Midazolam

Midazolam (, and marketed in English-speaking countries under brand names Dormicum, Hypnovel, and Versed) is a short-acting drug in the benzodiazepine class that is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It has potent anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties. 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. Paradoxical effects occasionally occur and are most common in children, the elderly, Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The benzodiazepine drug alprazolam was synthesised in 1976 from midazolam and introduced to the United States market in 1981. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerged as an effective treatment for convulsive status epilepticus. , it is the most commonly used benzodiazepine in anesthetic medicine. 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. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility.

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. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. 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, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation. There is evidence buccal and intranasal midazolam is easier to administer and more effective than rectally administered diazepam in the emergency control of seizures. 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. 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, but the need for this is more rare. 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.

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, it is not used for patients who have trouble staying asleep through the night; moderate to long acting benzodiazepines, such as 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.

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. 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. 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. Midazolam is effective for 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.

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 water-soluble benzodiazepine available. It becomes soluble when the injectable solution is buffered to a pH of 2.9–3.7. Midazolam is also available in liquid form. intrathecally, intranasally, or orally. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow angle glaucoma, shock, hypotension or 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. Other neonatal withdrawal symptoms include hyperexcitability, tremor and gastrointestinal upset (diarrhea or vomiting). Breast feeding by mothers using midazolam is not recommended.

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.

Elderly

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

Long-term use of benzodiazepines has been associated with long-lasting deficits of memory, and show only partial recovery six months after stopping benzodiazepines. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur.

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 CNS effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnea becomes more likely.

Tolerance, dependence and withdrawal

A benzodiazepine dependence occurs in about one third of individuals who are treated with benzodiazepines for longer than 4 weeks,

Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines.

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).

Symptoms of midazolam overdose can include:

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. 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. 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.

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. St John's wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.

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. In the United Kingdom midazolam is a Schedule III controlled drug.

See also

Long term effects of benzodiazepines

Dexmedetomidine

References

External links

PubPK - Midazolam Pharmacokinetics

Rx-List - Midazolam (Versed)

Inchem - Midazolam

Category:Imidazobenzodiazepines Category:Organofluorides Category:Organochlorides Category:Hoffmann-La Roche