Medications for the Treatment of Asthma – Are They Safe and Effective?
A number of products that block the histamine receptor (anti-histamines) have been developed to treat the allergies that trigger attacks in those suffering from atopic asthma attacks. These include hydroxyzine (Atarax, Vistaril) and its breakdown product cetirizine (Zyrtec). These medications cause sleepiness. Other side effects include dry mouth and urinary retention, and more rarely, confusion, nightmares, nervousness, and irritability. Chlorpheniramine (Chlor-trimeton), cyproheptadine (Periactin), and diphenhydramine (Benadryl) are other older antihistamines. They can be associated with anti-cholinergic side effects (dry mouth, confusion, urinary retention), in addition to the side effects of Atarax.
The so-called second-generation antihistamines supposedly cause less drowsiness than the older products, but this is more hype than hope. They claim to specifically block the H-1 antihistamine receptor, and include fexofenadine (Allegra), loratadine (Claratin), and azelastine (Astelin). Side effects are similar to the older antihistamines. Drowsiness with all of the antihistamines is dose dependent. It is best to start with a low dose and work up.
One of the best selling allergy medications on the market is desloratadine (Clarinex). Clarinex is a newer generation anti-histamine medication that is marketed as a magic bullet for allergies. However what most people don’t know is that Clarinex is merely an old drug, loratadine (Claritin), marketed by the drug company as new and improved. However Clarinex doesn’t add anything to Claritin (other than more money for the coffers of its manufacturer, since Clarinex is still on patent). Clarinex is merely a metabolite (breakdown product) of its precursor, Claritin. That means that 20 minutes after you take Claritin, you will be getting Clarinex, but you’ll be paying much less for it than if you took Clarinex. Folks have been getting Clarinex for years, even though they didn’t know it, every time they took Claritin. The company patented the metabolite of their original product, and then did a misleading study where they compared differing doses of the two medications, coming to the erroneous conclusion that Clarinex was less sedating than the old drug. This was misleading because if a drug causes sedation, then higher doses of the drug will cause more sedation, so if you are not comparing the same doses of the drug, you are not making a fair comparison. This allowed them to promote Clarinex, which costs much more than the old drug that went off patent, and which in 2004 was bringing in close to a billion dollars a year in sales. Claritin and Clarinex as far as you are concerned are the same drug; so take Claritin and save some money.
Over the counter (OTC) epinephrine inhalers such as Primatene Mist are commonly used for the treatment of mild asthma. Over 115 million Primatene Mist inhalers have been sold over the past 20 years. These inhalers, however, are not as benign as they appear. About 20% of patients using OTC inhalers have severe asthma that needs medical care. Unfortunately, many asthma patients delay professional medical treatment while they use their OTC inhalers, often due to a lack of health insurance, to the point where it may be too late. OTC inhalers can also increase heart rate, and should not be used in patients with heart or thyroid disease. Thirteen deaths, mostly cardiovascular, have been reported to be associated with the use of OTC inhalers over the last 20 years. If you have a history of chronic asthma or a history of hospitalization for asthma you should not use OTC inhalers. If asthma symptoms do not resolve in 20 minutes after using an OTC inhaler, you should seek emergency treatment. Delaying medical treatment when you are using OTC inhalers may contribute to the overall severity and chronic nature of the disease over the lifetime.
Prescription short acting bronchodilators (²-2 agonists) are inhaled and promote dilation of airways. The most commonly prescribed inhalers are albuterol (Proventil) and levalbuterol (Xopenex). Side effects include tremors, jitters, and nervousness. There are no known long-term side effects. These medications are designed for temporary relief. If you find yourself using them often or with increasing frequency that means your asthma is getting worse and you need further evaluation by a doctor.
Asthma patients can also be treated with steroids in pill form for a short period of time. Corticosteroids can inhibit growth in children and decrease bone mineral density, although growth inhibition is reversible. Steroids suppress the immune response, increasing risk of infection, and decrease bone mineral density. Other side effects of steroids include low blood sugar, changes in consciousness, nauseas, seizures, or in rare cases death. You can also develop symptoms like Cushing’s Disease (an excess production of cortisol in the body). These include deposits of fat on the upper back and face, high blood pressure, diabetes, slow wound healing, osteoporosis, cataracts, acne, muscle weakness, ulcers, thinning of the skin, and mood changes. When patients are treated for a long period of time, deaths from adrenal insufficiency have occurred with transfer from oral to inhalation steroids, especially during stressors like surgery. You should not be on steroids for long periods of time.
Non-allergic asthma is a chronic problem, and needs to be treated somewhat differently than allergic asthma, which may come and go with avoidable triggers and seasonal changes. Chronic asthma sufferers are more at risk for fatalities if they are not treated.
Patients with chronic asthma should be treated with inhaled corticosteroids. These include fluticasone (Flonase, Flovent), beclomethasone (Qvar, Beconase, Vancenase), flunisolide (Aerobid), budesonide (Rhinocort, Pulmicort), and triamcinolone (Azmacort, Nasacort). Inhaled corticosteroids have the same side effects of systemic steroids, but to a much lesser degree. Corticosteroids can inhibit growth in children and decrease bone mineral density, although growth inhibition is reversible. Steroids suppress the immune response, increasing risk of infection, and decrease bone mineral density. Other side effects of steroids include low blood sugar, changes in consciousness, nauseas, seizures, or in rare cases death. You can also develop symptoms like Cushing’s Disease (an excess production of cortisol in the body). These include deposits of fat on the upper back and face, high blood pressure, diabetes, slow wound healing, osteoporosis, cataracts, acne, muscle weakness, ulcers, thinning of the skin, and mood changes. Studies have shown that inhaled corticosteroids (budesonide) can be used intermittently; there is no advantage to regular use of these medications.
Theophylline (theodur, slophyllin) and the related aminophylline drugs are xanthine derivatives related to caffeine that act to dilate the bronchi. Aminophylline can cause rash in some people. They can be given either orally or intravenously for asthma emergencies. Toxicity results in seizures, irregular heartbeats, and pounding heartbeat. It interacts with ciprofloxacine and the other fluoroquinolone antibiotics (i.e. those ending with -xacine) as well as caffeine. They are not used much any more due to safety concerns and side effects.
Long acting beta-2 agonists have been promoted as reducing the need for inhaled quick relief medication. Drugs on the market include salmeterol (Serevent) and formoterol (Foradil). Serevent, approved in 1994, dilates breathing passages by stimulating the beta-2 adrenergic receptor. At least 300,000 children take this drug.
Serevent was isolated as one of five dangerous drugs still on the market by Dr. David Graham of the FDA in testimony to congress in November of 2004. In that testimony he described Serevent users “dying while clutching their inhalers.”
In 1996, based on reports of paradoxical bronchospasm (a contraction of the breathing airway or bronchus that impairs breathing and can be fatal) with Serevent, the manufacturer undertook a large multi site randomized placebo controlled trial, the Salmeterol Multi-center Asthma Research Trial (SMART). This was a 28-week safety study comparing salmeterol (Serevent) and placebo in the treatment of asthma.115 In addition to their usual asthma therapy, patients received either Serevent or a placebo. The study was stopped in 2002 by the study’s Data Safety Monitoring Board because of an increase in asthma related deaths. Analysis of 26,355 patients showed statistically significantly higher rates of asthma related deaths (13 versus 3, relative risk greater than four fold) in patients on Serevent.
In African Americans, who made up 17% of the study population, the study showed a statistically significant greater number of respiratory related deaths and life threatening events. Many had to get intubated, or have a tube put down their throat to let them breath related to respiratory causes (20 versus 5 for placebo, a four fold increase). In addition, there was a more than four fold increase in asthma-related deaths and life threatening respiratory events in patients taking salmeterol compared to those taking placebo. Overall the risk of death from any cause or having a life-threatening event was doubled in African Americans, another finding that was statistically significant. The data suggested that the risks of Serevent were greater in African Americans than in whites. About half of the patients were also taking an inhaled corticosteroid. In those patients not taking an inhaled corticosteroid, there were significantly more asthma-related deaths in all patients taking salmeterol compared to those taking placebo.
The manufacturers of Serevent initially showed data to the FDA that included the results from the 28-week trial plus a 6 month follow up period. The results for this time period were better than the initial 28 weeks alone. However the initial study protocol was for a 28 week trial, and the FDA appropriately requested the 28 week outcomes, which they posted on their web site in 2005. However the potential risks of long-acting beta agonists have long been known.116 A long acting beta agonist drug marketed in New Zealand was associated with an increase in asthma related deaths and was pulled from the market there in 1976. A recent meta analysis (where data from all published studies were combined) looking at trials from the past 20 years involving a total of 33,826 asthma patients treated with long acting beta agonists showed that all drugs in this class are dangerous.116 Overall there was a statistically significant increase in a number of parameters, including an increase in asthma exacerbations requiring hospitalizations by 2.6 fold, increased life threatening exacerbations of asthma by 1.8, and increased risk of asthma related death by 3.5 fold.
Based on these findings, I do not recommend use of a long-acting beta-2-agonist.
Advair, which contains Serevent and a steroid, also carries the same black box warning about increased asthma related deaths. This hasn’t stopped it from running up 2 billion dollars in sales per year. Based on the SMART study we cannot conclude that long acting beta agonists when administered with steroids are safe; in studies where 75% of patients were taking a steroid there was still a 2-fold increased risk of asthma related death.
Montelukast (Singulair) and zafirlukast (Accolate) are part of a new generation of asthma medications that are leukotriene antagonists. These medications work by inhibiting the cysteinyl leukotriene CysLT-1 receptor, which is involved in the inflammatory response. In rare cases they may be associated with Churg-Strauss syndrome, which involves inflammation of the blood vessels. Zileuton (Zyflo) can cause lupus and liver toxicity and requires blood to be checked every six months. They are expensive and have not been shown to be more effective than steroids and antihistamines.
Other new drugs are the mast cell stabilizers like nedocromil (Tilade) and omalizumab (Xolair). Xolair is given by injection every 2-4 weeks. These meds have only recently been approved by the FDA, and so we have to adopt a wait and see attitude.