Valium
Diazepam
Generic Name
Diazepam
Mechanism
Diazepam is a long‑acting benzodiazepine that enhances the effect of the inhibitory neurotransmitter gamma‑aminobutyric acid (GABA).
• Binds to the GABA‑A receptor at a site distinct from benzodiazepine‑induced chloride channel opening.
• Increases chloride conductance → hyperpolarization of the neuron and reduced likelihood of action potential firing.
• Results in anxiolytic, anticonvulsant, muscle‑relaxant, sedative, and amnestic properties.
Pharmacokinetics
- Absorption: Rapid, 70‑90 % orally, well‑absorbed across the gut.
- Distribution: Large volume of distribution (250–400 L), highly lipophilic; penetrates CNS and crosses placenta.
- Metabolism: Hepatic CYP2C9, CYP3A4 → active metabolite desmethyldiazepam (diazepam‑N‑oxide).
- Elimination: 30‑60 h half‑life of parent drug; metabolites have 80–100 h half‑life; total duration of action > 2 days.
- Excretion: Renal (≈ 25 %) and biliary.
Indications
- Acute anxiety/panic attacks (short‑term).
- Seizure disorders – status epilepticus bridging, adjunct in generalized tonic‑clonic or absence seizures.
- Muscle spasm – acute musculoskeletal spasm, spasticity.
- Premedication for sedation (e.g., endoscopy, regional anesthesia).
- Alcohol withdrawal – severe agitation, delirium tremens.
- Short‑term treatment of insomnia (high‑dose, not first choice).
Contraindications
- Absolute contraindications: history of benzodiazepine abuse, severe respiratory insufficiency, acute narrow‑angle glaucoma, pregnancy (especially 3rd trimester), lactation.
- Relative contraindications: hepatic or renal impairment, severe heart failure, myasthenia gravis.
- Warnings:
- Cumulative CNS depression with alcohol or other sedatives.
- Short‑term tachyphylaxis, rebound anxiety or seizures.
- Possible respiratory depression in overdose.
- Abrupt discontinuation can precipitate withdrawal, seizures, or anxiety.
Dosing
- Adults (anxiety): 5–10 mg PO q4‑6 h PRN; maximum 40 mg/day.
- Adults (seizures): 5‑10 mg PO or 1–10 mg IV every 8 h; loading dose 10–30 mg IV.
- Adolescents: 2.5 mg PO q12 h; careful titration.
- Elderly/renal/hepatic impairment: start 1/4 dose and titrate slowly.
- IV formulation: 2–10 mg in 50 mL NS, 2–5 mg/min infusion; monitor cardiac rhythm.
Administration tips
• Oral: with or without food; food reduces peak concentration but improves tolerance.
• IV: avoid rapid bolus >10 mg/min to reduce myocardial depression.
Adverse Effects
- Common: drowsiness, dizziness, weakness, ataxia, dry mouth, blurred vision, insomnia (paradoxical).
- Serious:
- Respiratory depression (especially with poly‑substance use).
- Paradoxical agitation, aggression, hallucinations.
- Myoclonus, especially with high doses or CNS disease.
- Hepatotoxicity (rare, idiosyncratic).
- Withdrawal seizures, delirium after abrupt discontinuation.
Monitoring
| Parameter | Frequency | Rationale |
| Mental status / sedation level | Baseline, 1 h post‑dose, then q6–8 h | Detect CNS depression |
| Respiratory rate & oxygen saturation | Baseline, 1–2 h post‑dose, then q6–8 h in high doses | Prevent respiratory depression |
| Liver function tests (ALT/AST) | Baseline, then q4–6 wks in chronic use | Early detection of hepatotoxicity |
| Blood pressure & pulse | Baseline, 1 h post‑dose, then q6–8 h | Identify hypotension / bradycardia |
| Electrolytes / renal function | Baseline, periodic in chronic therapy | Adjust dose if renal/hepatic impairment |
| Drug‑level (if therapeutic drug monitoring needed) | Not routinely required; used in severe withdrawal cases | Ensure therapeutic window |
Clinical Pearls
- Taper, don’t stop: Aim for a slow taper (e.g., 5 mg every 1–2 weeks) to prevent rebound anxiety or seizures.
- Long‑acting “back‑up”: Diazepam’s active metabolites keep therapeutic levels for days; suitable for bridge therapy while starting a short‑acting agent.
- Cross‑over for benzodiazepine abuse: Use flumazenil as a reversal agent but be cautious of withdrawal‑induced seizures.
- Pregnancy category: Contraindicated in the 3rd trimester; use isomeric clonazepam only if benefits outweigh risks in 2nd trimester.
- Drug interactions: Strong CYP3A4 inhibitors (ketoconazole, erythromycin) can double diazepam levels; adjust dose accordingly.
- Muscle spasms: For chronic spasticity, consider baclofen or tizanidine as alternatives; diazepam is usually first for acute crises.
- Painful neuropathy: Adjunct to NSAIDs may provide analgesic synergy, but monitor for sedation.
- Cognitive dysfunction in the elderly: Prefer short‑acting benzodiazepines with minimal residual effect (e.g., lorazepam) if diazepam is necessary.
*Reference:* FDA label (2003), Goodman & Gilman’s Pharmacological Basis of Therapeutics, 13th ed.