Phenylephrine: An ALPHA1 Andrenegic Receptor

Phenylephrine: An Alpha1 Andrenegic Receptor With Limited Effectiveness

Phenylephrine has come largely to replace pseudoephedrine as the preferred method of treatment for decongestant and other cold related symptoms. Phenylephrine is an Alpha1-adrenegic (a1 andrenegic) receptor that functions as an agonist in specific reactive functions within the body. (Bylund et al., 1) in addition to its function as a decongestant, other reactive functions which it is used to promote include the increase of blood pressure, the dilation of pupils and in balance with the effects of anesthetics on the circulatory system. In all of such instances, the structure of the receptor is the catalyst in promoting the desired process and physiological outcomes. Accordingly, this discussion recognizes phenylephrine as possessing operational traits based on its categorization as a glycoprotein (G protein), the umbrella category to the a1 andrenegic receptor.

To the point, our research indicates that "Alpha1-adrenergic receptors are members of the G. protein-coupled receptor superfamily. Upon activation, a heterotrimeric G. protein, Gq, activates phospholipase C (PLC). The PLC cleaves phosphatidylinositol 4,5-biphosphate (PIP2) which in turn causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG)." (Wikipedia, 1) the outcome of this process is an interaction with the circulation of calcium in the bloodstream, resulting in an increase or decrease in the presence of calcium which will in turn invoke the intended treatment response. Particularly, phenylepherine works as a glycoprotein which "shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion" (CMI, 1) This function makes it an increasingly prominent way of addressing congestive conditions in the nasal passage, Eustachian tubes or other clogged respiratory channels. (CMI, 1)

As will be discussed hereafter, the degree to which it is effective in achieving its aims varies, but phenylepherine has been in popular pharmacological use for roughly 30 years, coinciding with the discovery and naming of glycoproteins. To this point, we now know "P-gp, a protein first identified in 1976, sits in the membrane that surrounds human cells, including those in the gut, intestine, kidney, and brain, where it functions as a gate keeper, shooing out potentially harmful agents." (ALS, 1) the glycoprotein as a more general receptor category helps to illuminate the way in which a substance such as phenylephrine works, denoting a structure that essentially works as a motor in carrying out the processes described above. According to the Treatment Action Group (2000), "P-glycoprotein (P-gp) is a plasma membrane protein which acts as a localized drug transport mechanism, actively exporting drugs out of the cell. The effects of P-gp on the distribution, metabolism and excretion of drugs -- including protease inhibitors -- in the body is great." (TAG, 1)

In the case of phenylephrine, the metabolic organs are targeted, with receptors working in the membranes of the stomach and intestines to move reactions along to the bloodstream. This means that phenylephrine will be absorbed through the lining of the stomach and thusly, at least partially metabolized by stomach acids on its bath to the bloodstream. This manner of delivery has actually cast significant doubt on the form which phenylephrine has increasingly taken. Namely, the formerly popular primary ingredient in over-the-counter nasal decongestants -- which deliver the substance directly to the point of treatment -- differs from the now popular pill-ingested form intended to serve as a substitute for pseudoephedrine. This intended substitute is delivered to receptors which can dilute its effect, reducing what is known as its bioavailability. According to the minutes of a meeting for the Medicines Classification Committee (2004), it was resolved that "phenylephrine had variable bioavailability with up to 38% bioavailability due to metabolism through the gut wall. Some other agents which are metabolised through the gut wall and have low bioavailability had been subject to important drug interactions. However, this seemed unlikely with phenylephrine according to communications with an interactions expert." (MCC, 1)

This is to cast a doubt on the effectiveness of phenylephrine for those uses which have been more recently foisted upon it. Though its dangers or side-effects are modest in most instances, there remain a great many drawbacks in terms of its apparent treatment effectiveness relative to the pseudoephedrine which it has today been constructed to replace. Indeed, one may find phenylephrine in such products as Sudafed, Tylenol Cold, Benadryl and most other common household decongestant and cold or flu treatment solutions. However, its lower bioavailability indicates that lesser treatment methods are now being used to replace what was seen as a modestly effective pharmacy approach for many years prior.

The change is underscored not by prevailing logic in the field of pharmacy, but instead in response to various social and political conditions inciting a newly restrictive policy on pseudoephedrine. Particularly, as a result of its higher bioavailability, pseudoephedrine is said to bear such negative side-effects as anxiety, nervousness and sweating. And more importantly, it is argued that certain ingredients in the substance as well as certain effects of its intake such as the above described side effects may stimulate addictive tendencies and further, may function as a gateway into the use of methamphetamines. It would be this shared set of perceptions which would allow lawmakers to slide new restrictions on the drug into the U.S. Patriot Act. Such restrictions would demand that these substances now be sold with greater regulation and accountability.

Thus, according to a report by Homewood (2004), as the requirement "to move medications containing pseudoephedrine behind the counter looms, many pharmaceutical companies are reformulating some of their common cold and allergy medications to keep them readily available on store shelves. Most companies are switching to phenylephrine, which cannot be used to make methamphetamine." (Homewood, 1) This distinction serves to lawmakers as a primary impetus for turning to a drug that will essentially and knowingly be less effective in countering those conditions for which it is only now being formulated. However, most pharmacists have posited the argument that the commonality of rendering methamphetamine from pseudophedrine is just not significant enough to justify a wholesale reduction in the effectiveness of such public health treatment conventions.

The compromise is perceived as a negative one, with some studies even going so far as to identify this form of phenylephrine as little better than a placebo. Where there is a wholesale endorsement on the part of pharmacists of nasal sprays and vapor rubs that address the immediate site of an ailment, the metabolized version which relies on receptors on the stomach lining is simply not seen as efficient. Accordingly, "Paul Doering, a University of Florida professor of pharmacy who teaches about over-the-counter medications, said that phenylephrine has rarely been used in oral decongestants, and for good reason. 'As pharmacists we have always avoided this drug,' Doering said. 'We all know that it isn't absorbed into the bloodstream well enough.'" (Homewood, 1) This consensus in the pharmaceutical community has not been sufficient to undermine the imperative created by legal doctrine and social theory concerning drug abuse. This is a problematic outcome which will have the impact of reducing phenylephrine's rational usage while simultaneously doing very little to impact the problems perceived as relating to pseudoephedrine. Accordingly, a study by Eccles (2007) indicated that "studies in the U.S.A. indicate that restricting the sale of PDE to the public as a medicine has had little impact on the morbidity and number of arrests associated with methamphetamine abuse. Restricting the sale of PDE in order to control the illicit production of methamphetamine will deprive the public of a safe and effective nasal decongestant and force the pharmaceutical industry to replace PDE with PE, which may be an ineffective decongestant." (Eccles, 10)

Thus, the increased production of phenylephrine has been done with little in the way of a rational imperative, and will more than likely have the effect of reducing public health. Indeed, it may be seen as somewhat remarkable and ill-informed that pharmacy industries have been forced to pursue this change as a way of replacing what was previously an over-the-counter item considering that as recently as the study by Hatton et al. (2007), there existed no reviews on the efficacy of phenylephrine as a metabolized decongestant. With legal conditions invoking its use thusly as early as 2002, it should be seen as surprising, problematic and irresponsible on the part of drug companies to actively work to promote this as a replacement for pseudoephedrine. Thus, all indications from the research are that those seeking to treat cold and flu symptoms will be better served by purchasing the behind-the-counter pseudoephedrine-based treatment rather than over-the-counter phenylephrine-based substitutes.