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HCID 4192Erstellt: 4. November 2026

Midazolam

5-a)(1,4)benzodiazepine,8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo( · 8-Chloro-6-(o-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine · Midazolam · Midazolam-d · MidazolaM-d7 · MidazolaM API · MIDAZOLAM USP · MIDAZOLAM,BP,EP

https://huagongshe.com/de/chemical/4192

Molekülstruktur von Midazolam

Identifikatoren & physikalische Daten

CAS No.59467-70-8
SummenformelC18H13ClFN3
Durchschnittliche Molmasse325,8 g/mol
Monoisotopische Masse325,0782033 g/mol
SMILESCc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
InChIKeyDDLIGBOFAVUZHB-UHFFFAOYSA-N
PubChem CID4192
ChEMBLCHEMBL655
ChEBICHEBI:6931
EC No.261-774-5
DTXSIDDTXSID5023320
Lokaler NameMidazolam

Chemische & physikalische Eigenschaften

XLogP2,5
Polarare Oberfläche (TPSA)30,2
H-Brücken-Donoren0
H-Brücken-Akzeptoren3
Frei drehbare Bindungen1
Schwere Atome23
Formalladung0
Komplexität471
ArzneimittelDEA NFLIS-Drug Category -> BenzodiazepinesDEA Schedule IV Controlled Substance -> DepressantsPharmaceuticals -> Listed in ZINC15Pharmaceuticals -> BenzodiazepinesPharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds
LogP (Verteilungskoeffizient)3.0
Color/FormColorless crystals from ether/methylene chloride/ hexaneWhite to light yellow crystalline
Löslichkeit54mg/L9.87e-03 g/LPractically insoluble in water, freely soluble in acetone and in ethanol (96 per cent), soluble in methanol.54mg/L(24 ºC)
Human DrugsBreast FeedingLactationMilk, HumanAnticonvulsantsHypnotics and SedativesAnti-Anxiety AgentsBenzodiazepinesAnesthetics, IntravenousFDA approved drugs -> Active ingredientEMA approved medicines: Human medicinePharmaceuticalsAntiseizure medicines
Siedepunkt496.9±55.0496.9±55.0 °C(Predicted)
DecompositionWhen heated to decomposition it emits toxic fumes of /hydrogen fluoride, hydrogen chloride and nitrogen oxides/.
Schmelzpunkt161-164158-160 °CCrystals from ethanol/ether, MP: 114-117 °C (solvated) /Midazolam maleate/159 °C161-164°C
Physical DescriptionSolid
Stability/Shelf LifeMidazolam hydrochloride is reportedly stable at a pH of 3-3.6.Stable under recommended storage conditions.
Dissociation ConstantspKa = 5.5 (calc)
Collision Cross Section172.8 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]
Dichte1.3136 (estimate)
Flammpunkt9 °C
LagerbedingungenControlled Substance, -20°C Freezer
pKa (Säurekonstante)pKa 1.7±0.16.15± 0.1 (Uncertain)
AggregatzustandSolid:crystalline
BCS Class1
Hauptanwendungenclinical testing
InChI1S/C18H13ClFN3/c1-11-21-9-13-10-22-18(14-4-2-3-5-16(14)20)15-8-12(19)6-7-17(15)23(11)13/h2-9H,10H2,1H3
InChIKeyDDLIGBOFAVUZHB-UHFFFAOYSA-N
SMILESCc1ncc2CN=C(c3ccccc3F)c4cc(Cl)ccc4-n12
LogP (Verteilungskoeffizient)2.73
CAS Datenbank59467-70-8(CAS DataBase Reference)
NIST chemische InformationenMidazolam(59467-70-8)

Sicherheit & Vorschriften

GHS-EinstufungDangerH301 (77.9%): Toxic if swallowed [Danger Acute toxicity, oral]P203, P233, P260, P261, P263, P264, P270, P271, P272, P273, P280, P284, P301+P316, P301+P317, P302+P352, P304+P340, P317, P318, P321, P330, P333+P317, P342+P316, P362+P364, P391, P403, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 77 reports by companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
Regulatorische InformationenDEA schedule IV controlled substanceREACH registered substance: Midazolam (EC: 261-774-5)Midazolam: Does not have an individual approval but may be used under an appropriate group standard
FDA-AnforderungenThe Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including midazolam hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Depressants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation: Midazolam (DEA Code Number: 2884) is included on this list.
Special ReportsKhanderia U, Pandit SKClin Pharm 6 (7): 533-47 (1987). The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage, and cost and availability of midazolam hydrochloride are reviewed.
Hazard Classes and CategoriesAcute Tox. 3 (77.9%)
Hazardous Reactivities and IncompatibilitiesIncompatible materials: Strong oxidizing agents.
Firefighting HazardsSpecial hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), hydrogen chloride gas, hydrogen fluoride.

Anwendungen & Verwendung

Beschreibung

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.

Verwenden

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

BrandbekämpfungsverfahrenSuitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.
LagerbedingungenMidazolam hydrochloride injection should be stored at 15-30 °C and protected from light. When stored as recommended, the commercially available injection has an expiration date of 2 yr following the date of manufacture. The injection was physically stable when frozen for 3 day periods and allowed to thaw at room temperature.Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 °C.
ReinigungsverfahrenAccidental Release Measures. Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapours, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.
EntsorgungsverfahrenSRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Waste treatment methods. Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.
Preventive MeasuresPrecautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire protection.Appropriate engineering controls: General industrial hygiene practice.Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.
Personal Protective Equipment (PPE)Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).Skin protection: Handle with gloves.Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).
TreatmentTreatment of midazolam overdosage is the same as that followed for overdosage with other benzodiazepines. Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate counter-measures. Gastrointestinal decontamination with lavage and/or activated charcoal once the patient's airway is secure is also recommended. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of midazolam and may be used in situations when an overdose with a benzodiazepine is known or suspected. (L1712)
WechselwirkungenHigh dose buprenorphine is used as substitution treatment in human heroin addiction. Deaths have been reported in addicts using buprenorphine, frequently in association with benzodiazepines. /The current study/ observed the effects of buprenorphine and midazolam alone and in combination on arterial blood gases. Four groups of 10 male Sprague-Dawley rats received a parenteral injection of aqueous solvent, buprenorphine (30 mg/kg, iv), midazolam (160 mg/kg, ip), or buprenorphine (30 mg/kg, iv) plus midazolam (160 mg/kg, ip). Serial blood gases were obtained over 3 hours. There was a mild but significant effect of buprenorphine alone in comparison with the aqueous solvent on PaCO2 at 60 min (6.24 vs. 5.65 kPa, p< 0.01). There was also a mild but significant effect of midazolam alone in comparison with aqueous solvent on arterial pH at 90 min (7.33 vs. 7.41,p< 0.001) and PaCO2 at 60 min (6.52 vs. 5.65 kPa,p< 0.01). The combination of midazolam and buprenorphine produces a rapid, profound, and prolonged respiratory depression, as demonstrated by an increase in PaCO2 at 7.65 +/- 0.12 kPa at 20 min and a decrease in arterial pH at 7.25 +/- 0.02 at 20 min, with appearance of delayed hypoxia with a decrease in PaO2 at 8.74 +/- 0.20 kPa at 120 min. These data show that high doses of midazolam and buprenorphine alone have limited effects on arterial blood gases in rats while midazolam and buprenorphine appear to act in an additive or synergistic fashion to depress ventilation in rats.The effects of concomitant administration of midazolam and /histamine H2-receptor antagonist/ cimetidine or ranitidine have not been fully elucidated. Orally administered cimetidine or ranitidine did not substantially alter the pharmacokinetics of either iv or oral midazolam in one study in healthy adults. However, in another study, plasma midazolam concentrations were increased by about 30% following oral administration of cimetidine, but not ranitidine, in healthy adults receiving midazolam iv. Oral bioavailability of midazolam may be increased by up to about 30% when cimetidine or ranitidine is given concomitantly, possibly secondary to a pH-dependent enhancement of gastric absorption of midazolam and/or a reduction in hepatic clearance of the drug. In another study, concomitant administration of oral midazolam concentration and AUC of midazolam by 6-138 and 10-102%, respectivelyand concomitant administration of oral midazolam and ranitidine (150 mg, 2 or 3 times daily or 300 mg, once daily) increased the peak plasma concentration and AUC of midazolam by 15-67% and 9-66%, respectively.Midazolam may potentiate the action of other CNS depressants, including opiate agonists or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol, possibly resulting in respiratory depression and profound and/or prolonged underventilation or apnea. In addition, opiate agonists can impair the ventilatory response to carbon dioxide, and appear to increase the risk of hypotension and prolong the recovery compared with midazolam alone. Severe hypotension, possibly secondary to increased venous pooling, has occurred when midazolam was used concomitantly with high dose fentanyl. When midazolam is used concomitantly with a depressant drug, caution should be exercised and appropriate dosage adjustments made to avoid overdosage. /Midazolam/Concomitant administration of oral midazolam and /the cardiovasular agents/ diltiazem or verapamil has resulted in an increase in the peak plasma concentration of midazolam of 105 or 97% and an increase in the AUC of midazolam of 275 or 195%, respectively. In another study, the half-life of midazolam was increased from 5 to 7 hours when the drug was administered in conjunction with diltiazem or verapmil...For more Interactions (Complete) data for Midazolam (37 total), please visit the HSDB record page.
Gesundheitliche AuswirkungenThey cause slurred speech, disorientation and "drunken" behavior. They are physically and psychologically addictive.
HepatotoxicityMidazolam, like other benzodiazepines, is rarely associated with serum ALT or alkaline phosphatase elevations. Clinically apparent liver injury from midazolam has not been reported and must be extremely rare, if it occurs at all. Isolated single cases of clinically apparent liver injury have been reported with other benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, and triazolam. The clinical pattern of acute liver injury from benzodiazepines is typically cholestatic, but hepatocellular patterns of injury have been reported with clorazepate and clotiazepam. The injury is usually mild to moderate in severity with a time to onset of 1 to 6 months and rapid recovery once the benzodiazepine is stopped. Fever and rash are uncommon as is autoantibody formation.
Unerwünschte WirkungenThe common adverse effects associated with midazolam use are hiccups, cough, nausea, and vomiting. Thrombophlebitis, thrombosis, and pain on injection are other adverse effects. The incidence of thrombophlebitis is lower with diazepam but similar to that of thiopental. Midazolam causes anterograde amnesia, drowsiness, ataxia, falls, and confusion in older patients. Residual hangover effect can happen with nighttime administration of midazolam, which can impair cognitive and psychomotor abilities, resulting in falls in the older adult population and impaired coordination during driving. Hypotension and tachycardia can occur with rapid intravenous administration. A higher dose can result in respiratory depression, which requires continuous ventilator support. Paradoxical effects of midazolam are possible in individuals with a history of alcohol abuse and aggressive behavior, potentially leading to involuntary movements, verbalization, uncontrollable crying, and aggressive behavior. Respiratory depression can happen with a dose of 0.15 mg/kg, and the risk increases when used along with fentanyl. Concomitant use of midazolam with other CNS depressants can result in severe respiratory depression and death even at therapeutic doses.
ExpositionspfadeRapidly absorbed after oral administration. The absolute bioavailability of the midazolam syrup in pediatric patients is about 36%. The absolute bioavailability, if given intramuscularly (IM), is greater than 90%. Cmax, IM = 90 ng/mLTmax, IM = 0.5 hours. Following IM administered, Cmax for midazolam and its 1-hydroxy metabolite were approxiately one-half of those achieved after intravenous injection.
Milk ConcentrationsEXPERIMENTAL: Two women ... were studied at 2-3 months postpartum. In six paired milk and serum samples collected up to 6 hours after a 15 mg dose, the mean milk:plasma ration was 0.15. Based on an average milk concentration of 10 nmol/L, a nursing infant would ingest an estimated 0.33 ug of midazolam and 0.34 ug of metabolite per 100mL of milk if nursed within 4-6 hours of the maternal dose.EXPERIMENTAL: Midazolam is excreted into breast milk. In a study published in 1990, 12 women in the immediate postpartum period took 15 mg orally at night for 5 nights. No measurable concentrations of midazolam or the metabolite, hydroxy-midazolam, were detected (<10 nmol/L) in milk samples collected a mean 7 hours (range 6-8 hours) after drug intake during the 5 day period. One mother, however, who was accidentally given a second dose (total dose 30 mg) did have a milk concentration of 30 nmol/L (milk:plasma ratio 0.20) at 7 hours.
ToxizitätsübersichtIDENTIFICATION AND USE: Midazolam is a white to light yellow crystalline insoluble in water. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions. It is a benzodiazepine, commonly used in the emergency department to provide sedation prior to procedures such as laceration repair and reduction of dislocations. Midazolam is also effective in the treatment of generalized seizures, status epilepticus, and behavioral emergencies, and as an induction agent for rapid sequence endotracheal intubation. Midazolam is often employed as probe to measure cytochrome P450 3A4 activity. HUMAN EXPOSURE AND TOXICITY: Changes in vital signs (respiratory rate, blood pressure, pulse rate) are the most frequent adverse effects associated with parenteral midazolam administration. Overdosage of midazolam hydrochloride is likely to produce symptoms that are mainly extensions of the usual pharmacologic effects of benzodiazepines, such as sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and alterations in vital signs. Adverse ocular effects occur in less than 1% of patients receiving parenteral midazolam, principally in those receiving the drug iv, and include blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbances, and focusing difficulty. Midazolam is metabolized by the cytochrome P450 enzyme system to several metabolites and Cytochrome P450 inhibitors, such as cimetidine, can profoundly reduce the metabolism of midazolam. Midazolam has been associated with respiratory depression and cardiac arrest when used in combination with an opioid, particularly in the elderly, although all ages are at risk for respiratory depression. Many of the adverse effects associated with midazolam can be reversed rapidly by the administration of flumazenil, a competitive benzodiazepine receptor antagonist. ANIMAL STUDIES: Subchronic oral studies over 13 weeks in doses of 5, 15 and 45 mg/kg/day in the dog and 50, 100 and 200 mg/kg/day in the rat have demonstrated minimal toxicity for midazolam, as for other benzodiazepines. High doses produced increased liver weight in the rat and the expected increases in alkaline phosphatase in the dog (species-specific reaction). Detailed blood and urine analyses as well as histological examination of organs produced no indication of changes relevant for man. Subchronic parenteral studies (i.v. and i.m. for five weeks) using up to 6 mg/kg/day in dogs and rats showed the compound to be not only systemically, but also locally, well tolerated. In albino rabbits of New Zealand, midazolam administered at single dose by the intrathecal route may have neurotoxic effects on the neurons and myelinated axons at 24 hr and 6 days following administration. In baboons, chronic self-injection of 1.0 and 0.25 mg/kg midazolam did produce physical dependence as reflected in classic benzodiazepine spontaneous and flumazenil-precipitated withdrawal syndromes, including tremor, vomiting and, in one instance, seizure. Reproduction toxicology studies have shown that midazolam is neither embryotoxic nor teratogenic and that it has no effect on the fertility and post-natal development of animals. Midazolam was shown to have no mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79) or in the micronucleus test in mice. However, in another study using low passage-number cultured Chinese hamster cells, midazolam treatment produced dose-dependent reductions in the number of diploid cells, with midazolam inducing significant levels of hyperdiploidy and midazolam induced low levels of chromosome aberrations, indicating potential genotoxicity.Signs and Symptoms of OverdoseIt is thought that the actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the brain. Benzodiazepines increase the activity of GABA, thereby producing a calming effect, relaxing skeletal muscles, and inducing sleep. Benzodiazepines act as agonists at the benzodiazepine receptors, which form a component of the benzodiazepine-GABA receptor-chloride ionophore complex. Most anxiolytics appear to act through at least one component of this complex to enhance the inhibitory action of GABA.
Human Toxicity Excerpts/HUMAN EXPOSURE STUDIES/ The purpose of this study is to compare the safety and efficacy of midazolam and fentanyl in children who undergo repeated lumbar puncture and bone marrow examinations. /This study/ used a randomized, double-blind crossover design to compare midazolam with fentanyl. Midazolam was given at 0.2 mg/kg and fentanyl at 2-4 mcg/kg, both IV over 10 minutes. Patients were monitored for oxygen saturation and vital signs during the procedure. /This study/ assessed patients with a visual analog scale, parent questionnaire, and the observational scale of Behavioral Distress. To date, 24 patients have been enrolled. Two patients have dropped out for reasons unrelated to the study. Thirteen of the remaining 22 patients have completed both treatments. Parents choose fentanyl or midazolam for subsequent procedures. Midazolam has been chosen 7 times and fentanyl 6 times. In 11/13 procedures done with midazolam the patients had no memory of the procedure, compared with 5/22 for fentanyl. Side effects included back pain post procedure (3/13 with midazolam, 1/22 with fentanyl), vomiting (2/13 with midazolam, 14/22 with fentanyl), itching (1/22 with fentanyl), and rash (1/22 with fentanyl). Patient and parent satisfaction with midazolam and fentanyl have been high despite the side effects. Final recommendations cannot be made until all data has been collected./HUMAN EXPOSURE STUDIES/ Conflicting data concerning the ventilatory effects of benzodiazepines may be caused by the large variability in investigational conditions. Respiratory effects of three different intravenous doses of midazolam (0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg) and placebo were measured in a double-blind and randomized fashion in eight healthy volunteers. The respiratory variables were analyzed by means of a noninvasive method, thereby avoiding interferences associated with the stimulating effects of mouthpiece and nose clip. After injection of midazolam, tidal volume decreased by 40% with the three doses and respiratory frequency increased to the same extent, minute ventilation remained constant. Only the largest dose of the drug produced a significant decrease (P less than 0.05) in O2 saturation that was related to the longer duration of apnea. Intravenous naloxone (0.015 mg/kg) injected 5 min after midazolam did not change any measured respiratory or hemodynamic variable. /It is concluded/ that the respiratory effects of midazolam are poorly dose related and not reversed by naloxone. The observed compensatory increase in respiratory frequency which is not noted in other studies, is probably related to the noninvasive measurement technique used./SIGNS AND SYMPTOMS/ Overdosage of midazolam hydrochloride is likely to produce symptoms that are mainly extensions of the usual pharmacologic effects of benzodiazepines, such as sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and alterations in vital signs. The manufacturer states that organ toxicity specific to midazolam overdosage would not be expected./SIGNS AND SYMPTOMS/ Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic.For more Human Toxicity Excerpts (Complete) data for Midazolam (18 total), please visit the HSDB record page.
Carcinogen ClassificationNo indication of carcinogenicity to humans (not listed by IARC).
Drug Induced Liver InjuryDrug-Induced Liver Injury Severity and Toxicity (DILIst)midazolamDILI NegativeOralDOI:10.1016/j.drudis.2019.09.022
Non-Human Toxicity Excerpts/LABORATORY ANIMALS: Acute Exposure/ ... /The current study/ observed the effects of buprenorphine and midazolam alone and in combination on arterial blood gases. Four groups of 10 male Sprague-Dawley rats received a parenteral injection of aqueous solvent, buprenorphine (30 mg/kg, iv), midazolam (160 mg/kg, ip), or buprenorphine (30 mg/kg, iv) plus midazolam (160 mg/kg, ip). Serial blood gases were obtained over 3 hours. There was a mild but significant effect of buprenorphine alone in comparison with the aqueous solvent on PaCO2 at 60 min (6.24 vs. 5.65 kPa, p< 0.01). There was also a mild but significant effect of midazolam alone in comparison with aqueous solvent on arterial pH at 90 min (7.33 vs. 7.41,p< 0.001) and PaCO2 at 60 min (6.52 vs. 5.65 kPa,p< 0.01). The combination of midazolam and buprenorphine produces a rapid, profound, and prolonged respiratory depression, as demonstrated by an increase in PaCO2 at 7.65 +/- 0.12 kPa at 20 min and a decrease in arterial pH at 7.25 +/- 0.02 at 20 min, with appearance of delayed hypoxia with a decrease in PaO2 at 8.74 +/- 0.20 kPa at 120 min. These data show that high doses of midazolam and buprenorphine alone have limited effects on arterial blood gases in rats while midazolam and buprenorphine appear to act in an additive or synergistic fashion to depress ventilation in rats./LABORATORY ANIMALS: Acute Exposure/ Ketamine and atropine are often combined in a single syringe for im injection for pediatric conscious sedationhowever, the effort of adding midazolam to this combination has not been studied. /This study/ investigated the single im injection of ketamine, atropine and midazolam (KAM) to determine if it causes histologic damage around the injection site in a rat model. Group 1 (n = 12) received a single in injection of ketamine, atropine and midazolam in the proportion given during pediatric conscious sedation. Group 2 (n = 12) received an equal volume of isotonic saline im. Group 3 (n = 5) received ketamine and atropine (KA), and a single rat (normal) received no injection. Four rats from each group were sacrificed at 1, 3 and 7 days post-injection, except group 3 KA rats were all sacrificed at 7 day. The injected limbs were harvested, fixed in formalin, decalcified in hydrochloric acid, cut, and mounted on slides. A pathologist examined the slides blinded to the slide label. On day 1 the injection sites of all groups had myocyte degeneration and necrosis with histiocytic infiltrates as well as perimysial edema and hemorrhage. These changes in varying degrees through day 3. By day 7 all histopathological processes had resolved in the saline injected rats and there was mild to no damage in the KA-injected rats. All rats that received KAM injections still had persistent pathologic changes 7 day post-injection. There was histologic evidence that ketamine, atropine and midazolam combination may lead to long-lasting, degenerative changes at the site of the im injection./LABORATORY ANIMALS: Acute Exposure/ The lung provides a portal of entry that could be used to rapidly deliver anticonvulsant substances to the brain to treat seizures. /The present study demonstrates/ that midazolam, a water-soluble anticonvulsant benzodiazepine, confers potent seizure protection when administered via the intrapulmonary route. High dose (100 mg/kg) intraperitoneal midazolam induced loss-of-righting reflex in mice. Lower doses of midazolam (100-1000 ug/kg) when administered intraperitoneally did not induce loss-of-righting reflex but protected animals against pentylenetetrazol (PTZ)-induced seizures. Intrapulmonary administration of midazolam via a tracheal cannula protected against intraperitoneal PTZ seizures at lower doses. The minimal intraperitoneal and intravenous doses of midazolam required to elevate the threshold for seizure signs induced by intravenous PTZ were 500 and 100 ug/kg, respectively, whereas the minimal intrapulmonary midazolam dose was 12.5 ug/kg. Intratracheal midazolam caused a large increase in intravenous PTZ threshold 5 min after administration but the effect declined rapidly over 60 min and no antiseizure activity was evident at 120 min. The minimal intraperitoneal doses of midazolam required to elevate the threshold for seizure signs induced by intravenous picrotoxin and kainic acid were 100 and 2000 ug/kg, respectivelythe corresponding values for intratracheal midazolam were 25 and 100 ug/kg, respectively. /It is concluded/ that midazolam is a highly effective anticonvulsant when administered by the intrapulmonary route. Midazolam is substantially more potent when delivered into the lung than when administered intraperitoneally or intravenously. Inhalation could be an alternative to other routes of administration for the delivery of midazolam to rapidly abort acute seizures./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In humans, the benzodiazepine midazolam has been reported to exert an antinociceptive action after subarachnoid injections. It has been shown that subarachnoid midazolam given to rabbits produces significant pathology in spinal cord morphology, as detected with light microscopy. In order to further characterize these changes, this study was performed, using a more sensitive histologic technique, including electron microscopy as well as unbiased morphometry. The histopathology of the rat lumbar spinal cord was investigated after chronic subarachnoid administration of a commercially available preparation of midazolam. After daily injections of 100 micrograms of midazolam, the animals were transcardially perfused on the twentieth day with a mixture of formaldehyde and glutaraldehyde. Morphometric evaluation of cell number and mean cell volume (MCV) by the disector method revealed a significant lower (P <0 .05) cell number and a tendency toward higher MCV in the midazolam-injected group (n = 6), compared to the rats injected with saline (n = 6). The higher MCV, in combination with a reduced number of nerve cells, indicated a loss of small neurons. The electron microscopic findings confirmed that midazolam caused neuronal death, since degenerated cell somata, fibers, and terminals were observed in most of the rats. Furthermore, an increased number of microglial cells phagocytosing nerve structures were also seen mainly in the dorsal horn. ...Chronic subarachnoid administration of midazolam gives objective signs of neurotoxicity in the rat spinal cord. /This finding is/ in contrast to those of an earlier light microscopic study in the rat. The present results emphasize both the necessity of morphometric and ultrastructural studies before spinal administration of novel drugs to humans and the neurotoxic potential of midazolam. Since neurotoxicity of midazolam now has been demonstrated in both rats and rabbits, there may be reason to be skeptical of the use of subarachnoid midazolam in humans.For more Non-Human Toxicity Excerpts (Complete) data for Midazolam (16 total), please visit the HSDB record page.
Wassergefährdungsklasse (WGK)2
UN-Transportnummer3249
Zollcode2933910000
R-Sätze (R)11-23/24/25-39/23/24/25
GefahrensymboleF,T
Sicherheitshinweise (S)7-16-36/37-45
Gefahrenklasse6.1(b)Acute Tox. 3 DermalAcute Tox. 3 InhalationAcute Tox. 3 OralFlam. Liq. 2STOT SE 1
VerpackungsgruppeIII
Lagerklasse3 - Flammable liquids
Gefahrstoffdaten59467-70-8(Hazardous Substances Data)
DEA Controlled SubstancesCSCN: 2884CAS SCH: IVNARC: N