Midazolam

Midazolam is one of the 35 benzodiazepines that are currently used in medical practice. ^[13] It was synthesized in 1976 by Walser and Fryer at Hoffmann – La Roche in the United States. ^[14] It was found that due to its solubility in water, midazolam causes thrombophlebitis less frequently than similar drugs. ^{[15] [16]} In the same year, the benzodiazepine drug alprazolam was synthesized from midazolam ^{[17] [18]} and was introduced to the US pharmacological market in 1981. ^{[19] The} anticonvulsant properties of midazolam were studied in the late 1970s, but it was not used until the 1990s until its effectiveness in treating convulsive status epilepticus was revealed. ^[20] As of 2010, it is the most commonly used benzodiazepine in anesthesiology. ^[21] In critical state medicine, midazolam is becoming more popular than other benzodiazepines, such as lorazepam and diazepam, because it is of shorter action, is more powerful and causes less pain at the injection site. ^[13] Midazolam is also becoming increasingly popular in veterinary medicine due to its solubility in water. ^[22]

Midazolam is indicated intravenously for sedation (often in combination with an opioid , such as fentanyl ), as well as for premedication in the preoperative period, for the induction of anesthesia and for sedation of patients with mechanical ventilation in the intensive care unit. ^{[9] [10]} Midazolam is superior to diazepam in memory depression in endoscopic procedures, but propofol has a faster recovery time and has a better memory inhibition effect. ^[8] This is the most popular benzodiazepine in the intensive care unit (ICU) because of its short half-life combined with its solubility in water and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferable because of its long duration of action ^[23] and propofol has advantages over midazolam when used in ICU for sedation in cases of short excommunication and early tracheal extubation. ^[24] It has been proven that intrabuccal (absorption through the cheeks) and intranasal (through the nose) administration of midazolam is easier and more effective than rectal administration of diazepam in controlling seizures. ^{[25] [26] [27]} Patients with incurable pathologies may be given midazolam subcutaneously in low doses in the last hours or days of life to reduce arousal, myoclonus , anxiety or anxiety. ^[28] The use of higher doses of midazolam during the last weeks of life is considered preferred in palliative therapy for continuous and deep sedation, when it is necessary to alleviate the patient's unbearable suffering with the ineffectiveness of other methods of treatment; ^[29] but the need for this is rarer. ^[30] Midazolam is also sometimes used in newborns who have mechanical ventilation, but morphine is preferable in this situation, since it is safer. ^[31]

Midazolam is indicated orally for the short-term treatment of moderately severe insomnia in patients in whom other sleeping pills have been found to be ineffective and who constantly have trouble falling asleep. Since midazolam has an extremely short duration of action, it is not prescribed for patients who have problems staying in sleep all night; in such situations, medium and long-acting benzodiazepines are used ( temazepam , nitrazepam , flunitrazepam ).

Available in the form of maleate and hydrochloride. In structure and action, it is close to benzodiazepine tranquilizers . It has a calming, anticonvulsant, muscle relaxant effect, enhances the effect of sleeping pills, drugs, analgesics.

A characteristic feature of midazolam is a pronounced hypnotic (hypnotic) effect, in connection with which the drug is used mainly in anesthetic practice for sedation, anesthesia and maintenance of anesthesia.

Midazolam is administered intravenously and intramuscularly. The drug does not last long. For premedication, midazolam is administered 20-30 minutes before anesthesia intramuscularly at 0.05-0.1 mg / kg. It can be used alone or in combination with anticholinergics and analgesics.

For anesthesia, they are administered intravenously for 15 minutes at the rate of 0.15-0.25 mg / kg, together with analgesics. To maintain anesthesia, additional doses are administered. Midazolam and ketamine can be combined.

With the intravenous administration of midazolam, respiratory depression may develop, therefore its use is allowed only if ventilation is possible.

Midazolam should not be used for severe myasthenia gravis, circulatory failure, in the first 3 months. pregnancy.

15 mg midazolam tablets are also available, used as a tranquilizing and sleeping pill and for sedation.

Benzodiazepines require caution when used in the elderly, pregnant women, children, people with alcohol or drug addiction, as well as patients with concomitant mental disorders . ^[32] Extra caution is required in critically ill patients, as midazolam and its active metabolites may accumulate. ^[33] Impaired renal or hepatic function may slow the elimination of midazolam, leading to its longer duration. ^{[3] [34]} Contraindications include hypersensitivity, acute angle-closure glaucoma , shock, hypotension , and head injuries. Most of them are relative contraindications.

Pregnancy

The use of midazolam during the third trimester of pregnancy can lead to a serious risk for the newborn , including benzodiazepine withdrawal syndrome with possible symptoms, including hypotension, apnea , cyanosis and metabolic reactions to cold stress. Symptoms of hypotension and benzodiazepine withdrawal symptoms in newborns have been reported to persist from several hours to several months after birth. ^[35] Other manifestations of withdrawal in newborns include increased irritability, tremors, and gastrointestinal upsets ( diarrhea or vomiting ). Breastfeeding a mother receiving midazolam is not recommended. ^[36]

Newborns

Midazolam is sometimes used in neonatal intensive care units. When used in newborns, extra care is required; midazolam should not be used for more than 72 hours because of the risk of tachyphylaxis , the possibility of developing a withdrawal syndrome of benzodiazepines, as well as neurological complications. Intravenous jet injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. ^[37]

Elder

Extra care is also required when using midazolam in the elderly, since they are more sensitive to the pharmacological effects of benzodiazepines, and the metabolism of benzodiazepines is slower. Elderly people are more prone to side effects, including drowsiness , amnesia , especially anterograde, ataxia , a hangover effect, confusion and falling. ^[eleven]

Side effects of midazolam include tolerance, withdrawal symptoms, confusion, amnesia, especially anterograde, ataxia, drowsiness, cognitive impairment, sedation, and an increased risk of falls in old age. ^[11] People who experience amnesia as a side effect of midazolam are generally unaware that their memory is getting worse. ^[38]

Long-term use of benzodiazepines is associated with a prolonged memory deficit and its partial recovery occurs only 6 months after cessation of intake. ^[11] It remains unclear whether complete recovery occurs after a long period of abstinence from taking. Benzodiazepines can cause or worsen depression. ^[11] Sometimes, when taking benzodiazepines, paradoxical agitation occurs, including worsening seizures. Children, the elderly, individuals with alcohol abuse or aggressive behavior, a history of anger are at an increased risk of paradoxical effects. ^[11] Paradoxical reactions especially occur with intravenous administration. ^[12] After an overnight intake of midazolam, the residual “hangover” effect (ie drowsiness, impaired psychomotor and cognitive functions) may persist the next day. This can impair the ability of the midazolam user to drive safely and may increase the risk of hip falls and fractures . ^[39] Sedation, respiratory depression, hypotension (as a result of a decrease in total vascular resistance), and an increase in heart rate may occur. ^{[3] [40]} Hypotension may occur with rapid administration of midazolam.

In susceptible individuals, midazolam, as you know, can cause paradoxical reactions. At the same time, a person may be anxious, he may experience involuntary movements, aggressive behavior, uncontrolled crying and other similar effects. It is believed that this is due to an altered state of consciousness or disinhibition caused by the drug. The patient often does not remember the paradoxical behavior because of the amnesia caused by the drug. In extreme situations, flumazenil can be used to inhibit or reverse the effect of midazolam. Antipsychotic drugs, such as haloperidol , can also be used for this purpose. ^[41]

Midazolam is known to cause respiratory depression. In healthy people, 0.15 mg / kg of midazolam can cause respiratory depression. ^[42] When midazolam is administered in combination with fentanyl, the occurrence of hypoxemia or apnea becomes more likely. ^[43]

Benzodiazepine addiction occurs in about one third of people who are treated with benzodiazepines for more than 4 weeks. ^[11] Dependence usually leads to tolerance and withdrawal syndrome of benzodiazepines (with a rapid reduction in dose). Midazolam infusions can cause tolerance and withdrawal symptoms within a few days. Risk factors for addiction include personality addiction, the use of short-acting and highly active benzodiazepines, as well as long-term therapy with benzodiazepines. The symptoms of midazolam withdrawal can range from insomnia and anxiety to cramps and psychosis . The withdrawal symptoms can sometimes be similar to the symptoms of the underlying disease in the patient. A gradual decrease in the dose of midazolam after regular use can minimize the symptoms of withdrawal. The emergence of tolerance and withdrawal syndrome may be associated with impaired regulation of receptors and changes in the expression of GABA _A receptor genes, which leads to long-term changes in the function of GABAergic system neurons. ^{[11] [44] [45]}

In patients receiving midazolam for a long time, the therapeutic effect of the drug is reduced due to the development of tolerance to benzodiazepine. ^{[46] [47]} Prolonged infusion of midazolam leads to the development of tolerance; if midazolam is given intravenously for several days or more, withdrawal syndrome may occur. Therefore, in order to prevent the withdrawal syndrome, the termination of a long infusion should be gradual, and sometimes, if necessary, a continued dose reduction with the oral administration of long-acting benzodiazepine, for example, clorazepate dipotassium . When signs of midazolam tolerance occur during intensive care, the use of opioids or propofol for additional sedation is recommended. Withdrawal symptoms may include irritability , the occurrence of pathological reflexes , tremors , muscle twitching, hypertonicity, delirium , seizures , nausea , vomiting and diarrhea , tachycardia , hypertension and tachypnea . ^[48]

In several US states , it has been used several times as a component of the death injection during the execution of the death penalty ^{[49] [50]} .