Midazolam – use, action, dosage, side effects

Proven content

Midazolam, i.e. a benzodiazepine drug used for anesthesia, to calm down before the procedure, in case of sleep problems and strong agitation. It is also useful in treating seizures. Midazolam can be administered orally, intravenously, or injected into a muscle, or by spraying into the nose. When injected into a vein it usually starts working within five minutes and when injected into a muscle within 15 minutes. Its effects last from one to six hours. It is included in the list of essential medicines of the World Health Organization. It is a controlled substance in many countries.

Midazolam – application

Midazolam and epileptic seizures

Midazolam is sometimes used in the acute treatment of seizures. Long-term use in the treatment of epilepsy is not recommended due to the high risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation.

The advantage of midazolam is that in children it can be administered directly to the inside of the cheek or nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus that has not improved with other therapies or for when the drug cannot be given intravenously. It also has the advantage of being water soluble, acting quickly, and not causing the metabolic acidosis from the propylene glycol carrier (which is not required for water solubility) that occurs with other benzodiazepines.

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Midazolam and procedural sedation

Intravenous midazolam is indicated for operative sedation (often in combination with an opioid such as fentanyl), for preoperative sedation, for induction of general anesthesia, and for sedation of ventilated patients in intensive care units.

It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with water solubility and the possibility of continuous infusion. However, for long-term sedation, lorazepam is preferred because of its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, e.g. pre-intubation.

Midazolam is sometimes used in neonatal intensive care units. In the case of its use, additional caution is required in newborns; midazolam should not be used for more than 72 hours due to the risk of tachyphylaxis and possible benzodiazepine withdrawal syndrome as well as neurological complications.

Bolus injections should be avoided due to an increased risk of cardiovascular depression as well as neurological complications. Midazolam is also sometimes used in neonates undergoing mechanical ventilation, although morphine is preferred due to its better safety profile in this indication.

Sedation with midazolam can be used to relieve anxiety and control behavior in children undergoing dental treatment.

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Midazolam at schizophrenia

Midazolam in combination with an antipsychotic is indicated for the acute treatment of schizophrenia when it is associated with aggressive or uncontrolled behavior.

Midazolam – another use

In the end stages of palliative care, midazolam is routinely used in low doses by subcutaneous injection to help with muscle breakdown, anxiety or anxiety in the last hours or days of life. At higher doses in the last weeks of life, midazolam is considered the first agent for palliative, continuous, deep sedation when it is necessary to alleviate unbearable suffering that is unresponsive to other forms of therapy, but the need is rare.

Midazolam – dosage

The appropriate dose of midazolam depends on factors such as:

1. body weight,
2. patient’s age,
3. comorbidities,
4. the severity of the symptoms.

In addition, it is recommended to take midazolam at bedtime, and after oral ingestion of the drug substance, the patient should be allowed to rest for at least eight hours.

The recommended dose is between 7.5 mg and 15 mg. It should be added here that the lowest effective dose is assumed for the shortest possible time. A maximum of midazolam can be used for 14 days. If midazolam is discontinued, this should be done by gradual dose reduction.

In elderly patients, patients with moderate renal or hepatic insufficiency, the dose of midazolam should be appropriately reduced due to the risk of potentiation of the active substance and the increased likelihood of undesirable effects.

Midazolam – contraindications

Benzodiazepines require special care when used in the elderly, in pregnant women, in children, in people addicted to alcohol or other drugs, or with comorbid psychiatric disorders. Additional caution is required in critically ill patients as accumulation of midazolam and its active metabolites may occur. Renal or hepatic impairment may slow the elimination of midazolam, leading to a prolonged and enhanced effect.

Contraindications include:

1. hypersensitivity,
2. angle-closure glaucoma,
3. shock,
4. hypotension,
5. Head damage.

Most are relative contraindications.

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Midazolam – side effects

Additional caution is required in the elderly as they are more sensitive to the pharmacological effects of benzodiazepines, metabolize them more slowly, and are more susceptible to side effects including somnolence, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.

Long-term use of benzodiazepines is associated with long-term memory deficits and shows only partial recovery six months after withdrawal of benzodiazepines. It is unclear whether full recovery occurs after extended periods of abstinence.

It should also be added that benzodiazepines can cause or worsen depression. With benzodiazepines, agitation occasionally occurs, including an increase in seizures. Children and the elderly, or those with a history of excessive alcohol use, and those with a history of aggressive behavior or anger attacks, are more likely to experience these types of effects. These reactions are especially associated with intravenous administration.

After overnight administration of midazolam, residual hangover effects, such as somnolence and impaired psychomotor and cognitive functions, may persist into the next day. This can impair patients’ ability to drive safely and increase the risk of falls and hip fractures. Sedation, respiratory depression, and hypotension may occur due to decreased systematic vascular resistance and an increase in heart rate.

Hypotension may occur if midazolam is administered intravenously too quickly. The “midazolam infusion syndrome” may result from high doses and is characterized by a delayed activation of several hours or days after discontinuation of midazolam and may lead to a prolongation of the necessary respiration.

Midazolam is known to cause side effects such as restlessness, involuntary movements, aggressive or violent behavior, uncontrolled crying or verbalization and other similar effects in susceptible individuals. This appears to be related to the altered state of consciousness or drug-induced disinhibition. These types of effects are often not remembered by the patient due to the amnesic properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. For this purpose, antipsychotics such as haloperidol have also been used.

Midazolam is also known to cause respiratory depression. In healthy people, 0,15 mg / kg midazolam may cause respiratory depression, which is thought to be a central nervous system (CNS) effect. Hypoxaemia or apnea is more likely to develop when midazolam is administered in combination with fentanyl.

Although the incidence of depression / respiratory arrest is low (0,1-0,5%) when midazolam is administered alone at normal doses, concomitant use with CNS drugs, mainly opioids, may increase the potential for hypotension, respiratory depression, and respiratory arrest. breathing and death, even at therapeutic doses. Potential interactions involving at least one CNS depressant were observed in 84% of midazolam users who subsequently had to receive flumazenil, a benzodiazepine antagonist. Therefore, efforts to monitor drug interactions and prevent injuries caused by midazolam are expected to have a significant impact on the safe use of this drug.

Midazolam – pregnancy and breastfeeding

Midazolam taken during the third trimester of pregnancy may pose a risk to the newborn, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotension, apnea attacks, cyanosis, and metabolic disturbances. It has also been noted that symptoms of hypotension and neonatal benzodiazepine withdrawal syndrome persist from several hours to several months after birth. Other withdrawal symptoms in newborns include hyperactivity, tremors, and gastrointestinal disturbances (diarrhea or vomiting). Breast-feeding is not recommended for mothers taking midazolam.

See also: Fetal development stages – the first, second and third trimesters of pregnancy

Midazolam – addiction

Benzodiazepine dependence occurs in about one third of people treated with benzodiazepines for more than 4 weeks, usually resulting in tolerance and benzodiazepine withdrawal syndrome when the dose is tapered too quickly. Midazolam infusions can induce tolerance and a withdrawal syndrome within a few days. Risk factors for addiction are personality disorders, short-acting benzodiazepine use, potency and long-term use of benzodiazepines.

Symptoms of withdrawal from midazolam may include insomnia and anxiety, seizures and psychosis. Gradual reduction of midazolam after regular use can minimize withdrawal and rebound effects. Tolerance and the resulting withdrawal syndrome may be due to downregulation of the receptor and alterations of the GABAA receptor in gene expression, resulting in long-term changes in the function of the GABAergic neural system.

Frequent users of benzodiazepines who are administered midazolam experience reduced therapeutic effects of midazolam due to their tolerance to benzodiazepines. Prolonged infusions with midazolam develop tolerance; withdrawal syndrome may occur when midazolam is administered over several days or longer. Therefore, the prevention of withdrawal syndrome requires the gradual withdrawal of the prolonged infusion and sometimes a further reduction in the dose of a long-acting oral benzodiazepine such as dipotassium clorazepate. In case of signs of tolerance to midazolam, the addition of an opioid or propofol during sedation in an intensive care unit is recommended.

Withdrawal symptoms can include:

1. irritability,
2. abnormal reflexes,
3. trembling,
4. clones,
5. hypertonicity,
6. delirium and seizures
7. nausea,
8. vomiting,
9. diarrhea
10. tachycardia,
11. hypertension,
12. rapid breathing.

In severely dependent people, stopping treatment suddenly may result in withdrawal symptoms, such as status epilepticus, which may be fatal.

Midazolam – overdose

An overdose of midazolam is considered a medical emergency and generally requires immediate attention by a healthcare professional. Overdosage of benzodiazepines in healthy people is rarely life threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids or tricyclic antidepressants. Benzodiazepine overdose toxicity and risk of death are also increased in the elderly and those with obstructive pulmonary disease, or when administered intravenously.

Treatment is supportive; activated charcoal can be taken within an hour of overdosing. The antidote to overdose with midazolam (or any other benzodiazepine) is flumazenil. Although it is effective in reversing the effects of benzodiazepines, it is not used in most cases because it can cause seizures in people who have overdosed on several drugs and in those who are addicted to benzodiazepines.

Symptoms of a midazolam overdose may include:

1. action,
2. dyzartrie,
3. nystagmus,
4. gibberish pronunciation,
5. somnolence,
6. confusion
7. hypotension,
8. respiratory arrest
9. angioedema collapse,
10. impaired motor functions,
11. reflex disorders,
12. coordination disorders,
13. balance disorders,
14. dizziness,
15. coma,
16. death.

See also: Poisoning with neuroleptic drugs

Midazolam – detection

The concentration of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum or whole blood to monitor safety in those receiving the drug for therapeutic purposes, to confirm the diagnosis of poisoning in hospitalized patients.

Patients with renal dysfunction may show a prolonged elimination half-life of both the parent drug and its active metabolite, with the accumulation of these two substances in the bloodstream and the development of undesirable depressive effects.

See also: Blood morphology – what is this test, what are the standards?

Midazolam – interactions with drugs and active substances

Protease inhibitors nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam leading to prolonged action. St. John’s wort, rifapentine, rifampicin, rifabutin, phenytoin increase the metabolism of midazolam, leading to its reduction. Sedative antidepressants, antiepileptic drugs such as phenobarbital, phenytoin, and carbamazepine, sedative antihistamines, opioids, antipsychotics, and alcohol enhance the sedative effects of midazolam.

Midazolam is almost completely metabolized by the cytochrome P450-3A4. Administration of atorvastatin with midazolam reduces the elimination rate of midazolam. St. John’s wort reduces the level of midazolam in the blood.