Chemical formula: C₁₈H₁₃ClFN₃ Molecular mass: 325.767 g/mol PubChem compound: 4192
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 midazolam to form the hydrochloride salt with acids.
The pharmacological action of midazolam is characterised by short duration because of rapid metabolic transformation. Midazolam has a 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 remember events that occurred during the maximal activity of the compound).
After oromucosal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes in children. The absolute bioavailability of oromucosal midazolam is about 75% in adults. The bioavailability of oromucosal midazolam has been estimated at 87% in children with severe malaria and convulsions.
Absorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 minutes. The absolute bioavailability after i.m. injection is over 90%.
Midazolam is highly lipophilic and distributes extensively. The steady state volume of distribution following oromucosal administration is estimated to be 5.3 l/kg.
Approximately 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.
When midazolam is injected i.v., 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.
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-hydroxy-midazolam. Following oromucosal administration in children the area under the curve ratio for alpha-hydroxy midazolam to midazolam is 0.46.
In a population pharmacokinetic study, the metabolite levels are shown to be higher in younger than older paediatric patients and thus likely to be of more importance in children than in adults.
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.
Plasma clearance of midazolam in children following oromucosal administration is 30 ml/kg/min. The initial and terminal elimination half-lives are 27 and 204 minutes, respectively. Midazolam is excreted mainly by the renal route (60-80% of the injected dose) and recovered as glucuroconjugated alphahydroxy-midazolam. Less than 1% of the dose is recovered in urine as unchanged medicinal product.
In healthy volunteers, the elimination half-life of midazolam is between 1.5 – 2.5 hours. Plasma clearance is in the range of 300 – 500ml/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 i.v. infusion, its elimination kinetics do not differ from those following bolus injection.
In adults over 60 years of age, the elimination half-life may be prolonged up to four times.
The elimination half-life after i.v. 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.
In neonates the elimination half-life is on average 6 – 12 hours, probably due to liver immaturity and the clearance is reduced.
The mean half-life is greater in obese than in non-obese patients (5.9 versus 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.
The elimination half-life in cirrhotic patients may be longer and the clearance lower as compared to those in healthy volunteers.
The elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.
The elimination half-life of midazolam is prolonged up to six times in the critically ill.
The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects.
Simulated exposure data show that the overall AUC approximately doubles when a second dose is administered at 10, 30 and 60 minutes following the first dose. A second dose at 10 minutes results in a significant increase in mean Cmax of between 1.7 to 1.9 fold. At 30 and 60 minutes, significant elimination of midazolam has already occurred and therefore the increase in mean Cmax is less pronounced; 1.3 to 1.6 and 1.2 to 1.5 fold respectively.
In a rat fertility study, animals dosed up to ten times the clinical dose, no adverse effects on fertility were observed.
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