Diazepam

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Contents 1 Introduction 2 Indications 3 Dosage 4 Pharmacokinetics 5 Adverse-effects 6 Drug-interactions 7 Laboratory 8 Mechanism-of-action 9 More General Terms 10 Additional Terms 11 Internet Database 12 References

Introduction

• Tradename: Valium. DEA-controlled substance: class 4.

Indications

• treatment of anxiety
• short-term management of panic attacks
• muscle spasms
• alcohol withdrawal
• acute management of seizures, including status epilepticus
• long-term sedation of ventilated patients
• NOT for sleeping disorders

Dosage

• 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]

• treatment of anxiety

• 2-10 mg PO TID/ QID [1].
• 6-40 mg/24 hours PO QD/ BID/ TID/ QID [2].

• Tabs: 2, 5, 10 mg. Solution: 5 mg/5 mL. Rectal gel.
• Injectable form also works given rectally [7]

Pharmacokinetics

• well absorbed orally
• absorption is increased by food [6]
• erratic absorption when given IM
• onset of action is 1-5 minutes
• metabolized by liver to 3 active metabolites

• oxazepam, desmethyldiazepam
• metabolized by cyt P450 2C19 & 3A4

• 1/2life is 20-50 hour, increased in elderly & in patients with liver failure
• t1/2 of major metabolite desmethyldiazepam is 50-100 hours
• phase 2 metabolism by glucuronyl transferase can be saturated
• excreted in urine
  

• elimination via kidney
• 1/2life = 20-90 hours
• protein binding = 96-99 %
• elimination by hemodialysis = -

Adverse-effects

• 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

• 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

• uncommon (< 1%)

• menstrual irregularities, blood dyscrasia, reflex slowing, drug dependence

• others

• urinary incontinence, hiccups, cardio- respiratory depression, hallucinations, relaxation of lower esophageal sphincter ( GERD), liver impairment
  
• drug adverse effects of sedatives
• drug adverse effects of anticonvulsants
• drug adverse effects of benzodiazepines

Drug-interactions

• disulfiram, nefazodone, fluoxetine, fluvoxamine, cimetidine, estrogens, erythromycin, isoniazid, valproic acid & grapefruit juice inhibit diazepam metabolism
• CNS depressants in combination increase CNS depressant effects
• anticonvulsants & rifampin increase metabolism of diazepam
• flumazenil directly antagonizes benzodiazepines
• antacids inhibit diazepam absorption
• any drug which inhibits cyt P450 2C19 or 3A4 can increase diazepam levels
• any drug which induces cyt P450 2C19 or 3A4 can diminish diazepam levels
  
• drug interaction(s) of antipsycotics with benzodiazepines
• drug interaction(s) of antidepressants with benzodiazepines
• drug interaction(s) of beta-adrenergic receptor antagonists with benzodiazepines
• drug interaction(s) of beta-adrenergic receptor antagonists with benzodiazepines

Laboratory

• specimen: serum, plasma ( EDTA)
• methods: HPLC, GLC, RIA
• interferences:

• GLC: clorazepate & chlordiazepoxide (some methods); amitriptyline
• RIA: cross reaction with metabolites

Mechanism-of-action

• potentiates inhibitory effect of GABA by increasing neuronal permeability to Cl-

More General Terms

• benzodiazepine
• anticonvulsant
• skeletal muscle relaxant

Additional Terms

• 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)

Internet Database

PubChem: 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#: [1] (subscription needed) [2]

diazepam (Vallium, Diastat)