Midazolam: The Anesthetic That Makes You Forget

  It is amazing how far medicine has progressed. Can you imagine that only a little over 100 years ago the most common form of treating an illness was bloodletting? Today there are thousands of different medications and drugs available to make a successful treatment. For example, midazolam, often called by its brand name Versed, is a type of oral or injectable drug that is used prior to medical procedures. It is well known for its fast-acting anxiolytic and amnestic properties (MedlinePlus). “I use it for all of my cases from simple hernia operations to complex cardiac procedures…and I imagine [it is used in] over 95% of all cases done in the OR,” says Dr. Kaya Sarier, an anesthesiologist at the Hackensack University Medical Center. This common yet crucial anesthetic causes drowsiness, reduces anxiety, and most interestingly erases the memory of an event. How exactly? Let’s take a closer look.

The Molecule

The molecular formula for midazolam is C18H13ClFN3. This specific structure with the core of a benzene ring bonded to a diazepine ring allows it to be categorized as a benzodiazepine. If you are interested, this article from the Handbook of Experimental Pharmacology gives a general background on benzodiazepine.

When midazolam is taken, it moves through the body and into the cerebrospinal fluid. There, cytochrome P450 3A4 enzymes metabolize the midazolam. The end product binds to the gamma-aminobutyric acid (GABA) receptor on a neuron. This opens up a channel, and higher concentrations of GABA are released, which bind to the GABA receptors. As a result, this causes chlorine ions to enter the neuron, and the sudden presence of electronegative chlorine ions in the neuron stops the neuron from sending signals to the brain. The neural inhibition that results is the reason why midazolam relaxes the mind and makes you forget the events that transpire under its effects. Check out the animation in this link to see how benzodiazepines react with GABA receptors.

Action Potentials

Now that the general pharmacokinetics of midazolam have been established, let’s compare it to the regular process of a neuron’s response to stimuli. Neurons have a certain point called rest potential, which is the potential difference between two sides of a neuronal membrane when the neuron is not transmitting a signal. The approximate rest potential is -70mV. Neurons naturally respond to events in the environment by depolarization, which starts by the opening of Na+ channels. If enough pass through the membrane and reach -55mV, the neuron will proceed to send the signal. This point is called the action threshold. Voltage-gated channels will allow more Na+ ions to increase the interior potential to +30mV. Then repolarization starts. The voltage-gated channels of Na+ close while those of K+ open. The K+ ion channels are much slower than the Na+ channels, and so more K+ions can leave the neuron. The repolarization aims to go back to rest potential, but the process will typically go to -90mV. This is called hyperpolarization. What this does is stops the neuron from receiving and transmitting any other source of stimuli during this time besides the one it is in the process of sending. If hyperpolarization did not occur, the first stimulus that is being sent may change directions and be sent back down the axon to the neuron instead of to the brain; the result would be an unceasing loop of stimuli never being processed and transmitted. The releasing and receiving of K+and Na+ ions by diffusion eventually bring the neuron back to its rest potential, the stimulus information sent. However, if the interior potential incessantly decreases, the neuron will forever be in hyperpolarization and cease to carry out its functions. A step-by-step description of this process is available on this link and this video as well.

How does this tie into midazolam? Midazolam causes hyperpolarization. The Cl ions that are released due to the GABA are brought into the neuron via the GABA receptors. These chlorine ions have a negative charge, causing hyperpolarization in neurons at rest potential and increasing the time needed to send a signal when a neuron is in the process of sending an impulse to the brain. Therefore, the anxiolytic and amnestic effects of midazolam at the correct dosage are not damaging, as all neurons themselves go through hyperpolarization. The main difference is that midazolam causes hyperpolarization in neurons that are not even active, eradicating any chance of an impulse being sent. This is why no stimuli are being received while under the drug’s effects, no memories to remember.

Production of Midazolam

Since midazolam is such a common drug, it is made through a relatively simple process called a condensation reaction. This process is used for producing most benzodiazepine rings, and it involves reacting two amine groups with a ketone. During this reaction, water is lost, classifying it as a condensation reaction. Sulfamic acid is used as a catalyst during the reaction to help the reactants bond and to stabilize the complex.

For the reaction itself, two amine groups bond to the ketone, forming a double bond between the nitrogen and carbon atoms. Then an intramolecular reaction occurs that forms the diazepine ring. The resulting products are benzodiazepine and water. The figure to the below shows the synthesis of a benzodiazepine from o-phenylenediamine.

Drawbacks and the Antidote

While midazolam has its benefits, there are many cases of overdosage due to various factors, such as the patient’s age and metabolism. “The most common side effect would be hypoventilation,” says Dr. Sarier. “This can happen quite often. [The anesthesiologist] would assist in the patient’s ventilation and could administer oxygen via a nasal cannula or place a mask over both the mouth and nose to force oxygen into the lungs.”

In addition to this method, research in the British Journal of Clinical Pharmacology shows that a rising alternative solution is the use of a GABA receptor antagonist/ partial agonist called flumazenil. This drug works by binding to the GABA receptors, thereby reducing the amount of receptors that the midazolam binds to. This reverses the effects of midazolam with proven swiftness of recovering from the side effects. Therefore, flumazenil has been called the “antidote” to any benzodiazepine. For more information on flumazenil, take a look at Netdoctor and PubChem.

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