Practice
ABC of chronic obstructive pulmonary disease
Pharmacological management?oral treatment
Graeme P Currie, specialist registrarRespiratory Unit, Aberdeen Royal Infirmary, Aberdeen.
Daniel K C Lee, specialist registrar
Department of Respiratory Medicine, Papworth Hospital, Papworth Everard, Cambridge.
Brian J Lipworth, professor
Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee.
Inhaled treatment forms the cornerstone of drug management of chronic obstructive pulmonary disease (COPD). However, some patients?especially those who are elderly, cognitively impaired, or with upper limb musculoskeletal problems?are unable to use inhaler devices successfully.
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Theophylline
Theophylline is one of the oldest oral bronchodilators available for the treatment of COPD. It has a similar chemical structure to caffeine, which is also a bronchodilator in large amounts.
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Theophylline is a non-selective phosphodiesterase inhibitor, and it causes an increase in the intracellular concentration of cyclic AMP in various cell types and organs (including the lung). Increased cyclic AMP concentrations are implicated in inhibition of inflammatory and immunomodulatory cells. One result is that phosphodiesterase inhibition causes smooth muscle relaxation and airway dilation.
Other potentially beneficial mechanisms of action of theophylline in COPD have been suggested, including
- Reduction of diaphragmatic muscle fatigue
- Increased mucociliary clearance
- Respiratory centre stimulation
- Inhibition of neutrophilic inflammation
- Suppression of inflammatory genes by activation
of histone deacetylases
- Inhibition of cytokines and other
inflammatory cell mediators
- Potentiation of anti-inflammatory effects
of inhaled corticosteroids
- Potentiation of bronchodilator effects of
2 agonists.
Clinical use of theophylline
Consider a long acting theophylline preparation in patients
with advanced COPD, especially when symptoms persist despite
the use of inhaled long acting bronchodilators or in patients
unable to use inhaler devices. Studies have shown that theophylline
generally confers modest benefits in lung function when combined
with different classes of inhaled bronchodilators (anticholinergics
and 2 agonists). In a meta-analysis of 20 randomised
controlled trials, theophylline conferred some improvement in
lung function and arterial blood gas tensions compared with
placebo, although the incidence of nausea was significantly
higher with the active drug.
The slow onset of action of theophylline combined with the need to titrate the dose to achieve suitable plasma levels mean that most benefit may not be observed until after several weeks. Clinical efficacy should be assessed according to improvements in a variety of end points, such as lung function, symptoms, exacerbations, exercise capacity, quality of life, and patient tolerability and acceptability. As with most drugs for COPD, clinicians should stop treatment if a therapeutic trial is unsuccessful.
Adverse effects
One of the main limitations preventing more extensive use of
theophylline is its tendency to cause adverse effects. In addition,
several patient characteristics and commonly prescribed drugs
alter its half life in the body. Target levels are 10-20 mg/l
(55-110 ?M), and at higher concentrations the frequency of
adverse effects tends to increase to an unacceptable extent.
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Explain to patients that it may be necessary to titrate the dose of theophylline slowly upwards until a stable therapeutic level is achieved. During an exacerbation of COPD, reduce the theophylline dose by 50% if a macrolide (such as erythromycin) or fluoroquinolone (such as ciprofloxacin) is prescribed. Selective phosphodiesterase 4 inhibitors have recently been developed with the aim of retaining the beneficial properties of theophylline but avoiding its unwanted effects. The most clinically advanced of these inhibitors are roflumilast and cilomilast, and they show a superior adverse effect and pharmacokinetic profile compared with theophylline.
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Oral corticosteroids
Oral corticosteroids have only a limited role in the management of stable COPD, and few data suggest which patients (if any) derive benefit from long term use. Indeed, they have been shown to increase mortality in patients with advanced disease in a dose dependant manner. Prolonged treatment with prednisolone should generally be avoided, although guidelines acknowledge that for some severely affected patients with advanced airflow obstruction it is difficult to stop corticosteroids after an exacerbation. However, this difficulty may in part be due to their mood enhancing effects. When complete withdrawal is impossible, long term use should be limited to the lowest possible dose (such as 5 mg/day of prednisolone).
Managing corticosteroids' adverse effects
Before starting treatment with oral corticosteroids, ensure
that patients are aware of the dose to be taken, the anticipated
duration, and potential adverse effects. Explain to patients
receiving long term oral corticosteroids that treatment should
not be stopped suddenly and that the dose must be reduced slowly.
Immediate withdrawal after prolonged administration may lead
to acute adrenal insufficiency and even death. Issue all patients
receiving oral corticosteroids with a treatment card alerting
others to the problems associated with abrupt discontinuation.
Courses of oral corticosteroids that last less than three weeks
(such as for an exacerbation of COPD) do not generally need
to be tapered before stopping.
The risk of corticosteroid induced osteoporosis is
related to
cumulative dose. This means that patients who frequently require
short courses of corticosteroid, as well as those taking long
term maintenance treatment, may experience this complication.
Patients taking 
7.5 mg/day of prednisolone (or equivalent)
for three months are at heightened risk of adverse effects,
as are those older than 65 years.
Bisphosphonates reduce the rate of bone turnover and are therefore useful in limiting corticosteroid related osteoporosis. Dual emission x ray absorptiometry (DEXA) can facilitate early identification of patients at risk of osteoporosis and are often requested for patients attending specialist clinics. DEXA scans also highlight which patients should ensure adequate dietary intake of calcium and vitamin D3 and, where necessary, start taking weekly bisphosphonate (such as risedronate or alendronate). Patients aged more than 65 years and those who have previously sustained a low velocity fracture should receive bisphosphonate treatment, irrespective of bone density, if they are to use oral corticosteroids on a long term basis.
Mucolytics
Sputum overproduction is common in patients with COPD. Oral mucolytics are thought to reduce the viscosity of sputum in the airways and help patients expectorate. Despite these drugs having no effect on lung function, some studies have found that their regular use reduces the frequency of exacerbations of COPD and is associated with fewer days of ill health.
Two mucolytic agents are currently licensed for use in the United Kingdom (carbocisteine and mecysteine hydrochloride) and are generally well tolerated. They may be tried in patients with productive cough who are troubled by frequent exacerbations, although further data are required to clarify their place in COPD management. Increased oxidative stress has been implicated in the inflammatory response in COPD, and N-acetyl cysteine, another mucolytic, may confer some benefit in terms of its antioxidant properties.
Other drugs
There are no convincing data that prophylactic antibiotics are of use in stable COPD. Indeed, such treatment may only encourage the emergence of strains of bacteria resistant to conventional antibiotics. Cough is a troublesome symptom in many patients, but it may be advantageous, especially in individuals who produce copious amounts of sputum. Cough suppressants are not known to provide any benefit other than perhaps short term symptomatic control of cough, and their regular use is not indicted.
In patients with cor pulmonale there is little evidence
that
drugs such as angiotensin converting enzyme inhibitors, digoxin,
or calcium channel blockers are of any benefit. However, if
measures such as leg elevation and, where appropriate, long
term oxygen therapy fail to control symptomatic peripheral oedema,
low dose diuretics can be tried.
The ABC of chronic obstructive pulmonary disease is edited by Graeme P Currie. The series will be published as a book by Blackwell Publishing in autumn 2006.
Competing interests: GPC has received funding for attending international conferences and honoraria for giving talks from pharmaceutical companies GlaxoSmithKline, Pfizer, and AstraZeneca. BJL has received funding for attending conferences, payment for speaking and consulting activity, and research funding from pharmaceutical companies AstraZeneca, Atlanta, Aerocrine, Sepracor, MSD, Neolab, Cipla, Innovata, UCB-Celltech, and Schering-Plough.
The figure of the additive effects of
theophylline and salmeterol was reproduced with permission
from Zu Wallack et al. Chest 2001;119:
1661-70.