Diazepam IV is a highly lipid-soluble benzodiazepine with a more prolonged duration of action compared with midazolam.
Diazepam IV is dissolved in organic solvents (propylene glycol, sodium benzoate) because it is insoluble in water. Dilution with water or saline causes cloudiness but does not alter the potency of the drug. Injection by either the IM or IV route may be painful.
Cimetidine inhibition of oxidative enzyme function impairs the clearance of diazepam IV, but it has no effect on lorazepam.
Age decreases and smoking increases the clearance of diazepam IV, but neither has a significant effect on midazolam biotransformation.
Habitual alcohol consumption increases the clearance of midazolam. Race, because of differences in isoenzymes responsible for hydroxylations, produces genetic differences in drug metabolism.
The high frequency of mutated alleles in Asians in the genes coding for CYP2C19 may explain the reduced hepatic biotransformation of diazepam.
The metabolites of the benzodiazepines can be important. Diazepam IV forms two active metabolites, oxazepam and desmethyldiazepam, which add to and prolong the drug’s effects.
Patients given continuous infusions of midazolam or repeated boluses over days should awaken faster than patients given diazepam IV or lorazepam.
Factors that may influence the pharmacokinetics of benzodiazepines are age, gender, race, enzyme induction, and hepatic and renal disease. Diazepam is sensitive to some of these factors, particularly age.
Increasing age tends to reduce the clearance of diazepam significantly and the clearance of midazolam to a lesser degree.
The binding of benzodiazepines to their respective receptors is of high affinity and is stereospecific and saturable; the order of receptor affinity (potency) of the three agonists is lorazepam > midazolam > diazepam. Midazolam is approximately 3 to 6 times, and lorazepam 5 to 10 times, as potent as diazepam IV.