Dormicum Mechanism of Action

Therapeutic/Pharmacologic Class of Drug: Pharmacotherapeutic group: Hypnotics and sedatives: benzodiazepine derivatives. ATC code: N05CD08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Midazolam (Dormicum) has a hypnotic and sedative effect characterized by a rapid onset and short duration of action. It also exerts anxiolytic, anticonvulsant and muscle-relaxant effects. Midazolam (Dormicum) impairs psychomotor function after single and/or multiple doses but causes minimal hemodynamic changes.
The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines, the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.
Solution for injection: Chemically midazolam is a derivative of the imidazobenzodiazepine group. Although 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 (Dormicum) to form water‑soluble salts with acids. This together with rapid metabolic transformation are the reasons for rapid onset and short duration of effects. Because of its low toxicity, midazolam has a wide therapeutic range.
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).
Clinical/Efficacy Studies: No text.
Pharmacokinetics: Absorption: Film-coated tablet: Midazolam is absorbed rapidly and completely after oral administration.
Due to the substantial first-pass effect, the absolute bioavailability of oral midazolam ranges 30-70%. Midazolam exhibits linear pharmacokinetics following oral doses of 7.5-20 mg.
After a single administration of a Midazolam (Dormicum) 15 mg tablet, maximum plasma concentrations of 70-120 ng/mL are reached within one hour. Food prolongs the time to peak plasma concentration by around one hour, pointing to a reduced absorption rate of midazolam. The absorption half-life is 5-20 minutes.
Solution for injection: Absorption after I.M. injection: 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%.
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: Film-coated tablet: The tissue distribution of midazolam is very rapid and in most cases a distribution phase is not apparent or is essentially completed within 1-2 hours after oral administration.
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 cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter fetal circulation. Small quantities of midazolam are found in human milk. Midazolam is not a substrate for drug transporters.
Solution for injection: When midazolam is injected I.V., the plasma concentration‑time curve shows one or two distinct disposition phases. 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 binding protein is 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 fetal circulation. Small quantities of midazolam are found in human milk. Midazolam is not a substrate for drug transporters.
Metabolism: Film-coated tablet: Midazolam is almost entirely eliminated by biotransformation. Midazolam is hydroxylated by Cytochrome P450, CYP3A isozymes. Both isozymes, CYP3A4 and also CYP3A5 are actively involved in the two key pathways for the hepatic oxidative metabolism of midazolam. The metabolism of midazolam after oral administration relies to a comparable extent on intestinal CYP3A and on hepatic CYP3A.
There are two main oxidized metabolites 1'-hydroxymidazolam (also named α-hydroxymidazolam) and 4-hydroxymidazolam. 1'-hydroxymidazolam is the major urinary and plasma metabolite. Plasma concentrations of 1'-hydroxymidazolam may reach 30-50% those of the parent compound. 1'-hydroxymidazolam is pharmacologically active and contributes significantly (about 34%) to the effects of oral midazolam.
Solution for injection: Midazolam is almost entirely eliminated by biotransformation. Midazolam is hydroxylated by the cytochrome P450, CYP3A4 and CYP3A5 isozymes and the major urinary and plasma metabolite is 1'-hydroxymidazolam (also known as α-hydroxymidazolam). Plasma concentrations of 1'-hydroxymidazolam are 12% of those of the parent compound. 1'-hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam.
Elimination: Film-coated tablet: In young healthy volunteers, the elimination half-life of midazolam ranges from 1.5 to 2.5 hours. The elimination half-life of 1'-hydroxymidazolam is shorter than 1 hour; therefore after midazolam administration the concentration of the parent compound and the main metabolite decline in parallel. Less than 1% of the dose is recovered in urine as unchanged drug. 60-80% of the dose is glucuronidated and excreted in the urine in the form of 1'-hydroxymidazolam conjugate. Midazolam is a non-accumulating drug when given once daily. Repeated administrations of midazolam do not induce drug-metabolizing enzymes.
Solution for injection: In young healthy volunteers, the elimination half‑life of midazolam ranges from 1.5 to 2.5 hours. The elimination half-life of the metabolite is shorter than 1 hour; therefore after midazolam administration the concentration of the parent compound and the main metabolite decline in parallel. Plasma clearance of midazolam is in the range of 300‑500 mL/min. Midazolam's metabolites are excreted mainly by the renal route: 60-80% of the dose is excreted in urine as glucuroconjugated 1'-hydroxymidazolam. Less than 1% of the dose is recovered in urine as unchanged drug.
When midazolam is given by I.V. infusion, its elimination kinetics do not differ from those following bolus injection. Repeated administrations of midazolam do not induce drug-metabolizing enzymes.
Pharmacokinetics in Special Populations: Film-coated tablet: Elderly: In elderly male subjects over 60 years of age, the elimination half‑life of midazolam was significantly prolonged by a factor 2.5 as compared with younger male subjects. Total midazolam clearance was significantly reduced in male elderly subjects and the bioavailability of the oral tablet was significantly increased. However, no significant differences were observed in elderly female compared to younger subjects.
Patients with hepatic impairment: The pharmacokinetics of midazolam were significantly modified in patients with chronic liver disease including advanced liver cirrhosis. In particular, as a consequence of a decreased liver clearance, the elimination half-life was prolonged and the absolute bioavailability of oral midazolam was significantly increased in cirrhotic patients compared to control.
Patients with renal impairment: The pharmacokinetics of unbound midazolam are not altered in patients with severe renal impairment.
The pharmacologically mildly active major midazolam metabolite, 1'-hydroxymidazolam glucuronide, which is excreted through the kidney, accumulates in patients with severe renal impairment. This accumulation produces a prolonged sedation. Oral midazolam should therefore be administered carefully and titrated to the desired effect (see Special Dosage Instructions under Dosage & Administration).
Obese patients: In obese patients, the volume of distribution of midazolam is increased. As a consequence, the mean elimination half-life of midazolam is longer in obese than in non-obese patients (5.9 hours vs 2.3 hours). The oral bioavailability of the midazolam tablet was not different in obese patients compared to non-obese patients.
Solution for injection: Elderly: In adults over 60 years of age, the elimination half‑life may be prolonged up to four times. See General and Use in the Elderly under Precautions.
Children: The rate of rectal absorption in children is similar to that in adults but the bioavailability is lower (5-18%). However, the elimination half-life (t_1/2) after I.V. and rectal administration is shorter in children 3-10 years as compared with that in adults (1-1.5 hr). The difference is consistent with an increased metabolic clearance in children. See General and Use in Children under Precautions.
Newborn: In preterm and term newborn infants, the elimination half-life is on average 6-12 hours, probably due to liver immaturity and the clearance is reduced.
Neonates with asphyxia-related hepatic and renal impairment are at risk of generating unexpectedly high serum midazolam concentrations due to a significantly decreased and variable clearance. See General under Precautions.
Obese: The mean half-life is greater in obese than in non-obese patients (8.4 vs 2.7 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 clearance in cirrhotic patients may be reduced and the elimination half-life may be longer when compared to those in healthy volunteers. See General under Precautions.
Patients with renal impairment: The pharmacokinetics of unbound midazolam are not altered in patients with severe renal impairment. The pharmacologically mildly active major midazolam metabolite, 1'-hydroxy-midazolam glucuronide, which is excreted through the kidney, accumulates in patients with severe renal impairment. This accumulation produces a prolonged sedation. Midazolam should therefore be administered carefully and titrated to the desired effect. See General and Use in Special populations: Renal impairment under Precautions.
Critically ill patients: The elimination half-life of midazolam is prolonged in the critically ill. See General under Precautions.
Patients with cardiac insufficiency: The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects. See General under Precautions.
Toxicology: Preclinical Safety: Solution for injection: There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the monograph.
Carcinogenicity: No text.
Mutagenicity: No text.
Impairment of Fertility: No text.
Teratogenicity: No text.
Other: No text.