Pharmacology: Pharmacodynamics: Midazolam, is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic substance with low solubility in water. The basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables the active ingredient of midazolam injection to form water-soluble salts with acids.
The pharmacological action of midazolam is characterized by rapid onset and, because of rapid metabolic transformation, short duration. Because of its low toxicity, midazolam has a wide therapeutic range.
Midazolam injection has a very rapid sedative and sleep-inducing effect of pronounced intensity. It also exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect.
After i.m. or i.v. administration anterograde amnesia of short duration occurs (the patient does not recall events that occurred during the peak of activity of the compound).
Pharmacokinetics: Absorption after IM injection: Absorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 minutes. The absolute bioavailability after IM injection is over 90%.
Absorption after rectal administration: After rectal administration midazolam is absorbed quickly. Maximum plasma concentration is reached in about 30 minutes. The absolute bioavailability is about 50%.
Distribution: When midazolam is injected IV, the plasma concentration-time curve shows one or two distinct phases of distribution. The volume of distribution at steady state is 0.7-1.2 l/kg. 96-98 % of midazolam is bound to plasma proteins. The major fraction of plasma protein binding is due to albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation. Small quantities of midazolam are found in human milk.
Biotransformation: Midazolam is almost entirely eliminated by biotransformation. The fraction of the dose extracted by the liver has been estimated to be 30-60%. Midazolam is hydroxylated by the cytochrome P4503A4 isozyme and the major urinary and plasma metabolite is alpha-hydroxymidazolam. Plasma concentrations of alpha-hydroxymidazolam are 12% of those of the parent compound. Alpha-hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam.
Elimination: In healthy volunteers, the elimination half-life of midazolam is between 1.5-2.5 hours. Plasma clearance is in the range of 300-500 ml/min. Midazolam is excreted mainly by renal route (60-80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxymidazolam. Less than 1 % of the dose is recovered in urine as unchanged drug. The elimination half-life of alpha-hydroxy-midazolam is shorter than 1 hour. When midazolam is given by IV infusion, its elimination kinetics do not differ from those following bolus injection.
Pharmacokinetics in special populations: Elderly: In adults over 60 years of age, the elimination half-life may be prolonged up to four times.
Children: The rate of rectal absorption in children is similar to that in adults but the bioavailability is lower (5-18%). The elimination half-life after IV and rectal administration is shorter in children 3-10 years old (1-1.5 hours) as compared with that in adults. The difference is consistent with an increased metabolic clearance in children.
Neonates: In neonates the elimination half-life is on average 6-12 hours, probably due to liver immaturity and the clearance is reduced.
Obese: The mean half-life is greater in obese than in non-obese patients (5.9 vs 2.3 hours). This is due to an increase of approximately 50% in the volume of distribution corrected for total body weight. The clearance is not significantly different in obese and non-obese patients.
Patients with hepatic impairment: The elimination half-life in cirrhotic patients may be longer and the clearance smaller as compared to those in healthy volunteers.
Patients with renal impairment: The elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.
Critically ill patients: The elimination half-life of midazolam is prolonged up to six times in the critically ill.
Patients with cardiac insufficiency: The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects.