Question About Albuterol Atrovent Neb. Tx

MunoRN, RN · May 28, 2011

You can not compare "dosages" when you now have two different chemical configurations.
You can also look at other medications which also have similar differences with the isomers.
L-epinephrine1:1000 and Racemic Epinephrine 2.25% are good examples.
You could also take a look at the albuterol dosage in DuoNeb (or the generic) and the single unit dose.
Duoneb contains 3.0 mg (0.1%) of albuterol sulfate, the equivalent to 2.5 mg (0.083% of albuterol base).

As you point out in the very same post you can compare the two using equivalency ratios, (" Duoneb contains 3.0 mg (0.1%) of albuterol sulfate, the equivalent to 2.5 mg (0.083% of albuterol base)" that's how the two are compared.

GreyGull · May 28, 2011

As you point out in the very same post you can compare the two using equivalency ratios, (" Duoneb contains 3.0 mg (0.1%) of albuterol sulfate, the equivalent to 2.5 mg (0.083% of albuterol base)" that's how the two are compared.

Okay you got me there. However, Levalbuterol 1.25 mg or a half dose of Albuterol.

MunoRN, RN · May 28, 2011

Okay you got me there. However, Levalbuterol 1.25 mg or a half dose of Albuterol.

That's usual conversion. Racemic (R,S) albuterol has an exactly even amount of ® and (S) albuterol, so 1.25mg ®-albuterol (aka levalbuterol) is considered equivalent to 2.5mg albuterol. Yet 0.625 mg or even less levalbuterol has been shown to be as or more effective than 2.5mg albuterol.

wooh, BSN, RN · May 28, 2011

I was told by my former DON that a Pt can receive a breathing tx every hour and it not be harmful. Under what circumstances would this be true?

Lots of dickering over protocols. My hospital's ED does one thing, ICU does another, floors do another, and when needed, the floors do something else. And the discharge home instructions say something else.

Easy answer to the OP question:

When the patient needs it.

What I see most often across that continuum, at least with peds, if continuous admins of continuous treatments aren't working, then hopefully at that point you're trying something else. Steroids, mag, PEP, whatever.

But back to OP: Think about which is more harmful- frequent breathing treatments or not breathing?

GilaRRT · May 28, 2011

That's usual conversion. Racemic (R,S) albuterol has an exactly even amount of ® and (S) albuterol, so 1.25mg ®-albuterol (aka levalbuterol) is considered equivalent to 2.5mg albuterol. Yet 0.625 mg or even less levalbuterol has been shown to be as or more effective than 2.5mg albuterol.

In fact, I believe for any medication to be called a racemic mixture it must essentially contain a 1:1 ratio of left and right handed molecules. In theory, this make comparing conversions relatively easy.

GilaRRT · May 28, 2011

Racemic albuterol was developed with the goal of producing ®-albuterol, or levalbuterol. The closest they could get at the time was to split a larger molecule producing ®-albuterol and it's chiral counterpart (S)-albuterol. The combination of the two was effective and a better option than racemic albuterol, and since they didn't know how to separate the two at the time they just left the (S)-albuterol in the mix and deemed it an inert byproduct. It wasn't until many years later when ® and (S)-albuterol were successfully isolated and could be studied.
There have been both in vitro and in vivo studies on the effects of (S)-albuterol, the abstract of this study from 2004 sums it up: "Pro-constrictory and proinflammatory properties of (S)-albuterol have been widely reported both under in vivo and in vitro conditions. However, underlying mechanisms are unclear." http://www.ncbi.nlm.nih.gov/pubmed/15007354
You really only need look at the well established dosages and administration intervals for levalbuterol and albuterol particularly when given in larger doses and to treat more severe symptoms; given the same amount of ®-albtuerol, levalbuterol requires a smaller dosage for the same effect, the result of containing a component with opposing effects to levalbuterol.

I am still not convinced that the evidence strongly supports using Xopenex over Albuterol however. It may be arguable in some situations, but I'm still do not find the evidence overwhelming compelling. Regarding the term "by-product," I guess it's more of an interpretation of terminology that bothers me. I feel as though something very important about the fact that we are talking about two molecules with the same number of atoms in a mirror image configuration gets lost in the translation. Clearly, I don't think you are unaware of that distinction.

Thank you for the continued dialogue.

MunoRN, RN · May 28, 2011

I am still not convinced that the evidence strongly supports using Xopenex over Albuterol however. It may be arguable in some situations, but I'm still do not find the evidence overwhelming compelling. Regarding the term "by-product," I guess it's more of an interpretation of terminology that bothers me. I feel as though something very important about the fact that we are talking about two molecules with the same number of atoms in a mirror image configuration gets lost in the translation. Clearly, I don't think you are unaware of that distinction.
Thank you for the continued dialogue.

Chiral isomers are mirror images of each other, but typically have different actions as drugs. All isomers are molecules with identical atomic make-up but with different structures, this different structure causes different isomers to interact differently with other molecules. A "By-product" is a secondary or unintended product that results from a manufacturing process. The (S) isomer was not the intended molecule and serves no beneficial purpose.

While representatives from albuterol producing companies have successfully muddied the waters (Dr. Barnes with GSK being the most prominent), the evidence is thoroughly in favor of levalbuterol when larger doses and more acute conditions are studied. 3 studies that looked at levalbuterol use in the ED with over 1000 subjects total found that patients where 1/3 to 1/6th less likely to be admitted if treated with levalbuterol in the ED and had a length of stay that was shorter by nearly a full day compared to treatment with albuterol. In terms of adverse effects, the FDA labeling for albuterol 2.5mg neb lists a paradoxical bronchospasm rate of 15%, compared to 0% for 1.25mg levalbuterol. There really aren't any reputable sources that show levalbuterol and albuterol are equal when using larger doses and treating acute conditions, the main argument has been one of cost not efficacy. Now that levalbuterol is generic the costs are much closer, and cost savings such as lower admission rates, shorter lengths of stay, and fewer side effects often outweigh the cost differences.

Racemic albtuerol is essentially a poison packaged with the antidote, it produces negative effects but also treats those negative effects, except when the ® albuterol levels drop and (S) albuterol levels remain elevated due to their differing half-lives. Imagine you are a patient and you have diarrhea. Your nurse brings you immodium as well as a stool softener, you only need the immodium but the hospital saves a couple bucks if they give it along with the stool softener. Overall the immodium over powers the stool softener until the immodium wears off before the stool softener leaving you with worse diarrhea than you had before, that's essentially what we do when we give albuterol since we have the choice now not to give the (S)albuterol portion of albuterol.

MunoRN, RN · May 29, 2011

Racemic albuterol was developed with the goal of producing ®-albuterol, or levalbuterol. The closest they could get at the time was to split a larger molecule producing ®-albuterol and it's chiral counterpart (S)-albuterol. The combination of the two was effective and a better option than racemic albuterol, and since they didn't know how to separate the two at the time they just left the (S)-albuterol in the mix and deemed it an inert byproduct. It wasn't until many years later when ® and (S)-albuterol were successfully isolated and could be studied.
There have been both in vitro and in vivo studies on the effects of (S)-albuterol, the abstract of this study from 2004 sums it up: "Pro-constrictory and proinflammatory properties of (S)-albuterol have been widely reported both under in vivo and in vitro conditions. However, underlying mechanisms are unclear." http://www.ncbi.nlm.nih.gov/pubmed/15007354
You really only need look at the well established dosages and administration intervals for levalbuterol and albuterol particularly when given in larger doses and to treat more severe symptoms; given the same amount of ®-albtuerol, levalbuterol requires a smaller dosage for the same effect, the result of containing a component with opposing effects to levalbuterol.

That was supposed to say "racemic epinephrine", my bad.

GilaRRT · May 29, 2011

Unfortunately, there may also be publication bias for xopenex as well. There exist many studies for and against each agent. I have also found paradoxical bronchospasm listed as a caution for Xopenex. Even popular references such as epocrates list paradoxical bronchospasm as an adverse reaction. My point being that the literature is all over the place, experts are all over the place and I've yet to see a clear winner. Both agents appear to have efficacy and depending on how things are spun and how evidence is cherry picked, you can make compelling arguments for both sides. I'm not convinced yet that Xopenex has a clear advantage.

At this point, I will continue to use albuterol as my primary rescue inhaler, but we will see what the future brings. Additionally, I can get my albuterol dirt cheap and while prices may be going down, the prices that I'm looking at for Xopenex at my local pharmacy are still significantly higher than albuterol at this time.

caliotter3 · May 29, 2011

I enjoy coming across educational threads such as this one.

MunoRN, RN · May 29, 2011

When used for mild to moderate symptoms, in smaller less frequent doses, there is little evidence to support a clinically significant difference between the two in most patients. In the case of OP's question, where ER sizes doses are being needed hourly, the difference becomes more apparent in the evidence. Both tylenol and dilaudid might bring someone's pain down from 2/10 to 0, but that doesn't necessarily mean they are equally effective. For less frequent control of mild to moderate symptoms, the extra cost may not be worth it, when used to treat acute exacerbations such as in the ER, the extra $1 or 2 a dose would seem to be well worth it.

Being an inhaled beta2 agonist, xopenex was required by the FDA to include warnings associated with beta2 agonists. Many drug references include FDA labelling usually word for word, which in this case goes "Like other inhaled beta-adrenergic agonists, Xopenex ( levalbuterol) Inhalation Solution can produce..." There have been cases reported of paradoxical effects but not many, only three that I can find. One of the case studies started off with "Levalbuterol has been reported to have a greater affinity for the β-receptor and less sympathetic irritation than the racemic form, therefore decreasing the incidence of paradoxical bronchospasm.5 Although paradoxical bronchospasm is listed in levalbuterol's drug label and is associated with new inhalation canisters,6 few published studies document this adverse effect.7 We report a case of paradoxical bronchoconstriction in a man recently diagnosed as having new-onset asthma." The one reference given for "few published studies document this adverse effect" was a case report that claimed to be the first, although another case study that came out about the same time (2006) also claimed to be the first.

I'd be curious what studies are "against" albuterol. There is a long list of studies with thousands of subjects that showed dramatic differences between the two in clinical settings (Gawchik, Handley, Milgrom, Truitt, Schreck, Graves, Donohue, Drazen, and more). The main, and essentially only, study pointed to by defenders of albuterol (and it's makers profits) is the Quereshi study. One thing evident in the studies is that differences are less noticeable with lower and less frequent dosing and in patients with less severe symptoms and healthier baselines. The Quereshi study looked at 124 pediatric asthma patients with mainly mild to moderate symptoms. Although the study did find an FEV1 that improved by an extra 15% with levalbuterol, it was not as impressive as other studies. Aside from the conditions that predictably made the results less dramatic, the study also used 2mg/kg of steroid as a control, which is on for a study essentially meant to test for the presence of pro-inflammatory action, which would have been significantly dulled by the use of steroids.

As with any drug company war, publication bias abounds. Which is why it's best to avoid the commentary and stick to the evidence itself. It is amazing how evidence can be twisted and turned a complete 180, with the pro-albuterol group making some of the most impressive logical twists seen in any territorial drug company dispute. One of my favorites was Dr. Barnes, who sits on the board of GSK, the original and still largest maker of albuterol, who argued that there were a couple of studies that showed "no difference in bronchodilator responses", even those the two studies he referred to showed that 4-8 times as much of an equivalent dose of albuterol was needed to produce the same beneficial effect as levalbuterol. So in other words, they're equal so long as you 8 times as much albuterol. I have many more examples of his impressive statistical gymnastics if you're interested, including referencing his own previously published opinion piece as a supposed independent fact. In the end, it comes down to money. Sepracor, the makers of levalbuterol, is relatively very small, compared to the multitude of large drug makers who's interest it is to defend their territory, and even with the profound imbalance of evidence, those with most money to get their voices out there, regardless of the amount evidence to support them, always win.

MunoRN, RN · May 30, 2011

.....
I'd be curious what studies are "against" albuterol. There is a long list of studies with thousands of subjects that showed dramatic differences between the two in clinical settings (Gawchik, Handley, Milgrom, Truitt, Schreck, Graves, Donohue, Drazen, and more). The main, and essentially only, study pointed to by defenders of albuterol (and it's makers profits) is the Quereshi study. One thing evident in the studies is that differences are less noticeable with lower and less frequent dosing and in patients with less severe symptoms and healthier baselines. The Quereshi study looked at 124 pediatric asthma patients with mainly mild to moderate symptoms. Although the study did find an FEV1 that improved by an extra 15% with levalbuterol, it was not as impressive as other studies. Aside from the conditions that predictably made the results less dramatic, the study also used 2mg/kg of steroid as a control, which is on for a study essentially meant to test for the presence of pro-inflammatory action, which would have been significantly dulled by the use of steroids....

My bad again, I meant levalbuterol here. I noticed there are other typos as well, my apologies for making an already long-winded post more difficult to read, I was on my way to a ball game.