Midazolam

Midazolam is a Central nervous system (CNS) depressant belonging to the Short-acting benzodiazepine class.

Midazolam is a short-acting benzodiazepine with rapid onset that is commonly used in seizures, anesthesia, and anxiety disorders.

Midazolam is Rapidly absorbed. Its Bioavailability is 40-50% from oral route and >90% via Intra-Muscular. Time taken to reach peak plasma concentration is 0.5-1 hour via IM and 0.17-2.65 hours via oral route. Midazolam is Widely distributed in the body, including CSF. Crosses the placenta and enters the breastmilk. It is having Volume of distribution of about 1-3.1 L/kg, increased in females, elderly and obesity. Plasma protein binding: Approx 97%, mainly albumin. Midazolam is Extensively metabolized in the liver by CYP3A isoenzyme; 60-70% of bio transformed midazolam is 1-hyrdoxy-midazolam or α-hydroxy midazolam (active metabolite). It is mainly excreted Oral Via urine (approx. 90% within 24 hours; mainly as glucuronide conjugates [60-70%]; <3% as unchanged drug); faeces (approx. 2-10% over 5 days).

Midazolam shows side effects like Nausea, vomiting, rash, etc.

Midazolam is available in the form of Oral syrup and Injectable solution.

Midazolam is available in India, Canada, UK, France, Berlin, US, Sweden, Germany, Italy, Japan, China, Sapin, and Malaysia.

Midazolam belongs to the Short-acting benzodiazepine class and acts as Central nervous system (CNS) depressant.

Midazolam binds stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at various sites within the CNS, including limbic system and reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to Cl ions, which results in hyperpolarization and stabilization.

The Onset and Duration of action of Midazolam is not clinically established.

The Time to peak plasma concentration of Midazolam is approximately 0.5-1 hour (Injectable); 0.17-2.65 hours (oral).

Midazolam is available in the form of Oral syrup and Injectable solution.

Midazolam syrup is taken orally usually in divided dose while Injectable solution is given via intravenous route.

Midazolam is a medication used to induce drowsiness, relieve anxiety, and prevent memory of events before minor surgery, dental work, or other medical procedures. It may also be used for short-term treatment of insomnia (difficulty falling asleep). Midazolam works by slowing activity in the brain, causing relaxation and decreased consciousness.

Midazolam is a Central nervous system (CNS) depressant belonging to the Short-acting benzodiazepine class.

Midazolam binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at various sites within the CNS, including limbic system and reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to Cl ions, which results in hyperpolarisation and stabilisation.

Midazolam is approved for use in the following clinical indications

• Short-term management of insomnia
• Seizures
• Preoperative sedation
• Premedication in surgery
• Sedation
• Induction of anaesthesia

• Short-term management of insomnia

Oral Adult Dose: 7.5-15 mg at night. Max: 15 mg.

Oral Dose for Elderly: 7.5 mg at night.

• Seizures

Oral Pediatric Dose: 3-6 months Hospital setting: 2.5 mg; >6 months to <1 year 2.5 mg; 1-<5 years 5 mg; 5-<10 years 7.5 mg; 10-<18 years 10 mg. Doses are given as single dose.

• Preoperative sedation

Oral Pediatric Dose: 6 months to 16 years 0.25-1 mg/kg as single dose 15-30 minutes prior to procedure, depending on patient status and desired effect. Max: 20 mg.

• Premedication in surgery

Parenteral Adult Dose: 0.07-0.1 mg/kg (approx. 5 mg) via IM inj, given 20-60 minutes before surgery. Alternatively, 1-2 mg via IV inj, repeated, if necessary, given 5-30 minutes before surgery.

Parenteral Child Dose: 1-15 years 0.08-0.2 mg/kg via IM inj given 15-30 minutes before surgery.

Parenteral Dose for Elderly: 0.025-0.05 mg/kg given approx 20-60 minutes before surgery via IM inj. Alternatively, 0.5 mg given IV 5-30 minutes before procedure, repeated slowly if required.

• Sedation

Oral Adult Dose: Conscious sedation for procedures; for dental and minor surgical procedures: Initially, 2-2.5 mg given at a rate of 2 mg/minute 5-10 minutes before procedure, with increments of 0.5-1 mg at intervals of at least 2 minutes if required until the desired endpoint is achieved.

Oral Child Dose: 6 months to 5 years Initially, 0.05-0.1 mg/kg, up to 0.6 mg/kg if necessary. Max: 6 mg; 6-12 years Initially, 0.025-0.05 mg/kg, up to 0.4 mg/kg if necessary. Max: 10 mg. >12 years Same as adult dose. Initial doses are given over 2-3 minutes, 5-10 minutes before procedure, with an additional interval of 2-5 minutes before giving further doses.

Oral Dose for Elderly: Initially, 0.5-1 mg at a max rate of 2 mg/minute, 5-10 minutes before procedure, with increments of 0.5-1 mg if required. Max total dose: 3.5 mg or until the desired endpoint is achieved.

• Induction of anaesthesia

Oral Adult Dose: Premedicated patient: 0.15-0.2 mg/kg via slow IV inj. non-premedicated patient: 0.3-0.35 mg/kg via slow IV inj. For resistant cases, a total dose up to 0.6 mg/kg may be given. For sedation in combined anaesthesia: 0.03-0.1 mg/kg by inj repeated as required or by infusion in a dose of 0.03-0.1 mg/kg/hour.

Oral Dose for Elderly: >60 years Premedicated patient: 0.05-0.15 mg/kg. Non-premedicated patient: 0.15-0.3 mg/kg.

Midazolam is available in various strengths as 2 mg/mL, 1mg/mL and 5mg/mL.

Midazolam is available in the form of Oral syrup and Injectable solution.

• Dosage Adjustment in Kidney Patient

Dose reduction may be necessary.

• Dosage Adjustment in Hepatic impairment Patient

Severe: Contraindicated.

Avoid consumption of grapefruit or grapefruit juice while taking Midazolam.

Midazolam is contraindicated in patients with

• Midazolam Injection is contraindicated in patients with a known hypersensitivity to midazolam.

• Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including Midazolam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation. Trained personnel administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.

• Abuse, Misuse, and Addiction

The use of benzodiazepines, including Midazolam Injection, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Before prescribing Midazolam Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of Midazolam Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Midazolam Injection along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

• Dependence and Withdrawal Reactions After Use of Midazolam Injection More Frequently Than Recommended

For patients using Midazolam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Midazolam Injection (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

• Risks of Cardiorespiratory Adverse Reactions

Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations, particularly in patients with hemodynamic instability. Hypotension occurs more frequently in patients premedicated with a narcotic. The danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve; patients with COPD are highly sensitive to the respiratory depressant effect of midazolam. Midazolam Injection should be administered with caution to patients in shock or coma with depression of vital signs. Trained personnel administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.

• Risks from Concomitant Use of Central Nervous System Depressants

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Midazolam Injection should be administered with caution to patients in acute alcohol intoxication with depression of vital signs. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the central nervous system (CNS). Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Trained personnel administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management. For information regarding withdrawal.

• Impaired Cognitive Function

Midazolam is associated with a high incidence of partial or complete impairment of recall for several hours following an administered dose. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits.

• Glaucoma

Benzodiazepines, including Midazolam Injection, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with Midazolam Injection. Midazolam Injection is not recommended in patients with narrow-angle glaucoma.

• Neonatal Sedation and Withdrawal Syndrome

Use of Midazolam Injection late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to Midazolam Injection during pregnancy or labor for signs of sedation and monitor neonates exposed to Midazolam Injection during pregnancy for signs of withdrawal; manage these infants accordingly.

Midazolam is excreted in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of midazolam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Midazolam Injection and any potential adverse effects on the breastfed child from Midazolam Injection or from the underlying maternal condition.

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Avoid consumption of grapefruit or grapefruit juice while taking Midazolam.

Common

Anterograde amnesia, CNS depression, hypotension, paradoxical reactions (e.g. hyperactive or aggressive behaviour), suicidal ideation, withdrawal symptoms, Bradycardia, tachycardia, Nausea, vomiting, constipation, dry mouth, hiccups, Fatigue, injection site reactions (e.g. erythema, pain, phlebitis, thrombosis), Falls, fractures, Muscle weakness, Sedation (prolonged and post-operative), decreased alertness, somnolence, headache, dizziness, drowsiness, ataxia, Confusion, euphoric mood, depression, hallucinations, physical drug dependence, withdrawal syndrome, Dyspnoea, laryngospasm, bronchospasm, cough, Rash, urticaria, pruritus.

Rare

Cardiorespiratory effects (e.g., respiratory depression, respiratory arrest, apnoea, cardiac arrest).

Effect of Concomitant Use of Benzodiazepines and Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids. Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants and Alcohol

The sedative effect of Midazolam Injection is accentuated by concomitantly administered medication that depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), secobarbital, and droperidol, and also by alcohol.

Cytochrome P450-3A4 Inhibitors

Caution is advised when Midazolam Injection is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system (e.g., cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole). These drug interactions may result in prolonged sedation caused by a decrease in plasma clearance of midazolam.

The common side effects of Midazolam include the following

Common side effects

Nausea, vomiting, rash.

Rare side effects

Agitation, restlessness, uncontrollable shaking of a part of the body, stiffening and jerking of the arms and legs, aggression, slow or irregular heartbeat.

• Pregnancy

Pregnancy Category D

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

• Nursing Mothers

Midazolam is excreted in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of midazolam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Midazolam Injection and any potential adverse effects on the breastfed child from Midazolam Injection or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Benzodiazepines are not recognized as a treatment for status epilepticus in neonates and should not be used in this population.

• Geriatric Use

Of the total number of patients from the intent-to-treat (ITT) population in the clinical trial of a different midazolam injection, 14.9 percent were 65 years of age and over, while 8.3 percent were 75 years of age and over. Geriatric patients may have altered drug distribution; diminished hepatic and/or renal function; longer elimination half-lives for midazolam and its metabolites, and subjects over 70 years of age may be particularly sensitive. Administration of IM midazolam to elderly patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other CNS depressants capable of depressing respiration, especially narcotics. Close monitoring of geriatric patients is recommended.

Symptoms: Sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and deleterious effects on vital signs.

Management: Symptomatic and supportive treatment. Monitor respiration, pulse rate, blood pressure and hepatic function. Maintain adequate airway and support of ventilation, including administration of oxygen. IV fluid therapy, repositioning, judicious use of appropriate vasopressors may be done in case of hypotension. Gastrointestinal decontamination (e.g., lavage, activated charcoal) may be considered within 1-2 hours after ingestion or once the patient's airway is secured. Flumazenil may be given as an antidote.

• Pharmacokinetics

Absorption

Midazolam is Rapidly absorbed. Its Bioavailability is 40-50% from oral route and >90% via Intra-Muscular. Time taken to reach peak plasma concentration is 0.5-1 hour via IM and 0.17-2.65 hours via oral route.

Distribution

Midazolam is Widely distributed in the body, including CSF. Crosses the placenta and enters the breastmilk. It is having Volume of distribution of about 1-3.1 L/kg, increased in females, elderly and obesity. Plasma protein binding: Approx 97%, mainly albumin.

Metabolism and Excretion

Midazolam is Extensively metabolized in the liver by CYP3A isoenzyme; 60-70% of bio transformed midazolam is 1-hyrdoxy-midazolam or α-hydroxy midazolam (active metabolite). It is mainly excreted Oral Via urine (approx. 90% within 24 hours; mainly as glucuronide conjugates [60-70%]; <3% as unchanged drug); faeces (approx. 2-10% over 5 days).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216359s000lbl.pdf
• https://go.drugbank.com/drugs/DB00683
• https://medlineplus.gov/druginfo/meds/a609003.html#:~:text=Midazolam is given to children,class of medications called benzodiazepines.
• https://www.drugs.com/dosage/midazolam.html