Midazolam

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Midazolam
140px
140px
Systematic (IUPAC) name
8-chloro- 6-(2-fluorophenyl)- 1-methyl- 4H-imidazo[1,5-a] [1,4]benzodiazepine
Clinical data
Pregnancy
category
Routes of
administration		 Oral, I.M., I.V., parenteral
Legal status
Legal status
Pharmacokinetic data
Bioavailability Oral ~36%
I.M. 90%+
Metabolism Hepatic
Biological half-life 1.8-6.4 hours
Excretion Renal
Identifiers
CAS Number 59467-70-8
ATC code N05CD08 (WHO)
PubChem CID 4192
DrugBank APRD00680
ChemSpider 4047
Chemical data
Formula C18H13ClFN3
Molar mass 325.78[[Script error: No such module "String".]]
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Midazolam (pronounced /mɪˈdæzəlæm/, and marketed in English-speaking countries under brand names Dormicum,[1] Hypnovel,[2] and Versed[3]) is a short-acting drug in the benzodiazepine class that is used for treatment of acute seizures and for inducing sedation and amnesia before medical procedures. It has potent anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties.[4][5][6] Midazolam has a fast recovery time and is the most commonly used benzodiazepine as a premedication for sedation; less commonly it is used for induction and maintenance of anesthesia. Flumazenil is a benzodiazepine antagonist drug that can be used to treat an overdose of midazolam as well as to reverse sedation.[5] However, flumazenil can trigger seizures in mixed overdoses and in benzodiazepine dependent individuals so is not used in most cases.[7][8]

Administration of midazolam by nose or the buccal route (absorption via the gums and cheek) as an alternative to rectally administered diazepam is becoming increasingly popular for the emergency treatment of seizures in children.[9] Midazolam is also used for endoscopy[10] procedural sedation and sedation in intensive care.[11][12] The anterograde amnesia property of midazolam is useful for premedication before surgery to inhibit unpleasant memories.[13] Midazolam, like many other benzodiazepines, has a rapid onset of action, high effectiveness and low toxicity level. Drawbacks of midazolam include drug interactions, tolerance, withdrawal syndrome as well as adverse events including cognitive impairment and sedation.[13] Paradoxical effects occasionally occur and are most common in children, the elderly,[13] and particularly after intravenous administration.[14]

History

Midazolam is among about 35 benzodiazepines which are currently used medically,[15] and was synthesised in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States.[16] Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs.[17][18] The benzodiazepine drug alprazolam was synthesised in 1976 from midazolam[19][20] and introduced to the United States Market in 1981.[21] The anticonvulsant properties of midazolam were studied in the late 1970s, but it was not until the 1990s that it emerged as an effective treatment for convulsive status epilepticus.[22] As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine.[23] 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.[15] Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility.[24]

Indications

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), for preoperative sedation, for the induction of general anesthesia, and for sedation of ventilated patients in critical care units.[11][12] Midazolam is superior to diazepam in impairing memory of endoscopy procedure but propofol has a quicker recovery time and a better memory impairing effect.[10] 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,[25] and propofol has advantages over midazolam when used in the ICU for sedation such as shorter weaning time and earlier tracheal extubation.[26] There is evidence that buccal and intranasal midazolam is easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.[27][28][29] In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to alleviate agitation, myoclonus, restlessness or anxiety in the last hours or days of life.[30] 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 unresponsive to other treatments;[31] but the need for this is more rare.[32] Midazolam is also sometimes used in neonates who are receiving mechanical ventilation, although morphine is preferred owing to its better safety profile for this indication.[33]

Oral midazolam is indicated for the short term treatment of moderately severe insomnia in patients who have not reacted adequately to other hypnotics, and who have persistent trouble in falling asleep. Because of midazolam's extremely short duration, midazolam is not used for patients who have trouble staying asleep through the night; moderate to long acting benzodiazepines like temazepam, nitrazepam, flunitrazepam and lormetazepam are used for those purposes. Like other benzodiazepines, midazolam produces a decrease in delta activity, though the effect of benzodiazepines on delta may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep; it is thought to reflect sleep quality, with lower levels of delta sleep reflecting poorer sleep. Thus midazolam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to nitrazepam in the treatment of insomnia as it enhances sleep quality based on EEG studies.[34]

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.[35] It is also is sometimes used for the acute management of seizures such as status epilepticus. Long-term use for the management of epilepsy is not recommended however, due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation.[36] A benefit of midazolam is that in children it can be administered buccally or intranasally at home or at school for emergency control of acute seizures including status epilepticus.[9][37] Midazolam is effective for refractory status epilepticus and has advantages of being water soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle which occurs with other benzodiazepines. Drawbacks include a high degree of breakthrough seizures—due to the short half life of midazolam—in over 50 percent of people treated as well as treatment failure in 14–18 percent 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][38]

Availability

Dormicum brand midazolam is marketed by Roche as white, oval 7.5 mg tablets in boxes of 2 or 3 blisterstrips of 10 tablets, and as blue, oval 15 mg tablets in boxes of 2 blisterstrips 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 ml, 3 ml and 10 ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3 ml and 5 ml ampoules. Midazolam is the only benzodiazepine available which is water-soluble. Midazolam becomes soluble when the injectable solution is buffered to a pH of 2.9–3.7. Midazolam is also available in liquid form.[13] Midazolam can be administered intramuscularly,[37] intravenously,[39] intrathecally,[40] intranasally,[28] buccally,[41] or orally.[13]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[42] Additional caution is required in critically ill patients as accumulation of midazolam and its active metabolites may occur.[43] Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects.[5][44] Contraindications include hypersensitivity, acute narrow angle glaucoma, shock, hypotension, head injury. Most are relative contraindications.

Pregnancy

Midazolam when taken during the third trimester of pregnancy may cause severe risk to the neonate, including benzodiazepine withdrawal syndrome with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.[45] Other neonatal withdrawal symptoms include hyper-excitability, tremor and gastro-intestinal upset (diarrhea or vomiting). Breast feeding by mothers using midazolam is not recommended.[46]

Neonates

Midazolam is sometimes used in neonatal intensive care unit care. When used, additional caution is required in neonates; 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.[47]

Elderly

Additional caution is required in the elderly as they are more sensitive to the pharmacological effects of benzodiazepines and also metabolise benzodiazepines more slowly and are more prone to adverse effects including drowsiness, amnesia especially anterograde amnesia, ataxia, hangover effects, confusion and falls.[13]

Side effects

File:Midazolam.JPG
Injectable midazolam in 1 mg/ml and 5 mg/ml strengths

Side effects of midazolam include tolerance, withdrawal symptoms, confusion, amnesia including anterograde amnesia, ataxia, drowsiness, cognitive impairment, sedation and an increased risk of falls in the elderly.[13] People experiencing amnesia as a side effect of midazolam are generally unaware that their memory is impaired.[48]

Long-term use of benzodiazepines has been associated with long-lasting deficits of memory showing only partial recovery after 6 months after stopping benzodiazepines.[13] It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression.[13] Paradoxical excitement occasionally occurs with benzodiazepines including a worsening of seizures. Children and elderly individuals or those with a history of alcohol abuse and individuals with a history of aggressive behavior or anger are at increased risk of paradoxical effects.[13] Paradoxical reactions are particularly associated with intravenous administration.[14] After nighttime administration of midazolam, residual 'hangover' effects—such as sleepiness and impaired psychomotor and cognitive functions—may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures.[49] Sedation, respiratory depression and due to a reduction in systematic vascular resistance hypotension and an increase in heart rate can occur.[5][37] If IV midazolam is given too quickly, hypotension may occur. A “midazolam infusion syndrome” may result from high doses and is characterised by delayed arousal hours to days after discontinuation of midazolam and may lead to an increase in the length of ventilatory support needed.[50]

In susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazapines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behavior, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behavior is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Anti-psychotic medications such as haloperidol have also been used for this purpose.[51]

Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system effect.[52] When midazolam is administered in combination with fentanyl, the incidence of hypoxemia, or apnea becomes more likely.[53]

Tolerance, dependence and withdrawal

A benzodiazepine dependence occurs in about one third of individuals who are treated with benzodiazepines for longer than 4 weeks,[13] which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine which is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a persons underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression which results in long-term changes in the function of the GABAergic neuronal system.[13][54][55]

Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines.[56][57] Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore in order to prevent a withdrawal syndrome a prolonged infusion needs to be gradually withdrawn and sometimes if necessary continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium, and seizures, nausea, vomiting and diarrhea, tachycardia, hypertension and tachypnea.[50]

Overdose

See also: Benzodiazepine overdose

A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life threatening; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and risk of death is also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil (Anexate).[5] While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.[7][8]

Symptoms of midazolam overdose can include:[7][8]

Detection in body fluids

The concentrations of midazolam and/or its major metabolite, 1-hydroxymidazolam glucuronide, may be quantified in plasma, serum or whole blood in order to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.[58]

Pharmacology

Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of one to four hours; however, in the elderly, as well as young children and adolescents, the elimination half life is longer.[6][14] Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite.[59] However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally with only 50 percent of the drug reaching the bloodstream.[13] Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. 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 neurotransmitter GABA on the GABAA receptors (↑ 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, hypnotic, anxiolytic, anterograde amnesia, muscle relaxation and anti-convulsant.[5]

Interactions

HIV protease inhibitors, nefazodone, sertraline, grapefruit juice, 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, opiates, 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.[60] St John's wort decreases the blood levels of midazolam.[61] Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.[62]

Legal status

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.[63] In the United Kingdom midazolam is a Schedule III controlled drug.[64]

See also

References

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External links

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de:Midazolam es:Midazolam eu:Midazolam fa:میدازولام fr:Midazolam it:Midazolam hu:Midazolám nl:Midazolam ja:ミダゾラム no:Midazolam pl:Midazolam pt:Midazolam ro:Midazolam ru:Мидазолам fi:Midatsolaami

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  55. ↑ Cho HH, O'Connell JP, Cooney MF, Inchiosa MA (2007). "Minimizing tolerance and withdrawal to prolonged pediatric sedation: case report and review of the literature". J Intensive Care Med. 22 (3): 173–9. doi:10.1177/0885066607299556. PMID 17569173. 
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  60. ↑ Mc Donnell, CG; Harte, S; O'driscoll, J; O'loughlin, C; Van Pelt, FN; Shorten, GD (2003). "The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam". Anaesthesia. 58 (9): 899–904. doi:10.1046/j.1365-2044.2003.03339.x. PMID 12911366. 
  61. ↑ Hu, Z.; Yang, X.; Ho, PC.; Chan, SY.; Heng, PW.; Chan, E.; Duan, W.; Koh, HL.; Zhou, S. (2005). "Herb-drug interactions: a literature review". Drugs. 65 (9): 1239–82. doi:10.2165/00003495-200565090-00005. PMID 15916450. 
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  64. ↑ Blackpool NHS Primary Care Trust (2007). "Medicines Management Update" (PDF). United Kingdom: National Health Service. 
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