Characteristic:
A hypnotic from the group of benzodiazepine derivatives. Midazolam is a white or slightly yellowish crystalline substance, insoluble in water. Midazolam hydrochloride is soluble in water.
pharmachologic effect
Pharmacology:
Pharmacological action: hypnotic, sedative. Interacts with specific benzodiazepine receptors located in the postsynaptic GABA_A receptor complex, increases the sensitivity of GABA receptors to the mediator (GABA). At the same time, the frequency of opening of ion channels for incoming currents of chlorine ions increases, hyperpolarization of the membrane occurs and neuronal activity is inhibited. Prevents the reuptake of GABA, promoting its accumulation in the synaptic cleft. There is evidence that excessive accumulation of GABA at neuronal synapses causes the induction of general anesthesia. When taken orally, it is quickly and completely absorbed from the gastrointestinal tract, has a “first pass” effect through the liver (30-60% of midazolam is metabolized). C_max in the blood is achieved within 1 hour (eating increases the time to reach C_max). With intramuscular administration, absorption is fast and complete, C_max is achieved within 30-45 minutes, bioavailability is more than 90%. In the blood, it is 95-98% bound to proteins, mainly albumin. Quickly distributed in the body. Volume of distribution 1-3.1 l/kg. Passes through histohematic barriers, incl. BBB, placental, passes into breast milk in small quantities. It penetrates into the cerebrospinal fluid slowly and in small quantities. It undergoes biotransformation in the liver by hydroxylation with the participation of the isoenzyme of the cytochrome P450 3A4 system. The main metabolites - 1-hydroxymidazolam, also called alpha-hydroxy-midazolam (about 60%), and 4-hydroxy-midazolam (5% or less) have pharmacological activity, but lower than the parent compound. Excreted by the kidneys in the form of glucuronic conjugates (less than 1% unchanged). T_1/2 - 1.5-3 hours. T_1/2 may increase in patients over 60 years of age, in patients with congestive heart or liver failure, in obese patients (due to increased distribution of midazolam in adipose tissue), in newborns. Midazolam is characterized by a rapid onset and short duration of hypnotic effect. Shortens the phase of falling asleep and increases the overall duration and quality of sleep without changing the phase of paradoxical sleep. It quickly induces sleep (within 20 minutes) and has virtually no aftereffect. It has sedative, central muscle relaxant, anxiolytic, anticonvulsant and amnestic effects. The sedative effect in adults with intramuscular administration develops after 15 minutes, with intravenous administration after 1.5-5 minutes. The time to achieve maximum sedative effect with intramuscular administration is 30-60 minutes. When administered intravenously for induction of anesthesia, the effect appears after 1.5-3 minutes, and against the background of premedication with narcotic drugs after 0.75-1.5 minutes. Recovery time from anesthesia is 2 hours (up to 6 hours). The amnestic effect is observed mainly with parenteral administration. Amnesia (including during endoscopic procedures) was observed with intramuscular administration in 40% of adult patients after 60 minutes, in 73% after 30 minutes. With intravenous administration, a similar effect was observed in approximately 80% of patients. In some cases, episodes of amnesia were observed after taking midazolam orally. When administered parenterally, the onset of action depends on the dose, route of administration, as well as the combined use of narcotic analgesics and anesthetics. Carcinogenicity studies were conducted in two-year studies in mice that received midazolam with food at doses of 1, 9 and 80 mg/kg/day. With long-term administration at a dose of 80 mg/kg/day, a significant increase in the incidence of liver tumors was observed in female mice. In males, at the highest doses there was a small but statistically significant increase in the incidence of benign thyroid tumors, while at a dose of 9 mg/kg/day (25 times the human dose of 0.35 mg/kg/day) an increase in the incidence of tumors not found. The significance of this effect is unclear, given the short-term effect of midazolam on the human body. No mutagenic activity was detected (using a number of tests). When studying reproduction in rats when midazolam was administered in doses up to 10 times higher than the dose for intravenous administration in humans - 0.35 mg/kg, no effect on fertility was detected in male and female rats. Administration of midazolam in the same doses to rats did not lead to adverse effects during pregnancy and breastfeeding. When studying teratogenicity in rabbits and rats at doses 5-10 times higher than the human dose - 0.35 mg/kg, no teratogenic effect was found. The formation of physical dependence (from weak to moderate severity) in monkeys after taking midazolam for 5-10 weeks has been shown.
Side effects
Inside, parenterally.
From the nervous system and sensory organs: drowsiness, lethargy, muscle weakness, dullness of emotions, decreased reaction speed, headache, dizziness, ataxia, diplopia, anterograde amnesia (dose-dependent), paradoxical reactions (agitation, psychomotor agitation, aggressiveness, etc.) .
Other: dyspeptic symptoms, skin reactions, local reactions (erythema and pain at the injection site, thrombophlebitis, thrombosis).
The development of tolerance, drug dependence, and o syndrome is possible (see “Precautions”).
With parenteral administration: decrease in tidal volume and/or respiratory rate (in 23.3% of patients after i.v. and in 10.8% after i.m. administration), temporary cessation of breathing (in 15.4% of patients after i.v. administration) and/or heart disease, sometimes leading to death - the effects are dose-dependent and are observed mainly in elderly patients with chronic diseases when used simultaneously with narcotic analgesics, as well as with rapid intravenous administration; laryngospasm, shortness of breath; excessive sedation, convulsions (in premature and newborn babies), withdrawal syndrome (with sudden cancellation of long-term IV use); vasodilation, decreased blood pressure, tachycardia; nausea, vomiting, hiccups, constipation; allergic, incl. skin (rash, urticaria, itching) and anaphylactoid reactions.
Dosage and method of administration
Directions for use and dosage:
Inside, intramuscularly, intravenously, rectally. The dose should be selected individually, and the withdrawal regimen for the treatment of sleep disorders is individual. For sleep disorders: adults, orally (without chewing, with liquid), immediately before bedtime, an average dose of 7.5-15 mg once. The course of treatment should be short-term (several days, maximum 2 weeks). Elderly and debilitated patients, as well as patients with impaired liver function, should begin treatment with the lowest doses. In anesthesiology and intensive care: adults and children - IM, IV (slow), rectally (for premedication in children), orally (for premedication in adults, if IM is not indicated). The dosage regimen (rate of administration, dose size) is selected strictly individually depending on the indications, physical condition and age of the patient, as well as the drug therapy received. In patients at high risk, incl. over 60 years of age, debilitated people or patients with chronic diseases use smaller doses. Precautions: IV administration should be carried out only in medical institutions with resuscitation equipment, as well as personnel trained for its use (due to the possibility of inhibition of myocardial contractile function and respiratory arrest). After parenteral administration, patients should be monitored for at least 3 hours. It should be borne in mind that too rapid intravenous administration (especially in children with unstable cardiovascular conditions and in newborns) can cause apnea, hypotension, bradycardia, cardiac arrest or breathing. The development of paradoxical reactions is most often observed in children and elderly and senile patients. Caution should be exercised when driving vehicles, as well as when performing work that requires increased concentration and precise coordination of movements within 24 hours after using midazolam. You should not drink alcoholic beverages or use other drugs that cause CNS depression within 24 hours after taking midazolam. With repeated use over several weeks, addiction may occur (the hypnotic effect may weaken somewhat), as well as drug dependence, incl. when taking therapeutic doses. With an abrupt cessation of treatment, withdrawal syndrome may occur (headache and muscle pain, anxiety, tension, in severe cases - depersonalization, hallucinations, etc.), as well as the development of the “recoil” phenomenon - a temporary increase in the original symptoms (insomnia).
Interaction
Potentiates the effects of tranquilizers, antidepressants, other hypnotics, analgesics, anesthetics, neuroleptics, anesthetic drugs, alcohol (mutually). Midazolam solution is incompatible in the same syringe with alkaline solutions. IV administration of midazolam reduces the minimum alveolar concentrations of halothane required for general anesthesia. IM administration of midazolam during premedication may necessitate a reduction in the dose of sodium thiopental by 15%.
Itraconazole, fluconazole, erythromycin, saquinavir increase T1/2 of midazolam administered parenterally (when prescribing large doses of midazolam or carrying out long-term induction, it is necessary to reduce its dose). The systemic effect of midazolam is enhanced by inhibitors of the CYP3A4 isoenzyme: ketoconazole, itraconazole and fluconazole (co-administration is not recommended), erythromycin, saquinavir, diltiazem and verapamil (simultaneous administration requires a reduction in the dose of midazolam by 50% or more), roxithromycin, azithromycin, cimetidine and ranitidine (clinically significant interaction is unlikely). Inducers of the CYP3A4 isoenzyme (carbamazepine, phenytoin, rifampicin) reduce the systemic effect of midazolam (when taken orally) and necessitate increasing its doses.
Midazolam
International name of the medicinal substance:
Midazolam The list of drugs containing the active substance Midazolam is given after the description.
Pharmacological action:
A hypnotic from the group of benzodiazepine derivatives.
It also has central muscle relaxant, anxiolytic and antiepileptic effects. It has some depressant effect on the cardiovascular system and causes anterograde amnesia. It quickly causes the onset of sleep (within 20 minutes), has little effect on the structure of sleep, and has virtually no aftereffect. Onset of action: sedative - 15 minutes (i.m. administration), 1.5-5 minutes (i.v. administration); introductory general anesthesia with intravenous administration - 0.75-1.5 minutes (with premedication with narcotic drugs), 1.5-3 minutes (without premedication with narcotic drugs). The duration of the amnestic effect is directly dependent on the dose. The recovery time from general anesthesia is on average 2 hours. Pharmacokinetics:
When taken orally, it is quickly and completely absorbed from the gastrointestinal tract, bioavailability is 36%. Has a “first pass” effect through the liver. After intramuscular administration, it is absorbed quickly and completely. Cmax is reached within 15-60 minutes. Bioavailability - over 90%. Penetrates through histohematic barriers, incl. BBB and placental barrier. The volume of distribution averages 1-2.5 (from 0.95 to 6.6) l/kg, binding to plasma proteins is 97% in healthy people and 93.5% in patients with renal failure. Rapidly metabolized to form 1-hydroxymethylmidazolam and 4-hydroxymidazolam, which have lower activity than midazolam. The metabolism of the drug involves isoenzymes CYP3A4, CYP3A5 and CYP3A7. T1/2, alpha phase - 15 minutes, beta phase - 2.5 hours (usually from 1 to 5 hours; rarely up to 12.3 hours). In patients with CHF it can increase 2-3 times, in patients with obesity T1/2 is longer; in both cases the total clearance remains unchanged. Excreted by the kidneys in the form of glucuronides (0.03% unchanged).
Indications:
Premedication before surgical interventions or diagnostic procedures, induction and maintenance of general anesthesia, long-term sedation in intensive care, induction and main general anesthesia in children (IM in combination with ketamine), insomnia (short-term treatment).
Contraindications:
Hypersensitivity, sleep disorders in psychosis and severe depression, myasthenia gravis, muscular dystrophy, myotonia, COPD (severe), acute pulmonary failure, pregnancy (first trimester), labor, lactation. With caution.
Organic brain damage, acute alcohol intoxication with depression of vital functions, coma, shock, CHF, respiratory failure, liver failure, chronic renal failure, obesity, apnea (during sleep), childhood. Side effects:
From the cardiovascular system: decreased blood pressure, tachycardia, arrhythmia.
From the respiratory system: depression of the respiratory center, stridor or difficulty breathing, respiratory and/or cardiac arrest, laryngospasm, shortness of breath. From the digestive system: hiccups, nausea, vomiting. From the nervous system: headache, acute delirium (confusion, disorientation, hallucinations, unusual anxiety, agitation, nervousness or agitation), excessive sedation, drowsiness, muscle tremors, anterograde amnesia, paradoxical reactions (agitation, psychomotor agitation, aggressiveness ), involuntary movements, convulsions (in premature and newborn babies). Local reactions: pain and thrombophlebitis at the injection site. Allergic reactions: skin rash, urticaria, angioedema, anaphylactoid reactions. Other: withdrawal syndrome (sudden withdrawal after prolonged intravenous use), drug dependence. Overdose. Symptoms: myasthenia gravis, amnesia, deep sleep, paradoxical reactions, at extremely high doses - coma, areflexia, depression of the respiratory center and cardiac activity, apnea. Treatment (depending on the severity of the condition): mechanical ventilation, measures aimed at maintaining the activity of the cardiovascular system. In case of an overdose of the tablet form, gastric lavage performed immediately after taking the drug can be effective. Overdose phenomena are well controlled by the benzodiazepine antagonist, flumazenil. Interaction:
Enhances the effect (CNS depression) of antipsychotic drugs (neuroleptics), hypnotics, anxiolytics, antidepressants, narcotic analgesics and ethanol, anesthetics, antiepileptic, sedative and antihistamine drugs.
The simultaneous use of cimetidine, erythromycin, antipsychotic drugs (neuroleptics) and amiodarone reduces the hepatic clearance of the drug and slows down its elimination. Special instructions:
Not prescribed for the primary treatment of insomnia in psychosis and severe forms of depression.
You should not take ethanol during treatment, especially in the first 6 hours after administration. During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Preparations containing the active ingredient Midazolam:
Dormicum, Midazolam, Midazolam-hamelin, Flormidal, Fulsed
The information provided in this section is intended for medical and pharmaceutical professionals and should not be used for self-medication. The information is provided for informational purposes only and cannot be considered official.
Overdose
Symptoms: muscle weakness, lethargy, confusion, paradoxical reactions, amnesia, deep sleep; at very high doses - respiratory and cardiac depression, apnea, areflexia, coma.
Treatment: induction of vomiting and administration of activated charcoal (if the patient is conscious), gastric lavage through a tube (if the patient is unconscious), mechanical ventilation, maintaining the functions of the cardiovascular system. Administration of a specific antidote—the benzodiazepine receptor antagonist flumazenil (in a hospital setting).
Contraindications
Contraindications:
Hypersensitivity, sleep disorders in psychosis and severe depression, myasthenia gravis, pregnancy (first trimester), childbirth, breastfeeding, childhood (for oral administration). Restrictions on use: Organic brain damage, cardiac and/or respiratory and/or liver failure, sleep apnea, pregnancy (II and III trimester), childhood (for induction of anesthesia). Use during pregnancy and breastfeeding: Contraindicated in the first trimester of pregnancy and during childbirth. In the second and third trimester it is possible if the expected effect of therapy exceeds the potential risk to the fetus. Breastfeeding should be stopped during treatment.
