 3 days until medication is completely withdrawn.

Elderly: Initiate with low doses and observe closely

SUPPLIED:
Tablet: 0.5 mg, 1 mg, 2 mg
Tablet, orally-disintegrating [wafer]: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg

diazepam (Valium ®):

Long half-life

Dosing (Adults):
Anxiety/sedation/skeletal muscle relaxant:
Oral: 2-10 mg 2-4 times/day
I.M., I.V.: 2-10 mg, may repeat in 3-4 hours if needed

Sedation in the ICU patient: I.V.: 0.03 to 0.1 mg/kg every 30 minutes to 6 hours

Status epilepticus: I.V.: 5-10 mg every 10-20 minutes, up to 30 mg in an 8-hour period; may repeat in 2-4 hours if necessary

Rapid tranquilization of agitated patient (administer every 30-60 minutes): Oral: 5-10 mg; average total dose for tranquilization: 20-60 mg

Elderly: Oral: Initial:
Anxiety: 1-2 mg 1-2 times/day; increase gradually as needed, rarely need to use >10 mg/day (watch for hypotension and excessive sedation)

Skeletal muscle relaxant: 2-5 mg 2-4 times/day

Dosing adjustment in hepatic impairment: Reduce dose by 50% in cirrhosis and avoid in severe/acute liver disease

Administration
Intensol® should be diluted before use; diazepam does not have any analgesic effects
In children, do not exceed 1-2 mg/minute IVP; adults 5 mg/minute

SUPPLIED:
Gel, rectal (Diastat®):
Adult rectal tip [6 cm]: 5 mg/mL (15 mg, 20 mg)
Pediatric rectal tip [4.4 cm]: 5 mg/mL (2.5 mg, 5 mg)
Universal rectal tip [for pediatric and adult use; 4.4 cm]: 5 mg/mL (10 mg)

Injection, solution: 5 mg/mL (2 mL, 10 mL)
Solution, oral: 5 mg/5 mL (5 mL, 500 mL)
Solution, oral concentrate (Diazepam Intensol®): 5 mg/mL (30 mL)

Tablet (Valium®): 2 mg, 5 mg, 10 mg

estazolam (ProSom ®):

Intermediate half-life

Dosing (Adults):
Short-term management of insomnia:
Oral: 1 mg at bedtime, some patients may require 2 mg; start at doses of 0.5 mg in debilitated or small elderly patients

SUPPLIED:
Tablet: 1 mg, 2 mg

eszopiclone (Lunesta ® ):

Non-Benzodiazepine (Sedative)

Dosing (Adults): Insomnia: Initial: 2 mg before bedtime (maximum dose: 3 mg). Concurrent use with strong CYP3A4 inhibitor: 1 mg before bedtime; if needed, dose may be increased to 2 mg.

Dosage adjustment in hepatic impairment:
Mild-to-moderate: Use with caution; dosage adjustment unnecessary
Severe: Maximum dose: 2 mg

Supplied: 1 mg, 2 mg, 3 mg tablet.

flurazepam (Dalmane ®):

Long half-life

Dosing (Adults):
Short-term treatment of insomnia: 15-30 mg at bedtime

Elderly: Insomnia: Oral: 15 mg at bedtime; avoid use if possible

SUPPLIED:
Capsule, as hydrochloride: 15 mg, 30 mg

lorazepam (Ativan ®):

Intermediate half-life

Prolonged infusions have been associated with toxicity from propylene glycol and/or polyethylene glycol.

IV: Do not exceed 2 mg/minute
Dosing (Adults):
Anxiety/sedation: 1-10 mg orally in 2-3 divided doses. Usual dose: 2-6 mg/day in divided doses. Initial dose should not exceed 2 mg in debilitated patients.
Insomnia: 2-4 mg orally at bedtime.
Operative amnesia: I.V.: Up to 0.05 mg/kg; maximum: 4 mg/dose.
Status epilepticus: 4 mg IV over 2 to 5 minutes. May repeat in 10-15 minutes.
Usual maximum dose: 8 mg.

Agitation in the ICU patient --------------
Continuous infusion:
1 to 20 mg/hr (0.01 to 0.1 mg/kg/hour).
Intermittent:
I.V.: 0.02-0.06 mg/kg every 2-6 hours

PHARMACODYNAMICS / KINETICS
Onset of action:
Hypnosis: I.M.: 20-30 minutes
Sedation: I.V.: 5-20 minutes
Anticonvulsant: I.V.: 5 minutes, oral: 30-60 minutes.

Severe Hyperosmolar Metabolic Acidosis Due to a Large Dose of Intravenous Lorazepam.
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Previous cases of propylene glycol toxicity secondary to high-dose lorazepam infusion have occurred in patients with compromised renal function. Our patient's renal function remained stable throughout the hospital course, which caused us to look further for an explanation for the propylene glycol-induced lactic acidosis. Based on the Naranjo probability scale, propylene glycol was determined to be the probable cause of lactic acidosis. Since this case occurred, our intensive care unit has instituted recommendations for the prevention of lorazepam-associated propylene glycol toxicity.
CONCLUSIONS: Our case highlights the development of propylene glycol-induced lactic acidosis secondary to high-dose lorazepam infusion not associated with renal dysfunction.
----
The lorazepam solvents polyethylene glycol (PEG) and propylene glycol (PG) have been implicated as the cause of reversible acute tubular necrosis, lactic acidosis, and hyperosmolar states after prolonged high-dose infusions. The dosing threshold for this effect has not been prospectively defined, but these case reports described doses that exceeded 18 mg/hr and continued for longer than four weeks and higher doses (>25 mg/hr) continuing for hours to days.119–121 It seems prudent to avoid doses of this magnitude. Alternatively, lorazepam and diazepam may be administered via the enteral route in tablet or liquid form.122 Large doses of liquid lorazepam (i.e., 60 mg of 2 mg/mL every six hours) may lead to diarrhea because of the high PEG and PG content.

midazolam (Versed ®)

Intermediate half-life

Intubated patients (Continuous infusion): 1 to 7 mg/hr.
Dosing (Adults):
Preoperative sedation:
I.M.: 0.07-0.08 mg/kg 30-60 minutes prior to surgery/procedure; usual dose: 5 mg; Note: Reduce dose in patients with COPD, high-risk patients, patients >/= 60 years of age, and patients receiving other narcotics or CNS depressants
I.V.: 0.02-0.04 mg/kg; repeat every 5 minutes as needed to desired effect or up to 0.1-0.2 mg/kg

Conscious sedation: I.V.: Initial: 0.5-2 mg slow I.V. over at least 2 minutes; slowly titrate to effect by repeating doses every 2-3 minutes if needed; usual total dose: 2.5-5 mg; use decreased doses in elderly. Healthy Adults <60 years: Initial: Some patients respond to doses as low as 1 mg; no more than 2.5 mg should be administered over a period of 2 minutes. Additional doses of midazolam may be administered after a 2-minute waiting period and evaluation of sedation after each dose increment. A total dose >5 mg is generally not needed. Maintenance: 25% of dose used to reach sedative effect.

Anesthesia: I.V.: Induction: Unpremedicated patients: 0.3-0.35 mg/kg (up to 0.6 mg/kg in resistant cases)
Premedicated patients: 0.15 to 0.35 mg/kg.
Maintenance: 0.05-0.3 mg/kg as needed, or continuous infusion 0.25-1.5 mcg/kg/minute.

Sedation in mechanically-ventilated patients: I.V. continuous infusion: 100 mg in 250 mL D5W or NS (if patient is fluid-restricted, may concentrate up to a maximum of 0.5 mg/mL); initial dose: 0.02-0.08 mg/kg (~1 mg to 5 mg in 70 kg adult) initially and either repeated at 5-15 minute intervals until adequate sedation is achieved or continuous infusion rates of 0.04-0.2 mg/kg/hour and titrate to reach desired level of sedation.

DOSING: ELDERLY — The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Decrease dose (by ~30%) if narcotics or other CNS depressants are administered concomitantly. I.V.: Conscious sedation: Initial: 0.5 mg slow I.V.; give no more than 1.5 mg in a 2-minute period. If additional titration is needed, give no more than 1 mg over 2 minutes, waiting another 2 or more minutes to evaluate sedative effect. A total dose >3.5 mg is rarely necessary.

Supplied: Injection, solution: 1 mg/mL (2 mL, 5 mL, 10 mL); 5 mg/mL (1 mL, 2 mL, 5 mL, 10 mL)

PHARMACODYNAMICS / KINETICS
Onset of action: I.M.: Sedation: ~15 minutes; I.V.: 1-5 min.
Peak effect: I.M.: 0.5-1 hour.
Duration: I.M.: Up to 6 hours; Mean: 2 hours.
Half-life elimination: 1-4 hours; prolonged with cirrhosis, congestive heart failure, obesity, and elderly.

Oxazepam (Serax ®):

Short half-life

Dosing (Adults):
Anxiety: 10-30 mg 3-4 times/day

Ethanol withdrawal: 15-30 mg 3-4 times/day

Hypnotic: 15-30 mg

Elderly: Oral: Anxiety: 10 mg 2-3 times/day; increase gradually as needed to a total of 30-45 mg/day. Dose titration should be slow to evaluate sensitivity.

SUPPLIED:
Capsule: 10 mg, 15 mg, 30 mg
Tablet: 15 mg

ramelteon (Rozerem ® ):

Non-Benzodiazepine (Sedative)

Melatonin receptor agonist.
Dosing (Adults):
Insomnia: 8 mg orally taken within 30 min of bedtime.

Supplied: 8 mg tablet.

temazepam (Restoril ®):

Intermediate half-life

Dosing (Adults):
Short-term treatment of insomnia
15-30 mg at bedtime

Elderly or debilitated patients: 15 mg

SUPPLIED:
Restoril®: 7.5 mg, 15 mg, 30 mg

triazolam (Halcion ®):

Short half-life

Dosing (Adults):
Short-term treatment of insomnia
0.125-0.25 mg at bedtime (maximum dose: 0.5 mg/day)

Preprocedure sedation (dental): 0.25 mg taken the evening before oral surgery; or 0.25 mg 1 hour before procedure

Elderly: Insomnia (short-term use): 0.0625-0.125 mg at bedtime; maximum dose: 0.25 mg/day

SUPPLIED:
Tablet: 0.125 mg, 0.25 mg

zaleplon (Sonata ® ):

Non-Benzodiazepine (Sedative)

Dosing (Adults):
Short-term (7-10 days) treatment of insomnia (has been demonstrated to be effective for up to 5 weeks in controlled trial): 10 mg at bedtime (range: 5-20 mg).

Elderly: 5 mg at bedtime

Dosage adjustment in hepatic impairment: Mild to moderate impairment: 5 mg; not recommended for use in patients with severe hepatic impairment

SUPPLIED:
Capsule: 5 mg, 10 mg

zolpidem (Ambien ®):

Non-Benzodiazepine (Sedative)

Dosing (Adults):
Short-term treatment of insomnia
Duration of therapy should be limited to 7-10 days
Oral: 10 mg immediately before bedtime; maximum dose: 10 mg

Elderly: 5 mg immediately before bedtime

Dosing adjustment in hepatic impairment: Decrease dose to 5 mg

SUPPLIED:
Tablet, as tartrate: 5 mg, 10 mg

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