Advair – for asthma and COPD

Hello friend!

Greetings! Let’s talk about breath. Can you think of anything more important to life than breath? What if you find it difficult to breathe? That’s what happens with conditions like asthma and chronic obstructive pulmonary disease (COPD). 

Advair is the brand name of an inhaler combination of two drugs, fluticasone (a steroid derivative – a very mild dose, don’t worry) and salmeterol (a beta-2 agonist), used for control of asthma, COPD and chronic bronchitis. It is available all over the world under different brand names – for example, it is available as Seretide in the United Kingdom, and as ForAir in India.

What is asthma? It is a chronic disease of the respiratory system. It’s when the immune system of the body becomes overprotective. It starts looking at simple things like dust and pollen as the enemy (remember the movie Conspiracy Theory starring Mel Gibson? – our body starts behaving like Mel Gibson’s character). The airways get constricted, and there is release of mucus along with inflammation. As a result, there is difficulty breathing, and in acute episodes, wheezing, shortness of breath and cough.

The mechanism of constriction of the airways in the lungs is blockage of the beta-2-adrenergic receptors of the smooth muscle by an immune system component, Immunoglobulin E.  This is accompanied by inflammation. Until recently, the main theory advanced has been that immune cells called helper T cells were the main culprits creating the inflammation response.

Recently, a couple of Boston researchers advanced another theory – the main players may not be helper T cells, but natural killer T cells (http://www.news.harvard.edu/gazette/2006/03.16/01-asthma.html). Natural killer T cells are also immune system cells. Of course, a lot more research has to be done before establishing in detail the role of natural killer T cells. There is a possibility that this discovery may be the beginning of even more advances in the medicinal treatment of asthma.

Genetic and environmental factors are involved. Children seem to suffer from asthma more in developed countries. A hypothesis that has been suggested is that due to increased hygiene and aggressive use of antibiotics in children, certain beneficial bacteria in the gastro-intestinal tract of children are wiped out. This modifies the immune system, resulting in asthma. Emotional stress can also cause asthma, the suggested mechanism involving the immune system. Environmental factors such as automobile and industrial pollution, cigarette smoke and extensive exposure to cold air act as triggers to evoke an asthma attack, especially when there is a predisposition due to genetics or a compromised immune response.

The practice of yoga has been reported to reduce asthma. A journal report (Thorax 2002 Feb;57(2):110-5) -Sahaja yoga in the management of moderate to severe asthma: a randomised controlled trial, by Manocha et al from the Natural Therapies Unit, Royal Hospital for Women, NSW, Australia draws the following conclusion: “This randomised controlled trial has shown that the practice of Sahaja yoga does have limited beneficial effects on some objective and subjective measures of the impact of asthma. Further work is required to understand the mechanism underlying the observed effects and to establish whether elements of this intervention may be clinically valuable in patients with severe asthma”. Yoga is known to reduce stress. Since it is known that stress is a contributor to asthma, could the reduction in stress be one of the mechanisms by which yoga controls asthma?

COPD. Very similar to asthma, except that the constriction of the airways is not easily reversible, and progressively gets worse with age. With time, the lung tissue gets destroyed and causes emphysema. The cause of COPD is partly genetic, coupled with cigarette smoke, pollution, occupational air hazards, frequent lung infection and a diet that includes a lot of cured meat. Even a history of cigarette smoking that leads to long-term inflammation in the lungs can spark an auto-immune response leading to COPD, many years after cessation of the smoking habit. In later stages, COPD can lead to pulmonary high blood pressure and cor pulmonale (right ventricular dilation and hypertrophy in the heart).

Fluticasone, the steroid component of Advair, reduces inflammation in the airways. In the inhaled form, it is directly delivered to the lungs where the inflammation has occurred, and is not significantly delivered to the rest of the body, resulting in fewer steroid side-effects.

Salmeterol is a long-acting beta-2 agonist or LABA. It acts on the beta-2 adrenergic receptor, thus relaxing the muscles around the airways to prevent wheezing and shortness of breath.

For the long-term treatment of asthma and COPD, Advair is inhaled by mouth twice daily.

Advair is not to be used for acute symptoms of asthma or COPD. For these, your doctor will have prescribed a short-acting beta-2 agonist. Also, do not use Advair if you have a severe allergy to milk proteins. This medication has not been approved for use during pregnancy or while breast-feeding.

Common side-effects are upper respiratory infections, thrush in the mouth and throat, headache, hoarseness and voice changes, bronchitis, cough and nausea/vomiting. In children with asthma, Advair may cause infections in the ear, nose and throat. Make sure you rinse your mouth with water after each dose, and spit the water out.

Now for some controversy. Salpeter at al at the Santa Clara Valley Medical Center published an article in 2006 (”Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths” Ann Intern Med 144 (12): 904–12). The authors say in a press release: “These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms. Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market”. Essentially, they are saying that symptoms are the body’s way of asking for help. When we mask the symptoms, the disease continues to worsen, but the lack of symptoms prevent us from realizing it – and that can and has lead to death.

Here’s a response to the above opinion: “Salpeter and colleagues … assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts.” – Harold Nelson and Paul Dorinsky, 2006, Annals of Internal Medicine, 145 (9), 706.

Dr. Salpeter’s response to the above letter: “It is true that the asthma death rate increased after salmeterol was introduced, then peaked and is now starting to decline despite continued use of the long-acting beta-agonists. This trend in death rates can best be explained by examining the ratio of beta-agonist use to inhaled corticosteroids… In the recent past, inhaled corticosteroid use has increased steadily while long-acting beta-agonist use has begun to stabilize and short-acting beta-agonist use has declined… Using this estimate, we can imagine that if long-acting beta-agonists were withdrawn from the market while maintaining high inhaled corticosteroid use, the death rate in the United States could be reduced significantly …” 2006, Annals of Internal Medicine, 145 (9), 708-710.

As a result of published research, beginning 2005, the Advair label has a warning that the drug might increase the chance of asthma attacks that can result in death.

Here’s the bottom line. The benefits of using Advair far outweigh the risk, even of death. The incidence of death is about one in a 1000. On the other hand, the use of Advair improves the quality of life, and saves lives by allowing patients to breathe better and longer.

Until next week, breathe deeply. Live well. Please take care of yourself and your health.

Dr. Ajit Damodaran