TYK90
Which of the following is true concerning oral midazolam premedication?
A. When using commercial oral midazolam preparations, sedation and anxiolysis is similar with doses of 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg.
B. IV midazolam may be diluted with oral acetaminophen, apple juice or grapefruit juice with similar effects compared to the commercially prepared oral midazolam.
C. The onset of effect is generally 30-45 minutes.
D. Ranitidine will decrease the plasma concentrations of orally administered midazolam.
Answer
The answer is A.
First, we must distinguish the COMMERCIALLY prepared oral midazolam[1] (Versed(R) syrup) versus the mixture that some of us may still use. With the commercially prepared stuff, each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, color dyes, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 - 3.6 with hydrochloric acid. The IV formulation of midazolam that many of us still use has a variable pH (depends on what you mix it with, how much, etc.). This creates a real problem because midazolam and its absorption is HIGHLY pH dependent.
Under the acidic conditions required to solubilize midazolam in the syrup (why they add hydrochloric acid to it), midazolam exists in an equilibrium of 2 (ring) forms.The amount of open-ring form is dependent upon the pH of the solution. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such. So anything that would change the pH of the stomach (oral antacids and ranitidine) would alter the absorption in the biologically active form. More basic equals more active medication. Now, the pH of the IV preparation is pretty acidic also, but the stuff we add to the IV formulation to mask the bitterness really screws with the pH. End result, you really don't know what absorption you are going to get. Why do we use the IV form then? It is generally cheaper and more available (some countries and places do not have availability of oral formulation).
Dilution with acetaminophen and apple juice will give you different results than oral preparations (usually more sedation for the same dose). And don't even get me started on grapefruit juice. Since midazolam undergoes extensive first pass metabolism by the liver enzymes (cytochrome P) and grapefruit juice inhibits them, the effective plasma concentration may increase by up to 50-60%!![2] But what kid drinks grapefruit juice to make something less bitter? End result is that grapefruit juice is like Cimetidine, it is almost ALWAYS the wrong answer.
Cote et. al.[3] and Brosius et. al. [4] studied the use of midazolam and found similar sedation scores between the doses, however the "cooperation score" they reported (read ability to tolerate the mask or sedation under stressed conditions) was dose dependent. So, even though the sedation was similar, interventions and cooperation needed a higher dosage.
Notes
- ↑ http://www.rxlist.com/midazolam-hydrochloride-syrup-drug.htm
- ↑ Weldon, B. Craig, Mehernoor F. Watcha, and Paul F. White. "Oral midazolam in children: effect of time and adjunctive therapy." Anesthesia & Analgesia 75.1 (1992): 51-55.
- ↑ Coté, Charles J., et. al. "A comparison of three doses of a commercially prepared oral midazolam syrup in children." Anesthesia & Analgesia 94.1 (2002): 37-43.
- ↑ Midazolam Premedication in Preadolescents and Adolescents Brosius, Keith K.; Bannister, Carolyn F. Anesthesia & Analgesia. 94(1):31-36, January 2002.