The Salbutamol Saga

Science

ByTheMinLife

According to an article put out by 'VeloNews,' Chris Froome's salbutamol defence has been rejected by the UCI, and the case is being sent to an anti-doping court, meaning that disciplinary proceedings are a possibility. For anyone who isn't familiar with the story, Froome had an adverse analytical finding last September, when the concentration of salbutamol in his urine was twice the allowed limit. (2000ng/ml as opposed to the limit of 1000ng/ml). For this to be viewed as acceptable, Froome would have to prove by means of a controlled study (testing carried out in a lab, under controlled conditions) that he didn't exceed the allowed dose of salbutamol that day, which is a maximum of 1600 micrograms over 24 hours. Salbutamol should be taken in divided doses, when needed, so the guidelines state that 800 micrograms should not be exceeded in the 12 hours after taking the previous dose.

So, what is salbutamol? Salbutamol is a beta-2 agonist, which probably means nothing to people who've never heard of it! Basically, it'll open up your airways, which is what an asthmatic person needs when experiencing an asthma attack. Salbutamol is supplied a 'reliever' inhaler, and so will be used when an exacerbation of asthma has occurred. 'Preventer' inhalers are used to prevent exacerbations, and they will generally contain corticosteroids. For anyone who isn't asthmatic, if you can imagine a balloon, fully inflated. You're trying to get more air into the balloon, but you're restricted because it can't stretch any further. That's a rough idea of what it feels like. Salbutamol basically allows more space in the balloon, allowing more air in, and the person can breathe! The recommended dose of salbutamol is to take one or two puffs when required, and this can be taken up to 4 times a day if necessary. One puff of the inhaler contains 100 micrograms, so this dosing would result in no more than 800 micrograms in a day (it is generally assumed that no doses will be taken whilst asleep). Realistically, if someone was needing more than this, it's probably something that would need urgent medical treatment, because salbutamol *should be* effective when used correctly.

Obviously, salbutamol is a necessary medication for people experiencing exacerbations, and having needed it myself, it is SCARY when you can't breathe! It would be easy to say that there's no way that anyone would be taking this for performance-enhancing reasons, but what does science say? Anyone with asthma will generally be using salbutamol in the form of an inhaler, and occasionally, it may be inhaled by means of a nebuliser (usually in more severe cases). However, there is evidence that if salbutamol is taken in the form of a tablet, or if it is injected, it can mimic the action of clenbuterol, which is also a beta-2 agonist, but with the added effects of improving an athlete's lean muscle mass:fat ratio. COUNTLESS athletes have been banned for the use of clenbuterol. These effects will be seen with long-term use, but will not occur if the athlete is using an inhaler as prescribed according to accepted guidelines. (Don't even get me started on the fact that clenbuterol is advertised as a 'natural alternative.' YIKES)

What do these urine levels mean? After inhalation of salbutamol, it is absorbed into the lung tissue, and eventually will be broken down by enzymes in the liver. These break-down products, known as metabolites, are smaller molecules, which can be easily passed out in the urine. A small amount of salbutamol will also be passed out unchanged, and so would be detected as pure salbutamol in the urine. An important point is that we are not all cardboard cut-outs of each other, and different people can metabolise drugs in different ways. One person may have more of the enzyme necessary for breakdown than another person, and so that drug may be broken down more quickly. When calculating upper limits of the concentration of any drug present in the urine, this will have been taken into account by WADA. Most of the time, either 95% or 99% confidence limits will be used, meaning that if 100 people had taken the same dose of salbutamol, and had their urine levels tested, 99 of them would be within the limits specified. Basically, the chances of someone having a level above 1000ng/ml are very low.

Team Sky have put forward some potential arguments for the finding. According to this article, http://www.velonews.com/2018/03/the-outer-line/the-outer-line-can-science-rescue-chris-froome_460424, possible reasons put forward include interactions with food, other medicines, or dehydration. Let's take each of these in turn; 1. Food I found an interaction with caffeine and salbutamol, but this wouldn't have increased the concentration in the urine, it would just have increased the risk of side-effects such as shaking, and an increased heart rate (so, not a good idea!). 2. Medicines There are a number of medicines which interact with salbutamol, in that, like caffeine, they'll increase the risk of side-effects. According to the article linked above, there is an interaction with a type of antidepressant which can increase the urinary concentration of salbutamol. Now, that's all well and good, but the class of antidepressant mentioned is rarely used nowadays due to a wide range of side-effects (there are a lot of safer alternatives), and also, they're banned by WADA. 3. Dehydration For me, this is the most interesting one, and it's potentially the most plausible. Obviously, if you're well hydrated, you produce more urine, and a large proportion of it is water. So, the same amount of salbutamol in a higher volume of water will give a lower concentration of salbutamol. (More millilitres, same number of ng, less ng per millilitre). Conversely, if you are dehydrated, which you very well might be during exercise, the kidneys 'hold on' to water, and less is passed out in the urine. This gives a lower volume, but the amount of salbutamol would still be the same, giving a higher concentration. (Less millilitres, same number of ng, more ng per millilitre). If it's easier, imagine putting a tea bag in a full cup of water, compared with a tea bag in half a cup of water. The half-cup will be stronger. This all sounds great and could well be accepted as a defence, however, research has already been carried out! Haase et al (2016) examined the urinary concentrations of salbutamol in healthy male volunteers after being at rest, after exercise, and also, after exercise whilst dehydrated. They did find that the concentration of salbutamol in the urine increased, however, not to the same extent to which Froome's level was increased. The highest recorded conentration is 1300ng/ml, which after correction for fluids lost during sweating, still exceeded 1000mg/l, but certainly not by 1000mg/l. Dr. Bill Apollo, cardiologist and author of the linked article has identified that the most likely cause of Froome's finding was an inhaled dose over the threshold, but made the point that Froome has long been diagnosed with asthma, and has plenty of passed doping controls, so it doesn't necessarily point towards planned performance-enhancing behaviour.

From my own knowledge, I remembered about different drug metabolisms and how they vary between people, I wanted to check whether it could be anything to do with different levels of enzymes present in different people, as I have previously mentioned. Luckily, this research has also been carried out before (Sjosward et al, 2003), and whilst they found that asthmatic patients did have reduced levels of certain enzymes present in the liver, they have also noted that this made no significant difference on the urinary concentrations of salbutamol, and it only changed the levels present in the plasma.

In conclusion, salbutamol is a staple drug in the life of anyone with asthma, and to see it with the potential for use as a performance-enhancing agent is challenging. Whilst it is difficult to deny the clenbuterol-like effects it can bring with specific usage, the potential side-effects are a recipe for disaster. Even at therapeutic doses, salbutamol can cause side-effects like headaches, shaking hands, increased heart rate and palpitations. The risk of these are increased with higher doses, and seem completely counter intuitive for professional athletes. Although, this doesn't stop athletes who are determined to break rules anyway. Whatever the outcome of this case, I will be following along eagerly and listening to the explanations put forward.

Mike Barry

Anna, another excellent article in laymans language. Keep this going. Cheers.!! M.

Steph

Good work Anna, thanks. I think the outcome of Froome's case will have as much to do with lawyers as it does science but still it is unlikely he'll get away without a ban of some sort.

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