Diazepam - Short Note

Drug Class & Basic Profile

Mechanism of Action

• Katzung's Basic and Clinical Pharmacology, 16th Ed. - Miller's Anesthesia, 10th Ed.

Pharmacokinetics

• Miller's Anesthesia, 10th Ed. - Kaplan & Sadock's Comprehensive Textbook of Psychiatry

Available Formulations

• Oral tablets: 2 mg, 5 mg, 10 mg
• Oral solution: 1 mg/mL, 5 mg/mL (contains 19% alcohol)
• Injection (IV/IM): 5 mg/mL
• Rectal gel (Diastat/Diastat AcuDial): 2.5 mg, 10 mg, 20 mg pre-filled syringes
• Nasal spray (Valtoco): 5 mg, 7.5 mg, 10 mg per 0.1 mL

• Harriet Lane Handbook, 23rd Ed.

Indications & Dosing

Anxiety / Sedation / Muscle Relaxant

• Adults: Initially 2-10 mg PO 2-4 times daily
• Children: 0.12-0.8 mg/kg/24 hr PO divided Q6-12 hr; max 10 mg/dose
• IV/IM (children): 0.05-0.2 mg/kg/dose Q6-12 hr; max 0.6 mg/kg in 8 hr

Muscle Spasticity (Katzung)

• Initial: 4 mg/day, gradually increased up to 60 mg/day
• Useful for nearly any origin of muscle spasm (local trauma, cord injury, etc.)
• Caveat: produces sedation at doses needed to reduce muscle tone

Status Epilepticus

• IV is first-line; onset of anticonvulsant effect: 1-3 minutes IV, 2-10 min rectal, <5 min intranasal
• Must be followed by a long-acting anticonvulsant (phenytoin, valproate, etc.)
• Rectal gel dosing by age:
  • 2-5 yr: 0.5 mg/kg/dose
  • 6-11 yr: 0.3 mg/kg/dose
  • ≥12 yr/adult: 0.2 mg/kg/dose; max 20 mg/dose
  • Repeat no more than once every 5 days and no more than 5 times/month

• Harriet Lane Handbook, 23rd Ed.

Adverse Effects

• CNS: Sedation, ataxia, dizziness, headache, anterograde amnesia
• Respiratory: Respiratory depression - especially with opioids (risk of coma, death)
• Cardiovascular: Hypotension
• Intranasal route: Nasal discomfort, dysgeusia, epistaxis
• Rectal gel: Ataxia, headache, dizziness, rash
• Long-term: Tolerance, physical dependence, withdrawal syndrome on abrupt cessation

Contraindications

• Myasthenia gravis
• Severe respiratory insufficiency
• Severe hepatic failure
• Sleep apnea syndrome
• Concurrent use with protease inhibitors

Important Drug Interactions

• Opioids: Profound sedation, respiratory depression, coma, death - use with extreme caution
• CNS depressants, cimetidine, erythromycin, itraconazole, valproic acid: Enhance diazepam effects
• CYP substrates: Diazepam is metabolized by CYP2B6, 2C8, 2C9, 3A5-7 (minor substrate/inhibitor of CYP2C19 and 3A4); interactions at these enzymes affect drug levels

Special Considerations

• Dependence risk: Higher than many other benzodiazepines; it is more likely to cause dependence than shorter-acting congeners
• Elderly: Significantly reduced clearance - dose accordingly (risk of accumulation due to long-acting metabolites with t1/2 up to 200 hours)
• Hepatic/renal dysfunction: Use with caution; reduce dose
• Deprescribing: Due to its long half-life, diazepam is often used as a switch-over agent when tapering shorter-acting benzodiazepines (e.g., lorazepam 1 mg ≈ diazepam 10 mg; alprazolam 1 mg ≈ diazepam 10 mg; clonazepam 1 mg ≈ diazepam 20 mg)
• IV administration: Give undiluted, no faster than 2 mg/min; do not mix with IV fluids

• Maudsley Deprescribing Guidelines - Harriet Lane Handbook, 23rd Ed.