Midazolam

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Structural formula
Midazolam structural formula
General
Non-proprietary name Midazolam
other names

8-chloro-6- (2-fluorophenyl) -1-methyl-4 H -imidazo [1,5- a ] [1,4] benzodiazepine

Molecular formula C 18 H 13 ClFN 3
Brief description

white to yellowish, crystalline powder

External identifiers / databases
CAS number
PubChem 4192
DrugBank DB00683
Wikidata Q423071
Drug information
ATC code

N05 CD08

Drug class

Hypnotic Benzodiazepine Sedative

properties
Molar mass
  • 325.77 g · mol -1 (midazolam)
  • 362.23 g · mol -1 (· midazolam hydrochloride)
Physical state

firmly

Melting point

158-160 ° C (midazolam)

solubility

soluble in water (midazolam hydrochloride)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Midazolam is a drug from the group of short-acting benzodiazepines . Midazolam has a sleep-promoting , calming , anxiety-relieving ( anxiolytic ) and relaxing ( relaxing ) effect on the skeletal muscles. There are dosage forms for buccal , oral , rectal and parenteral administration.

The name midazolam is derived from imidazole .

Clinical information

application areas

Midazolam is used in anesthesiology and emergency services. Another indication is in patients who suffer from epilepsy, in children with forms of epilepsy such as B. West Syndrome and Lennox-Gastaut Syndrome .

Anaesthesiology and Intensive Care Medicine

As a sedative, midazolam is used in anesthesiology for premedication before operations. As part of an analgesic sedation with ( S ) - ketamine (esketamine), midazolam is administered at the same time in order to induce anterograde amnesia (reduced memory for upcoming consciousness). The guidelines of the anesthesiologists describe this as necessary because the associated pseudo-hallucinations caused by esketamine represent an extreme burden for patients and can subsequently lead to recurrent disorders , mostly post-traumatic stress disorder (PTSD) or anxiety disorders.

Another application in intensive care medicine is the administration of a continuous infusion via a perfusor ( syringe pump ) for several days of sedation .

Similar to the (emergency) short-term hypnotics propofol and etomidate, midazolam has no analgesic (pain reliever ) effect. The additional administration of an analgesic is therefore essential in painful conditions. Sedation with midazolam alone is possible, but this is a rather rare indication.

Anticonvulsant therapy for epilepsy

Under the trade name Buccolam , midazolam is used in the oral cavity ( buccal ) to stop prolonged seizures in babies, toddlers, children and adolescents (between 3 months and under 18 years of age). It should only be used in infants aged 3 months to less than 6 months in a clinic with monitoring facilities and appropriate resuscitation equipment. This medicine should only be given by parents / carers if the child has been diagnosed with epilepsy .

Off-label nasal administration in younger patients is described.

Use during pregnancy and breastfeeding

There is clear evidence of risks to the human fetus associated with benzodiazepine administration during pregnancy. Particular caution is required if benzodiazepines are used towards the end of pregnancy and during childbirth, as irregular heart rates and hypotension in the fetus and inadequate suction, respiratory depression , decreased activity and decreased muscle tone ( floppy infant syndrome ) in the newborn. as well as withdrawal symptoms and hypothermia can occur. In animal experiments there was also evidence of behavioral disorders in the offspring of dams who were administered benzodiazepines during pregnancy. Midazolam should therefore not be used during pregnancy unless clearly necessary. Since midazolam can pass into breast milk in small amounts (approx. 0.6%) , it should not be used in breastfeeding mothers. After a single dose, it may not be necessary to wean.

Addictive potential

After a short period of use, psychological dependence can develop. In the higher-dose dosage forms, the substance only plays a subordinate role - not least because it is subject to the Narcotics Act . On the other hand, it is successfully used to break epileptic seizures .

Use in executions

As a substitute for the previously in the United States used pentobarbital midazolam was first in on January 16, 2014 execution of Dennis McGuire injected. Although multiple executions subsequently took 40 minutes to two hours to die, the United States Supreme Court dismissed a death row lawsuit in Oklahoma on June 29, 2015 and continues to allow the drug to be used in executions. In 2017, US midazolam stocks were nearing shelf life. Therefore, for the first time after 2005, more executions were scheduled. Pharmaceutical manufacturers of the substances used tried to stop the executions in court, and European countries protested against the procedure.

Pharmacological and toxicological properties

Mechanism of action

The pharmacological effect arises from the allosteric modulation of special receptors of nerve cells , the α3-GABA A receptors, which, as with all benzodiazepines in the central nervous system (CNS), increases the effect of the body's own transmitter substance γ-aminobutyric acid (GABA). GABA mostly has an inhibitory effect on the nerve cells in the CNS. Midazolam also has moderate anticonvulsant effects.

Uptake, distribution and elimination

Midazolam is rapidly absorbed; maximum plasma concentrations are reached within 30 minutes after buccal, intramuscular and rectal administration and after approximately 1 hour after oral administration. In adults, the bioavailability after intramuscular administration is over 90%, after application in the oral cavity approx. 75%, after rectal administration approx. 50% and after oral administration - due to a high first-pass effect - approx. 30-70% .

Midazolam is very lipophilic and is widely distributed in adipose tissue. After i. v. Injection, the plasma concentration-time curves show one to two distinct distribution phases. The volume of distribution in the steady state is, according to i. v. administration around 0.7–1.2 l / kg, after application in the oral cavity an estimated 5.3 l / kg. An accumulation can result in a significant increase in the duration of action. Midazolam is 96–98% bound to plasma proteins in the plasma.

Most midazolam is eliminated via biotransformation; only less than 1% is found unchanged in the urine. In the liver cells , hydroxylation takes place first using the cytochrome P450 system. The main metabolite is 1-hydroxymidazolam, which is also pharmacologically active (but to a lesser extent than midazolam) and contributes to the effect. The hydroxylation as the first step of inactivation can be caused by other drugs, as well as by rare diseases such as z. B. the Crigler-Najjar syndrome can be disabled. Conjugation with a glucuronic acid follows . The glucuronated metabolites are excreted in the bile . The elimination half-life for midazolam in healthy volunteers is given as 1.5 to 2.5 hours, for 1-hydroxymidazolam it is less than 1 hour. After buccal administration, an initial half-life of 27 minutes on average and a terminal half-life of 204 minutes on average were determined in children and adolescents.

The pharmacokinetics are changed in certain patient groups. The elimination half-life can be up to four times longer in patients over 60 years of age. In children, the bioavailability after rectal absorption is lower than in adults, the elimination half-life after i. v. and rectal application is shorter than in adults at 1–1.5 hours. The elimination half-life in newborns averages 6–12 hours. In overweight patients, the mean half-life is greater than in non-overweight patients, due to an increase in the volume of distribution corrected for total body weight. The clearance is comparable in overweight and normal weight people.

toxicology

The effect of midazolam can be quickly reversed by giving the antidote flumazenil . The terminal half-life of flumazenil is shorter than that of midazolam. It is therefore possible that midazolam will start working again because the antidote has been metabolized. The administration of the antidote must be monitored.

Triggers paradoxical reactions

Of 2617 children who had received midazolam as a sedative during endoscopic treatments , 1.4% showed a paradoxical reaction . Instead of dampening, the remedy had an exciting effect here. Furthermore, there are detailed case descriptions where the arousal in patients led to tears and aggressive behavior. As a successful and fast-acting antidote ( antidote ) has in such cases flumazenil proven. Typically, after the paradoxical reaction has been resolved, the patients have no memory of their behavior under midazolam, which is attributed to the substance's prevention of new memory contents ( anterograde amnesia ).

Chemical and pharmaceutical aspects

Midazolam is a derivative of the imidazobenzodiazepine series . In addition to the free base , salts of maleic acid and hydrochloric acid are marketed, as are midazolamaleate and midazolam hydrochloride . These two salts do not differ in biological activity from the free base.

Due to the acidic pH of the midazolam preparations, the ring structure opens and midazolam becomes water-soluble. With the intranasal application of midazolam preparations, which can be done in exceptional cases, the acidic solution therefore leads to an unpleasant burning sensation. Once introduced into the body, the ring structure of midazolam closes and it becomes fat-soluble so that it can cross the blood-brain barrier.

Legal status

In Germany, midazolam is a narcotic within the meaning of the BtMG (Appendix III). Exceptions to this are preparations with a maximum of 0.2% midazolam or 15 mg midazolam per divided unit, as is the case with Buccolam, which is approved for ending a prolonged seizure in infants, toddlers, children and adolescents . Thus, medications containing midazolam are generally subject to prescription in Germany . In the Netherlands, midazolam is one of the List II drugs of the Opium Act (Opiumwet). Midazolam is listed under Table IV Drugs on the Controlled Substances Lists of the Convention on Psychotropic Substances . Midazolam is on List III of Controlled Drugs in the UK.

Trade names

Midazolam is sold by Roche under the trade name Dormicum and is now also available as a generic drug. It is marketed by ViroPharma, a Shire plc company , under the name Buccolam to stop a prolonged seizure (epilepsy) . Midazolam is marketed under the name Versed in the United States . Ratiopharm also sells a liquid solution for oral use.

Others

Midazolam was of particular interest to CIA doctors because the drug can cause memory loss, among other things .

Web links

  • Poisons Information Monograph (PIM) for midazolam

Individual evidence

  1. ↑ Midazolam data sheet (PDF) at EDQM , accessed on June 23, 2008.
  2. ^ A b The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; P. 1066, ISBN 978-0-911910-00-1 .
  3. ↑ Midazolam hydrochloride data sheet from Sigma-Aldrich , accessed on April 10, 2011 ( PDF ).
  4. ^ A b c A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2001) Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 .
  5. ↑ Buccolam package leaflet.
  6. ↑ HJ Koch, F. Matthiessen: Nasal application - On the direct route to the site of action , Pharmazeutische Zeitung, issue 50/2006.
  7. ↑ a b c d e Specialist information Dormicum injection solution (Roche Pharma (Switzerland) AG); Information as of November 2015.
  8. ↑ a b c d e Specialist information Dormicum film tablets (Roche Pharma AG); Information as of November 2017.
  9. ↑ M. muskal: Ohio execution: New drug protocol, but 15 minutes to the. In: Los Angeles Times . January 16, 2014, accessed May 5, 2014 .
  10. ↑ After torturous executions: Supreme US court rejects sedative suit , Der Spiegel , June 29, 2015.
  11. ↑ Death Penalty: Arkansas executes prisoner for the first time in twelve years. In: Zeit Online. April 21, 2017. Retrieved April 21, 2017 .
  12. ↑ http://m.faz.net/aktuell/gesellschaft/kriminalitaet/arkansas-richten-zwei-haeftlinge-an-einem-tag-hin-14986623
  13. ↑ a b c d Technical information on Buccolam .
  14. ↑ S3-guideline for analgesia, sedation and delirium management in intensive care medicine , AWMF registration number 001/012, available online as a pdf ; Retrieved December 12, 2015.
  15. ↑ C. Robin, N. Trieger: Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature. In: Anesthesia progress. Volume 49, Number 4, 2002, pp. 128-132, PMID 12779114 , PMC 2007411 (free full text) (review).
  16. ↑ AA Weinbroum, O. Szold, D. Ogorek, R. Flaishon: The midazolam-induced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature. In: European journal of anaesthesiology. Volume 18, Number 12, December 2001, pp. 789-797, PMID 11737177 (review), PDF .
  17. ^ Franz Kehl: Anesthesia questions and answers 1655 facts for the specialist examination and the European diploma for anesthesiology and intensive medicine (DESA) . Springer, Berlin 2013, ISBN 978-3-642-35034-4 .
  18. ↑ BtMG: Annex III (to § 1 Paragraph 1) marketable and prescription narcotics .
  19. ↑ The Fight Against Terrorism: CIA Searched For "Truth Serum". n-tv , November 14, 2018, accessed November 14, 2018 .
  20. ↑ CIA doctors considered using 'truth serum' on terror suspects. The Guardian , November 14, 2018, accessed November 14, 2018 .