Pharmacological Options

We have several pharmacological options. In the table I have placed bronchodilators on the left side, anti-inflammatory therapy on the right. The bronchodilators are further divided into how they act and how long their effects last.

The short-acting bronchodilators, albuterol for example, start working in a few minutes but the effect will only last for 4-6 hours. Over the years these were the only medications that we had available. We had to ask our patients to use them—albuterol and ipratropium—alone or in combination every 4 to 6 hours continuously. Patients' lung function continued to decline and their condition continued to deteriorate.

In long-lasting bronchodilators there are two large classes: the long-acting beta2-agonists, salmeterol and formoterol, and the long-acting anti-cholinergic tiotropium. The two long-acting beta2-agonists are not the same. Formoterol has a more rapid onset of action. The effects of both medications last around the same period of time but they have different characteristics. One is hydrophilic, the other is lipophilic, and that has to be taken into consideration when using these medications because it will impact the onset of action. In some places, like in Europe, these have been used as a rescue medication due to the rapid onset of action in the case of formoterol.

There is only one long-acting anti-cholinergic, tiotropium, available. It is a once a day medication, and the effect will last up to 36 hours in most patients.

On the right side are the anti-inflammatories. We have corticosteroids and the truth is that systemic and parenteral type of corticosteroids should only be used in patients who are hospitalized and patients who have COPD exacerbation. If you’re going to use systemic corticosteroids, my advice is to use 20 to 30 mg of prednisone for five days, then stop. There is no need to give huge doses, like 1g of Solu Medrol, every four to six hours, even in patients with exacerbations. We now understand that these medications can be detrimental and have more significant side effects and more impairment in patients in the long term. Use systemic corticosteroids at a low dose for short time periods. Patients should not be on oral corticosteroids for extended time periods.

I have listed only two anti-inflammatory corticosteroids, fluticasone and budosonide, because these are the most up-to-date that have been approved and are less likely to have side effects. We used to have triamcinolone and beclomethasone, but a lot of those medications have significant side effects. The FDA has recently approved ciclesonide for asthma but it has not been approved for COPD. Ciclesonide is an inhaled corticosteroid.

This is a very active field of research. Everyone is trying to find the best antiinflammatory inhaled corticosteroid. In many cases, we don’t give them alone. We give them in combination with long-acting bronchodilators and there are fixed combinations with long-acting beta2-agonists.

This table shows what happens when you use the long-acting anti-cholinergics. On day number one patients have an acute response. The important data to look at is what happens to these patients one year later. By the end of one year, all of the patients’ baseline FEV1s are higher, sometimes 10% to 15% higher than before. Some patients will be 20% higher than where they began.

Using this same analysis in the next chart, the patients that were listed under placebo were the patients who were taking the short-acting bronchodilators - ipratropium and albuterol, alone or in combination. At the end of one year these patients had lost close to 80 cc in lung function. Clinical studies today show that these patients can have a loss, depending on the severity of the disease, of up to 100 ccs per year. If a patient starts with an FEV1 of 1.5 and loses an average of 100 cc per year, it won't be too many years before he or she is going to be incapacitated.

Once the FEV1 starts going down to the 900s and 800s, patients are going to be impaired. What this table tries to show is not only the acute effect of the long-acting anti-cholinergic, but also what happens a year later. How can you change or shift the baseline to increase the FEV1 in patients who are not receiving long-acting bronchodilators and are losing lung function – patients in whom the disease continues to progress? This is an effect that has also been shown with long-acting beta2-agonists. A recent publication has demonstrated these effects in patients taking the long-acting beta2-agonists in combination with inhaled corticosteroids.Some of these effects could be due to reduction of complications. Patients with COPD have eriods of flare-up of their symptoms that we call exacerbations. These patients are going to have more shortness of breath. They are going to cough more, the sputum is going to change color. Very often it is associated with an infection. Initially it could be a viral infection, later it could be bacterial infection. These exacerbations are the driving factor of significant morbidity and mortality in COPD.

There are several clinical studies that have looked at this particular issue. If you use long-acting bronchodilators with ipratropium, you have a 20% reduction in exacerbations and this translates to an almost 49% reduction in the need for hospitalization. This medication doesn't just make the patient breathe better for four to six hours. The implications are for the long-term. The capacity of the lung has increased and patients have fewer complications as reflected with fewer exacerbations. The goal is to halt the dyspnea spiral that the patients are on.

As you can see in this chart, patients have dyspnea on exertion. As a consequence of that they are going to abstain from exercise. They are going to have muscle atrophy and eventually all they are going to be able to do is sit in a chair and watch TV. They will be severely impaired, they might even be too depressed to watch TV. With harmacotherapy we stop this spiral, stop this progression of the disease. We can prevent most of the deconditioning and prevent the patient from becoming incapacitated. Patients will be able to exercise, to live their lives as fully as possible.

One of the important physiological consequences of COPD is airway hyperinflation. Hyperinflation means that you have more air in your lungs than you’re supposed to have. That occurs in big holes inside the lungs. Air can get in but air cannot get out so it gets trapped. The patient becomes inflated. Hyperinflation is responsible for patients being short-winded. It is responsible for the limitations and spiral shown in the previous table. Hyperinflation flattens the diaphragm and makes patients have to breathe using their accessory muscles. Hyperinflation is easy to identify. If you walk into a roomful of people and see a person sitting there who leans forward and takes a small short inspiration and long expiration, you know that patient may have lung disease or some type of airway obstruction. He or she has to have an active expiratory effort in order to empty the lungs. Hyperinflation is an important physiological mechanism.

A patient’s symptoms can improve with pharmacotherapy. When you use long-acting bronchodilators, tiotropium, long-acting beta2-agonists alone or in combination when you have corticosteroids, patients will report feeling better because clinical studies have shown that the patients have a significant decrease in airway hyperinflation. With long-acting bronchodilation the airway remains open for a longer time period and the patient's baseline gains from 10% to 15%. The end result is that, with each breath, more air can go out and less air gets trapped in.

Today, hyperinflation is believed to be the cornerstone, the secret mechanism that is responsible for the problems that these patients experience. This mechanism can be overcome when the patient has chronic bronchodilation. Many patients notice this when they exercise. With long-acting bronchodilation they are going to be able to exercise more and for longer periods of time.

Do patients notice a difference? Are they experiencing that they are less short-winded, that they can exercise more?

This table uses an indicator of shortness of breath and how dyspneic the patients are. This is called the TDI Focal Score and it measures how short-winded and how limited the patient is. You can see with the use of the long-actin anti-cholinergics with ipratropium, the patients’ scores are better. They will have sustained improvement in their symptoms that will translate into increased exercise capacity and will translate into decreased complications.

I want to make a couple of points about the long-acting drugs and the beta2-agonists. Mainly, these medications have different mechanisms of action. Although they are bronchodilators, it has been identified that there may be some effect on bacterial adherence and they may have some effect on mucociliary clearance.

When you look at long-acting beta2-agonists, there are going to be differences between formoterol and salmeterol. The peak action of formoterol occurs within thirty minutes with the onset of action within five minutes, while salmeterol can take one to two hours to have that effect. That is why salmeterol is not indicated in patients who have an acute exacerbation.

One of the major advantages of these medications and the long-acting bronchodilators is a sustained improvement in lung function. When patients have fewer symptoms during the day and during the night, they are able to sleep. It will improve their quality of life. Clinical studies have also shown with long-acting beta2- agonists that there will be a reduction in complications like exacerbations.

We need to add long-acting bronchodilators in patients whose symptoms are not improving with pharmacotherapy or whose lung function has continued to deteriorate. In patients who have a nocturnal component of COPD with a lot of reactive airway disease, these medications given twice a day will have a significant impact in the quality of life and exercise capacity.

Let’s talk about anti-inflammatory medications and airway inflammation. As I said before, corticosteroids are what we have today. Airway inflammation in COPD is a different pattern of airway inflammation than is present in asthma. This pattern of inflammation is associated with the development of structural abnormalities. These abnormalities may explain why patients treated with inhaled corticosteroids alone may not have much improvement in lung function and may not have a decrease in the frequency of their exacerbations.

The different guidelines recommend who should get inhaled corticosteroids based on the results of large, randomized, controlled trials. There was a study concluded in 2007 called the TORCH study that compared long-acting beta2-agonists to inhaled corticosteroids and to the combination of both. That study showed that patients who use inhaled corticosteroids alone actually may do worse in the long-term. The maximum benefit has been shown in patients who have more severe impairment in lung function with FEV1s less than 50%, who are symptomatic and/or have frequent exacerbations. You should consider giving inhaled corticosteroids in combination with a long-acting bronchodilator. Inhaled corticosteroids should not be used alone because there will be very little improvement in lung function. If you give them in combination with long-acting beta2-agonists, they will help improve lung function and also decrease complications like exacerbations.

In this table, I show the relative rates of exacerbations in a meta-analysis in patients with COPD. These are different clinical studies, using different inhaled preparations. Today, we have been able to identify that there is a significant improvement in the reduction in exacerbations that these patients will experience.

What I am going to do in the last part of the discussion of treatment is look at some of the data in combination therapy of inhaled corticosteroids and long-acting beta2-agonists. For patients with more severe lung disease the advantage of these medications is that they come in different amounts of corticosteroids. There are different commercial preparations available that you can give your patients. You can tailor the dose of corticosteroids based on the patient’s needs. For example, your patient may have an acute exacerbation and a persistent worsening of symptoms. At this point the patient may not be stable, so you begin with a combination of fluticasone and salmeterol, with a dose of fluticasone of 250 mcg. But when your patient starts improving, you can lower the dose to 100 mcg. Depending on the dose of corticosteroids, the dose of the long-acting beta2-agonist is going to remain constant.

This next table shows clinical studies of budesonide and formoterol. I must point out that these combinations are not currently approved in the United States for use in COPD. There is extensive data from Europe in this patient population and this is one of those clinical studies. You can see that the combination of budesonide and formoterol provides some additional improvement in lung function, but most of the effect that you are seeing is the effect of formoterol, the bronchodilation effect of the long-acting beta2-agonists.

You can see on the table on the following page, that if you combine the inhaled corticosteroid fluticasone with the long-acting beta2-agonist salmeterol, you can have a similar effect. This table shows the data from Dr. Nicola Hanania’s publication in Chest 2003. This patient has a higher improvement in the FEV1 after using the combination therapy than with either component used alone.

When we summarize the pharmacotherapy of COPD, we have many options available. What we have to do is look at the patient's symptoms, at the severity of the patient’s disease. Symptomatic patients must be treated with long-acting bronchodilators. The short-acting bronchodilators should be given as a rescue medication. Your goal is to have your patient come to see you at the end of the year and tell you, “Doc, you know you gave me this inhaler that I’m supposed to use when I get short-winded? I haven’t used it, my prescription expired, and I need a new prescription.” That tells you that his disease is well-controlled with the long-acting bronchodilators.

Which long-acting bronchodilators to use? We have the choice of long-acting beta2-agonists and long-acting anti-cholinergics. Clinical studies suggest that the long-acting anti-cholinergics are more effective, safer and less likely to develop tachyphylaxis.

Once the patient’s disease progresses and meets the criteria for inhaled corticosteroids, you want to give the long-acting anti-cholinergic in combination with a long-acting beta2-agonist. For some of these patients you can titrate the dose of inhaled corticosteroid based on the severity of the disease. These patients, in many circumstances, will need to have three-part combination of therapy—the long-acting anti-cholinergic with ipratropium, then the inhaled corticosteroids and either formoterol, salmeterol, budosonide, or fluticasone, whichever formulation your patient can tolerate best.

You can see we have changed the management of this condition. Now what we do is we try to change the course of the disease. We give bronchodilators that last longer and as a consequence we have more lasting effects which makes a more significant impact in our patients.