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Benzodiazepine
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Benzodiazepine
, Sedative-Hypnotic, Benzodiazepine Metabolism
See Also
Benzodiazepine Overdose
Indications
Outpatient
Sedation in surgical, Medical and Psychiatric procedures
Seizure
disorder
Alcohol Withdrawal
and withdrawal from other drugs
Anxiety Disorder
Consider limiting to short-term stabilization until
SSRI
or
SNRI
(e.g.
Venlafaxine
) takes effect
Adjunct to
Cognitive Behavioral Therapy
and other
Anxiety Management
Insomnia
Consider alternative agents and methods (
Trazodone
,
Melatonin
,
CBT-I
,
Sleep Hygiene
)
Consider
Benzodiazepine Receptor Agonist
instead (e.g.
Ambien
)
Muscle spasm
Consider alternative agents and methods (e.g.
Flexeril
,
NSAID
s, back
Exercise
s, physical therapy)
Contraindications
Myasthenia Gravis
Acute narrow-angle
Glaucoma
Substance Abuse
(relative contraindication)
Mechanism
Potentiates activity of gamma-aminobutyric acid (GABA)
GABA is an inhibitory neurotransmitter in the CNS
Muscle relaxant
Anticonvulsant
Anxiolytic
Anti-aggressiveness
Sedation
Precautions
Benzodiazepines have significant risks
Double the risk of
Motor Vehicle Accident
s, and falls (and
Hip Fracture
s) in the elderly (see
Beer's List
)
Double the risk of
COPD
exacerbations
Associated with rising
Overdose
deaths in the United States (FDA black box warning in 2020)
Benzodiazepine misuse and abuse is common
Hospital admissions for
Benzodiazepine Abuse
have increased three-fold since the early 2000s
Alprazolam
is among the most addictive Benzodiazepines
Responsible for 10% of drug-misuse related visits to the Emergency Department
Rapid onset is associated with euphoria, short half-life is associated with rebound symptoms
Avoid combining Benzodiazepines if possible
Risk of falls, memory problems, excessive sedation
Occasional, as needed dosing of a short acting Benzodiazepine may be approriate longterm in some patients
However, longterm regular or scheduled use is generally not recommended
Frequent prn dosing should prompt re-evaluation
Consider tapering off Benzodiazepine or switching to long-acting Benzodiazepine dose
Non-Benzodiazepine
Sedative
s (e.g.
Ambien
) can have additive effects with Benzodiazepines
References
(2014) Presc Lett 21(8): 45
Zigman (2012) J Psychopharmacol 26: 1507-11 [PubMed]
Advantages
Rapid onset of action
Anxiolytic
effect within 1-2 days
Tolerance develops rapidly to adverse effects
Tolerance does not develop for
Anxiolytic
effect
Few
Drug Interaction
s
Good safety profile
Preparations
Long Acting Benzodiazepines
Chlordiazepoxide
(
Librium
)
Diazepam
(
Valium
, Valrelease)
Flurazepam
(
Dalmane
)
Chlorazepate
(
Tranxene
)
Clonazepam
(
Klonopin
)
Quazepam
(
Doral
)
Halazepam
(
Paxipam
)
Medium Acting Benzodiazepines
Lorazepam
(
Ativan
)
Temazepam
(
Restoril
)
Short acting Benzodiazepines
Oxazepam
(
Serax
)
Alprazolam
(
Xanax
)
Triazolam
(
Halcion
)
Estazolam
(
Prosom
)
Midazolam
(
Versed
)
Absorption
Preparations with most rapid absorption
Diazepam
(
Valium
)
Clorazepate
Alprazolam
(
Xanax
) taken sublingually
Preparations with slowest absorption
Oxazepam
(
Serax
)
Co-administration of Benzodiazepine with medication
Maalox
Gelusil
Metabolism
Renal Excretion
Hepatic Metabolism
Microsomal oxidation
Conjugation by glucuronyl transferases
Metabolic pathways
Clonazepam
metabolizes to 7-aminoclonazepam
Alprazolam
metabolizes to Alpha-hydroxyalprazolam
Chlordiazepoxide
metabolizes to
Oxazepam
(via Norchlordiazepoxide, Demoxepam, Nordiazepam)
Medazepam metabolizes to
Oxazepam
(via Nordiazepam) and
Diazepam
Diazepam
metabolizes to
Oxazepam
(via Nordiazepam) and
Temazepam
Temazepam
metabolizes to
Oxazepam
Agents that metabolize to
Oxazepam
via nordiazepam
Diazepam
Demoxepam
Halazepam
Chlorazepate
Prezapam
References
Valentine (1996) J Anal Toxicol 20(6): 416-24 +PMID:8889678
Dosing
Strategies
Initiate treatment with low dose Benzodiazepine
Prevent symptoms completely by using a regular regimen
Escalate dose slowly, no more often than every 2 weeks
Maintain lowest effective dose for several months
Start with 50% of typical dose in at risk cohorts
Elderly
Hepatic dysfunction
Renal dysfunction
Tapering dose
Periodically attempt to lower dose or ideally, titrate off completely
Indications for prolonged taper periods (2-4 weeks per dose step-down)
Higher Benzodiazepine doses
Longer duration of Benzodiazepine use
Short-acting Benzodiazepines (e.g.
Alprazolam
,
Lorazepam
)
Example taper protocol
Decrease dose by 25% for 1 week (2-4 weeks if prolonged taper indicated) THEN
Decrease dose by 25% for 1 week (or 2-4 weeks if prolonged taper indicated) THEN
Decrease dose by 10% per 1 week (or 2-4 weeks if prolonged taper indicated) until off
Change to longer half-life drug if symptom breakthrough
Example: Switch from
Xanax
to
Clonazepam
Dosing
Equivalent to
Valium
60 mg (for withdrawal)
High Potency Benzodiazepines
Alprazolam
(
Xanax
) 6 mg
Clonazepam
(
Klonopin
) 24 mg
Lorazepam
(
Ativan
) 12 mg
Low Potency Benzodiazepines
Chlordiazepoxide
(Limbitrol) 150 mg
Flurazepam
(
Dalmane
) 90 mg
Halazepam
(
Paxipam
) 240 mg
Oxazepam
(
Serax
) 60 mg
Temazepam
(
Restoril
) 60 mg
Safety
Pregnancy and
Lactation
Pregnancy Category: D
Lactation
: Not allowed
Adverse Effects
Drug Dependence
Risk
Benzodiazepine Withdrawal
(
Seizure
s may occur, especially if underlying
Seizure
disorder)
Sedation
Nausea
Blood dyscrasia
Anterograde amnesia
Cognitive
Impairment
Respiratory depression
Hyponatremia
or
Syndrome of Inappropriate Antidiuretic Hormone
(
SIADH
)
Monitoring
Consider in patients on longterm therapy
Complete Blood Count
Liver Function Test
s
References
(2020) Presc Lett 27(12): 68-9
Tasman (1997) Psychiatry, Saunders, p. 1641-6 [PubMed]
Katzung (1989) Pharmacology, Lange, p. 264-7 [PubMed]
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