Which drug is contraindicated in patients with chronic obstructive pulmonary disease

Medicines available for ED treatment of chronic obstructive pulmonary disease (COPD) include beta2-adrenoceptor agonists, anticholinergics, oxygen, methylxanthines, corticosteroids, some newer experimental classes of medication, and, possibly magnesium.

Terbutaline can be considered for patients with such significant exacerbations that they are not moving enough air to take full advantage of nebulizer therapy.

Beta2-adrenoceptor agonists

These agents are first-line therapy for COPD, both for acute exacerbations and for acute treatment. [11] Bronchodilators are given on an as-needed basis or on a regular basis to prevent or reduce symptoms. [2] Short-acting agents are usually used for immediate relief of symptoms, whereas long-acting inhaled agents are better for day-to-day mitigation of the disease. The longer-acting agent, indacaterol, is now approved and allows once-daily dosing. [12]

Combinations of bronchodilators may improve efficacy and reduce risk of adverse effects rather than increasing the dose of a single agent. Keep in mind that, based on several studies, the acute response to short-acting agents does not predict the future response to long-acting agents.

Most of the beta-agonists used are racemic compounds that contain both the R and S enantiomers of the agonist. Much of the pharmacologic activity seems to reside in the R enantiomer, with the S thought to induce the negative side effects. Recently, the R enantiomer of both the short-acting agent albuterol (levalbuterol) and the long-acting agent formoterol (aformoterol) were approved for use in COPD. However, the cost effectiveness of these agents, in light of marginal observed clinical differences, remains controversial and needs further exploration.

Although the major action of beta2-agonists is relaxation of airway smooth muscles, they have also been shown to have several other potential effects. They seem to inhibit airway smooth muscle proliferation and inflammatory mediator release, as well as stimulation of mucociliary transport, cytoprotection of the mucosa, and attenuation of neutrophil recruitment and activation.

Multiple studies have demonstrated enhanced benefits of action when coadministered with inhaled anticholinergics and with corticosteroids.

The greatest single problem that persists in the acute phase is the under dosing of beta-agonists and the nonutilization of anticholinergics. Although only a small subset of patients respond to beta-agonists, a reasonable dose approaches continuous nebulization, as is seen in current asthma treatment.Keep in mind that with larger doses and continuous nebulization, elevated lactate levels are possible (see Workup).

Note that, in mild or moderate exacerbations, the use of MDIs with an aerosol chamber in higher doses (6-12 puffs) can achieve equivalent bronchodilation as the use of a nebulizer. This is particularly important in the office and prehospital setting.

Epinephrine or terbutaline can be administered subcutaneously when intravenous access is not possible or the patient is moving so little air that nebulizer therapy is ineffective. Terbutaline is thought to be safer in older patients, and it has shown to be more efficacious than epinephrine.

Anticholinergics

Anticholinergics have an important role in the acute treatment of COPD exacerbations. The anticholinergics reduce airway tone and improve expiratory flow limitation, primarily by blocking parasympathetic activity in the large and medium-sized airways. They also block the release of acetylcholine, which has been linked to increased bronchial smooth muscle tone and mucus hypersecretion.

These are not as effective as beta-agonists in acute attacks, but they have synergistic properties with the beta-agonists, and the combination of both agents is superior to either by themselves. They act by antagonizing the vagal innervation of the tracheobronchial tree. Vagal tone can be increased by as much as 50% in patients with COPD.

Anticholinergic agents include short-acting agents appropriate for management of acute exacerbations (eg, ipratropium) and long-acting agents (eg, tiotropium, aclidinium, and umeclidinium).

Methylxanthines

These agents (eg, theophylline) increase collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. Despite this, many questions exist as to their true efficacy, and they have no real role in the acute exacerbation of COPD, except to increase the risk of adverse effects. [13] Patients may subjectively feel better, but no data suggest any real change in measureable outcomes or disease progression.

In general, if the patient is already on theophylline and has a subtherapeutic level, a mini-loading dose could be considered but is certainly not considered first-line therapy. If the patient is not on theophylline, the delay before benefit of the oral form makes it not worth using. Intravenous aminophylline has a propensity to cause arrhythmias, especially in a population that already has cholinergic excess coupled with coronary disease.

Phosphodiesterase-4 (PDE-4) inhibitors

Selective PDE-4 inhibitors increase intracellular cyclic adenosine monophosphate (cAMP) and result in bronchodilation. Additionally, they may improve diaphragm muscle contractility and stimulate the respiratory center. Theophylline is a nonspecific phosphodiesterase inhibitor and is now limited to use as an adjunctive agent.

Antibiotics

These patients are almost uniformly heavily colonized with Haemophilus influenzae, streptococcal pneumonia, and others [3] ; however, researchers have not proven these organisms to be the cause of the exacerbation. In fact, viruses are thought to be the instigating factor in as many as half of the cases.

The particular antibiotic chosen seems to have much less effect on outcome than the particular host factors of the patient in some studies, with other studies suggesting fluoroquinolones are the best strategy. This may really be a factor of the severity of the exacerbation and whether antibiotics are really indicated for minor exacerbations. [14] However, in a retrospective study of 84,621 hospitalized patients, improved outcomes were seen for all patients with COPD with early antibiotic treatment regardless of disease severity. [15]

If antibiotics are given, the choice should provide coverage against pneumococcus, H influenzae,Legionella species, and gram-negative enterics.

Daniels et al conducted a randomized, placebo-controlled trial that compared the addition of doxycycline to corticosteroids on clinical outcome in patients hospitalized with acute exacerbation of COPD (n=223). [16] In addition to clinical outcome, other parameters were measured, including microbiological outcome, lung function, and systemic inflammation. The 223 patients enrolled in the study represented 265 COPD exacerbations. In addition to systemic corticosteroids, patients received either doxycycline 200 mg or placebo for 7 days. Results at 30 days were similar between the 2 groups. At 10 days, the doxycycline group showed superiority for clinical success compared with placebo in the intention-to-treat arm but not in the per-protocol arm. Also at day 10, doxycycline was superior for clinical cure, microbiological outcome, use of open label antibiotics, and symptoms.

In cases of severe acute exacerbations of chronic bronchitis (AECB), guidelines suggest using fluoroquinolone antibiotics as first-line therapy. [17, 18] This suggestion is based on level I evidence from several trials that show clinical and microbial superiority of these agents.

Use of fluoroquinolones has also been shown to shorten hospital stay, reduce recurrences, and lower costs.

Fortunately, resistance to these agents is still very low, and reserving them for use in populations at risk should preserve their effectiveness for some time. Be aware of the potential for complications with Clostridium difficile colitis, QT prolongation, and musculoskeletal damage from fluoroquinolones, especially in this patient group.

Magnesium

Though controversial, administration of magnesium is thought to produce bronchodilation through the counteraction of calcium-mediated smooth muscle constriction. The addition of intravenous magnesium is now considered to have class B evidence supporting its use in difficult and life-threatening exacerbations.

Heliox

Heliox usually is a 60:40 mixture of helium and oxygen. Helium is a smaller particle than oxygen and in small airways promotes laminar flow and facilitates both oxygen transport and carbon dioxide diffusion. Many patients who seem to breathe better on Heliox return to a worsened respiratory state when removed from Heliox.

Because of helium's low density, some class B evidence now exists for its use as the medium to drive nebulizer therapy. In theory, a mixture of helium and oxygen could improve gas exchange in patients who have an airway obstruction. In the realm of COPD exacerbations, however, the evidence is more slight, and more investigation is needed.

Leukotriene receptor antagonists

Intravenous leukotriene receptor antagonists have been shown to have benefit in asthma in limited studies, but, at this time, they have no role in COPD exacerbations.

Corticosteroids

These also have bronchodilatory properties, although they primarily act by decreasing inflammation in the tracheobronchial tree. Although 8-12 hours are required for full effect, corticosteroids should be administered in the ED, as some mild improvements may be noted much earlier.

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