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.
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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.
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
IV
- 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
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
IV
- 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
- headache
- drowsiness
- Abdominal or stomach pain
- cold or flu symptoms such as stuffy nose, sore throat, fever;
- Constipation
- hiccups
- coughing
- pain, redness, or hardening of the skin at the injection site
- Nausea ,vomiting,
- painful or swollen gums
- numbness or heavy feeling in the jaw
- dull, aching pain in the hip, groin, or thigh
- stomach pain,
- headache,
- reversible hair loss or thinning, and
- fever
Common
- chills or fever
- headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in chest
- excessive sweating
- sudden drowsiness or need to sleep
- coughing up blood
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite,
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
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.
References
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