α 1 -antitrypsin deficiency, neutrophil elastase destroys the
alveolar wall, leading to early-onset emphysema which is
rapidly progressive. Such patients usually die of respiratory
failure. Diagnosis is by measurement of α 1 -antitrypsin
concentrations in the blood. Replacement therapy with
α 1 -antitrypsin can be given. Replacement therapy with heat-
treated (HIV- and hepatitis virus-negative) pooled plasma
from donors is given intravenously weekly. The t1/2ofα 1 -
antitrypsin is 5.2 days and its only adverse effect is post-infu-
sion fever. Plasma concentrations rise into the normal range
and several small longitudinal clinical studies with weekly
dosing suggest reduction in the rate of decline in FEV 1 com-
pared to historical controls. Aerosolized administration on a
weekly basis appears safe and effective in children. The use of
recombinant α 1 -antitrypsin is being more widely investigated
andα 1 -antitrypsin gene therapy is now in early stage clinical
investigation.
DRUG-INDUCED PULMONARY DISEASE
The lungs may be adversely affected by drugs in many impor-
tant ways. Physical irritation by dry powder inhalers can pre-
cipitate cough/bronchospasm in asthmatics. Allergy to drugs
of the immediate variety (type I) is particularly common in
atopic individuals. Specific reaginic antibodies (IgE) to drugs
can produce disturbances ranging from mild wheezing to
laryngeal oedema or anaphylactic shock. Delayed bron-
chospasm may be due to drug interactions involving IgG anti-
bodies (type III). Any drug may be responsible for allergic
reactions, but several antibiotics are powerful allergens.
β-Adrenoceptor antagonists can produce prolonged and
sometimes fatal bronchospasm in asthmatics. Aspirinand
other non-steroidal anti-inflammatory drugs (Chapters 25, 26
and 30) cause bronchoconstriction in sensitive asthmatic
individuals (an estimated 2–7% of asthmatics have such
sensitivity) who may also have nasal polyps and urticaria.
Parasympathomimetic drugs (e.g. bethanechol,methacholine)
and acetylcholinesterase inhibitors, such as physostigmine,
can promote bronchial secretions and increase airways
resistance. A dry cough can be caused by cytokines or more
commonly (9–30% of patients) by angiotensin-converting
enzyme (ACE) inhibitors (Chapters 28 and 29) and is dose
dependent.
Pulmonary eosinophilia presents as dyspnoea, cough and
fever. The chest x-ray shows widespread patchy changing
shadows, and there is usually eosinophilia in the peripheral
blood. The pathogenesis of the condition is not fully under-
stood, but several drugs have been implicated, including
aspirin, ACE inhibitors, clarithromycin,imipramine,isoni-
azid,montelukast, NSAIDs, penicillin, sulphonamides, sim-
vastatin. The lungs can be involved by pleuritic reactions,
pneumonia-like illness and impaired respiratory function
due to small, stiff lungs in drug-induced systemic lupus
erythematosus. Examples of drugs that cause this include
hydralazine,bromocriptineandprocainamide. Many drugs
can produce interstitial pulmonary fibrosis, including
amiodarone,bepredil,bleomycin,cyclophosphamide,gem-
citabine,gold salts,methotrexateandrituximab.DRUG-INDUCEDPULMONARYDISEASE 243Case history
A 35-year-old woman with a history of mild asthma in
childhood (when she was diagnosed as being sensitive to
aspirin) was seen in the Medical Outpatients Department
because of sinus ache, some mild nasal stuffiness and itchy
eyes. She had hay fever. For her asthma she was currently
taking prn salbutamol (2 100 μg puffs) and beclometha-
sone 500μg/day. She was given a prescription for an anti-
histamine, ketotifen 2 mg twice daily. She took the
prescription to her local chemist rather than the hospital
chemist, and started taking the tablets that day. She awoke
in the early hours of the next morning very breathless and
wheezy, and was rushed to hospital with acute severe
bronchospasm requiring ventilation, but recovered.
Fortunately, at the time of her admission her husband
brought in all of the prescribed medications she was tak-
ing, and this led to her physicians establishing why she had
deteriorated so suddenly.
Question
What led to this severe asthma attack? How could it have
been avoided?
Answer
This patient was successfully treated with oxygen, IPPV, glu-
cocorticosteroids and nebulized bronchodilators. Among
her medications they found a bottle of ketoprofen (an
NSAID) which she had started that morning (two 100 mg
tablets twice a day). The pharmacist had not checked for
NSAID sensitivity and the patient was not expecting an
NSAID prescription after what the hospital doctor had told
her about ketotifen. As the literature suggests, 2–7% of
asthmatics are aspirin/NSAID sensitive, it is always import-
ant to check this with the patient.
On reviewing the prescription, the handwriting could
have been thought to read ‘ketoprofen’, but the practi-
tioner was adamant that she had written ‘ketotifen’. The
second issue in this case was a poorly written prescription
for a drug with which the patient was unfamiliar, namely
ketotifen, an antihistamine that may have additional cro-
moglicate-likeproperties, but whose anti-allergic effects
have been disappointing in clinical practice. The impor-
tance of clearly written appropriate drug prescriptions can-
not be over-emphasized. Computerized prescribing may
minimize such errors in the future. Possible ‘look-alike’ drug
pairs which have the potential for confusion include amio-
darone and amlodipine, alprazolam and alprostadil, chlor-
pheniramine and chlorpromazine, digoxin and doxepin,
esmolol and ethambutol, fexofenadine and fenfluramine,
metoprolol and misoprostol, and omeprazole and omal-
izumab. Proprietary names further multiply the opportuni-
ties for ‘sound-alike–look-alike’ confusion.FURTHER READING AND WEB MATERIAL
Barnes PJ. Drug therapy: inhaled glucocorticoids for asthma. New
England Journal of Medicine1995; 332 : 868–75.
British Thoracic Society; Scottish Intercollegiate Guidelines Network.
British guideline on the management of asthma. Thorax2003; 58
(Suppl. 1): s1–94 and http://www.sign.ac.uk/pdf/grg63.pdf