Midazolam

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Midazolam

Midazolam, (marketed under brand names Versed®, Hypnovel® and Dormicum®, pronounced mɪˈdæzəlæm) is a drug which is a benzodiazepine derivative. It has powerful anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties. It is considered a fast-acting benzodiazepine, with a short elimination half-life.

Midazolam was first synthesized in 1976 by Fryer and Walser.

This drug is considered quite addictive ^*, as should be expected given its potent anxiolytic properties and rapid onset of action.

Pharmacology

Unlike other benzodiazepines such as diazepam and lorazepam, midazolam is water soluble because the benzodiazepine ring is open at pH under 4. However, when it is injected and the pH is 7.4, the benzodiazepine ring closes 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 unionised (>90%) at physiological pH, accounts for its rapid onset of action and its high protein binding in the blood (up to 97%).

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 anesthesiologists for sedating patients prior to surgery or other invasive medical procedures, such as endoscopy. The patient typically does not actually lose consciousness.

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:
- Preoperative sedation, anxiolysis, amnesia,
- Treatment of epileptic seizures.
Intravenous:
- For sedation, anxiolysis, and amnesia prior to endoscopic procedures. Often used in combination with other CNS depressants.
- For general anesthesia, often in combination with other anesthetic agents.
Continuous I.V. infusion:
- For sedation of intubated patients in an intensive care setting.

Midazolam's (Versed's) ability to alter consciousness, inhibitions, and memory have led to its use as a component in drug cocktails used in interrogation. Famously, a combination of midazolam and scopolamine was (and perhaps is) used by USA intelligence services during the Vietnam War and Cold War eras during which time many such drug combinations were experimented with. Because mainstream research cannot be performed ethically, its efficacy as a "truth serum" is not known. As with so many supposed interrogative agents, the action and efficacy of midazolam alone or with other drugs is unpredictable, and would require the supervision of a medical professional. This raises ethical and practical issues which present further obstacles to the use of midazolam as an interrogative agent.

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

Benzodiazepines are powerful chemical agents and therefore all have side effects relative to their dose. In the case of midazolam (Versed), however, the fast acting and highly potent nature of the drug lead to far more complications at far lower doses than other benzodiazapines which are used largely outside of a clinical setting. Alprazolam (Xanax), clonazepam (Klonopin) and others are often used to treat anxiety, seizure, and other disorders and are often drugs of abuse.

However, Midazolam is generally only administered in a hospital setting as a part of an anesthetic package prior to endotrachial intubation or surgery as its potency and rapidity of onset can lead to respiratory depression and arrest, as well as airway obstruction (which in its clinical setting is meaningless as it is often injected as a precursor to a paralytic agent such as succinalcholine and the point of endotrachial intubation is respiratory assistance to begin with).

Midazolam is categorized as a Schedule IV controlled substance, meaning it has low abuse potential compared to substances such as hydrocodone or oxycodone. When abused, it is often combined with opiates to enhance its euphoric properties. In combination with opiates, the risk of respiratory depression or arrest is vastly increased. Midazolam can also cause a host of relatively minor adverse reactions ranging from nausea to increased salivation, however the primary risk of abuse is its action as a respiratory depressant.

For those who are addicted to midazolam (Versed), as with all benzodiazapines, withdrawal poses a host of dangers as well. Generally speaking the rule concerning anticonvulsant withdrawal is that the symptoms are the opposite of the effects of the drug. In the case of midazolam or ANY benzodiazapine, convulsions (up to and including full blown seizures), hallucinations, tremors, abdominal and muscle cramps, vomiting and sweating can be experienced depending on the severity of the abuse, the rapidity of the withdrawal of the drug, and the incidence of benzodiazapine abusers having seizure disorders.

One benefit of Midazolam (Versed) as it's used in a clinical setting, is its ability to sedate a patient without causing unconsciousness. For this reason it is often used in a number of invasive, but relatively less painful procedures such as colonoscopy. Midazolam also induces temporary amnesia following administration (and sometimes very minor retrograde amnesiac symptoms are reported), which is beneficial for the person to whom it has been administered prior to what would otherwise be traumatic emergency procedures, but has led to its abuse as a (very rare) "date rape" drug, sometimes in combination with alcohol. Importantly, in memory studies, participants under the influence of midazolam are unaware that their memory is impaired (Merritt, Hirshman, Hsu & Berrigan, 2005).

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.

Virtually all interactions between midazolam and other drugs result in increased periods of sedation, and/or higher risk of respiratory complications and arrest. As with all benzodiazapines, midazolam interacts strongly with alcohol to increase sedation and respiratory depression, airway obstruction, and the possibility of respiratory arrest. This can lead to injury or death. Midazolam also interacts with opiates yielding similarly dire results, although the mechanism of interaction is different. In both cases, the interaction is almost always a result of the use of midazolam in a non-clinical situation. Interactions which are of more concern to clinical administration of midazolam are the aforementioned inhibitors of CYP3A4 isozymes. The following are broad families which match this description. As mentioned previously, the primary result of interaction is an extended period of sedation, and respiratory complications.

Azole Antimycotics

Protease Inhibitors

Calcium Channel Antagonists

Macrolide Antibiotics

Contraindications

Hypersensitivity, Acute narrow angle glaucoma, Shock, Hypotension, Head Injury, and Drug or Alcohol Use.

Overdose

Symptoms of midazolam overdose include:

Respiratory Despression, Respiratory Arrest, and Airway Obstruction all of which can lead to Anoxia/Hypoxia and resultant injury leading to unconsciousness, coma, brain damage and eventually death.
Somnolence (difficulty staying awake)
Mental confusion
Hypotension
Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- 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®).

Midazolam is contraindicated for patients with a history of Opiate or Benzodiazapine abuse in all settings save anesthesia, and consideration should always be given to the possibility of drug seeking behaviour when administering Midazolam for any purpose except anesthesia prior to endotrachial intubation or other procedures. As a potent Benzodiazapine, Midazolam can be the target of both addicts seeking a "fix" by pseudosiezures or other behaviour, and ALSO by more mentally disturbed individuals who may be engaged in the same behaviour and believe they are having seizures, but are in fact engaging in an attempt to seek sedation or intoxication.

Legal Status

Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances ^*.

External links

References

Status Epilepticus: Clinical Analysis of a Treatment Protocol Based on Midazolam and Phenytoin, Brevoord, J. D. et al., Journal of Child Neurology 2005;20(6):476-48
Successful treatment of 75 patients in status epilepticus with intravenous midazolam., Galvin GM, Jelinek GA., Emerg Med 1992;4:11-12.
Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis, Johnson, TN, et al, Br J Anaesth 2002:89(3)428-437.
Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model, Bjorkman, S et al, J Pharm Sci 2001:90(9)1226-1241.
Metamemory withouth the memory: Are participants aware of midazolam induced amnesia?, Merritt,P et al, Psychopharmacology 2005:177 336-343.

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