Midazolam

Article Author:
Thejasvi Lingamchetty
Article Editor:
Abdolreza Saadabadi
Updated:
10/9/2019 2:47:55 PM
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Midazolam

Indications

Intravenous midazolam is used for the induction of anesthesia and also in the management of acute seizures. Because of its water-soluble nature, midazolam has a rapid onset of action and can be used to manage status epilepticus when intravenous administration of other medications is not feasible. Midazolam has a high rate of tolerance and dose can be increased to maintain the therapeutic effect. Because of its easy mode of administration through buccal and intranasal route, it is a viable option in children for the management of seizures. For its use in anesthesia, the response to the induction dose is more variable compared to thiopental. Midazolam can be used for anxiolysis and hypnosis during the maintenance phase of general anesthesia and is also superior to thiopental in the maintenance of anesthesia because of the less need for adjunct medications. Midazolam is used as an adjunct medication to regional and local anesthesia for a wide range of diagnostic and therapeutic procedures and has greater patient and physician acceptance.[1][2][3]

Mechanism of Action

Midazolam has poor oral absorption and has an elimination half-life of 1.5-2.5 hours. Midazolam converts into its active metabolite alpha-1 hydroxy midazolam which contributes to 10% of drug action. Midazolam metabolism occurs via hepatic CYP450 enzymes and glucuronide conjugation. The mechanism of action of midazolam indirect and is related to GABA accumulation and its affinity to benzodiazepine receptor. Two separate receptors for GABA and benzodiazepine are coupled to a common chloride channel. It increases the frequency of chloride channel opening. Occupation of both the receptors cause membrane hyperpolarization and neuronal inhibition. The anticonvulsant activity of midazolam is related to the excess GABA action on motor circuits in the brain. Midazolam acts on glycine receptors and produces muscle relaxation effect. Almost all the pharmacologic effects including sedation, anxiolysis, anterograde amnesia, and anticonvulsant effect can are explainable through its action on GABA receptors. Age-related deficits, hepatic and renal insufficiency also affect the pharmacokinetics of midazolam.[4][5][6][7]

Administration

Midazolam administration can be through oral, intranasal, buccal, intravenous, and intramuscular routes. For the perioperative use of midazolam, the induction dose is 0.15-0.40 mg/kg via the intravenous route. For the premedication, the dose is 0.07-0.10 mg/kg with the intramuscular route. For intravenous sedation, the dose is titrated at 0.05-0.15 mg/kg. For children 1-5 months old, an intranasal dose of 0.2mg/kg is recommended. For children 6 months and older, 0.2-0.3 mg/kg intranasal dose is recommended.[1]

Adverse Effects

The common adverse effects associated with midazolam use are hiccoughs, cough, nausea, and vomiting. Thrombophlebitis, thrombosis, and pain on injection are other adverse effects. The incidence of thrombophlebitis is less than with diazepam but similar to that of thiopental. Midazolam causes anterograde amnesia, drowsiness, ataxia, falls and confusion in the elderly. Residual hangover effect can happen with nighttime administration of midazolam which can impair the cognitive and psychomotor abilities, which can result in falls in elderly and impaired coordination during driving. Hypotension and tachycardia can occur with rapid intravenous administration. A higher dose can result in midazolam infusion syndrome and respiratory depression. Instances of midazolam infusion syndrome require continuous ventilator support. Paradoxical effects of midazolam are possible in individuals with a history of alcohol abuse and aggressive behavior, potentially leading to involuntary movements, verbalization, uncontrollable crying, and aggressive behavior. Respiratory depression can happen with a dose of 0.15 mg/kg and the risk increases when used along with fentanyl. Concomitant use of midazolam with other CNS depressants can result in severe respiratory depression and death even at therapeutic doses.

Long-term use of midazolam is associated with lasting memory deficits which are only partially reversible after the discontinuation of the drug. For the pregnant women, the administration of the drug in third-trimester causes benzodiazepine withdrawal syndrome in the neonate resulting in hypotonia, cyanosis, and apnoeic spells. Neonate may suffer from diarrhea, tremors, and hyperexcitability. About one-third of individuals receiving midazolam can suffer from tolerance after using the drug for four weeks. Withdrawal syndrome can occur if the dose is tapered rapidly. Symptoms due to the withdrawal of benzodiazepine include irritability, clonus, hypertonicity, nausea, vomiting, diarrhea, tachycardia, and hypertension. Sudden discontinuation of midazolam can result in status epilepticus.[8][9][10][11]

Contraindications

Contraindications for the use of midazolam include the acute angle closure glaucoma, hypotension, and shock. Careful dose adjustment is necessary in cases of kidney and liver diseases, alcohol and drug dependent individuals. Caution must be exercised in pregnant individuals, children and individuals with comorbid psychiatric conditions. In elderly individuals and acutely ill patients, caution should be exercised to prevent accumulation of active metabolites. Extra precautions should be taken in critically ill individuals as dose accumulation can occur.[12][13]

Monitoring

Frequent monitoring of blood levels of midazolam and its metabolites is a requirement during the treatment of midazolam overdose. Levels of midazolam and its metabolites can are measurable in blood, plasma, and serum. Monitoring is essential for elderly individuals and individuals with liver and kidney disease. The elimination of both the drug and its metabolite decreases with renal insufficiency. Monitoring is also necessary for drug interactions with erythromycin, clarithromycin, diltiazem, sertraline, protease inhibitors, rifampin, phenytoin, phenobarbital, carbamazepine, opioids, antipsychotics, and alcohol. Induction and inhibition of CYP450 3A4 play a role in decreased and increased levels of the drug in the circulation. Grapefruit juice reduces the activity of CYP 450 enzyme and increases the level of the drug. St. John's wort induces the enzyme and reduces the blood level of midazolam.[1][14][7]

Toxicity

Toxicity with midazolam is rare but can happen when combined with other CNS depressants like alcohol, opioids, and other tricyclic antidepressants. The risk increases with intravenous administration and in elderly individuals with COPD. Symptoms of overdose include ataxia, nystagmus, hypotension, slurred speech, slurred speech, impaired motor coordination, coma, and death. Impaired reflexes, impaired balance and dizziness, dysarthria, and vasomotor collapse can also occur. Flumazenil is the antidote for midazolam toxicity[15] Supportive treatment is the initial therapy course. Activated charcoal may be used within 1 hour of intoxication. In many instances, flumazenil is not prudent, as it can precipitate seizures when used in a mixed overdose of CNS depressants. Rapid intravenous infusion in elderly individuals having COPD can also result in overdose.[15][6]

Enhancing Healthcare Team Outcomes

All healthcare workers who use midazolam should know what to do in case of an overdose. Resuscitative equipment and flumazenil must be available in the room when using this agent. The drug is relatively safe but is known to cause respiratory depression, especially when combined with fentanyl.


References

[1] Reves JG,Fragen RJ,Vinik HR,Greenblatt DJ, Midazolam: pharmacology and uses. Anesthesiology. 1985 Mar     [PubMed PMID: 3156545]
[2] Appleton R,Macleod S,Martland T, Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. The Cochrane database of systematic reviews. 2008 Jul 16     [PubMed PMID: 18646081]
[3] Walker M, Status epilepticus: an evidence based guide. BMJ (Clinical research ed.). 2005 Sep 24     [PubMed PMID: 16179702]
[4] Richter JJ, Current theories about the mechanisms of benzodiazepines and neuroleptic drugs. Anesthesiology. 1981 Jan     [PubMed PMID: 6109471]
[5] Spina SP,Ensom MH, Clinical pharmacokinetic monitoring of midazolam in critically ill patients. Pharmacotherapy. 2007 Mar     [PubMed PMID: 17316150]
[6] Olkkola KT,Ahonen J, Midazolam and other benzodiazepines. Handbook of experimental pharmacology. 2008     [PubMed PMID: 18175099]
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