Product Description

Unlike other benzodiazepines such as diazepam and lorazepam, midazolam is water soluble because the imidazoline ring is open at pH under 4. However, when it is injected, the slightly alkaline (pH about 7.4) environment of the bloodstream causes the imidazoline ring to close, and it becomes much more lipid soluble, facilitating its rapid uptake into nerve tissue. This, and the fact that it has a pKa of 6.15 and is therefore predominantly un-ionised (>90%) at physiological pH, accounts for its rapid onset of action.

Metabolism is by the hepatic Cytochrome p450 enzyme 3A3/3A4. It is hydroxylated to the active metabolite 1-hydroxy-midazolam and then glucuronidated before being renally excreted.

Indications

Midazolam is frequently used (usually in combination with other agents, such as morphine) by anaesthesia providers (nurse anaesthetists and anaesthesiologists) for sedating patients prior to surgery or other invasive medical procedures, such as endoscopy. The patient typically does not actually lose consciousness, but may lose the ability to form memories (anterograde amnesia).

Due to its high potency and fast onset of effects, it is rarely prescribed outside of hospitals. An exception is buccal midazolam, used for the rapid treatment of prolonged seizures. This is an off-label use usage of midazolam, although it has become increasingly common. When using it for this purpose, the drug is squirted slowly between the gums and the inside of the cheek, where it is absorbed directly into the blood stream.
Intramuscular or intravenous:o Preoperative sedation, anxiolysis, amnesia,o Treatment of epileptic seizures.
Intravenous:o For sedation, anxiolysis, and amnesia prior to endoscopic procedures. Often used in combination with other CNS depressants.o For general anaesthesia, often in combination with other anaesthetic agents.
Continuous I.V. infusion:o For sedation of intubated patients in an intensive care setting.

Dosage

The dosing of midazolam is highly variable depending on other patient factors and other concurrently administered drugs.
Preoperative anxiolysis: 0.5-2.5 mg.
Endoscopy: 3-5 mg (rarely 10mg) IV, often paired with short acting opiods in moderate dosage. For example, 50mg pethidine or equivalent dosage of fentanyl (2.5-5 micrograms).
Status epilepticus: 10mg intranasally or as buccal.

Side effects and abuse potential

Midazolam is categorized as a Schedule IV controlled substance, meaning it has low abuse potential compared to substances such as hydrocodone or oxycodone. As a benzodiazepine it shares similar side effects to other members of this drug family, however it is far less often abused given the ready availability of alternatives, and its primary use in hospital settings only. The mild amnesia caused by this drug is a side effect commonly used for its effect as a 'pre-med' before surgery. Rapid infusion of midazolam may cause transient apnoea, and occasionally, respiratory arrest.

Interactions

Midazolam is metabolized almost completely by cytochrome P450-3A4. Vmax in microsomes is reported as 850 pmol/min/mg microsomal protein. Km is reported as 3.7 uMol. Metabolism in the gut wall is reported as nearly equal to metabolism in liver by CYP3A4. Therefore, midazolam will interact with other 3A4 substrates and inhibitors. Grapefruit juice reduces intestinal 3A4 and results in less gut wall metabolism and higher plasma concentrations, which could result in overdose.

Contraindications

Hypersensitivity, acute narrow angle glaucoma, shock, hypotension, head injury, and drug or alcohol use.

Overdose

Symptoms of midazolam overdose include:
Somnolence (difficulty staying awake)
Mental confusion
Hypotension
Impaired motor functionso Impaired reflexeso Impaired coordinationo Impaired balanceo Dizziness
Coma

In animal models, the oral LD50 of midazolam is 825 mg/kg.

Midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil (Anexate®).