Benzodiazepine

Aka: Benzodiazepine, Sedative-Hypnotic, Benzodiazepine Metabolism

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II. Indications: Outpatient

  1. Sedation in surgical, Medical and Psychiatric procedures
  2. Seizure disorder
  3. Alcohol Withdrawal and withdrawal from other drugs
  4. Anxiety Disorder
    1. Consider limiting to short-term stabilization until SSRI or SNRI (e.g. Venlafaxine) takes effect
    2. Adjunct to Cognitive Behavioral Therapy and other Anxiety Management
  5. Insomnia
    1. Consider alternative agents and methods (Trazodone, Melatonin, CBT-I, Sleep Hygiene)
    2. Consider Benzodiazepine Receptor Agonist instead (e.g. Ambien)
  6. Muscle spasm
    1. Consider alternative agents and methods (e.g. Flexeril, NSAIDs, back Exercises, physical therapy)

III. Contraindications

  1. Myasthenia Gravis
  2. Acute narrow-angle Glaucoma
  3. Substance Abuse (relative contraindication)

IV. Mechanism

  1. Potentiates activity of gamma-aminobutyric acid (GABA)
  2. GABA is an inhibitory neurotransmitter in the CNS
    1. Muscle relaxant
    2. Anticonvulsant
    3. Anxiolytic
    4. Anti-aggressiveness
    5. Sedation

V. Precautions

  1. Benzodiazepines have significant risks
    1. Double the risk of Motor Vehicle Accidents, and falls (and Hip Fractures) in the elderly (see Beer's List)
    2. Double the risk of COPD exacerbations
    3. Associated with rising Overdose deaths in the United States (FDA black box warning in 2020)
  2. Benzodiazepine misuse and abuse is common
    1. Hospital admissions for Benzodiazepine Abuse have increased three-fold since the early 2000s
    2. Alprazolam is among the most addictive Benzodiazepines
      1. Responsible for 10% of drug-misuse related visits to the Emergency Department
      2. Rapid onset is associated with euphoria, short half-life is associated with rebound symptoms
  3. Avoid combining Benzodiazepines if possible
    1. Risk of falls, memory problems, excessive sedation
    2. Occasional, as needed dosing of a short acting Benzodiazepine may be approriate longterm in some patients
      1. However, longterm regular or scheduled use is generally not recommended
      2. Frequent prn dosing should prompt re-evaluation
        1. Consider tapering off Benzodiazepine or switching to long-acting Benzodiazepine dose
    3. Non-Benzodiazepine Sedatives (e.g. Ambien) can have additive effects with Benzodiazepines
  4. References
    1. (2014) Presc Lett 21(8): 45
    2. Zigman (2012) J Psychopharmacol 26: 1507-11 [PubMed]

VI. Advantages

  1. Rapid onset of action
    1. Anxiolytic effect within 1-2 days
  2. Tolerance develops rapidly to adverse effects
  3. Tolerance does not develop for Anxiolytic effect
  4. Few Drug Interactions
  5. Good safety profile

VII. Preparations

  1. Long Acting Benzodiazepines
    1. Chlordiazepoxide (Librium)
    2. Diazepam (Valium, Valrelease)
    3. Flurazepam (Dalmane)
    4. Chlorazepate (Tranxene)
    5. Clonazepam (Klonopin)
    6. Quazepam (Doral)
    7. Halazepam (Paxipam)
  2. Medium Acting Benzodiazepines
    1. Lorazepam (Ativan)
    2. Temazepam (Restoril)
  3. Short acting Benzodiazepines
    1. Oxazepam (Serax)
    2. Alprazolam (Xanax)
    3. Triazolam (Halcion)
    4. Estazolam (Prosom)
    5. Midazolam (Versed)

VIII. Absorption

  1. Preparations with most rapid absorption
    1. Diazepam (Valium)
    2. Clorazepate
    3. Alprazolam (Xanax) taken sublingually
  2. Preparations with slowest absorption
    1. Oxazepam (Serax)
    2. Co-administration of Benzodiazepine with medication
      1. Maalox
      2. Gelusil

IX. Metabolism

  1. Renal Excretion
  2. Hepatic Metabolism
    1. Microsomal oxidation
    2. Conjugation by glucuronyl transferases
  3. Metabolic pathways
    1. Clonazepam metabolizes to 7-aminoclonazepam
    2. Alprazolam metabolizes to Alpha-hydroxyalprazolam
    3. Chlordiazepoxide metabolizes to Oxazepam (via Norchlordiazepoxide, Demoxepam, Nordiazepam)
    4. Medazepam metabolizes to Oxazepam (via Nordiazepam) and Diazepam
    5. Diazepam metabolizes to Oxazepam (via Nordiazepam) and Temazepam
    6. Temazepam metabolizes to Oxazepam
    7. Agents that metabolize to Oxazepam via nordiazepam
      1. Diazepam
      2. Demoxepam
      3. Halazepam
      4. Chlorazepate
      5. Prezapam
  4. References
    1. Valentine (1996) J Anal Toxicol 20(6): 416-24 +PMID:8889678

X. Dosing: Strategies

  1. Initiate treatment with low dose Benzodiazepine
    1. Prevent symptoms completely by using a regular regimen
    2. Escalate dose slowly, no more often than every 2 weeks
    3. Maintain lowest effective dose for several months
    4. Start with 50% of typical dose in at risk cohorts
      1. Elderly
      2. Hepatic dysfunction
      3. Renal dysfunction
  2. Tapering dose
    1. Periodically attempt to lower dose or ideally, titrate off completely
    2. Indications for prolonged taper periods (2-4 weeks per dose step-down)
      1. Higher Benzodiazepine doses
      2. Longer duration of Benzodiazepine use
      3. Short-acting Benzodiazepines (e.g. Alprazolam, Lorazepam)
    3. Example taper protocol
      1. Decrease dose by 25% for 1 week (2-4 weeks if prolonged taper indicated) THEN
      2. Decrease dose by 25% for 1 week (or 2-4 weeks if prolonged taper indicated) THEN
      3. Decrease dose by 10% per 1 week (or 2-4 weeks if prolonged taper indicated) until off
    4. Change to longer half-life drug if symptom breakthrough
      1. Example: Switch from Xanax to Clonazepam

XI. Dosing: Equivalent to Valium 60 mg (for withdrawal)

  1. High Potency Benzodiazepines
    1. Alprazolam (Xanax) 6 mg
    2. Clonazepam (Klonopin) 24 mg
    3. Lorazepam (Ativan) 12 mg
  2. Low Potency Benzodiazepines
    1. Chlordiazepoxide (Limbitrol) 150 mg
    2. Flurazepam (Dalmane) 90 mg
    3. Halazepam (Paxipam) 240 mg
    4. Oxazepam (Serax) 60 mg
    5. Temazepam (Restoril) 60 mg

XII. Safety: Pregnancy and Lactation

  1. Pregnancy Category: D
  2. Lactation: Not allowed

XIII. Adverse Effects

  1. Drug Dependence
    1. Risk Benzodiazepine Withdrawal (Seizures may occur, especially if underlying Seizure disorder)
  2. Sedation
  3. Nausea
  4. Blood dyscrasia
  5. Anterograde Amnesia
  6. Cognitive Impairment
  7. Respiratory depression
  8. Hyponatremia or Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

XIV. Monitoring: Consider in patients on longterm therapy

  1. Complete Blood Count
  2. Liver Function Tests

XV. References

  1. (2020) Presc Lett 27(12): 68-9
  2. Tasman (1997) Psychiatry, Saunders, p. 1641-6 [PubMed]
  3. Katzung (1989) Pharmacology, Lange, p. 264-7 [PubMed]

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Related Studies

Ontology: Benzodiazepines (C0005064)

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
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Pharmacology

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