II. Indications: Inpatient and Emergency Department (IM or IV)
III. Indications: Outpatient (Oral)
- Seizure Disorder
- Sedation in surgical, Medical and Psychiatric procedures
- Alcohol Withdrawal and withdrawal from other drugs
-
Anxiety Disorder
- Consider limiting to short-term stabilization until SSRI or SNRI (e.g. Venlafaxine) takes effect
- Select longer acting agents (Clonazepam, Diazepam, Lorazepam)
- Diazepam has fastest onset of action (<1 hour), but Lorazepam has longer duration of CNS activity (despite Half-Life)
- Shorter acting agents (e.g. Alprazolam) are higher risk for withdrawal, rebound and abuse
- Adjunct to Cognitive Behavioral Therapy and other Anxiety Management
-
Panic Disorder
- As with Benzodiazepines for Anxiety Disorder, limit to short term use
- Brief use while starting SSRI or SNRI and instituting Cognitive Behavioral Therapy
-
Insomnia
- Consider alternative agents and methods (Trazodone, Melatonin, CBT-I, Sleep Hygiene)
- Consider Benzodiazepine Receptor Agonist (Z-Drug, e.g. Ambien) instead
- Temazepam (Restoril)
- Muscle spasm
IV. Contraindications
- Myasthenia Gravis
- Acute narrow-angle Glaucoma
- Substance Abuse (relative contraindication)
V. Mechanism
- Potentiates activity of Gamma-Aminobutyric Acid (GABA)
- Bind Benzodiazepine site on the GABA Receptor complex of Neurons
- Increases GABA mediated chloride influx, which inhibits Neuronal activity
-
GABA is an inhibitory Neurotransmitter in the CNS
- Muscle relaxant
- Anticonvulsant
- Anxiolytic
- Anti-aggressiveness
- Sedation
VI. Precautions
- Benzodiazepines have significant risks
- Double the risk of Motor Vehicle Accidents, and falls (and Hip Fractures) 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 (Xanax) 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 Sedatives (e.g. Ambien) can have additive effects with Benzodiazepines
- Diazepam, clorazepate, Chlordiazepoxide metabolize to the same long acting metabolite (Nordiazepam, aka Desmethyldiazepam)
-
Patient Education is critical
- Review risks of Benzodiazepine Abuse, tolerance, dependence and Benzodiazepine Withdrawal
- Review risk of falls and accidents
- Avoid in combination with Alcohol, Opioids
- Benzodiazepines are prescribed with an exit plan (not intended for longterm use)
- Safest use of Benzodiazepines is not to use them at all
- May have an as needed Benzodiazepine dose available for panic, but use other measures first
- Otherwise, the safest use of Benzodiazepines is for short-term, lowest dose at least frequency
- References
- (2014) Presc Lett 21(8): 45
- Zigman (2012) J Psychopharmacol 26: 1507-11 [PubMed]
VII. Advantages
- Rapid onset of Anxiolytic activity
- Tolerance develops rapidly to adverse effects
- Tolerance does not develop for Anxiolytic effect
- Few Drug Interactions
- Good safety profile for short-term use (when not combined with other CNS Depressants)
- High risk of dependence with longterm use
VIII. Medications: Benzodiazepines
- Long Acting Benzodiazepines
- Chlordiazepoxide (Librium)
- Diazepam (Valium, Valrelease)
- Flurazepam (Dalmane)
- Chlorazepate (Tranxene)
- Clonazepam (Klonopin)
- Quazepam (Doral)
- Halazepam (Paxipam)
- Medium Acting Benzodiazepines
- Short acting Benzodiazepines
IX. Medications: Other Sedative-Hypnotics
- Z-Drug (e.g. Zolpidem)
- Barbiturate (e.g. Barbiturates)
- Gamma Hydroxybutyrate (GHB)
- Gamma Butyrolactone
X. Absorption
XI. Metabolism
- Renal Excretion
- Hepatic Metabolism
- Microsomal oxidation
- Conjugation with glucuronic acid by glucuronyl transferases (Glucuronidation)
- Glucuronidation is the preferred metabolic pathway in elderly, debilitated and hepatic Impairment
- Lorazepam, Oxazepam, tamezapam all undergo Glucuronidation
- In contrast to Glucuronidation , drugs undergoing oxidative metabolism (CYP450) may accumulate
- Long acting agents (e.g. Diazepam, Chlordiazepoxide) are particularly higher risk for accumulation
- Glucuronidation is the preferred metabolic pathway in elderly, debilitated and hepatic Impairment
- 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
XII. 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
XIII. 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
XIV. Safety: Pregnancy and Lactation
- Pregnancy Category: D
- Lactation: Not allowed
XV. Adverse Effects
-
Drug Dependence
- Risk Benzodiazepine Withdrawal (Seizures may occur, especially if underlying Seizure Disorder)
- Taper off Benzodiazepines in age over 65 years or if use >4 weeks
- See Benzodiazepine Withdrawal for taper schedules
- Dependence may start within days of regular use
- Sedation
- Nausea
- Blood dyscrasia
- Anterograde Amnesia
- Cognitive Impairment
- Respiratory depression
- Hyponatremia or Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
XVI. Monitoring: Consider in patients on longterm therapy
XVII. References
- (2020) Presc Lett 27(12): 68-9
- (2020) Presc Lett, Resource #361206, Appropriate Use of Benzodiazepines
- Tasman (1997) Psychiatry, Saunders, p. 1641-6 [PubMed]
- Katzung (1989) Pharmacology, Lange, p. 264-7 [PubMed]
Images: Related links to external sites (from Bing)
Related Studies
| Definition (MSH) | A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring. |
| Definition (CHV) | a drug used to relieve nervousness, tension and anxiety |
| Definition (CHV) | a drug used to relieve nervousness, tension and anxiety |
| Definition (NCI) | Drugs from this chemical class are used for their central nervous system depressant properties including sedation, facilitation of sleep, seizure control, general anesthesia, anxiolytic, amnestic, and for detoxification from similar (cross tolerant) drugs |
| Definition (CSP) | bicyclic structure consisting of fused benzene and diazepine rings; many compounds with this structure have psychotropic and neurotropic properties, and are used as sedatives, anticonvulsants, muscle relaxants, and in related applications. |
| Concepts | Pharmacologic Substance (T121) , Organic Chemical (T109) |
| MSH | D001569 |
| SnomedCT | 349890003, 16047007, 372664007 |
| LNC | LP15014-1, MTHU001123 |
| English | Benzodiazepines, BENZODIAZEPINE CPDS, benzodiazepines (medication), benzodiazepines, Benzodiazepines [Chemical/Ingredient], Benzodiazepine, Benzodiazepine (product), Benzodiazepine (substance), benzodiazepine, Benzodiazepine, NOS, Benzodiazepine Compounds |
| Swedish | Bensodiazepiner |
| Czech | benzodiazepiny |
| Finnish | Bentsodiatsepiinit |
| French | Composés de benzodiazépine, Benzodiazépine, Benzodiazépines |
| Italian | Composti benzodiazepinici, Benzodiazepine |
| Russian | BENZODIAZEPINY, БЕНЗОДИАЗЕПИНЫ |
| Japanese | ベンゾジアゼピン, ベンゾジアゼピン誘導体 |
| Croatian | BENZODIJAZEPINI |
| Polish | Benzodiazepiny pochodne, Benzodwuazepiny pochodne |
| Norwegian | Benzodiazepiner, Benzodiazepin |
| Spanish | Benzodiacepinas, benzodiacepina (producto), benzodiacepina (sustancia), benzodiacepina, benzodiazepina (sustancia), benzodiazepina, Benzodiazepinas |
| German | Benzodiazepine |
| Portuguese | Benzodiazepinas |
Ontology: Tranquilizing Agents (C0040614)
| Definition (MSH) | A traditional grouping of drugs said to have a soothing or calming effect on mood, thought, or behavior. Included here are the ANTI-ANXIETY AGENTS (minor tranquilizers), ANTIMANIC AGENTS, and the ANTIPSYCHOTIC AGENTS (major tranquilizers). These drugs act by different mechanisms and are used for different therapeutic purposes. |
| Definition (CSP) | drug with a calming, soothing effect. |
| Concepts | Pharmacologic Substance (T121) |
| MSH | D014149 |
| SnomedCT | 45604009 |
| LNC | LP30812-9, MTHU015319 |
| English | Agents, Tranquilizing, Agents, Tranquillizing, Ataractics, Tranquillizing Agents, tranquilizer, Tranquilizing Drugs, Drugs, Tranquilizing, Drugs, Tranquillizing, Tranquillizing Drugs, ataractic, tranquilizers, tranquilizer drug, anxiety reducing drugs, tranquilliser, drugs tranquilizer, anxiolytic drug, tranquillisers, anxiolytic drugs, Tranquilizers, Tranquilizing drugs, Tranquilizer drug, Tranquilizer (substance), Tranquilizer, Tranquilliser drug, Tranquilliser, Tranquilizer drug, NOS, Tranquilizer, NOS, Tranquilizer agent, Tranquilliser agent, Tranquilizing Agents, Anxiety Reducing Drugs, Anxiolytic Drugs, Ataractic Drugs, Ataraxic Drugs |
| French | Médicaments tranquillisants, Agents tranquillisants, Tranquillisants |
| Swedish | Lugnande medel |
| Czech | ataraktika, trankvilizéry |
| Finnish | Rauhoittavat lääkkeet |
| Italian | Farmaci tranquillanti, Atarassici, Tranquillanti |
| Russian | TRANKVILIZATORY, ATARAKTIKI, ATARAKTICHESKIE SREDSTVA, АТАРАКТИКИ, АТАРАКТИЧЕСКИЕ СРЕДСТВА, ТРАНКВИЛИЗАТОРЫ |
| Croatian | TRANKVILIZATORI |
| Polish | Środki ataraktyczne, Trankwilizatory, Środki kojące |
| Japanese | 精神安定剤, 感情抑制薬, トランキライザ, 精神安定薬, 静穏薬, トランキライザー |
| Norwegian | Not Translated[Tranquilizing Agents] |
| Spanish | Efecto Tranquilizante, ansiolítico, fármaco ansiolítico, fármaco sedante, tranquilizante (sustancia), tranquilizante, Ataraxicos, Tranquilizantes |
| Portuguese | Efeito Tranquilizante, Ataráxicos, Tranquilizantes |
| German | Ataraktica, Tranquilizer |
Ontology: Hypnotic AND/OR sedative (C2584932)
| Concepts | Pharmacologic Substance (T121) |
| SnomedCT | 439304005 |
| English | Hypnotic AND/OR sedative, Hypnotic AND/OR sedative (substance) |
| Spanish | hipnótico y/o sedante (sustancia), hipnótico y/o sedante |
