Мидазолам: Қолданысы, қасиеттері және ескертулер

Benzodiazepine used for anesthesia and procedural sedation

Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organization's List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus or when intravenous access cannot be obtained, and has advantages of being water soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines. Drawbacks include a high degree of breakthrough seizures—due to the short half life of midazolam—in over 50% of people treated, as well as treatment failure in 14–18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half life may increase, up to days. Buccal and intranasal midazolam may be both easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), preoperative sedation, for the induction of general anesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half life, combined with its water solubility and its suitability for continuous infusion. However, for long term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation. Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication. Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.

Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out of control behaviour.

In the final stages of end of life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.

Routes of administration of midazolam can be oral, intranasal, buccal, intravenous, and intramuscular. +DosingPerioperative use0.15 to 0.40 mg/kg IVPremedication0.07 to 0.10 mg/kg IMIntravenous sedation0.05 to 0.15 mg/kg IV

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol or other drug dependent individuals or those with comorbid psychiatric disorders. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

Side effects of midazolam in the elderly are listed above. Long term use of benzodiazepines has been associated with long lasting deficits in memory, and show only partial recovery six months after stopping benzodiazepines. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnea becomes more likely. Although the incidence of respiratory depression/arrest is low (0.1–0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhea or vomiting). Breastfeeding by mothers using midazolam is not recommended.

Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls. Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhea, tachycardia, hypertension, and tachypnea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus.

Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John's wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. St John's wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.

Midazolam is a short acting benzodiazepine in adults with an elimination half life of 1.5–2.5 hours. In the elderly, as well as young children and adolescents, the elimination half life is longer. Midazolam is metabolised into an active metabolite alpha hydroxymidazolam. Age related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10% of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream. The half life (t1/2) of midazolam in HLM is 3.3 minutes.

Midazolam is among about 35 benzodiazepines currently used medically, Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. as of 2010, it is the most commonly used benzodiazepine in anesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using midazolam as a "truth serum" on terrorist suspects in project "Medication".

Midazolam is available as a generic medication. Dormicum brand midazolam is marketed by Roche as white, oval, 7.5 mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15 mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with "Roche" on one side and the dose of the tablet on the other side. Dormicum is also available as 1, 3, and 10 mL ampoules at a concentration of 5 mg/mL. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3 and 5 mL ampoules. Midazolam is the only water soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, midazolam HCl Syrup, 2 mg/mL clear, in a red to purplish red syrup, cherry in flavor. It becomes soluble when the injectable solution is buffered to a pH of 2.9–3.7. Midazolam is also available in liquid form. intrathecally, intranasally, or orally. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non narcotic agent with low potential for abuse.

In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the brand name Buccolam. Buccolam was initially approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric use marketing authorisation.

The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latter's manufacturer disallowed that drug's use for executions. Midazolam acts as a sedative but will fail to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner's breathing and heart, respectively. Since the condemned prisoner is not rendered unconscious but is merely sedated, the administration of vecuronium bromide and potassium chloride can cause extreme pain and panic in the person being executed. Midazolam has been used as part of a three drug cocktail, with vecuronium bromide and potassium chloride, in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two drug protocol in Ohio and Arizona. The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three drug lethal injection combination using 100mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Lockett's vein had ruptured. It is not clear whether his death was caused by one or more of the drugs or by a problem in the administration procedure, nor is it clear what quantities of vecuronium bromide and potassium chloride were released to his system before the execution was cancelled. According to news reports, the execution of Ronald Bert Smith in the state of Alabama on 8 December 2016 went awry soon after midazolam was administered, again putting the effectiveness of the drug in question. On 26 July 2017, Ronald Phillips was executed with a three drug cocktail including midazolam after the Supreme Court refused to grant a stay. Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Otte's lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017. On 24 April 2017, the state of Arkansas carried out a double execution, of Jack Harold Jones, 52, and Marcel Williams, 46. Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017. On 28 October 2021, the state of Oklahoma executed inmate John Marion Grant, 60, using midazolam as part of its three drug cocktail hours after the U. S. Supreme Court ruled to lift a stay of execution for Oklahoma death row inmates. The execution was the state's first since 2015. Witnesses to the execution said that when the first drug, midazolam, began to flow at 4:09p. m., Grant started convulsing about two dozen times and vomited. Grant continued breathing, and a member of the execution team wiped the vomit off his face. At 4:15p. m., officials said Grant was unconscious, and he was pronounced dead at 4:21p. m.

In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the U. S. Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives. The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.