DIAZEPAM
Clinical safety rating: avoid
CNS depressants including alcohol and opioids increase sedation risk Abrupt discontinuation can cause withdrawal symptoms.
Benzodiazepine that enhances GABA-A receptor activity by increasing the frequency of chloride channel opening, leading to neuronal hyperpolarization and inhibition.
| Metabolism | Hepatic via CYP2C19 and CYP3A4 to active metabolite desmethyldiazepam, then further metabolized to oxazepam and glucuronidated. |
| Excretion | Renal (70-80% as metabolites, primarily glucuronide conjugates; <5% unchanged), fecal (10-20% as metabolites), biliary (minor). |
| Half-life | Terminal half-life 30-56 hours (range 20-70 hours) in adults; prolonged in elderly (up to 100 hours), neonates (up to 100 hours), and cirrhosis (up to 100+ hours). |
| Protein binding | 98-99%, primarily to albumin. |
| Volume of Distribution | 0.8-1.5 L/kg (average 1.1 L/kg); high due to lipophilicity, distributes widely into tissues including brain and fat. |
| Bioavailability | Oral: 90-100%; IM: 90-100% (but variable, especially at gluteal site); Rectal: 50-90% (dose-dependent). |
| Onset of Action | IV: 1-3 minutes; IM: 15-30 minutes; Oral: 30-60 minutes; Rectal: 5-15 minutes. |
| Duration of Action | IV/IM: 15-60 minutes (single dose), due to redistribution; Oral: 6-8 hours (single dose), 12-24 hours with chronic dosing; Rectal: 30-60 minutes. |
| Molecular Weight | 284.74 |
Anxiety: 2-10 mg PO BID-QID; Sedation/Muscle spasm: 5-10 mg IV/IM q3-4h PRN; Status epilepticus: 0.15-0.2 mg/kg IV (max 10 mg) q10-15 min PRN.
| Dosage form | CONCENTRATE |
| Renal impairment | CrCl <10 mL/min: increase dosing interval or reduce dose; no specific GFR-based dose recommendations; use with caution. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid or reduce dose by 75%. |
| Pediatric use | Anxiety: 0.12-0.8 mg/kg/day PO divided q6-8h; Sedation/Status epilepticus: 0.1-0.3 mg/kg IV (max 10 mg) q15-30 min PRN; not recommended in neonates. |
| Geriatric use | Initial dose: 2-2.5 mg PO BID; increase cautiously; avoid long-term use due to fall risk and cognitive impairment. |
| 1st trimester | Avoid if possible; may increase risk of cleft palate (first trimester exposure associated with oral clefts in some studies). Use only if benefit outweighs risk. |
| 2nd trimester | Avoid unless essential; may cause fetal CNS depression. Use lowest effective dose for shortest duration. |
| 3rd trimester | Avoid; chronic use may lead to neonatal withdrawal and floppy infant syndrome (hypotonia, respiratory depression, poor feeding). Use only if clearly needed. |
Clinical note
CNS depressants including alcohol and opioids increase sedation risk Abrupt discontinuation can cause withdrawal symptoms.
| FDA category | Positive |
| Placental transfer | Crosses placenta readily; fetal serum concentrations may equal or exceed maternal levels. Rapid transfer and accumulation in fetal tissues, especially brain. |
■ FDA Black Box Warning
Concomitant use of opioids may result in profound sedation, respiratory depression, coma, and death. Reserve co-prescription for patients with no alternative treatments.
| Common Effects | alcohol withdrawal |
| Serious Effects |
Acute narrow-angle glaucomaSevere respiratory insufficiency (e.g., COPD with hypercapnia, sleep apnea)Myasthenia gravisSevere hepatic impairment (e.g., encephalopathy)Known hypersensitivity to diazepam or benzodiazepinesConcurrent use with norfloxacin, loxapine (increased CNS depression)
| Precautions | Risk of respiratory depression, especially with IV use, Potential for physical and psychological dependence with long-term use, Avoid abrupt discontinuation to prevent withdrawal symptoms, May cause anterograde amnesia, Use with caution in elderly and debilitated patients (lower doses recommended), May exacerbate narrow-angle glaucoma |
| Food/Dietary |
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| Breastfeeding |
| Diazepam and its active metabolite (nordazepam) are excreted into breast milk. Accumulation in neonates, especially with chronic use, may cause sedation, poor feeding, and weight loss. Short-term, single doses are relatively safe but monitor for drowsiness. Alternative agents (e.g., oxazepam, temazepam) are preferred due to shorter half-lives and less accumulation. |
| Lactation Rating | L3 (Moderately Safe; in short-term use, but caution with prolonged exposure). However, many sources classify as 'Avoid' for chronic therapy. |
| Teratogenic Risk | First trimester: Associated with increased risk of oral clefts (approximately 2-fold) based on some studies; risk is low in absolute terms. Second and third trimesters: Risk of hypotension, poor Apgar scores, respiratory depression, and hypothermia in the neonate. Chronic use near term may lead to neonatal withdrawal syndrome and floppy infant syndrome (hypotonia, lethargy, feeding difficulties). Avoid use during first trimester if possible; use only if clearly needed in later trimesters. |
| Fetal Monitoring | Maternal: Monitor for signs of sedation, respiratory depression, hypotension. Fetal/neonatal: Ultrasound for fetal growth if chronic use; after delivery, observe neonate for respiratory depression, hypotonia, withdrawal symptoms (tremors, irritability, hypertonia) for several days. Consider monitoring Apgar scores and neonatal abstinence syndrome scoring if chronic high-dose use near term. |
| Fertility Effects | Limited human data. Diazepam may affect hypothalamic-pituitary-ovarian axis; animal studies show impaired fertility at high doses. No robust evidence of significant fertility impairment in humans at therapeutic doses. In males, possible effect on sperm motility or morphology (inconsistent data). |
| Avoid alcohol; it can potentiate sedation and psychomotor impairment. Grapefruit juice may increase diazepam serum concentrations by inhibiting CYP3A4, leading to enhanced effects. Caffeine may reduce the anxiolytic effects. No known food restrictions other than these interactions. |
| Clinical Pearls | Diazepam is a long-acting benzodiazepine with active metabolites (desmethyldiazepam) that accumulate with chronic use, leading to prolonged sedation, especially in elderly or hepatically impaired patients. Use with caution in patients with respiratory compromise; avoid in acute narrow-angle glaucoma. Parenteral diazepam is not recommended for use in children under 6 months due to risk of respiratory depression. Onset of action is rapid with IV (within minutes) but IV administration can cause thrombophlebitis; use large veins and dilute if possible. Rectal gel is effective for acute seizure clusters. Tolerance develops to sedative effects but not to anxiolytic effects. Abrupt discontinuation after chronic use may cause withdrawal seizures. |
| Patient Advice | Do not stop taking this medication suddenly; tapering off is required to prevent withdrawal symptoms like seizures or anxiety. · Avoid driving or operating heavy machinery until you know how diazepam affects you; it can cause drowsiness and dizziness. · Do not consume alcohol or other central nervous system depressants while taking diazepam as it increases sedation and risk of overdose. · If you are pregnant, plan to become pregnant, or are breastfeeding, inform your healthcare provider; diazepam may harm the fetus or infant. · Store diazepam at room temperature away from light and moisture, and keep out of reach of children. · Notify your doctor if you experience worsening depression, suicidal thoughts, or unusual changes in mood. · Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · If you miss a dose, take it as soon as you remember unless it is almost time for the next dose; then skip the missed dose and resume regular schedule. Do not double dose. |