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Midazolam; Uses, Dosage, Side Effects, Interactions, Pregnancy

Midazolam is a short-acting benzodiazepine derivative with an imidazole structure and with anxiolytic, amnestic, hypnotic, anticonvulsant and sedative properties. Midazolam exerts its effect by binding to the benzodiazepine receptor at the gamma-aminobutyric acid (GABA) receptor-chloride ionophore complex in the central nervous system (CNS). This leads to an increase in the opening of chloride channels, membrane hyperpolarization and increases the inhibitory effect of GABA in the CNS. Midazolam may also interfere with the reuptake of GABA, thereby causing accumulation of GABA in the synaptic cleft.

Midazolam is a short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH.

Mechanism of Action of Midazolam

It is thought that the actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the brain. Benzodiazepines increase the activity of GABA, thereby producing a calming effect, relaxing skeletal muscles, and inducing sleep. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening.

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic and hypnotic activities. Benzodiazepine pharmacologic effects appear to result from reversible interactions with the (gamma)-amino butyric acid (GABA) benzodiazepine receptor in the CNS, the major inhibitory neurotransmitter in the central nervous system. The action of midazolam is readily reversed by the benzodiazepine receptor antagonist.

A consummatory conflict procedure that involves an abrupt reduction in magnitude of an expected reward (negative contrast) has been shown to be particularly sensitive to the effects of anxiolytic agents. Midazolam released suppressed consummatory performance in a dose-dependent manner. This effect was not due to a general appetite stimulation effect of the drug. The effects of three 5-HTantagonists on negative contrast were examined to evaluate the role serotonin may play in the anxiolytic action of benzodiazepine. Methysergide was found to be ineffective, cinanserin tended to reduce contrast at two intermediate doses, and cyproheptadine eliminated the contrast effect in a similar fashion as midazolam. The effectiveness of cyproheptadine may not be attributed to its anticholinergic or antihistaminergic actions since scopolamine and pyrilamine did not produce similar efects. The results are discussed in terms of the role serotonin may play in the anti-conflict action of benzodiaepine, as well as possible interactional effects of gamma-aminobutyric acid.

Indications of Midazolam

Treatment of moderately severe insomnia
Indicated for preoperative sedation anziolysis amnesia.
Seizures
Insomnia management
Premedication before anesthesia
Prolonged, acute and convulsive seizures in infants
Convulsive seizures in toddlers
Convulsive seizures in children
Sedation anziolysis amnesia prior to or during diagnostic, therapeutic, or endoscopic procedures.
Intravenously for induction of general anaesthesia.
Refractory seizure disorders
ICU Agitation
Light Sedation
Light Anesthesia
Mixed manic depressive episode
Panic disorders
Rapid eye movement sleep disorder
Restless legs syndrome (RLS)
The midazolam injection is indicated for preoperative sedation anziolysis amnesia. It is also an agent for sedation anziolysis amnesia prior to or during diagnostic, therapeutic, or endoscopic procedures. Midazolam can also be given intravenously for induction of general anaesthesia.

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Midazolam Injection (midazolam) is indicated

Intramuscularly or intravenously for preoperative sedation anxiolysis amnesia;
Intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiographyand cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants;
Intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia);

Therapeutic Indications of Midazolam

Adjuvants, Anesthesia; Anesthetics, Intravenous; Anti-Anxiety
Midazolam is a familiar agent commonly used in the emergency department to provide sedation prior to procedures such as laceration repair and reduction of dislocations.
Midazolam is also effective in the treatment of generalized seizures, status epilepticus, and behavioral emergencies, particularly when intravenous access is not available. Midazolam is often employed as an induction agent for rapid sequence endotracheal intubation.
For preoperative sedation and anxiolysis, and anterograde amnesia, midazolam is used IM or IV in adult or pediatric patients; the drug also is used orally in pediatric patients. When administered preoperatively, the drug relieves anxiety and provides sedation, light anesthesia, and anterograde amnesia of perioperative events.
Midazolam has been administered orally as a hypnotic for the short term management of insomnia. The drug also has been used orally for the prevention of night terrors in a limited number of children. Parenterally administered midazolam has been used in the management of acute agitation.
Continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.
Intravenously as an agent for sedation anxiolysis amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants.
Midazolam is used IV for induction of general anesthesia prior to administration of other anesthetic agents. Induction with IV midazolam results in anxiolysis, anterograde amnesia, and dose-related hypnotic effects (progressing from sedation to loss of consciousness), but not analgesia.
Midazolamalso is used as a component of balanced anesthesia (eg., nitrous oxide and oxygen) for maintenance of an anesthesia during short surgical procedures; use of the drug for maintenance of anesthesia in relatively long surgical procedures has not been fully evaluated to date.

Contra Indications of Midazolam

Acute alcohol intoxication
Acute narrow-angle glaucoma
Coma
Hypersensitivity
Intrathecal or epidural administration
Myasthenia gravis
Drug abuse
Wide-angle glaucoma
Closed angle glaucoma
Decreased lung function
Chronic lung disease
Liver problems
Severe liver disease
Temporarily stops breathing while wleeping
Abnormal liver function tests

Dosages of Midazolam

Light Sedation

Patients younger than 60 years

Usual dose: 0.07 to 0.08 mg/kg IM once, up to 1 hour before surgery

Usual dose: 1 to 2.5 mg slow IV every 2 minutes as necessary for sedation
Maintenance dose: After thorough clinical evaluation, additional doses may be given in increments of 25% of the initial dose used to reach sedation.
Maximum dose: 2.5 mg/dose

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Light Anesthesia

Patients younger than 55 years , Premedicated patients

Usual dose: 0.25 mg/kg IV once, administered over 20 to 30 seconds. Healthcare providers should allow 2 minutes for effect.

Unpremedicated patients

Initial dose: 0.3 to 0.35 mg/kg IV once, administered over 20 to 30 seconds. Healthcare providers should allow 2 minutes to for effect.
If induction is not complete after 2 minutes, inhalation anesthetics and/or further doses of this drug in increments of 25% of the initial dose may be given.
Maximum dose: 0.6 mg/kg

Geriatric Dose for Light Sedation

60 years and older ,IM

Usual dose: 0.02 to 0.05 mg/kg IM once up to 1 hour before surgery

Usual dose: 1 mg slow IV every 2 minutes as needed for sedation
Maintenance dose: 25% of the dose used to reach desired sedation level

Light Anesthesia

Over 55 years , Premedicated patients

Usual dose: 0.2 mg/kg IV once, administered over 20 to 30 seconds

Unpremedicated patients

Usual dose: 0.2 to 0.3 mg/kg IV once, administered over 20 to 30 seconds

Pediatric Light Sedation

6 months to 16 years

Usual dose: 0.25 to 1 mg/kg orally once before the procedure
Maximum dose: 20 mg

Parenteral, IM

Usual dose: 0.1 to 0.15 mg/kg IM once, with some patients requiring doses of 0.5 mg/kg
Maximum total dose: 10 mg

IV 6 months to 5 years

Initial dose: 0.05 to 0.1 mg/kg IV injection, with evaluation for sedation. If an optimal sedation levels is not reached after 2 to 3 minutes, doses may be readministered every 2 to 3 minutes, up to a maximum dose of 0.6 mg/kg.
Maximum total dose: 6 mg

6 years to 12 years

Initial dose: 0.025 to 0.05 mg/kg IV injection, with evaluation for sedation.
If an optimal sedation level is not reached, doses may be readministered every 2 to 3 minutes, up to a maximum dose of 0.4 mg/kg.
Maximum total dose: 10 mg

12 years and older

Usual dose: 1 to 2.5 mg slow IV every 2 minutes as necessary for sedation
Maintenance dose: After thorough clinical evaluation, additional doses may be given in increments of 25% of the initial dose used to reach sedation.
Maximum total dose: 10 mg

Side Effects of Midazolam

The most common

Common

Rare

Anxiety
change in vision
chest pain or tightness
confusion
cough
Agitation
arm, back, or jaw pain
blurred vision
chest pain or discomfort
convulsions
extra heartbeats
hallucinations
headache
irritability
lightheadedness
cold and clammy skin
fast and shallow breathing
swelling of your feet, legs, or hands purple spot on your skin caused by internal bleeding
fast or abnormal heart rate or palpitations
loss of appetite
lower back, side, or stomach pain
mental depression
muscle pain or cramps
Swelling of your feet or ankles
Shortness of breath
Nausea, fever, dark urine, loss of appetite
Depression
Ataxia
Somnolence (difficulty staying awake)
Mental confusion
Hypotension
Respiratory arrest
Vasomotor collapse

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Drug Interactions of Midazolam

Midazolam may interact with following drugs, supplyments, & may change the efficacy of drugs

antihistamines (e.g,. cetirizine, diphenhydramine, hydroxyzine, loratadine)
antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
aripiprazole
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
baclofen
barbiturates (e.g., butalbital, phenobarbital)
benzodiazepines (e.g.diazepam, lorazepam)
calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
carbamazepine
estradiol (birth control pills)
gabapentin
macrolide antibiotics (e.g., clarithromycin, erythromycin)
mirtazapine
muscle relaxants
phenytoin
proton pump inhibitors (e.g., lansoprazole, omeprazole)
quinolone antibiotics (e.g., ciprofloxacin, ofloxacin)
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
tapentadol
theophylline
tramadol
tricyclic antidepressasnts (e.g., amitriptyline, clomipramine, desipramine, trimipramine)

Pregnancy & Lactation of Midazolam

FDA Pregnancy Category D

Pregnancy

Midazolam, when taken during the third trimester of pregnancy, may cause 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). Breastfeeding by mothers using midazolam is not recommended.

Lactation

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.