Midazolam

Absorption

Intramuscular
Following IM administration of a single 10 mg midazolam dose to healthy subjects, midazolam was absorbed with median Tmax (range) of 0.5 (0.25 to 0.5) hours; midazolam's mean (±SD) Cmax and AUC0-∞ were 113.9 (±30.9) ng/mL and 402.7 (±97.0) ng?h/mL, respectively.
Rectal
After rectal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes. The absolute bioavailability is approximately 50%.
Intranasal Administration
Following the nasal administration of a single 5 mg midazolam dose to healthy adults, midazolam was absorbed with a median Tmax (range) of 17.3 (7.8 to 28.2) minutes; midazolam's mean (±SD) Cmax and AUC0-∞ were 54.7 (±30.4) ng/mL and 126.2 (±59) ng?h/mL, respectively. The mean absolute bioavailability is approximately 44%.
Oral
In pediatric patients from 6 months to <16 years old, the mean Tmax values across dose groups (0.25, 0.5, and 1.0 mg/kg) range from 0.17 to 2.65 hours. Midazolam also exhibits linear pharmacokinetics within this dose range (up to a maximum dose of 40 mg). Linearity was also demonstrated across the doses within the age group of 2 years to <12 years having 18 patients at each of the three doses. Due to first-pass metabolism, only 40-50% of the administered oral dose reaches the circulation. The absolute bioavailability of midazolam is about 36%, which is not affected by pediatric age or weight. Cmax and AUC0-∞ were also calculated to range from 28 to 201 ng/mL and 67.6 to 821 ng?h/mL respectively.
Buccal
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. Cmax and AUC0-∞ were also calculated to range from 87 to 148 ng/mL and 168 to 254 ng?h/mL respectively.

Toxicity

LD50=215 mg/kg, in rats.
Overdose
Signs of overdose include sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and deleterious effects on vital signs. Serious cardiorespiratory adverse reactions have occurred, sometimes ending in death or permanent neurologic effects, after the administration of midazolam.
A note on cardiac and respiratory depression
After administration of midazolam, continuous monitoring of respiratory and cardiac function is recommended until the patient is in stable condition. Serious and life-threatening cardiorespiratory adverse reactions, including hypoventilation, airway obstruction, apnea, and hypotension have been reported with the use of midazolam. Patients should be monitored in a setting with immediate access to resuscitative drugs if they are required. Resuscitation equipment and personnel trained in their use and skilled in airway management should be available when midazolam is administered.
The usual recommended intramuscular pre-medicating doses of midazolam do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults. Intravenous induction doses of midazolam depress the ventilatory response to carbon dioxide stimulation for at least 15 minutes longer than the duration of ventilatory depression following administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more severe in adult patients diagnosed with chronic obstructive pulmonary disease (COPD).
A note on dependence
When midazolam is used in long-term sedation in the ICU (intensive care unit) or other settings, physical dependence on midazolam may develop. The risk of dependence increases with dose and duration of treatment; this risk is also greater in patients with a medical history of substance abuse.
Special caution should be exercised when administering midazolam in the following populations
High-risk patients include adults over 60 years of age, chronically ill or debilitated patients, which may include patients with chronic respiratory insufficiency, patients with chronic renal failure, impaired hepatic function or with impaired cardiac function, pediatric patients (especially those with cardiovascular instability). These high-risk patients require lower dosages and should be monitored on a continuous basis for early signs of alterations of vital functions, so that appropriate management may be administered.
Mutagenesis
Midazolam was negative for genotoxicity during in vitro and in vivo assays.
Impairment of Fertility
When midazolam (0, 1, 4, or 16 mg/kg) was given orally to male and female rats before and during mating and continuing in females throughout gestation and lactation, no adverse effects on male or female fertility were observed. Midazolam plasma exposures (AUC) at the highest dose tested were approximately 6 times that in humans at the recomended human dose.

Description

Midazolam is a short-acting, rapid-onset benzodiazepine central nervous system depressant patented by Hoffmann-La Roche in 1976. In 1978, A. Walser and co-workers at the same company?published its synthesis. (The article was the 84th in a series on quinazolines and 1,4-benzodiazepines!) In the United States, midazolam is best known by its trade name Versed.
Midazolam is or has been used as an anesthetic, sedative, seizure medication, and insomnia treatment. Its short elimination half-life makes it useful in intensive care units. Its main adverse effects occur when it is used in children, the elderly, and patients in poor health. After midazolam has been used for extensive periods, patients who are taken off the medication may experience symptoms of withdrawal.

Description

Midazolam is the most commonly used parenteral sedative in anaesthetic practice. The structure of midazolam is altered by local changes in pH (tautomerism), and the two different forms confer either water or lipid solubility to the drug . At pH<4 the benzodiazepine nucleus opens because of an ionisable amine group in the molecule's structure, and this increases water solubility. At plasma pH the amine group is incorporated back into the unionised ring form of the molecule, which is highly lipid soluble and diffuses rapidly into the brain. A concentrated preparation (5mgml ?1 ) is available for i.m. injection and absorption is rapid compared with diazepam.

Chemical properties

White Crystaline Solid

Originator

Dormicum,Roche,Switz.,1982

The Uses of Midazolam

In many countries this product is controlled. An import permit may be required. Anesthetic; anticonvulsant; sedative; hypnotic

The Uses of Midazolam

Anti-Depressant

Background

Midazolam is a short-acting hypnotic-sedative drug with anxiolytic, muscle relaxant, anticonvulsant, sedative, hypnotic, and amnesic properties. It belongs to a class of drugs called benzodiazepines. This drug is unique from others in this class due to its rapid onset of effects and short duration of action. Midazolam is available by oral, rectal, intranasal, intramuscular (IM), and intravenous (IV) routes and has been used in various biomedical applications, including dentistry, cardiac surgery, and endoscopic procedures as pre-anesthetic medication, and as an adjunct to local anesthesia.
This drug was initially approved by the US FDA in 1985, and has been approved for various indications since. In late 2018, the intramuscular preparation was approved by the FDA for the treatment of status epilepticus in adults. In May 2019, the nasal spray of midazolam was approved for the acute treatment of distinctive intermittent, stereotypic seizure episodes in patients 12 years of age and older. Midazolam is considered a schedule IV drug in the United States due to the low potential for abuse and low risk of dependence.

Indications

Midazolam has different indications depending on its formulation by the FDA.
Nasal
For the nasal spray formulation, midazolam is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older.
Intravenous
For the intravenous injection formulation, midazolam is indicated as an agent for sedation/anxiolysis/amnesia and prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants. The sedative, anxiolytic and amnestic use of midazolam can also be employed pre-operatively. It can also be indicated for induction of general anesthesia, before administration of other anesthetic agents or as a component of intravenous supplementation of nitrous oxide and oxygen for a balanced anesthesia. A relatively narrower dose range of midazolam and a shorter period of induction can be achieved if midazolam is combined with narcotic premedication. Finally, midazolam can be indicated as a continous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.
Intramuscular
For the intramusuclar injection formulation, midazolam is indicated for preoperative sedation/anxiolysis/amnesia or for treatment of status epilepticus in adults.
Oral
Midazolam syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia. It is only approved in monitored settings only and not for chronic or home use.
In Europe, a buccal formulation of midazolam is also approved for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to < 18 years). For infants between 3-6 months of age treatment should be in a hospital setting where monitoring is possible and resuscitation equipment is available.

Definition

ChEBI: Midazolam is an imidazobenzodiazepine that is 4H-imidazo[1,5-a][1,4]benzodiazepine which is substituted by a methyl, 2-fluorophenyl and chloro groups at positions 1, 6 and 8, respectively. It has a role as a GABAA receptor agonist, an anticonvulsant, an anxiolytic drug, an apoptosis inducer, an antineoplastic agent, a muscle relaxant, a sedative, a general anaesthetic and a central nervous system depressant. It is an organochlorine compound, an imidazobenzodiazepine and a member of monofluorobenzenes.

Manufacturing Process

Acetic anhydride (7 ml) was added to a solution of 6.16 g of crude 2- aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was added to 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate, dried over sodium sulfate and evaporated to leave resinous 2- acetylaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH -l,4- benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150°C for 10 minutes. The cooled reaction mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue was chromatographed over 120 g of silica gel using 20% methanol in methylene chloride. The clean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1- methyl-4H-imidazo[1,5-a][1,4] - benzodiazepine.
A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1? hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1,5-a][1,4]benzodiazepine, melting point 152°C to 154°C. The analytical sample was recrystallized from methylene chloride/hexane.
A warm solution of 6.5 g (0.02 mol) of 8-chloro-6-(2-fluorophenyl)-1-methyl- 4H-imidazo[1,5-a] [1,4]-benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1.5-a] [1,4]-benzodiazepine maleate, melting point 148°C to 151°C.

brand name

Versed (Roche).

Therapeutic Function

Anesthetic

General Description

Midazolam is a benzodiazepine, sold as Dormicum, Hypnovel^?, and Versed as a sedative and treatment for insomnia and seizures. This Snap-N-Spike^? Reference Solution is suitable for many GC/MS or LC/MS applications from clinical toxicology and urine drug testing to pain prescription monitoring or forensic analysis.

Pharmacokinetics

General effects
Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepine drugs, include sedative, anxiolytic, amnestic, muscle relaxant, as well as hypnotic activities. Benzodiazepines enhance the inhibitory action of the amino acid neurotransmitter gamma-aminobutyric acid (GABA). Receptors for GABA are targeted by many important drugs that affect GABA function and are commonly used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, and aggressive behavior.
Sedation and memory
The onset of sedation after intramuscular administration in adults is 15 minutes, with maximal sedation occurring 30-60 minutes after injection. In one study of adults, when tested the following day, 73% of the patients who were administered midazolam intramuscularly had no recollection of memory cards shown 30 minutes following drug administration; 40% had no recollection of the memory cards shown 60 minutes after drug administration. Onset time of sedative effects in pediatric patients begins within 5 minutes and peaks at 15-30 minutes depending upon the dose administered. In the pediatric population, up to 85% had no memory of pictures shown after receiving intramuscular midazolam compared to 5% of the placebo control group.
Sedation in both adult and pediatric patients is reached within 3 to 5 minutes post intravenous (IV) injection. The time of onset is affected by the dose administered and the simultaneous administration of narcotic pre-medication. Seventy-one (71%) percent of the adult patients in clinical endoscopy studies had no memory of insertion of the endoscope; 82% of the patients had no memory of withdrawal of the endoscope.
Anesthesia induction
When midazolam is administered intravenously (IV) for anesthetic induction, induction of anesthesia occurs in about 1.5 minutes when narcotic pre-medication has been given and in 2 to 2.5 minutes without narcotic pre-medication/ other sedative pre-medication. Impairment in a memory test was observed in 90% of the patients.

Pharmacokinetics

Midazolam undergoes hepatic oxidative metabolism and has an elimination half-life of 2–4h. The major metabolite is 1-hydroxymidazolam, which is biologically active. Midazolam has been used as a sole hypnotic for TI VA and produces superior procedural amnesia compared with propofol, but CSHT increases significantly when used by continuous infusion, and this delays recovery. Clinical studies demonstrate the inferiority of midazolam in terms of time to onset of desired sedation score, slower recovery, less clear-headedness, and significantly longer period of postoperative amnesia compared with propofol.

Clinical Use

Benzodiazepine:
Sedation with amnesia in conjunction with local anaesthesia, premedication, induction
Status epilepticus (unlicensed)

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by erythromycin, clarithromycin and telithromycin (profound sedation); metabolism possibly accelerated by rifampicin.
Antidepressants: concentration of oral midazolam possibly reduced by St John’s wort.
Antifungals: concentration increased by itraconazole, fluconazole, ketoconazole, posaconazole and voriconazole (prolonged sedative effect).
Antipsychotics: increased sedative effects; increased risk of hypotension, bradycardia and respiratory depression when parenteral benzodiazepines are given with IM olanzapine.
Antivirals: concentration increased by atazanavir, boceprevir, efavirenz, indinavir, fosamprenavir, ritonavir, saquinavir and telaprevir increase risk of prolonged sedation; avoid with oral midazolam.
Ciclosporin: in vitro studies suggested that ciclosporin could inhibit the metabolism of midazolam. However, blood ciclosporin concentrations in patients given ciclosporin to prevent graft rejection were considered too low to result in an interaction.
Cobicistat: avoid with oral midazolam.
Cytotoxics: concentration increased by crizotinib and nilotinib; concentration reduced by enzalutamide.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.

Metabolism

In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by the cytochrome P450-3A4 (CYP3A4). This enzyme is present in gastrointestinal tract mucosa, as well as in the liver. The 1-hydroxy-midazolam (also termed alpha-hydroxymidazolam) metabolite comprises 60% to 70% of the biotransformation products of midazolam, while 4-hydroxy-midazolam constitutes 5% or less. Small amounts of a dihydroxy derivative have also been detected, but not quantified. Midazolam also undergoes N-glucuronidation via UGT1A4 after the process of hepatic oxidation by cytochrome enzymes.
Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxymidazolam is at least as potent as the parent compound, and may contribute to the net pharmacologic activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam.

Metabolism

Metabolised in the liver via the cytochrome P450 isoenzyme CYP3A4. The major metabolite, alpha hydroxymidazolam has some activity; its half-life is less than 1 hour. Midazolam metabolites are excreted in the urine, mainly as glucuronide conjugates.