Midazolam
Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation.[10] It induces sleepiness, decreases anxiety, and causes anterograde amnesia.[10]
"Versed" redirects here. For the book of poetry, see Versed (poetry collection).
The drug does not cause an individual to become unconscious, merely to be sedated.[10] It is also useful for the treatment of prolonged (lasting over 5 minutes) seizures.[12] Midazolam can be given by mouth, intravenously, by injection into a muscle, by spraying into the nose, or through the cheek.[10][12] When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working.[10] Effects last between one and six hours.
Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness.[10] Tolerance to its effects and withdrawal syndrome may occur following long-term use.[13] Paradoxical effects, such as increased activity, can occur especially in children and older people.[13] There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding.[14][15] Like other benzodiazepines, it works by increasing the activity of the GABA neurotransmitter in the brain.
Midazolam was patented in 1974 and came into medical use in 1982.[16] It is on the World Health Organization's List of Essential Medicines.[17] Midazolam is available as a generic medication.[14] In many countries, it is a controlled substance.[10]
Medical uses[edit]
Seizures[edit]
Midazolam is sometimes used for the acute management of prolonged seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation.[18] A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus.[19][20] Midazolam is effective for status epilepticus or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.
Drawbacks include a high degree of breakthrough seizures—due to the short half-life of midazolam—in over 50% of people treated, as well as treatment failure in 14–18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days.[13][21] Buccal and intranasal midazolam may be both easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.[22][23][24]
Procedural sedation[edit]
Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), preoperative sedation, for the induction of general anesthesia, and for sedation of people who are ventilated in critical care units.[25][26] Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect.[27] It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action,[28] and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.[29]
Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications.[30]
Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.[31]
Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.[32]
Agitation[edit]
Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.[33]
End of life care[edit]
In the final stages of , midazolam is routinely used at low doses via subcutaneous injection to help with agitation, restlessness or anxiety in the last hours or days of life.[34] At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments,[35] but the need for this is rare.[36]
Contraindications[edit]
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders.[37] Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur.[38] Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects.[39][40] Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.
Interactions[edit]
Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John's wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam.[13] Midazolam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam.[61] St John's wort decreases the blood levels of midazolam.[62] Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.[63]
Pharmacology[edit]
Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5–2.5 hours.[11] In the elderly, as well as young children and adolescents, the elimination half-life is longer.[42][64] Midazolam is metabolised into an active metabolite alpha-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite.[65] However, the active metabolite of midazolam is minor and contributes to only 10% of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream.[13] Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. Oxidation of midazolam is the major metabolite in human liver microsome (HLM).[66] The half life (t1⁄2) of midazolam in HLM is 3.3 minutes.[66] The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the endogenous neurotransmitter GABA on the GABAA receptors (increasing the frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.[39]
History[edit]
Midazolam is among about 35 benzodiazepines currently used medically,[67] and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States.[68] Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs.[69][70] The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus.[71] As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine.[72] In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site.[67] Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility.[73] In 2018 it was revealed the CIA considered using midazolam as a "truth serum" on terrorist suspects in project "Medication".[74]
Society and culture[edit]
Availability[edit]
Midazolam is available in the United States as a syrup or as an injectable solution.[75]
Dormicum brand midazolam is marketed by Roche as white, oval, 7.5 mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15 mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with "Roche" on one side and the dose of the tablet on the other side. Dormicum is also available as 1, 3, and 10 mL ampoules at a concentration of 5 mg/mL. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3 and 5 mL ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, midazolam HCl Syrup, 2 mg/mL clear, in a red to purplish-red syrup, cherry in flavor. It becomes soluble when the injectable solution is buffered to a pH of 2.9–3.7. Midazolam is also available in liquid form.[13] It can be administered intramuscularly,[20] intravenously,[76] intrathecally,[77] intranasally,[23] buccally,[78] or orally.[13]
Legal status[edit]
In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances.[79] In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug.[80] In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.[81]
Marketing authorization[edit]
In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the brand name Buccolam. Buccolam was initially approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.[82][83]