One such mechanism of enhancing drug delivery is through the design of prodrugs, which are derivatives of drug molecules that undergo an enzymatic process within the body to release the active drug, which will in turn, exhibit its desired effect. This is usually done to overcome barriers related to the physiochemical and/or pharmacokinetic properties of the active moiety, and in most instances, the solubility and permeability of the drug in various tissues and substances is enhanced with the prodrug. 

Phosphate esters are one example of prodrugs that are designed to increase the aqueous solubility of a number of compounds, especially those with side chains containing amino and/or hydroxyl groups. By taking advantage of the presence of endogenous enzymes such as alkaline phosphatase, the prodrug can undergo biotransformation to its active moiety. One drug that is commonly used in the emergency department (ED) that is considered to be a phosphate ester prodrug is fosphenytoin, which is approximately 7000 times more soluble than phenytoin, lending it to have a number of advantages such as rapid conversion within the bloodstream to phenytoin and reduced local irritation due to decreased precipitation at the site of injection. Another classic example of a phosphate salt that is commonly prescribed in the ED is dexamethasone sodium phosphate (commonly known as Decadron). 

At this point, you may be thinking, “Great. So who cares about a phosphate group?”

While phosphate esters pose these great advantages, they do have one pitfall specifically associated with their route and rate of administration that some clinicians may not necessarily be cognizant of when it comes to prescribing these medications. This is especially true as order sentences within our computerized provider order entry (CPOE) systems may be sophisticated enough to take into account the untoward adverse effect associated with these salts and may prevent prescribers from ordering these medications a certain way.

What is this adverse effect that I am alluding to? Believe it or not, it is perineal pruritus.While several case reports and controlled studies have been published regarding this adverse effect, unfortunately, the mechanism is not clearly understood. However, it is thought to be due to the phosphate group on these compounds, and commonly occurs as the drug is given as a rapid intravenous (IV) push. This same adverse effect was also demonstrated with rapid IV infusion of the agent fospropofol (which, as a side note, interestingly enough, has been discontinued from the US market since June 2012). The effect and any pain associated with perineal pruritus subsides as hydrolysis of the prodrug to the parent compound occurs, and there are generally no long-term consequences of the effect for the patient (other than the lasting memory of experiencing such an unpleasant reaction).

The potential of this adverse effect associated with these phosphate salts can be minimized in one of two ways. Both fosphenytoin and dexamethasone sodium phosphate can be administered as an intramuscular injection as an alternative route of administration. If IV access is obtained and necessary, dexamethasone can be mixed in 50 mL of diluent and given as an IV piggyback over five to ten minutes. In the case of fosphenytoin, we know that the rate of administration should not exceed 150 mg/min, and so this rate should be taken into account when administering the drug to a patient via the IV route.

Although much effort is exercised to ensure adequate delivery of a drug through the body, regardless of how well-intentioned efforts may be, the potential consequences can certainly be unanticipated and may go unrecognized as being associated with the drug delivery system of the compound. As the saying goes, “With great power…comes great responsibility.”

Selected References:

Huttunen KM, Raunio H, Rautio J. Prodrugs: from serendipity to rational design. Pharmacol Rev 2011; 63:750-771.

Perron G, Dolbec P, Germain J, et al. Perineal pruritus after IV dexamethasone administration. Can J Anaesth 2003; 50:749-750.

Singh M, Sharma CS, Rautela RS, et al. Intravenous dexamethasone causes perineal pain and pruritis. J Anesthe Clin Res 2011; S1:001.

Eldon MA, Loewan GR, Voightman RE, et al. Pharmacokinetics and tolerance of fosphenytoin and phenytoin administration intravenously to healthy subjects. Can J Neuro Sci 1993; 20:S810.

Pruitt RE, Cohen LB, Gibiansky E, et al. A randomized, open-label, multicenter, dose-ranging study of sedation with Aquavan injection (GPI 15715) during colonoscopy. Gastrointest Endosc 2005; 61:AB111.