MIDAZOLAM HCL
Chemistry - An imidazobenzodiazepine, midazolam occurs as a white to light yellow crystallinepowder with a pKa of 6.15. Midazolam HCl's aqueous solubility is pH dependent. At 25°C and apH of 3.4, 10.3 mg are soluble in 1 ml of water. The pH of the commercially prepared injection isapproximately 3.
Midazolam is reportedly compatible when mixed with the following products: D5W, normalsaline, lactated Ringer's, atropine sulfate, fentanyl citrate, glycopyrrolate, hydroxyzine HCl, ketamine HCl, meperidine HCl, morphine sulfate, nalbuphine HCl, promethazine HCl, sufantanilcitrate, and scopolamine Hbr. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized references for morespecific information.
Uses, Indications - In humans, midazolam has been suggested to be used as a premedicant beforesurgery, and when combined with potent analgesic/anesthetic drugs (e.g., ketamine or fentanyl), as aconscious sedative. In humans, midazolam reduces the incidences of "dreamlike" emergencereactions and increases in blood pressure and cardiac rate that ketamine causes.
When compared to the thiobarbiturate induction agents (e.g., thiamylal, thiopental), midazolam hasless cardiopulmonary depressant effects, is water soluble, can be mixed with several other agents, and does not tend to accumulate in the body after repeated doses. There is much interest in usingthe drug alone as an induction agent. Several veterinary anesthesiologists are studying the clinicalapplications of this agent in veterinary medicine and additional information regarding its use shouldbe forthcoming.
The drug is highly protein bound (94-97%) and rapidly crosses the blood-brain barrier. Becauseonly unbound drug will cross into the CNS, changes in plasma protein concentrations and resultantprotein binding may significantly alter the response to a given dose.
Midazolam is metabolized in the liver, principally by microsomal oxidation. An active metabolite(alpha-hydroxymidazolam) is formed, but because of its very short half-life and lowerpharmacologic activity, it probably has negligible clinical effects. The serum half-life and durationof activity of midazolam in humans is considerably shorter than that of diazepam. Elimination half-lives measured in humans average approximately 2 hours (vs. approx. 30 hrs for diazepam).
Contraindications/Precautions - The manufacturer lists the following contraindications for usein humans: hypersensitivity to benzodiazepines, or acute narrow-angle glaucoma. Additionally, intra-carotid artery injections must be avoided.
Use cautiously in patients with hepatic or renal disease and in debilitated or geriatric patients.
Patients with congestive heart failure may eliminate the drug more slowly. The drug should beadministered to patients in coma, shock or having significant respiratory depression very cautiously.
Although midazolam has not been demonstrated to cause fetal abnormalities, in humans otherbenzodiazepines have been implicated in causing congenital abnormalities if administered duringthe first trimester of pregnancy. Infants born of mothers receiving large doses of benzodiazepinesshortly before delivery have been reported to suffer from apnea, impaired metabolic response tocold stress, difficulty in feeding, hyperbilirubinemia, hypotonia, etc. Withdrawal symptoms haveoccurred in infants whose mothers chronically took benzodiazepines during pregnancy. The veterinary significance of these effects is unclear, but the use of these agents during the first trimesterof pregnancy should only occur when the benefits clearly outweigh the risks associated with theiruse. It is unknown if midazolam is distributed into milk, but other benzodiazepines and theirmetabolites are distributed into milk and may cause CNS effects in nursing neonates.
COPD. The following adverse effects have been reported in more than 1%, but less than 5% ofpatients receiving midazolam: pain on injection, local irritation, headache, nausea, vomiting, andhiccups.
The principle concern in veterinary patients is the possibility of respiratory depression occurring.
Overdosage - Very limited information is currently available. The IV LD50 in mice has been reported to be 86 mg/kg. It is suggested that accidental overdoses be managed in a supportive manner, similar to diazepam.
Storage, Stability, Compatibility
It is recommended to store midazolam injection at room temperature (15°-30°C) and protect from light. After being frozen for 3 days and allowed to thaw at room temperature, the injectable product was physically stable. Midazolam is stable at a pH from 3-3.6.Midazolam is reportedly compatible when mixed with the following products: D5W, normalsaline, lactated Ringer's, atropine sulfate, fentanyl citrate, glycopyrrolate, hydroxyzine HCl, ketamine HCl, meperidine HCl, morphine sulfate, nalbuphine HCl, promethazine HCl, sufantanilcitrate, and scopolamine Hbr. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized references for morespecific information.
Pharmacology - MIDAZOLAM HCL
Midazolam exhibits similar pharmacologic actions as other benzodiazepines(refer to the diazepam monograph for more information). Its unique solubility characteristics (watersoluble injection but lipid soluble at body pH) give it a very rapid onset of action after injection.Uses, Indications - In humans, midazolam has been suggested to be used as a premedicant beforesurgery, and when combined with potent analgesic/anesthetic drugs (e.g., ketamine or fentanyl), as aconscious sedative. In humans, midazolam reduces the incidences of "dreamlike" emergencereactions and increases in blood pressure and cardiac rate that ketamine causes.
When compared to the thiobarbiturate induction agents (e.g., thiamylal, thiopental), midazolam hasless cardiopulmonary depressant effects, is water soluble, can be mixed with several other agents, and does not tend to accumulate in the body after repeated doses. There is much interest in usingthe drug alone as an induction agent. Several veterinary anesthesiologists are studying the clinicalapplications of this agent in veterinary medicine and additional information regarding its use shouldbe forthcoming.
Pharmacokinetics - MIDAZOLAM HCL
Following IM injection, midazolam is rapidly and nearly completely (91%)absorbed. Although no oral products are being marketed, midazolam is well absorbed after oraladministration, but because of a rapid first-pass effect, bioavailibilities suffer (31-72%). The onsetof action following IV administration is very rapid due to the high lipophilicity of the agent. Inhumans, the loss of the lash reflex or counting occurs within 30-97 seconds of administration.The drug is highly protein bound (94-97%) and rapidly crosses the blood-brain barrier. Becauseonly unbound drug will cross into the CNS, changes in plasma protein concentrations and resultantprotein binding may significantly alter the response to a given dose.
Midazolam is metabolized in the liver, principally by microsomal oxidation. An active metabolite(alpha-hydroxymidazolam) is formed, but because of its very short half-life and lowerpharmacologic activity, it probably has negligible clinical effects. The serum half-life and durationof activity of midazolam in humans is considerably shorter than that of diazepam. Elimination half-lives measured in humans average approximately 2 hours (vs. approx. 30 hrs for diazepam).
Contraindications/Precautions - The manufacturer lists the following contraindications for usein humans: hypersensitivity to benzodiazepines, or acute narrow-angle glaucoma. Additionally, intra-carotid artery injections must be avoided.
Use cautiously in patients with hepatic or renal disease and in debilitated or geriatric patients.
Patients with congestive heart failure may eliminate the drug more slowly. The drug should beadministered to patients in coma, shock or having significant respiratory depression very cautiously.
Although midazolam has not been demonstrated to cause fetal abnormalities, in humans otherbenzodiazepines have been implicated in causing congenital abnormalities if administered duringthe first trimester of pregnancy. Infants born of mothers receiving large doses of benzodiazepinesshortly before delivery have been reported to suffer from apnea, impaired metabolic response tocold stress, difficulty in feeding, hyperbilirubinemia, hypotonia, etc. Withdrawal symptoms haveoccurred in infants whose mothers chronically took benzodiazepines during pregnancy. The veterinary significance of these effects is unclear, but the use of these agents during the first trimesterof pregnancy should only occur when the benefits clearly outweigh the risks associated with theiruse. It is unknown if midazolam is distributed into milk, but other benzodiazepines and theirmetabolites are distributed into milk and may cause CNS effects in nursing neonates.
Adverse Effects, Warnings
Few adverse effects have been reported in human patients receivingmidazolam. Most frequently effects on respiratory rate, cardiac rate and blood pressure have beenreported. Respiratory depression has been reported in patients who have received narcotics or haveCOPD. The following adverse effects have been reported in more than 1%, but less than 5% ofpatients receiving midazolam: pain on injection, local irritation, headache, nausea, vomiting, andhiccups.
The principle concern in veterinary patients is the possibility of respiratory depression occurring.
Overdosage - Very limited information is currently available. The IV LD50 in mice has been reported to be 86 mg/kg. It is suggested that accidental overdoses be managed in a supportive manner, similar to diazepam.