Midazolam
Midazolam
Generic Name
Midazolam
Mechanism
Midazolam potentiates the inhibitory neurotransmitter gamma‑aminobutyric acid (GABA) by binding to the benzodiazepine recognition site on the GABA_A receptor complex.
• ↑ chloride ion influx → hyperpolarization of neuronal membranes
• ↓ neuronal excitability → anxiolysis, amnesia, muscle relaxation, anticonvulsant, and hypnotic effects
The receptor binding is allosteric; it does not alter the receptor’s affinity for GABA but increases GABA‑mediated chloride flux.
Pharmacokinetics
| Parameter | Typical Value / Note | |
| Absorption | IV: 100 % bioavailability. Oral: ~30–40 % due to first‑pass hepatic metabolism. IM/SC: ~90 % after ~15 min. | |
| Distribution | Large volume of distribution (8–15 L/kg). High protein binding (~94 % to albumin and α‑1‑acid glycoprotein). Extensive lipid solubility – rapid CNS penetration. | |
| Metabolism | Hepatic cytochrome P450 (CYP3A4/3A5) → inactive glucuronides and hydroxylated metabolites. | |
| Elimination | Renal (≈50 %) and hepatic. Terminal elimination half‑life: 1.5–3 h (IV); 3–7 h (oral). Shorter in healthy adults; prolonged in hepatic dysfunction. | |
| Excretion | Mainly urine; <5 % fecal. |
Indications
- Induction of general anesthesia or rapid‑sequence intubation
- Peri‑operative or procedural sedation (endoscopy, minor surgery, dental procedures)
- Temporary management of seizures (status epilepticus)
- Pre‑operative anxiolysis
- Sedation in intensive‑care settings (mechanical ventilation, ventilator weaning)
- Acute treatment of severe phobia in a medical context
Contraindications
- Absolute:
- Bilateral or unilateral basal ganglia disease (e.g., hepatic encephalopathy) – risk of exacerbated CNS depression
- Percutaneous or intrathecal injection when contraindicated for local anesthetic agents (use with caution)
- Relative:
- Severe hypotension or shock (risk of additive vasodilation)
- Severe respiratory failure or chronic obstructive pulmonary disease (risk of respiratory depression)
- Recent supraventricular tachycardia/patency (tachyarrhythmias may be precipitated)
- Pregnancy – category C (use only if benefit > risk)
- Acute liver failure or severe hepatic impairment (metabolism impaired)
Warnings:
• Monitor for hypotension, respiratory depression, and cerebral hypoxia.
• Avoid concomitant use with other CNS depressants (opioids, alcohol, barbiturates) unless carefully monitored.
• In patients on CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin), expect prolonged effects and dose adjustment.
Dosing
| Population | Route | Typical Dose | Freq. / Duration | Notes |
| Adults | IV | 1–4 mg bolus (0.05 mg/kg) | 1–3 mg every 10–30 min as needed | Aim for sedation score 2–4 (Ramsay). |
| IM | 7.5–10 mg (0.15–0.2 mg/kg) | Single dose | Longer onset (5–10 min). | |
| Oral | 5–10 mg | 1–2 h pre‑procedure | Less reliable due to variable absorption. | |
| Children | IV | 0.05–0.1 mg/kg | Titrate as per sedation level | Weight‑based dosing critical. |
| IM | 0.2–0.25 mg/kg | Single dose | ||
| Pregnancy | — | — | — | Use only if no alternatives, under informed consent. |
| IV Sedation (ICU) | IV infusion | 0.15–5 mg/h | Continuous | Monitor sedation depth, pain score. |
*Adjust for hepatic dysfunction: use lower starting dose and increase slowly; consider 0.5–1 mg IV for induction in severe hepatic impairment.*
Adverse Effects
Common:
• Sedation / drowsiness
• Amnesia (anterograde)
• Nausea & vomiting (post‑procedural)
• Dysphasia (difficulty speaking)
• Transient visual or auditory hallucinations
Serious (life‑threatening):
• Respiratory depression → hypoventilation or apnea
• Hypotension/vasodilatory shock (especially in hypovolemic patients)
• Prolonged sedation (>24 h) in hepatic dysfunction or in drug‑interacting states
• Seizure recurrence when used for status epilepticus rescue (failure)
• Post‑procedural delirium or delirium tremens in chronic benzodiazepine users upon abrupt withdrawal
Dermatologic:
• Local injection site pain, erythema, absorption site irritation (rare).
Monitoring
- Sedation depth: Ramsay Sedation Scale or Richmond Agitation‑Sedation Scale (RASS)
- Respiratory: Rate, tidal volume, oxygen saturation, capnography if sedated > 2 h
- Hemodynamics: BP, HR, cardiac output (in ICU)
- Neurologic: Pupillary response, Glasgow Coma Scale (GCS)
- Biochemical: Liver function tests (elevated CK, AST, ALT) when prolonged dosing or hepatic impairment
- Duration of effect: Time to recovery of baseline consciousness and protective airway reflexes
Clinical Pearls
- “Quick‑take” sedative: Midazolam’s short half‑life makes it ideal for brief procedures, but it is also the reason why it should be avoided in outpatient settings with long recovery times (e.g., outpatient cardiac cath).
- Dose titration vs. weight titration: For procedural sedation in the OR, titrate to effect instead of strict weight dosing. A single 2–3 mg IV dose often suffices for many adults.
- Hepatic impairment caution: In patients with Child‑Pugh B/C liver disease, start at ≤ 0.5 mg IV and extend intervals to 1–2 h.
- Drug interactions: Co‑administration with strong CYP3A4 inhibitors (e.g., clarithromycin) can increase plasma concentrations by up to 5‑fold; reduce the dose by 50 %.
- Extubation & weaning: Short‑acting nature allows rapid assessment of level of consciousness, but beware of “re‑elation” due to metabolism inhibition later in the day.
- Elderly patients: Start at the lowest dose (often 1–2 mg IV); monitor for prolonged sedation and hypotension.
- Use in status epilepticus: As a rescue benzodiazepine, midazolam is effective when used by rapid‑sequence or continuous infusion; avoid if the patient has a known benzodiazepine allergy or reaction to flumazenil reversal.
These points, together with precise dosing tables and an emphasis on safe monitoring, will guide both fresh medical graduates and seasoned clinicians in the optimal use of midazolam for a wide array of therapeutic indications.