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diazepam (Vallium, Diastat)

Tradename: Valium. DEA-controlled substance: class 4. Indications: 1) treatment of anxiety 2) short-term management of panic attacks 3) muscle spasms, tetanus 4) alcohol withdrawal 5) acute management of seizures, including status epilepticus 6) long-term sedation of ventilated patients 7) amnesia [8] Contraindications: - sleeping disorders Dosage: 1) Status epilepticus: - 0.4-0.4 mg/kg up to 5-10 mg IV, or 0.3-0.5 mg/kg PR - 2.5-5 mg increments IV up to 0.2 mg/kg [1]. - 2.5-20 mg IV slowly [2] 2) poor seizure control - diazepam buccal film [10] 3) treatment of anxiety - 2-10 mg PO TID/QID [1]. - 6-40 mg/24 hours PO QD/BID/TID/QID [2]. 4) taper to discontinue, no cross taper necessary [9] Tabs: 2, 5, 10 mg. Solution: 5 mg/5 mL. Rectal gel. Injectable form also works given rectally [7] Pharmacokinetics: 1) well absorbed orally 2) absorption is increased by food [6] 3) erratic absorption when given IM 4) onset of action is 1-5 minutes 5) metabolized by liver to 3 active metabolites a) oxazepam, desmethyldiazepam b) metabolized by cyt P450 2C19 & cyt P450 3A4 6) 1/2life is 20-50 hour, increased in elderly & in patients with liver failure 7) t1/2 of major metabolite desmethyldiazepam is 50-100 hours 8) phase 2 metabolism by glucuronyl transferase can be saturated 9) excreted in urine Adverse effects: 1) common (> 10%) - drowsiness, fatigue, impaired coordination, lightheadedness, memory impairment, insomnia, dysarthria, anxiety, decreased libido, depression, headache, dry mouth, decreased salivation, constipation, nausea/vomiting, diarrhea, tachycardia, chest pain, blurred vision, sweating, rash, increased or decreased appetite 2) less common (1-10%) - confusion, nervousness, syncope, dizziness, akathesia, increased salivation, hypotension, rigidity, tremor, dermatitis, nasal congestion, weight gain or weight loss, hyperventilation, tinnitus, muscle cramps 3) uncommon (< 1%) - menstrual irregularities, blood dyscrasia, reflex slowing, drug dependence 4) others - urinary incontinence, hiccups, cardio-respiratory depression, hallucinations, relaxation of lower esophageal sphincter (GERD), liver impairment Drug interactions: 1) disulfiram, nefazodone, fluoxetine, fluvoxamine, cimetidine, estrogens, erythromycin, isoniazid, valproic acid & grapefruit juice inhibit diazepam metabolism 2) CNS depressants in combination increase CNS depressant effects 3) anticonvulsants & rifampin increase metabolism of diazepam 4) flumazenil directly antagonizes benzodiazepines 5) antacids inhibit diazepam absorption 6) any drug which inhibits cyt P450 2C19 or 3A4 can increase diazepam levels 7) any drug which induces cyt P450 2C19 or 3A4 can diminish diazepam levels Laboratory: 1) specimen: serum, plasma (EDTA) 2) methods: HPLC, GLC, RIA 3) interferences: a) GLC: clorazepate & chlordiazepoxide (some methods); amitriptyline b) RIA: cross reaction with metabolites Mechanism of action: - potentiates inhibitory effect of GABA by increasing neuronal permeability to Cl-

Interactions

drug interactions drug adverse effects (more general classes) monitor with anticonvulsants

Related

cytochrome P450 2C19 (cytochrome P450 2C17, cytochrome P450 11A, mephenytoin 4-hydroxylase, cytochrome P450 254C, CYP2C19) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) UDP-glucuronosyltransferase (UDPGT)

General

anticonvulsant benzodiazepine skeletal muscle relaxant (tranquilizer)

Properties

MISC-INFO: elimination route KIDNEY 1/2life 20-90 HOURS therapeutic-range 100-1000 NG/ML toxic-range >5000 NG/ML protein-binding 96-99% elimination by hemodialysis - pregnancy-category D safety in lactation -

Database Correlations

PUBCHEM cid=3016

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996.
  2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 7
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  6. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 470
  7. Prescriber's Letter 13(10): 2006 Alternative or 'Off-label' Routes of Drug Administration Detail-Document#: 221012 (subscription needed) http://www.prescribersletter.com
  8. Deprecated Reference
  9. Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  10. George J Diazepam Film Shows Promise for Poor Seizure Control. Buccal film placed successfully during seizure clusters. MedPage Today. Dec 06, 2018 - Jung C, et al. The usability of diazepam buccal soluble film as an oral treatment in adult patients with epilepsy. AmericanEpilepsy Society (AES) 2018; Abstract 3.468. - Rogawski M, et al. Pharmacokinetics of diazepam buccal soluble film in adult patients with epilepsy: comparison of bioavailability with peri-ictal and interictal administration. AmericanEpilepsy Society (AES) 2018; Abstract 2.453.