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Chronic Obstructive Lung Disease

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of COPD -- emphysema and/or chronic bronchitis.

Alternative Names

Alpha-1 Antitrypsin Deficiency; Bronchitis: Chronic; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Emphysema

Medications

Anticholinergic Agents

Anticholinergic agents relax the bronchial muscles. They are generally inhaled and act as a bronchodilator over time.

Brands and Benefits. Anticholinergics used for COLD include ipratropium (Atrovent) and tiotropium (Spiriva). Ipratropium is the older agent and experts recommend it as the first choice in treating COLD. It has a very slow onset and can be used as maintenance therapy for people with emphysema and chronic bronchitis. Anticholinergic agents have few severe side effects.They are less likely to impair sleep than the other standard inhaled medications.

A patient should not take more than 12 inhalations per day. Tiotropium (Spiriva) requires only one daily inhalation and evidence suggests it may be particularly effective for COLD patients. A single inhaler containing both ipratropium and the common beta2 agonist albuterol (Combivent) may prove to be better than either agent alone. Anticholinergics target the central airways and beta agonists target peripheral airways, thus explaining, so some doctors hypothesize, the additive benefits of the combination.

Side Effects. Some common side effects include blurred vision and urinary obstruction. Patients with allergies to soy or peanut products should not use these drugs. Those with glaucoma should be very careful to prevent being sprayed in the eye with the drug, which could worsen the condition.

Beta2 Agonists

Beta2 agonists are the most widely prescribed bronchodilators, most often for asthma. These drugs are generally inhaled using a metered-dose inhaler (MDI) or nebulizer. A nebulizer delivers a larger dose of the drug and is more expensive than the MDI. Experts recommend the inhaler for most patients and suggest reserving the nebulizer for patients with severe disease who are unable to use the MDI. Survival rates are similar. Beta2 agonists are also available in oral forms, although have more side effects than inhaled beta2 agonists and have a slower onset of action. Oral beta2 agonists should be reserved only for patients who cannot use other forms.

Short-Acting Beta2 Agonists. Short-acting bronchodilators are the primary agents for most COLD patients. Albuterol (Proventil, Ventolin), called salbutamol outside the US, is the standard short-acting beta2 agonist. Others include isoproterenol (Isuprel, Norisodrine, Medihaler-Iso), metaproterenol (Alupent, Metaprel), pirbuterol (Maxair), terbutaline (Brethine, Brethaire, Bricanyl), bitolterol (Tornalate), and isoetharine (Bronkometer, Bronkosol), which is available in nebulizers. Newer beta2 agonists, including levalbuterol (Xopenex), have more specific actions than the standard agents. Most are administered through inhalation and are effective for three to six hours.

Long-Acting Beta2 Agonists. Long-acting forms, salmeterol (Serevent) or formoterol (Foradil), are proving to be particularly effective for COLD. Major analyses suggest they reduce exacerbations by 20% to 25%. They may help inhibit bacteria from building up on the airways and may offer real improvements in lung function. In fact, unlike short-acting forms, these beta2 agonists may even have anti-inflammatory properties.

Inhalers that combine a long-acting beta 2 agonist and a corticosteroid (Advair, Seretide, Symbicort) are even more effective than either agent---reducing exacerbations by 30%. Some studies suggest they may offer significant improvements in lung function and even improve survival rates, but more research is needed to confirm such findings.

Side Effects. Side effects of both long-and short-acting beta2 agonists include anxiety, tremor, restlessness, and headaches. Patients may experience fast and irregular heartbeats. A physician should be notified immediately if such side effects occur, particularly in people with existing heart conditions. Such patients face an increased risk for sudden death from cardiac related causes. This risk is higher with oral or nebulized agents, but there have also been reports of heart attacks and angina in some patients using inhaled beta2 agonists.

Loss of Effectiveness and Overdose. There has been some concern that short-acting beta2 agonists become less effective when taken regularly over time, increasing the risk for overuse. The degree to which this affects the airways is uncertain. In some studies, the duration of action has declined but the peak effect appears to be preserved, making these drugs still useful for acute attacks. Regular use of long-acting beta2 agonists may reduce the effect of short-acting forms.

Its a major concern that patients who perceive beta2 agonists as being less effective may over-use them. Overdose can be serious and in rare cases even life-threatening, particularly in patients with heart disease.

Theophylline and Other Methylxanthines

Methylxanthines a number of actions in the lungs that should help COLD patients. They include opening airways, improving exchange of gases, reducing shortness of breath, improving mucus clearance, and stimulating the process of breathing. These agents are recommended by expert groups for patients with severe exacerbations or incomplete responses to bronchodilators.

Unfortunately, a major 2003 analysis indicated these agents do not produce any significant improvement in lung functions, symptoms, or overall outcomes after treatment for acute exacerbations. Some experts, then, believe that these modest benefits do not outweigh the risk for the toxic effects commonly associated with these agents.

Nausea and vomiting occur in a third of patients, which can be serious side effects in COLD patients. Headache and insomnia are common. Cardiac arrhythmias and convulsions are possible. A physician should be contacted immediately if any of these side effects occur. Certain conditions (e.g., liver disease) and medications increase the risk for toxicity. Such medications include some antibiotics, calcium channels blockers, and H2 blockers such as famotidine (Pepcid AC), cimetidine (Tagamet HB), or ranitidine (Zantac 75).

Theophylline. Theophylline (Theodur, Slo-bid, Uniphyl, Theo-24) is the standard methylxanthine and is available in oral and rectal forms. The oral form is preferred. Absorption is inconsistent using the rectal form, which therefore poses a higher risk for overdose. Chronic smokers metabolize theophylline much more quickly and require higher doses of the drug than nonsmokers. Prolonged-release versions are helpful for such people. If theophylline is taken as prescribed, no major problems should arise. If theophylline is not taken exactly as prescribed, an overdose and toxicity can easily occur.

Doxofylline. Doxofylline is a unique xanthine that may prove to be an effective bronchodilator without the adverse effects on the heart that theophylline and beta2 agonists have. More research is needed.

Corticosteroids

Corticosteroids, commonly called steroids, are powerful anti-inflammatory drugs.

Oral Corticosteroids. Oral corticosteroids are used to treat acute exacerbations of COLD. A major study also indicated patients who take them for 10 days after an exacerbation (along with antibiotics and bronchodilators) significantly reduce their risk for a relapse.

They are also often prescribed for patients with stable COLD in order to prevent acute exacerbations and reduce symptoms. It is not clear, however, if these benefits outweigh the potential side effects of steroids. In one analysis, patients given steroids were only 10% more likely to improve than those on placebo. Patients should be monitored regularly and should take the lowest dose possible for improvement.

Common oral corticosteroids include prednisone, prednisolone, methylprednisolone, and hydrocortisone. Adverse effects of long-term use can be very serious. They include cataracts, glaucoma, osteoporosis, diabetes, fluid retention, susceptibility to infections, weight gain, hypertension, capillary fragility, acne, excess hair growth, wasting of the muscles, menstrual irregularities, irritability, insomnia, and psychosis.

Long-term use of steroid medications also suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. Uncommonly, switching from oral to inhaled steroids has caused severe adrenal insufficiency and, in rare cases, has resulted in death. The risk increases during times of stress. Patients should discuss with their physician measures for preventing adrenal insufficiency, particularly during stressful times. No one should stop taking any steroids without consulting a physician first, and if steroids are withdrawn, regular follow-up monitoring is necessary.

Inhaled Corticosteroids. Inhaled corticosteroids are often used for treating chronic COLD. They include the following:

  • The most recent generation of inhaled steroids include (in order of potency) fluticasone (Flovent), budesonide (Pulmicort), triamcinolone (Azmacort and others), and flunisolide (AeroBid). In general, the newer agents, possibly with the exception of flunisolide, are more powerful than the older generation agents when used with standard inhalers.
  • The older corticosteroid inhalants are beclomethasone (Beclovent, Vanceril) and dexamethasone (Decadron Phosphate Respihaler and others). They are less powerful than the newer steroids when delivered with standard inhalers. New inhaler systems for, however, such as QVAR, which uses extra fine formulations of beclomethasone to allow deep delivery into the lungs may prove to be as effective as the newer, more potent steroids.
  • Inhalers that combine a long-acting beta 2 agonists and a corticosteroid (Advair, Seretide, Symbicort) are even more effective than either agent---reducing exacerbations by 30%. Some studies suggest they may offer significant improvements in lung function and even improve survival rates, but more research is needed to confirm such findings.

The widespread use of inhaled corticosteroids for COLD patients is under debate, particularly since other agents are equally or more effective. Studies are mixed on whether long-term use improves lung function. They also can have some significant adverse effects over time, particularly in reducing bone density. Combination inhalers that contain both a corticosteroid and a long-acting beta 2 agonist may prove to be a good option.

Common side effects of inhaled steroids are throat irritation, hoarseness, and dry mouth. Other possible but less common adverse effects include rashes, wheezing, facial swelling (edema), fungal infections (thrush) in the mouth and throat, and bruising.

Inhaled steroids are generally considered safe and effective. They rarely cause any of the more serious side effects reported with prolonged use of oral steroids. There are some risks with long term use however, A 2001 study, however, reported a higher risk for cataracts in patients over age 40. Others are reporting a higher risk for bone loss in patients who take inhaled steroids regularly. (A number of bone-preserving medications are now available that might safely offset this effect.) There is also some concern that the more potent agents, particularly fluticasone, may suppress the adrenal system (which secretes natural steroids) to a greater degree than other steroid inhalants. (This is a serious side effect of oral steroids.)

Antibiotics

Treating Acute Bronchitis or Pneumonia in COLD Patients. People with COLD are at heightened risk for pneumonia, but any lung infection can worsen symptoms and is dangerous in COLD patients. Aggressive therapy using powerful antibiotics is usually called for when acute bronchitis or pneumonia occurs. The most common organisms causing pneumonia in chronic obstructive lung disease patients include Streptococcus pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, and Legionella pneumophila. Of some concern is the increase in more unusual and difficult-to-treat organisms known as gram-negative bacteria.

The primary choice of agent still includes the less expensive antibiotics, such as amoxicillin/clavulanate, doxycycline and trimethoprim-sulfamethoxazole. Antibiotic classes known as the macrolides and quinolones appear to be beneficial as well. Detecting the specific organism causing the lung infection is often difficult. [For more information, seeWell-Connected Report #64, Pneumonia.]

Preventive (Prophylactic) Antibiotics in COLD Patients. In the past, antibiotics were given daily for patients with even mild COLD until studies found that they did not alter progression of either the disorder or the disabilities associated with it. Preventive antibiotics may be give one week a month with alternative agents. They are now prescribed only for COLD patients with one or more of the following conditions:

  • Having four or more episodes a year of acute infection with intensified COLD symptoms, including worsened shortness of breath and mucus production.
  • Having deficient immune systems.
  • Having bronchiectasis, an irreversible lung disease in which the airways in the lung are chronically dilated.

Antibiotic Options

Beta-Lactams

The beta-lactam antibiotics include penicillins, cephalosporins, and some newer similar agents. Their primary actions to interfere with bacterial cell walls.

Penicillins. Penicillin was the first antibiotic. There are many forms to this still-important agent:

  • Natural penicillins include penicillin G (for intravenous use) and V (for oral use).
  • Penicillin derivatives called aminopenicillins, particularly amoxicillin (Amoxil, Polymox, Trimox, Wymox, or any generic formulation), are now the most common penicillins used. Amoxicillin is both inexpensive and at one time was highly effective against the S. pneumoniae bacteria. Unfortunately, bacterial resistance to amoxicillin has increased significantly, both among S. pneumoniae and H. influenzae. Ampicillin is similar, and an alternative to amoxicillin, but requires more doses and has more severe gastrointestinal side effects than amoxicillin. Amoxicillin-clavulanate (Augmentin) is known as an augmented penicillin, which works against a wide spectrum of bacteria.

Many people have a history of an allergic reaction to penicillin, but some evidence suggests that the allergy may not persist in a significant number of adults. Skin tests are available to help determine if some people previously considered allergic could use these important antibiotics.

Cephalosporins. These agents have also become effective against S. pneumoniae or Staphylococcus aureus. Most are not very effective against bacteria that have developed resistance to penicillin. They are often classed in the following:

  • First generation includes cephalexin (Keflex), cefadroxil (Duricef, Ultracef), and cephradine (Velosef).
  • Second generation include cefaclor (Ceclor), cefuroxime (Ceftin), cefprozil (Cefzil), and loracarbef (Lorabid),
  • Third generation include cefpodoxime (Vantin), cefdinir (Omnicef) cefditoren (Sprectracef), cefixime (Suprax), and ceftibuten (Cedex). Ceftriaxone (Rocephin) is an injected cephalosporin. These are effective against a wide range of gram-negative bacteria.

Other Beta-Lactam Agents. Carbapenems (also known as thienamycins) include meropenem (Merrem), biapenem, faropenem, ertapenem (Invanz) and combinations (imipenem/cilastatin [Primaxin]). These agents cover a wide spectrum of bacteria. They are now used for serious hospital-acquired infection and for bacteria that have become resistant to other beta-lactam bacteria. Imipenem has serious side effects used alone so in given in combinations with another agent, cilastatin, to offset these adverse effects. The newer agents are less toxic, although they may not be as potent.

Sanfetrinem, a novel beta-lactam antibiotic known as a trinem, is proving to be effective against S. pneumoniae,H. influenzae, and M. catarrhalis.

Fluoroquinolones (Quinolones)

Fluoroquinolones (also simply called quinolones) interfere with the bacteria's genetic material so they cannot reproduce.

  • Ciprofloxacin (Cipro), a second-generation quinolone, remains the most potent antipseudomonal quinolone against Pseudomonas aeruginosa bacteria, but is not very effective for gram-positive bacteria.
  • Newer third-generation quinolones are currently the most effective agents against a wider range of common bacteria. They include levofloxacin (Levaquin), sparfloxacin (Zagam), gemifloxacin (Factive), and gatifloxacin (Tequin). Levofloxacin is the first drug approved specifically for penicillin-resistant S. pneumoniae. Some of the newer fluoroquinolones also only need to be taken once a day, which make compliance easier. Some, but not all, quinolones cause photosensitivity.
  • A fourth generation includes moxifloxacin (Avelox), trovafloxacin, and clinafloxacin, which are proving to be effective against anaerobic bacteria. Studies suggest that taking the moxifloxacin once a day offered fast relief for patients with acute exacerbations of chronic bronchitis.

Macrolides, Azalides, and Ketolides

Macrolides and azalides are antibiotics that also affect the genetics of bacteria. They include erythromycin, azithromycin (Zithromax), clarithromycin (Biaxin), and roxithromycin (Rulid). These antibiotics are effective against S. pneumoniae and M. catarrhalis, but there is increasing bacterial resistance to these agents. In one study, patients who took erythromycin during a common cold had a lower risk for worsened COLD symptoms than those not taking the antibiotic.

Ketolides are drugs derived from erythromycin that were developed to combat organisms that have become resistant to macrolides. Telithromycin (Ketek), the first antibiotic in the ketolide class, is being evaluated for FDA approval for treating community-acquired pneumonia (CAP), chronic obstructive lung disease, and acute sinusitis.

Tetracyclines

Tetracyclines inhibit bacterial growth. They include doxycycline, tetracycline, and minocycline. Doxycycline can be effective for COLD patients, but bacteria that are resistant to penicillin are also often resistant to doxycycline. Tetracyclines have unique side effects among antibiotics, including skin reactions to sunlight, possible burning in the throat, and tooth discoloration.

Aminoglycosides

Aminoglycosides (gentamicin, kanamycin, tobramycin, amikacin) are given by injection for very serious bacterial infections. They can be given only in combination with other antibiotics. Some are available in inhaled forms or by irrigation (applying a solution directly to mucous membranes, skin, or body cavity). They can have very serious side effects, including damage to hearing, sense of balance, and kidneys.

Lincosamide

Lincosamides prevent bacteria from reproducing. The most common lincosamide is clindamycin (Cleocin). This antibiotic is useful against S. pneumoniae and S. aureus but not against H. influenzae.

Glycopeptides

Glycopeptides (vancomycin, teicoplanin) is used for Staphylococcus aureus that have become resistant to standard antibiotics. They are available in intravenous and oral forms.

Trimethoprim-Sulfamethoxazole

Trimethoprim-sulfamethoxazole (Bactrim, Cotrim, Septra) is less expensive than amoxicillin and particularly useful for adults with mild bacterial upper respiratory infections who are allergic to penicillin. It is no longer effective, however, against certain streptococcal strains. It should not be used in patients whose infections occurred after dental work or in patients allergic to sulfa drugs. Allergic reactions can be very serious.

Oxazolidinone

Linezolid (Zyvox) is the first antibacterial drug in a new class of synthetic antibiotics called oxazolidinones. It has been proven effective against certain aerobic gram-positive bacteria, including Staphylococcus aureus (MRSA).

Others

Streptogrammins (quinupristin/dalfopristin [Syndercid]). In a major 2001 study of S. pneumonia resistance to antibiotics, there were no reports yet of resistance to this agent.

Treatment for AAT Deficiency

Replacement Treatment. Augmentation or replacement therapy supplements the existing alpha 1-antitrypsin (AAT) levels in the blood. The replacement AAT is derived from human blood, which has been screened for viruses and is injected weekly or bimonthly. One study reported that patients taking this supplement had a mortality rate that was two thirds of those not on this therapy. Replacement therapy may also reduce the severity and frequency of lung infections. Therapy is life long. Patients with inherited AAT deficiency, regardless of their smoking history, are eligible for this therapy. Unfortunately, this therapy is in short supply.

An inhaled AAT replacement treatment produced from the milk of genetically bred sheep is under investigation. An oral forms is also under investigation.

Other Investigative Treatments for AAT Deficiency. Aerosolized hyaluronic acid may protect lungs from injury by elastase, the enzyme that causes lung tissue to lose elasticity. A clinical trial is underway.

Agents That Loosen Lung Secretions

Patients with persistent coughing and sputum often use agents that loosen secretions and help move them out of the lungs. However, it is not clear if these agents offer any important benefits.

Expectorants. Expectorants, such as guaifenesin (found in common cough remedies), stimulate the flow of fluid in the airways and help move secretions using cilia motion (the hair-like structures in the lung) and coughing.

Mucolytics. Mucolytics contain ingredients such as iodinated glycerol or acetylcysteine that make sputum more watery and so easier to cough up. (Acetylcysteine also acts as an antioxidant, which could provide additional value.) Although there is some controversy over their value, an analysis of many studies indicated that oral mucolytics reduce the number of symptoms in patients with severe chronic bronchitis and have a small but significant effect on breathing function. They should not be used, however, during an acute attack, since they may worsen lung function. They also do not appear to be very helpful for patients with mild COLD.

Experimental Therapies

Selective Phosphodiesterase 4 Inhibitors. Cilomilast (Ariflo) and roflumilast (Daxas) are selective phosphodiesterase 4 (PDE4) inhibitors. They block PDE4, an enzyme that is overproduced in COLD and asthma and causes inflammation in the airways. Studies are very promising. A 2003 report on reflumilast, for example, found significant improvement in lung function and quality of life compared to placebo. The drugs can cause diarrhea and nausea, which may limit their tolerability.

Leukotriene-Antagonists. Leukotriene-antagonists (also called anti-leukotrienes) are oral medications that block leukotrienes. These are powerful chemicals in the immune system that, in excess, produce inflammation and spasms in the airways. Agents include zafirlukast (Accolate), montelukast (Singulair), zileuton (Ziflo), and pranlukast (Ultair, Onon). They are currently used for preventing asthma attacks. Studies are now indicating they also have benefits for people with COLD, although it is not clear if they have advantages over standard COLD agents

Retinoic Acid. All trans retinoic acid (ATRA), which is a derivative of vitamin A, may reverse some of the damage that occurs in emphysema. One such agent is being developed that researchers hope will grow new air sacs in the lungs.

Sildenafil. Interesting research is suggesting that some men with COLD who take sildenafil (Viagra) experience modest improvement in lung function.

Testosterone Replacement. People with COLD tend to have low levels of testosterone. Researchers are investigating testosterone replacement in both men and women with COLD for increasing muscle strength and function.

P2Y(2) Receptor Agonists. P2Y(2) receptor agonists are experimental agents that increase the action of the cilia (hair-like structures) in the lung and clear out mucus. The most promising agent to date is currently referred to as INS37217.

Other Investigative Agents. A number of agents are in very early stages of investigation. They include drugs called antiproteases (e.g., sivelestat ONO-6818. batimastat), new antioxidants, and many others.

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