Advairby James J. Galligan,  Ph.D., Associate  Chair,
Department of Pharmacology and  Toxicology

The outcomes of recent studies of the long-term effects of asthma treatment medications that contain a steroid and a long acting beta agonist (LABA) have led the Food and Drug Administration to develop new guidelines for the use of these combination products.

These guidelines and the rationale behind them have been reported in the New England Journal of Medicine.  These new guidelines have also been the subject of numerous stories in the popular press and have raised concerns for asthmatics and their families.

While there are several components to these new recommendations, the bottom line is that LABA drugs should be used only by patients whose asthma can not be controlled adequately by other medications and LABA drugs should only be used in conjunction with another asthma control medication such as an inhaled steroid.  The new recommendations are based on studies showing a small but statistically significant increase in the number of serious asthma complications, including death, in patients using LABA drugs alone or in combination with a steroid.

What is the pharmacological basis for the concerns discussed above?

First, we need to understand a little about asthma and control of airways.  The airways are composed partly of smooth muscle.  When the muscle contracts airway resistance increases and this makes breathing more difficult.  When the muscle relaxes, airway resistance decreases and it is easier to breathe.  Airway muscle is supplied by sympathetic nerves which release norepinephrine.  The adrenal gland is also part of the sympathetic nervous system and it releases epinephrine into the blood stream.  Norepinephrine and epinephrine act on beta adrenergic receptors in airway muscle to cause the muscle to relax.  The sympathetic nervous system becomes active during the “fight or flight response” which in the old days helped us to escape predators but now helps us to exercise more efficiently.  Increased sympathetic nerve activity relaxes airway muscle making it easier to suck in huge volumes of air while we run a marathon.

The LABA drugs mimic the effects of epinephrine and norepinephrine by relaxing airway muscle; they can do this for up to 12 hours after a single dose.  Asthma is an inflammatory disease in which the airways are chronically inflamed.  Chronic inflammation can cause the airway wall to become thicker and more rigid.  This causes an increase in airway resistance.  Inflamed airways are also hypersensitive and things like emotional stress or breathing cold air can cause the airways to constrict precipitating an asthma attack.  Corticosteroids are great drugs for suppressing inflammation and this is why inhaled corticosteroids are a frontline treatment for many asthma patients.

Why is the FDA concerned?

The LABA drugs used either alone or in combination products (Advair contains the steroid, fluticasone and the LABA, salmeterol) can hide inflammation-induced thickening of the airway wall.  The patient may not be aware that his or her asthma is actually getting worse.  Then, when the patient does experience an acute asthma attack it becomes a very severe episode that can require hospitalization.

The new recommendations support use of LABA containing medications during the time required for the patient to get their asthma under control.  Then the patient should reduce use of LABA drugs gradually to the point where they are only using an inhaled steroid to maintain control.  This will reduce the risk of a severe attack that results from the chronic but undetectable inflammatory changes that can occur in many asthma patients.