Midazolam - Drug Monograph

Introduction

Midazolam is a short-acting benzodiazepine medication primarily used for procedural sedation, preoperative anxiolysis, induction of anesthesia, and treatment of acute seizures. As a water-soluble compound with rapid onset and short duration of action, it has become a valuable agent in various clinical settings including emergency departments, intensive care units, and procedural areas.

Mechanism of Action

Midazolam exerts its effects by enhancing the activity of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. It binds to specific sites on the GABA-A receptor complex, increasing the frequency of chloride channel opening events. This hyperpolarizes neuronal membranes and reduces neuronal excitability, resulting in sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnestic effects.

Indications

• Preoperative sedation, anxiolysis, and amnesia
• Conscious sedation for diagnostic, therapeutic, or endoscopic procedures
• Induction of general anesthesia (as adjunct)
• Sedation of intubated and mechanically ventilated patients in critical care settings
• Treatment of acute convulsive states (status epilepticus)
• Sedation for minor surgical procedures

Dosage and Administration

• Preoperative sedation: 0.07-0.08 mg/kg IM (approximately 5 mg) 30-60 minutes preoperatively
• Conscious sedation: Initial IV dose of 1-2.5 mg, titrate slowly to effect
• Induction of anesthesia: 0.3-0.35 mg/kg IV (unpremedicated patients)
• ICU sedation: 0.02-0.1 mg/kg IV loading dose, then 0.02-0.1 mg/kg/hr infusion

Pharmacokinetics

Contraindications

• Hypersensitivity to midazolam or other benzodiazepines
• Acute narrow-angle glaucoma
• Severe respiratory depression
• Severe hepatic impairment
• Sleep apnea syndrome (unless mechanically ventilated)
• Shock or coma
• Pregnancy (first trimester except compelling indications)

Warnings and Precautions

• Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death
• Reserve concomitant prescribing for patients with inadequate alternative treatment options

• Risk of respiratory depression and apnea, especially with rapid IV administration or concomitant opioid use
• Potential for paradoxical reactions (excitement, agitation)
• Risk of hypotension, particularly in hemodynamically compromised patients
• Potential for prolonged sedation in elderly, debilitated patients, or those with hepatic impairment
• Risk of withdrawal symptoms with abrupt discontinuation after prolonged use
• Potential for drug dependence and abuse

Drug Interactions

• Opioids: Additive CNS and respiratory depression
• CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir): Significantly increased midazolam levels
• Alcohol: Enhanced sedative effects
• Other CNS depressants (antipsychotics, antidepressants, anticonvulsants): Additive sedation
• Protease inhibitors: Contraindicated due to profound CYP3A4 inhibition

• Calcium channel blockers: Possible increased midazolam effects
• Grapefruit juice: Inhibits metabolism, increasing bioavailability

Adverse Effects

• Respiratory depression (dose-related)
• Hypotension
• Nausea/vomiting
• Hiccups
• Headache
• Drowsiness, sedation
• Paradoxical reactions (agitation, restlessness)

• Apnea requiring ventilation support
• Cardiovascular collapse
• Laryngospasm
• Anaphylaxis
• Severe hypotension
• Prolonged sedation
• Withdrawal syndrome

Monitoring Parameters

• Respiratory rate, oxygen saturation (continuous monitoring during administration)
• Blood pressure and heart rate (frequent monitoring)
• Level of consciousness/sedation scores (e.g., Richmond Agitation-Sedation Scale)
• ECG in patients with cardiac risk factors
• Signs of paradoxical reactions
• Signs of withdrawal after prolonged use
• Hepatic and renal function in long-term use

Patient Education

• This medication will cause drowsiness and impair cognitive function - do not operate machinery or drive for at least 24 hours
• Avoid alcohol and other CNS depressants for 24 hours after administration
• The medication may cause temporary memory loss of events during and after administration
• Report any unusual reactions including agitation, restlessness, or breathing difficulties
• Use reliable contraception during treatment (for women of childbearing potential)
• Do not breastfeed for at least 4 hours after single use or until completely alert
• Inform all healthcare providers about midazolam use before any procedures

References

1. Midazolam hydrochloride injection prescribing information. US Food and Drug Administration. 2. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. 3. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57(5):449-461. 4. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. 5. Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. CMAJ. 1999;160(5):649-655. 6. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology. 2002;96(4):1004-1017.