Midazolam

Identification

Summary

Midazolam is a short-acting injectable benzodiazepine with rapid onset that is commonly used in seizures, anesthesia and anxiety disorders.

Brand Names

Buccolam, Nayzilam, Seizalam

Generic Name

Midazolam

DrugBank Accession Number

DB00683

Background

Midazolam is a short-acting hypnotic-sedative drug with anxiolytic, muscle relaxant, anticonvulsant, sedative, hypnotic, and amnesic properties.⁶ 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.⁶ 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.¹³

This drug was initially approved by the US FDA in 1985, and has been approved for various indications since.^Label In late 2018, the intramuscular preparation was approved by the FDA for the treatment of status epilepticus in adults.^Label 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.⁹

Type

Small Molecule

Groups

Approved, Illicit

Structure

Similar Structures

Weight: Average: 325.767
Monoisotopic: 325.078203343
Chemical Formula: C₁₈H₁₃ClFN₃

Synonyms

Midazolam
Midazolamum

External IDs

Dea No. 2884
Ro 21-3981/001
Ro 21-3981/003

Pharmacology

Indication

Intravenous

Indicated for promoting preoperative sedation, anxiolysis, anesthesia induction, or amnesia.¹²

Intramuscular

Indicated for the treatment of status epilepticus in adults.^Label

Nasal

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.¹¹

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Associated Conditions

Associated Therapies

Contraindications & Blackbox Warnings

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Pharmacodynamics

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.¹² 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.⁷

Sedation and memory

The onset of sedation after intramuscular administration in adults is 15 minutes, with maximal sedation occurring 30-60 minutes after injection.^Label 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.¹²

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.^Label

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.^Label

Mechanism of action

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 central nervous system. Benzodiazepines increase the activity of GABA, thereby producing a sedating effect, relaxing skeletal muscles, and inducing sleep, anesthesia, and amnesia. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening.¹² These receptors have been identified in different body tissues including the heart and skeletal muscle, although mainly appear to be present in the central nervous system.⁶

Target	Actions	Organism
AGABA(A) Receptor	positive allosteric modulator	Humans
AGABA(A) Receptor Benzodiazepine Binding Site	ligand	Humans

Absorption

Oral Absorption: Rapidly absorbed after oral administration. The absolute bioavailability, if given intramuscularly (IM), is greater than 90% ^Label. Due to first pass metabolism, only 40-50% of the administered oral dose reaches the circulation.⁶ The absolute bioavailability of the midazolam syrup in pediatric patients is about 36%.¹⁰

Intramuscular Absorption: The mean peak concentration (Cmax) and time to peak (Tmax) following the IM dose was 90 ng/mL (20% CV) and 0.5 hour (50% CV).^Label

Rectal administration: After rectal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes. The absolute bioavailability is approximately 50%.¹³

Intranasal Administration: Midazolam is absorbed rapidly after intranasal administration. Mean peak plasma concentrations are reached within 10.2 to 12.6 minutes. The bioavailability is between 55 and 57%.¹³

Volume of distribution

Female gender, old age, and obesity may increase the volume of distribution. Midazolam may also cross the placenta and has been detected in human milk and cerebrospinal fluid.^Label,12

Intravenous administration

1.24 to 2.02 L/kg [pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam] 1 to 3.1 L/kg [midazolam intravenously administered, healthy adults].¹²

Intramuscular administration

The mean apparent volume of distribution of midazolam after a single IM dose of 10 mg midazolam in healthy adults was 2117 (±845.1) mL/kg.^Label

Protein binding

Midazolam is approximately 97% bound to plasma protein, mainly albumin, in adults. The 1-hydroxy metabolite is approximately 89% bound to plasma protein.¹²

Metabolism

Midazolam is primarily metabolized in the liver and gut by CYP3A4 ^Label to its pharmacologic active metabolite, alpha-hydroxymidazolam (also known as 1-hydroxy-midazolam), and 4-hydroxymidazolam (which makes up 5% or less of the biotransformation products). This metabolite likely contributes to the pharmacological effects of midazolam. Midazolam also undergoes N-glucuronidation via UGT1A4 after the process of hepatic oxidation by cytochrome enzymes.⁶

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Midazolam

Route of elimination

The α-hydroxymidazolam glucuronide conjugate of midazolam is excreted in urine. No significant amount of parent drug or metabolites is found in urine before beta-glucuronidase and sulfatase deconjugation, suggesting that the urinary metabolites are excreted mainly as conjugates. The amount of midazolam excreted unchanged in the urine when given intravenously is less than 0.5%. 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate.¹²

Plasma clearance of midazolam is higher in patients that remain in supine position, because of a 40-60 percent increase in hepatic blood flow during supination. Pregnancy may also increase the metabolism of midazolam.⁶

Half-life

Intravenous: healthy adults = 1.8 to 6.4 hours (mean of 3 hours).¹²

Intramuscular: Following IM administration of 10 mg midazolam, mean (±SD) elimination half-life was 4.2 (±1.87) hours.^Label

Clearance

Intramuscular: apparent total body clearance, 367.3 (±73.5) mL/hr/kg.^Label Intravenous: total clearance (Cl), 0.25 to 0.54 L/hr/kg

Adverse Effects

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Toxicity

LD₅₀=215 mg/kg, in rats.^MSDS

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.^Label

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.^Label

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).¹²

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.⁹

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.⁹

Mutagenesis

Midazolam was negative for genotoxicity during in vitro and in vivo assays.^Label

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.^Label

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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1,2-Benzodiazepine	The risk or severity of adverse effects can be increased when Midazolam is combined with 1,2-Benzodiazepine.
Abacavir	Midazolam may decrease the excretion rate of Abacavir which could result in a higher serum level.
Abametapir	The serum concentration of Midazolam can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Midazolam can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Midazolam.
Abiraterone	The serum concentration of Midazolam can be increased when it is combined with Abiraterone.
Acalabrutinib	The serum concentration of Midazolam can be increased when it is combined with Acalabrutinib.
Aceclofenac	Aceclofenac may decrease the excretion rate of Midazolam which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Midazolam which could result in a higher serum level.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Midazolam.

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Food Interactions

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Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Midazolam hydrochloride	W7TTW573JJ	59467-96-8	PLYSCVSCYOQVRP-UHFFFAOYSA-N
Midazolam maleate	77520S18SE	59467-94-6	XYGVIBXOJOOCFR-BTJKTKAUSA-N

International/Other Brands

Anquil (General Pharma) / Benzosed (Pharmaceutical) / Dalam (Richmond) / Damizol (Specifar) / Demizolam (Dem Ilaç) / Doricum (Roche) / Dormicum (Roche) / Dormid (Scott) / Dormipron (Chalver) / Dormire (Cristália) / Dormitol (Square) / Dormixal (Demo) / Dormonid (Roche) / Drimnorth (Northia) / Epistatus (IFET) / Flormidal (Galenika) / Fulsed (Ranbaxy) / Fulsed Injection (Terapia) / Garen (Bio-Pharma) / Gobbizolam (Gobbi) / Hipnazolam (EMS) / Hipnoz (Pharos) / Hypnofast (Incepta) / Hypnovel (Roche) / Ipnovel (Roche) / Nocturna (Lafi) / Setam (Rimsa) / Talentum (Fisiopharma) / Terap (Sanitas) / Versed (Roche)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Buccolam	Solution		Buccal	Shire Services Bvba	2016-09-08	Not applicable
Buccolam	Solution		Buccal	Shire Services Bvba	2016-09-08	Not applicable
Buccolam	Solution		Buccal	Shire Services Bvba	2016-09-08	Not applicable
Buccolam	Solution		Buccal	Shire Services Bvba	2016-09-08	Not applicable
Midazolam HCl	Injection, solution	1 mg/1mL	Intravenous	Cantrell Drug Company	2013-06-28	Not applicable
Midazolam HCl	Injection, solution	0.5 mg/1mL	Intravenous	Cantrell Drug Company	2014-09-03	Not applicable
Midazolam Injection	Solution		Intramuscular; Intravenous	Mylan Pharmaceuticals	Not applicable	Not applicable
Midazolam Injection	Solution		Intramuscular; Intravenous	Fresenius Kabi	2001-03-26	Not applicable
Midazolam Injection	Solution		Intramuscular; Intravenous	Sandoz Canada Incorporated	1999-07-21	Not applicable
Midazolam Injection	Solution		Intramuscular; Intravenous	Pfizer Canada Ulc	2015-03-31	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Apo-midazolam Injectable 1 mg/ml	Liquid		Intramuscular; Intravenous	Apotex Corporation	2001-04-10	2013-08-02
Apo-midazolam Injectable 5 mg/ml	Liquid		Intramuscular; Intravenous	Apotex Corporation	2001-04-10	2013-08-02
Midazolam	Injection, solution	5 mg/1mL	Intramuscular; Intravenous	Fresenius Kabi USA, LLC	2014-10-03	Not applicable
Midazolam	Injection, solution	5 mg/1mL	Intramuscular; Intravenous	General Injectables and Vaccines, Inc.	2017-11-30	Not applicable
Midazolam	Injection, solution	5 mg/1mL	Intramuscular; Intravenous	The Medicines Company	2000-07-14	2016-03-31
Midazolam	Injection, solution	1 mg/1mL	Intramuscular; Intravenous	Almaject, Inc.	2020-04-14	Not applicable
Midazolam	Injection	1 mg/1mL	Intramuscular; Intravenous	General Injectables and Vaccines, Inc.	2018-03-05	Not applicable
Midazolam	Injection	5 mg/1mL	Intramuscular; Intravenous	Akorn, Inc.	2005-05-06	Not applicable
Midazolam	Injection	1 mg/1mL	Intramuscular; Intravenous	West-Ward Pharmaceuticals Corp.	2000-06-20	Not applicable
Midazolam	Injection, solution	1 mg/1mL	Intramuscular; Intravenous	The Medicines Company	2000-07-14	2016-02-29

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Midazolam HCl	Midazolam hydrochloride (1 mg/1mL)	Injection, solution	Intravenous	Cantrell Drug Company	2013-06-28	Not applicable
Midazolam HCl	Midazolam hydrochloride (0.5 mg/1mL)	Injection, solution	Intravenous	Cantrell Drug Company	2014-09-03	Not applicable
MIDOLAM 15 MG/3 ML IM/IV REKTAL COZELTI ICEREN AMPUL, 5 ADET	Midazolam (15 mg/3ml)	Injection	Intramuscular; Intravenous	PHARMADA İLAÇ SAN. VE TİC. A.Ş.	2020-08-14	Not applicable
MIDOLAM 5 MG/1 ML IM/IV REKTAL COZELTI ICEREN AMPUL, 5 ADET	Midazolam (5 mg/1ml)	Injection	Intramuscular; Intravenous	PHARMADA İLAÇ SAN. VE TİC. A.Ş.	2020-08-14	Not applicable
MIDOLAM 50 MG/10 ML IM/IV REKTAL COZELTI ICEREN AMPUL, 5 ADET	Midazolam (50 mg/10ml)	Injection	Intramuscular; Intravenous	PHARMADA İLAÇ SAN. VE TİC. A.Ş.	2020-08-14	Not applicable
MILOZ 5 MG/5ML 10 AMPUL	Midazolam (5 mg)	Injection, solution	Intravenous	BİEM İLAÇ SAN. VE TİC. A.Ş.	2020-08-14	Not applicable
MKH Dose Pack	Midazolam (3 mg/1) + Hydroxyzine hydrochloride (10 mg/1) + Ketamine hydrochloride (25 mg/1)	Troche	Sublingual	Imprimis Njof, Llc	2019-03-04	Not applicable
MKO Melt	Midazolam (3 mg/1) + Ketamine hydrochloride (25 mg/1) + Ondansetron hydrochloride dihydrate (2 mg/1)	Troche	Sublingual	Imprimis Njof, Llc	2018-12-01	2019-03-04
MKO Melt Dose Pack	Midazolam (3 mg/1) + Ketamine hydrochloride (25 mg/1) + Ondansetron hydrochloride (2 mg/1)	Troche	Sublingual	Imprimis Njof, Llc	2019-03-04	Not applicable

Chemical Identifiers

UNII: R60L0SM5BC
CAS number: 59467-70-8
InChI Key: DDLIGBOFAVUZHB-UHFFFAOYSA-N
InChI: InChI=1S/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
IUPAC Name: 12-chloro-9-(2-fluorophenyl)-3-methyl-2,4,8-triazatricyclo[8.4.0.0²,⁶]tetradeca-1(10),3,5,8,11,13-hexaene
SMILES: CC1=NC=C2CN=C(C3=CC=CC=C3F)C3=C(C=CC(Cl)=C3)N12

References

Synthesis Reference

US6262260

General References

Skerritt JH, Johnston GA: Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983 May 6;89(3-4):193-8. [Article]
Isojarvi JI, Tokola RA: Benzodiazepines in the treatment of epilepsy in people with intellectual disability. J Intellect Disabil Res. 1998 Dec;42 Suppl 1:80-92. [Article]
Garratt JC, Gent JP, Feely M, Haigh JR: Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential? Eur J Pharmacol. 1988 Jan 5;145(1):75-80. [Article]
Tokunaga S, Takeda Y, Shinomiya K, Hirase M, Kamei C: Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats. J Pharmacol Sci. 2007 Feb;103(2):201-6. Epub 2007 Feb 8. [Article]
Vermeeren A: Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs. 2004;18(5):297-328. [Article]
Nordt SP, Clark RF: Midazolam: a review of therapeutic uses and toxicity. J Emerg Med. 1997 May-Jun;15(3):357-65. [Article]
Jembrek MJ, Vlainic J: GABA Receptors: Pharmacological Potential and Pitfalls. Curr Pharm Des. 2015;21(34):4943-59. [Article]
Siegel GJ, Agranoff BW, Albers RW et al. (1999). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Lippincott Williams.
Drug Scheduling: United States Drug Enforcement Administration (DEA) [Link]
DailyMed: Midazolam [Link]
NAYZILAM® (midazolam) nasal spray - FDA Label [Link]
Intravenous Midazolam FDA label [File]
MedSafe NZ: Midazolam Inj [File]

External Links

Human Metabolome Database: HMDB0014821
KEGG Drug: D00550
KEGG Compound: C07524
PubChem Compound: 4192
PubChem Substance: 46507611
ChemSpider: 4047
BindingDB: 21363
RxNav: 6960
ChEBI: 6931
ChEMBL: CHEMBL655
ZINC: ZINC000095626706
Therapeutic Targets Database: DAP000241
PharmGKB: PA450496
Guide to Pharmacology: GtP Drug Page
PDBe Ligand: 08J
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Midazolam

AHFS Codes

28:24.08 — Benzodiazepines

PDB Entries

3u5k / 5te8

FDA label

Download (250 KB)

MSDS

Download (68.9 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Acute Lung Injury (ALI) / Acute Respiratory Distress Syndrome (ARDS) / Illness, Critical / Sleep	1
4	Active Not Recruiting	Treatment	Dental Caries in Children / Hydroxyzine / Meperidine / Midazolam / Pediatric Dental Sedation	1
4	Active Not Recruiting	Treatment	Driving Performance After Minor Ambulatory Surgery / Minor Surgical Procedures With Monitored Anesthesia Care	1
4	Completed	Not Available	Anaesthesia / Caudal epidural block therapy / Orthopaedic Disorders	1
4	Completed	Not Available	Disorders of Gallbladder, Biliary Tract and Pancrease	1
4	Completed	Not Available	Failed Moderate Sedation During Procedure	1
4	Completed	Not Available	Obesity, Morbid	1
4	Completed	Basic Science	Analgesic Drugs / Antinociceptive Agents	1
4	Completed	Basic Science	Pharmacokinetics	1
4	Completed	Basic Science	Rejection, Transplant	1

Pharmacoeconomics

Manufacturers

Apothecon inc div bristol myers squibb
App pharmaceuticals llc
Astrazeneca pharmaceuticals lp
Baxter healthcare corp anesthesia and critical care
Baxter healthcare corp anesthesia critical care
Bedford laboratories div ben venue laboratories inc
Ben venue laboratories inc
Claris lifesciences ltd
Hospira inc
International medicated systems ltd
International medication systems ltd
Taylor pharmaceuticals
Wockhardt ltd
Hlr technology
Apotex inc richmond hill
Hi tech pharmacal co inc
Paddock laboratories inc
Ranbaxy laboratories ltd
Roxane laboratories inc
Hoffmann la roche inc

Packagers

Akorn Inc.
APP Pharmaceuticals
A-S Medication Solutions LLC
B&B Pharmaceuticals
Baxter International Inc.
Bedford Labs
Ben Venue Laboratories Inc.
Cardinal Health
Cura Pharmaceutical Co. Inc.
Dispensing Solutions
Ebewe Pharma
Hi Tech Pharmacal Co. Inc.
Hospira Inc.
Mikart Inc.
Novex Pharma
Paddock Labs
Patheon Inc.
Pharmedium
Physicians Total Care Inc.
Ranbaxy Laboratories
Roxane Labs
Wockhardt Ltd.

Dosage Forms

Form	Route	Strength
Liquid	Intramuscular; Intravenous
Solution	Buccal
Injection	Intravenous
Injection	Intramuscular; Intravenous
Solution	Intramuscular; Intravenous; Rectal
Injection, solution	Parenteral
Solution	Intravenous	5 mg
Injection	Intramuscular; Intravenous; Rectal
Tablet	Oral
Tablet, coated	Oral
Solution	Intramuscular; Intravenous	15 mg
Injection, solution	Intramuscular; Intravenous
Injection, solution	Intramuscular; Intravenous	10 mg/2mL
Injection, solution	Intramuscular; Intravenous	2 mg/2mL
Solution	Parenteral
Solution	Intramuscular; Parenteral
Solution	Intramuscular; Intravenous	50 mg
Solution	Intramuscular; Intravenous	5 mg
Solution	Intravenous
Tablet, coated	Oral	7.5 mg
Injection, solution	Parenteral; Rectal
Injection, solution	Rectal
Injection, solution	Intravenous	0.5 mg/1mL
Injection, solution	Intravenous	1 mg/1mL
Injection	Intramuscular; Intravenous	1 mg/1mL
Injection	Intramuscular; Intravenous	10 mg/2mL
Injection	Intramuscular; Intravenous	2 mg/2mL
Injection	Intramuscular; Intravenous	5 mg/1mL
Injection, solution	Intramuscular; Intravenous	1 mg/1mL
Injection, solution	Intramuscular; Intravenous	5 mg/1mL
Syrup	Oral	10 mg/5mL
Syrup	Oral	2 mg/1mL
Injection, solution
Injection, solution	Intramuscular; Intravenous; Rectal
Solution	Intramuscular; Intravenous
Solution
Tablet, film coated	Oral
Injection
Injection, solution	Intravenous
Troche	Sublingual
Spray	Nasal	5 mg/0.1mL
Solution	Oral
Injection, solution	Intramuscular	5 mg/1mL

Prices

Unit description	Cost	Unit
Midazolam 5 mg/ml	3.9USD	ml
Midazolam-nacl 2 mg/ml inj	2.31USD	ml
Midazolam hcl 5 mg/ml vial	1.18USD	ml
Midazolam-nacl 1 mg/ml inj	1.13USD	ml
Midazolam hcl 2 mg/ml syrup	1.08USD	ml
Midazolam 1 mg/ml isecure syr	0.73USD	ml
Midazolam hcl 1 mg/ml vial	0.26USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9289432	No	2016-03-22	2028-01-18
US9687495	No	2017-06-27	2028-01-18
US8217033	No	2012-07-10	2028-01-18
US8809322	No	2014-08-19	2028-01-18

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	161-164	MSDS
boiling point (°C)	497	MSDS
water solubility	soluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.00987 mg/mL	ALOGPS
logP	3.89	ALOGPS
logP	3.33	ChemAxon
logS	-4.5	ALOGPS
pKa (Strongest Basic)	6.57	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	30.18 Å²	ChemAxon
Rotatable Bond Count	1	ChemAxon
Refractivity	99.43 m³·mol^-1	ChemAxon
Polarizability	32.7 Å³	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.9724
Caco-2 permeable	+	0.8866
P-glycoprotein substrate	Non-substrate	0.5074
P-glycoprotein inhibitor I	Inhibitor	0.5587
P-glycoprotein inhibitor II	Inhibitor	0.8388
Renal organic cation transporter	Inhibitor	0.7476
CYP450 2C9 substrate	Non-substrate	0.7366
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Substrate	0.7194
CYP450 1A2 substrate	Inhibitor	0.8586
CYP450 2C9 inhibitor	Inhibitor	0.7132
CYP450 2D6 inhibitor	Non-inhibitor	0.6887
CYP450 2C19 inhibitor	Inhibitor	0.6554
CYP450 3A4 inhibitor	Non-inhibitor	0.5214
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.9001
Ames test	Non AMES toxic	0.8024
Carcinogenicity	Non-carcinogens	0.7703
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	3.1488 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9827
hERG inhibition (predictor II)	Non-inhibitor	0.7379

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Mass Spectrum (Electron Ionization)	MS	splash10-03di-3839000000-42781254e15bcd5b31b6
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-004i-0009000000-2411220f611ba30ef225
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-004i-0009000000-c724b297ae99edb399d3
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-004l-0098000000-b57c162c4eeaad9ef111
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-0006-0090000000-a3133528f5491f4c9a6b
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-05fs-0290000000-ee126555f849ecfff795
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-004i-0009000000-4ae622c7b53369b0cfb1
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-004i-0019000000-00c3c9e2813a454acda1
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-002f-0093000000-a8ca99ef6c84536bff07
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-0006-0091000000-3edc4aa6f67d99b789a8
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-0abd-0290000000-aa5e16437618ad2adb86
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-05fs-0490000000-a323090224c5b01e3990
MS/MS Spectrum - , positive	LC-MS/MS	splash10-004i-0189000000-6e704a4a2a65211394ab
MS/MS Spectrum - , positive	LC-MS/MS	splash10-03di-0910000000-98021a5812f1663e9397

Targets

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Details1. GABA(A) Receptor (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: Yes
Actions: Positive allosteric modulator
Curator comments: The GABA(A) receptor is pentameric (i.e. comprising 5 subunit proteins) and therefore has a multitude of potential isoforms. The above target is a collection of all possible GABA(A) subunits that may participate in the formation of the pentameric receptor and is not meant to imply direct a drug-protein interaction for each individual subunit.

General Function: Inhibitory extracellular ligand-gated ion channel activity
Specific Function: Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:

Name	UniProt ID
Gamma-aminobutyric acid receptor subunit alpha-1	P14867
Gamma-aminobutyric acid receptor subunit alpha-2	P47869
Gamma-aminobutyric acid receptor subunit alpha-3	P34903
Gamma-aminobutyric acid receptor subunit alpha-4	P48169
Gamma-aminobutyric acid receptor subunit alpha-5	P31644
Gamma-aminobutyric acid receptor subunit alpha-6	Q16445
Gamma-aminobutyric acid receptor subunit beta-1	P18505
Gamma-aminobutyric acid receptor subunit beta-2	P47870
Gamma-aminobutyric acid receptor subunit beta-3	P28472
Gamma-aminobutyric acid receptor subunit delta	O14764
Gamma-aminobutyric acid receptor subunit epsilon	P78334
Gamma-aminobutyric acid receptor subunit gamma-1	Q8N1C3
Gamma-aminobutyric acid receptor subunit gamma-2	P18507
Gamma-aminobutyric acid receptor subunit gamma-3	Q99928
Gamma-aminobutyric acid receptor subunit pi	O00591
Gamma-aminobutyric acid receptor subunit theta	Q9UN88

References

Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]

Details2. GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: Yes
Actions: Ligand
Curator comments: Benzodiazepines modulate GABA(A) function by binding at the interface between alpha (α) and gamma (γ) subunits. Of the 6 α-subunits, only 4 (α-1, -2, -3, and -5) participate in the formation of this binding site. The above target is a collection of all α- and γ-subunits that are known to participate in the formation of the benzodiazepine binding site.

General Function: Inhibitory extracellular ligand-gated ion channel activity
Specific Function: Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:

Name	UniProt ID
Gamma-aminobutyric acid receptor subunit alpha-1	P14867
Gamma-aminobutyric acid receptor subunit alpha-2	P47869
Gamma-aminobutyric acid receptor subunit alpha-3	P34903
Gamma-aminobutyric acid receptor subunit alpha-5	P31644
Gamma-aminobutyric acid receptor subunit gamma-1	Q8N1C3
Gamma-aminobutyric acid receptor subunit gamma-2	P18507
Gamma-aminobutyric acid receptor subunit gamma-3	Q99928

References

Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]
Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]

Enzymes

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	>33000	N/A	N/A	A28806
IC 50 (nM)	8100	N/A	N/A	A15818

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Foti RS, Rock DA, Wienkers LC, Wahlstrom JL: Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos. 2010 Jun;38(6):981-7. doi: 10.1124/dmd.110.032094. Epub 2010 Mar 4. [Article]
Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H: Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica. 1998 Dec;28(12):1203-53. [Article]
Zhou S, Chan E, Lim LY, Boelsterli UA, Li SC, Wang J, Zhang Q, Huang M, Xu A: Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab. 2004 Oct;5(5):415-42. [Article]
Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, Wrighton SA: Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002 Aug;30(8):883-91. [Article]
Galetin A, Clarke SE, Houston JB: Quinidine and haloperidol as modifiers of CYP3A4 activity: multisite kinetic model approach. Drug Metab Dispos. 2002 Dec;30(12):1512-22. [Article]
Obach RS, Reed-Hagen AE: Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab Dispos. 2002 Jul;30(7):831-7. [Article]
Flockhart Table of Drug Interactions [Link]

Details2. UDP-glucuronosyltransferase 1-4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Protein homodimerization activity
Specific Function: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name: UGT1A4
Uniprot ID: P22310
Uniprot Name: UDP-glucuronosyltransferase 1-4
Molecular Weight: 60024.535 Da

References

Klieber S, Hugla S, Ngo R, Arabeyre-Fabre C, Meunier V, Sadoun F, Fedeli O, Rival M, Bourrie M, Guillou F, Maurel P, Fabre G: Contribution of the N-glucuronidation pathway to the overall in vitro metabolic clearance of midazolam in humans. Drug Metab Dispos. 2008 May;36(5):851-62. doi: 10.1124/dmd.107.019539. Epub 2008 Feb 6. [Article]
Hyland R, Osborne T, Payne A, Kempshall S, Logan YR, Ezzeddine K, Jones B: In vitro and in vivo glucuronidation of midazolam in humans. Br J Clin Pharmacol. 2009 Apr;67(4):445-54. doi: 10.1111/j.1365-2125.2009.03386.x. [Article]
Seo KA, Bae SK, Choi YK, Choi CS, Liu KH, Shin JG: Metabolism of 1'- and 4-hydroxymidazolam by glucuronide conjugation is largely mediated by UDP-glucuronosyltransferases 1A4, 2B4, and 2B7. Drug Metab Dispos. 2010 Nov;38(11):2007-13. doi: 10.1124/dmd.110.035295. Epub 2010 Aug 16. [Article]
Liu Y, She M, Wu Z, Dai R: The inhibition study of human UDP-glucuronosyltransferases with cytochrome P450 selective substrates and inhibitors. J Enzyme Inhib Med Chem. 2011 Jun;26(3):386-93. doi: 10.3109/14756366.2010.518965. Epub 2010 Oct 13. [Article]

Details3. Cytochrome P450 3A5

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Oxygen binding
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP3A5
Uniprot ID: P20815
Uniprot Name: Cytochrome P450 3A5
Molecular Weight: 57108.065 Da

References

Patki KC, Von Moltke LL, Greenblatt DJ: In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab Dispos. 2003 Jul;31(7):938-44. [Article]
Wandel C, Bocker R, Bohrer H, Browne A, Rugheimer E, Martin E: Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br J Anaesth. 1994 Nov;73(5):658-61. [Article]

Details4. Cytochrome P450 3A7

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Oxygen binding
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP3A7
Uniprot ID: P24462
Uniprot Name: Cytochrome P450 3A7
Molecular Weight: 57525.03 Da

References

Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, Wrighton SA: Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002 Aug;30(8):883-91. [Article]

Drug created on June 13, 2005 13:24 / Updated on May 10, 2021 04:39

Midazolam

Identification

Structure for Midazolam (DB00683)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

Components:

References

Components:

References

Enzymes

References

References

References

References