Which statement about midazolam pharmacokinetics is true in patients with severe hepatic impairment?

• A. The duration of action is shortened due to faster clearance
• B. Metabolism is unaffected in hepatic impairment
• C. Sedation duration can be prolonged due to accumulation of active metabolites in hepatic impairment
• D. Onset is significantly delayed, but duration remains short

Answer: (C)

In severe liver disease, midazolam’s clearance falls because its metabolism depends on hepatic enzymes (CYP3A4) to form active metabolites like 1-hydroxymidazolam. When the liver is impaired, both the parent drug and its active metabolite are cleared more slowly, so they accumulate. This prolongs the sedative effect beyond what you’d expect in a normal liver. The onset after IV administration remains rapid due to midazolam’s lipophilicity, but the duration of action is extended because the active metabolites stick around longer. So sedation can be prolonged in hepatic impairment due to accumulation of these active metabolites, rather than faster clearance, unchanged metabolism, or delayed onset with short duration.