Do blood pressure pills affect the BAC


Language: German | English

D. Ukena

Clinic for Pneumology and Respiratory Medicine, Interdisciplinary Lung Center, Züricher Strasse 40, 28325 Bremen, Germany

Clinic for Pneumology and Respiratory Medicine, Interdisciplinary Lung Center, Züricher Strasse 40, 28325 Bremen, Germany
Corresponding author.
Copyright © Springer Medizin Verlag 2007
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More than 350 drugs are known to have adverse effects on the lungs, bronchi and the adjacent structures of the thorax. The range of pathological changes is accordingly. The main symptoms are often a new dyspnoea that occurs under exertion and a usually dry cough. The further diagnosis includes an extended lung function test including determination of diffusion capacity, a high-resolution computed tomogram and a bronchoscopy with bronchoalveolar lavage. There is no pathological change specific to a defined drug. In case of doubt, the potentially pneumotoxic drug must be discontinued. If the functional impairment is significant, an attempt at therapy with systemic corticosteroids is initiated.

Keywords: Drug-induced lung changes, adverse drug reactions, interstitial lung disease, dyspnoea, bronchoscopy


It is well-known that more than 350 drugs can cause unwanted effects in the lungs, bronchi, and neighboring structures of the thorax with a corresponding spectrum of pathological changes. Cardinal symptoms are often new onset of dyspnea on exertion and a cough that is usually dry. Further diagnostic work-up includes comprehensive pulmonary function testing with determination of diffusing capacity, high-resolution computed tomography, and bronchoscopy with bronchoalveolar lavage. There is no specific pathological alteration for a defined drug. In case of doubt the potentially pneumotoxic drug should be discontinued. An attempt should be made to treat severely compromised lung function with systemic corticosteroids.

Keywords: Drug-induced lung changes, unwanted drug effects, interstitial lung disease, dyspnea, bronchoscopy

The term “drug-induced lung disease”, DILD, or “drug-induced pulmonary disease”, DIPD) encompasses those changes that affect the drugs in the bronchi and lung parenchyma, the pleura, the pulmonary vessels and the neuromuscular Structures and the mediastinum can cause undesirable effects. Such changes have currently been described for more than 350 drugs.

After reading the article, the reader should be able to name the most important drug-induced lung diseases.

Frequency and classification

Naturally, the frequency of drug-induced changes can only be estimated [7, 19]. It is assumed that 2–5% of all hospital admissions are for adverse drug reactions

About 2–5% of all hospital admissions are for adverse drug reactions

. Furthermore, 0.3% of deaths in hospitals are said to be causally related to drugs. Finally, it is estimated that <5% of all cases of DIPD are recorded or reported at all.

The Societe de Pneumologie de Langue Francaise (SPLF) and the Association Francaise des Centers de Pharmacovigilance (AFCP) under the direction of P. Foucher, P. Camus, P. Godard et al. GEPPI


(Groupe d’Etudes de la Pathologic Pulmonaire Iatrogene) founded [3, 4]. All information on drug-induced changes in the lungs is systematically recorded and can be called up with the associated references at A regular update takes place, most recently in November 2006.

The overviews provided by UpToDate® ( are also very informative and take into account the latest publications.

The GEPPI uses the following classification of pulmonary toxicity

Classification of pulmonary toxicity

made [3, 4]:

  1. Interstitial lung disease

  2. Pulmonary edema

  3. Pulmonary hemorrhage

  4. Respiratory diseases

  5. Pleural changes

  6. Vascular changes

  7. Mediastinal changes

  8. Involvement of the large airways

  9. Muscle and nerves

  10. Constitutional / systemic symptoms

  11. "Variegated effects"

These main groups are divided into further subgroups [3, 4]. As an example, here are the subgroups


of drug-induced interstitial lung diseases listed:

  1. Acute hypersensitivity pneumonitis and respiratory failure (diffuse and severe infiltrative lung disease)

  2. Subacute cellular interstitial pneumonitis (mild infiltrative lung disease)

  3. Pulmonary Infiltrates and Eosinophilia

  4. Organizing pneumonia and bronchiolitis obliterans (BOOP)

  5. Desquamative interstitial pneumonia (DIP)

  6. Lymphocytic Interstitial Pneumonia (LIP)

  7. Pulmonary fibrosis

  8. Subclinical cytological changes in the BAL cell profile

  9. Diffuse pulmonary calcification

  10. Mineral oil pneumonia with basal or more diffuse chronic lung changes

  11. Pulmonary nodules

  12. Diffuse alveolar damage

  13. Granulomatous Interstitial Lung Disease

Examples of drug-induced infiltrative lung diseases are shown in Tab. Tab. 1.1, for other clinically common constellations in Tab. Tab. 22.

Type of changeprototypefrequencySeverityNumber of drugs
Nonspecific interstitial pneumonia (NSIP)MethotrexateCommonSlightly89
Granulomatous interstitial pneumoniaBCG, methotrexateUnusualSlightly8
Eosinophilic pneumoniaAntibiotics, NSAIDs, ACE inhibitorsCommonMaybe difficult95
Organizing pneumoniaAmiodarone, bleomycinCommonMaybe difficult23
LIPPhenytoinVery rareSlightly1
Fibrosing NSIP or IPF-likeAmiodarone, chemotherapy drugsMore commonHeavy34
AIP / DADChemotherapy drugs, gold, methotrexateMore commonUsually difficult10
Alveolar space filled with “foamy” macrophagesAmiodarone, mineral oilMore commonVariable2
Alveolar hemorrhageAnticoagulants, fibrinolytics, penicillamineUnusualVariable25
Similar to proteinosisBusulfanRareNot clear1
Pulmonary infiltrates + eosinophiliaOrganizing pneumonia + bronchiolitis obliteransPleural effusion
ACE inhibitorsBleomycinBromocriptine
NSAIDsCarbamazepineCarmustine (BCNU)
β-blockersNitrofurantoinG (M) -CSF
Blood transfusionPhenytoinMethotrexate
G (M) -CSF Nitrofurantoin
Hydrochlorothiazide Penicillamine
X-ray contrast media containing iodine Phenytoin
L-tryptophan Procainamide
Methotrexate Propylthiouracil
Nitrofurantoin Sulfonamides

The following pathomechanisms become more fundamental


, which underlie drug-induced lung diseases, differentiated [7, 19]:

  • oxidative damage (by oxygen radicals): chronic nitrofurantointherapy,

  • direct cytotoxic effect: chemotherapeutic agents such as bleomycin,

  • Phospholipid deposition such as by amiodarone,

  • immunologically mediated toxicity, e.g. B. drug-induced lupus erythematosus, e.g. B. by hydralazine, procainamide, INH.

Clinical symptomatology / basic diagnosis

The majority of drug-induced lung diseases present clinically as dyspnoea, often initially with exertion. A generally unproductive cough is also characteristic.

In addition to these two cardinal symptoms, you may experience fever, pleural pain, weight loss, or general fatigue. Specific symptoms for DIPD do not exist

Specific symptoms for DIPD do not exist


The clinical-chemical values ​​are also usually in the normal range. In addition to leukocytosis, the LDH activity in the serum can be increased and the ESR accelerated.

The pulmonary function examination including blood gas analysis can show hypoxemia


result, a restrictive ventilation disturbance and typically a decrease in the diffusion capacity (meaningful, for example, a decrease of> 20%).

In addition to the X-ray examination

X-ray examination

of the thoracic organs is the high-resolution CT (HR-CT


) of central importance in the assessment of interstitial lung changes. Its importance results from the description of the morphological changes (also important for the differential diagnosis), the lack of invasiveness of the examination and the good reproducibility, which is important for follow-up examinations. Typical HR-CT findings are frosted glass opacity, consolidation, thickening of interlobular septa, and centrilobular nodules.

The bronchoscopy


including the bronchoalveolar lavage (BAL) and possibly the transbronchial lung biopsy (TBB) is important in several ways:

  • Confirmation of diagnosis and differential diagnostic delimitation of z. B. sarcoid, neoplasm (e.g. bronchoalveolar carcinoma, BAC), eosinophilic pneumonia,

  • in the case of infection, identification of a pathogen or, vice versa, exclusion of an infection.

  • The BAL cellularity can provide important clues such as: In the case of lymphocytosis, neutrophilia, eosinophilia, mixed cell picture or macrophage abnormality.

The pathological examination of lung tissue obtained e.g. B. by a transbronchial lung biopsy, can also provide important information as in the case of an organizing pneumonia or a BOOP, a sarcoid etc. It is important, however, that there are no pathological changes specific to drug-induced lung damage

There are no pathological changes specific to drug-induced lung damage

[17]. This also implies that if DIPD is suspected, there is usually no indication for an open lung biopsy.

Risk factors

It is completely unclear why drugs can damage the lungs of a relatively small group of patients. For most drugs that cause DIPD, there is no obvious correlation with the dose of the drug or the duration of therapy; That is, a DIPD is unexpected and idiosyncratic

A DIPD is unexpected and idiosyncratic

[3, 4].

Well-known constellations that favor the development of a DIPD are z. B. [3, 4]:

  • Basic disease such as rheumatoid arthritis, Crohn's disease, ulcerative colitis. So-called "disease modifying drugs" used for this purpose can increase the risk of DIPD;

  • Environmental influences, such as B. Asbestos exposure can increase susceptibility to harmful drug effects;

  • inter-individual qualitative and quantitative differences in drug metabolism;

  • Hepatic or systemic responses to drugs may be HLA phenotype or acetylator phenotype dependent;

  • Other drugs taken at the same time can alter drug metabolism (e.g. via cytochrome P450) or other pharmacokinetic properties;

  • potentiating influences e.g. B. with simultaneous administration of several chemotherapeutic agents, with cytostatic therapy and simultaneous radiation or cytostatic with high inspiratory oxygen concentration (FiO2).

Chemotherapy drugs

Methotrexate (MTX)

Serious and possibly life-threatening side effects of MTX therapy can include hepatic changes (cirrhosis / fibrosis), bone marrow changes (cytopenia of various cell lines) and pulmonary changes

Hepatic, bone marrow and pulmonary changes can occur in the serious side effects of MTX therapy

occur [2]. The latter are classified as follows:

  • inflammatory lung disease,

  • Infections,

  • neoplastic diseases.

Inflammatory lung disease

Hypersensitivity pneumonitis

Hypersensitivity pneumonitis

is the most common pulmonary toxicity associated with MTX. Other pulmonary changes are:

  • Bronchiolitis obliterans with organizing pneumonia (BOOP),

  • acute pulmonary lesion ("acute lung injury", ALI) with noncardiogenic pulmonary edema,

  • Pulmonary fibrosis,

  • Bronchitis with airway hyperresponsiveness.

The underlying pathomechanisms of pulmonary toxicity have not been clarified. Due to the constellation with fever, eosinophilia, increased CD4 + T cells in the BAL and the mononuclear cell infiltration with granulomatous inflammation, a hypersensitivity reaction is assumed. Further pathomechanisms are e.g. B. a direct toxic effect of the MTX on the lung tissue or a reduced defense against viral infections.


With ongoing MTX therapy, the risk of opportunistic infections by Pneumocystis jiroveci, CMV, varicella-zoster viruses, nocardia, mycobacteria or fungi is increased. In particular Pneumocystis jiroveci

Pneumocystis jiroveci

has been identified as a problem germ that is responsible for up to 40% of infectious complications [2, 11].

Neoplastic diseases

The occurrence of non-Hodgkin (B-cell) lymphomas has been observed, as has Epstein-Barr virus-associated lymphomas. A direct carcinogenic effect of the MTX has not been proven in patients with rheumatoid arthritis.

A number of risk factors

Risk factors

for the MTX-induced pulmonary toxicity was defined (Tab. (Tab. 3; 3; [1]).

Risk factorOdds ratio95% confidence interval)
Older age (> 60 years)5,11,2–21,1
Diabetes mellitus35,61.3 – infinite
Previous use of disease modifying drugs5,61,2–27,0
Pleuropulmonary involvement in rheumatoid arthritis7,11,1–45,4
Lung disease at the start of MTX therapy0,30,04–2,8
Male gender1,30,3–5,3


There are acute forms (manifestation within days), chronic forms (occurrence after several years of therapy) and, most frequently, subacute forms (manifestation within the 1st year after the start of therapy). Typical symptoms are dyspnoea, non-productive cough, fever, and dry rattles

Typical symptoms are dyspnoea, non-productive cough, fever, and dry rattles

. The further diagnostics mainly include the HR-CT examination and the lung function test including DLCO. However, a preclinical diagnosis of MTX pneumonitis is not possible even with serial pulmonary function examinations [2].

Bronchoscopy with BAL can rule out an infectious cause of pneumonitis and facilitate diagnosis by detecting CD4 + T cells and an increased CD4 / CD8 ratio. The pathological examination of lung tissue, e.g. B. by a transbronchial lung biopsy, enables the diagnosis of pneumonitis, but without being able to prove specific changes for MTX. It is used for differential diagnosis, e.g. B. Changes in the lung parenchyma in the context of rheumatoid arthritis are of importance.

A multiparameter score system was developed for scientific questions without its clinical benefit having been validated for clinical practice [2, 21].


Through folic acid substitution

Folic acid substitution

the risk of MTX-induced pulmonary toxicity is not reduced. The standard recommendation - discontinue the MTX and initiate systemic corticosteroid therapy

Corticosteroid therapy

(1 mg / kg body weight) - is not based on the results of qualified clinical studies, but reflects clinical experience. The dose reduction of the steroid should be made according to the clinical course. An infectious cause of the pulmonary changes must be ruled out. Usually there is a complete restitutio ad integrum. The mortality is <1%.


The taxanes paclitaxel and docetaxel are used to treat various solid tumors, e.g. B. also the non-small cell lung cancer (NSCLC), used. Paclitaxel in the usual dose range of 30-250 mg / m2 can cause pulmonary side effects, the frequency of which increases in the high dose range of chemotherapy. The type I hypersensitivity reactions observed in the initial studies, possibly accompanied by bronchospasm and hypotension, can be reduced by premedication with corticosteroids, antihistamines and H.2-Blockers can be reduced to an incidence of 1–3%.

The acute occurrence of bilateral, transient pulmonary infiltrates is associated with both taxanes

The acute occurrence of bilateral, transient pulmonary infiltrates is associated with paclitaxel and docetaxel

[13]. These can occur within hours to days after the tax has been given. The cause is seen in a cell-mediated type IV hypersensitivity reaction. In the high dose range of taxane therapy, pulmonary toxicity can be therapy-limiting. Similarly, pneumonitis can occur as part of a taxane-containing combination therapy. In the frequently practiced combination with radiation therapy (simultaneous chemotherapy / radiotherapy), a pneumonitis reaction can occur more frequently than with chemotherapy alone.

Taxane-induced pneumonitis

Taxane-induced pneumonitis

is an important differential diagnosis in the case of new pulmonary infiltrates during chemotherapy. Usually an HR-CT is done. Systemic corticosteroids are given for therapy.


This antibiotic isolated from Streptomyces strains is used to treat solid tumors and lymphomas. From a drug safety perspective, the predominant problem with bleomycin therapy is the potential, life-threatening interstitial pulmonary fibrosis

Interstitial pulmonary fibrosis

(fibrosing alveolitis) in up to 10% of patients. This reaction usually develops between 1 and 6 months after starting bleomycin therapy. Acute lung damage in the context of a hypersensitivity reaction, on the other hand, is less common. It occurs in about 1% of patients during the infusion [15].

The pathomechanism underlying the fibrosing process has not been clarified, but includes the release of oxygen radicals and proinflammatory cytokines.

Likely risk factors for bleomycin lung fibrosis are:

  • total cumulative dose> 450 mg / m2,

  • high FiO2,

  • Radiation therapy,

  • Renal failure.

Possible risk factors are:

  • older age,

  • Combination chemotherapy.

Treatment with bleomycin should be stopped if lung damage is suspected and proven and should not be restarted

Treatment with bleomycin should be stopped when the lungs are damaged and should not be restarted

. Systemic corticosteroids (starting with 1 mg / kg body weight) are used for short-term symptomatic improvement. The dose is reduced depending on the clinical course over several months. In animal experiments, numerous other drugs, such as. B. amifostine, pentoxifylline, or pirfenidone have been investigated with regard to their effects on bleomycin-induced pulmonary fibrosis [15].


This alkylating drug is used in combination chemotherapy for the treatment of numerous malignancies and, due to its immunosuppressive effects, also for certain autoimmune diseases, usually together with systemic corticosteroids. Cyclophosphamide-induced lung damage is probably a rather rare event [22]. However, the risk of this can arise with simultaneous radiation therapy, in combination with other potentially pneumotoxic drugs or with increased oxygen partial pressure (FiO2) can be increased [22].



can occur early during the cyclophosphamide treatment in contrast to the fibrosing, progressive changes that can manifest themselves after a long period of therapy over several months to years. This pulmonary fibrosis usually responds poorly to corticosteroids and usually leads to terminal respiratory failure [22].

Acute pneumonitis with cyclophosphamide is usually reversible after discontinuation and initiation of corticosteroid therapy and accordingly has a good prognosis.


This antibiotic is used for the therapy of urinary tract infections and also for the chronic treatment of the same. Its value as an antibiotic is viewed very critically.

Nitrofurantoin can cause acute to subacute lung damage with the signs of vasculitis, chronic interstitial inflammation, eosinophilia, etc.

Nitrofurantoin can cause acute to subacute lung damage with the signs of vasculitis, chronic interstitial inflammation, eosinophilia, etc.

, e.g. B. 24-48 hours after the start of therapy. Chronic lung damage presents as pulmonary fibrosis after several months to several years of therapy (also discontinuous) [25].

In the acute form, symptomatic improvement should occur within 1–2 days after the end of therapy. A positive role of corticosteroids has not been proven.

The recovery process in the chronic form can take several months. Despite poor data, systemic steroid therapy is usually initiated.

Drugs used to treat rheumatoid arthritis

If a patient with rheumatoid arthritis (RA) has new respiratory symptoms, drug-induced lung damage is an important differential diagnosis. Typically, rheumatic diseases can also lead to pulmonary involvement. With ongoing anti-rheumatic therapy, the appearance of pulmonary changes can also be an expression of a progression of the underlying disease

With ongoing anti-rheumatic therapy, the appearance of pulmonary changes can also be an expression of a progression of the underlying disease

. In addition, an increased incidence of infections is to be expected with anti-rheumatic therapy. The differential diagnostic spectrum for newly occurring lung changes thus includes, among other things. pulmonary involvement of the underlying disease, infectious diseases and drug-induced lung disease. At the present time it cannot be estimated to what extent the so-called biologicals from the group of disease-modifying antirheumatic drugs (DMARD) influence the incidence of drug-induced lung diseases caused by antirheumatic drugs [14].

An overview of potential pulmonary side effects of anti-inflammatory drugs is shown in Tab. Tab. 44. Currently of particular interest is the occurrence of tuberculosis in need of treatment due to drugs that can antagonize the effect of the tumor necrosis factor α (TNF)

Of particular interest is the occurrence of tuberculosis in need of treatment due to drugs that can antagonize the effect of TNF-α

. These include the TNF receptor fusion protein etanercept, the dimeric anti-TNF antibody infliximab and the monoclonal anti-TNF antibody adalimumab. In an initial survey of 147,000 patients treated with infliximab, 70 cases of tuberculosis requiring treatment were found [12]. According to Spanish surveys, the TNF blockade resulted in 1,893 cases of tuberculosis per 100,000 in 2000 and 1,113 cases per 100,000 in 2001 [9]. Tuberculosis occurs mainly in the first year of treatment, with a median of 3 months after the start of treatment and after application of 3 doses [14].

PneumonitisFibrosisBronchiolitis obliteransinfectionPulmonary edemaHemorrhageBronchospasm
MethotrexateMethotrexateD-penicillamineTNF inhibitors:ASA (in high dose)D-penicillamineASS
goldgoldgold- infliximabNSAIDs NSAIDs
D-penicillamineCyclophosphamideSulfasalazine- EtanerceptMethotrexate Methotrexate
NSAIDsChlorambucil - adalimumabCyclophosphamide  
CyclophosphamideAzathioprine IL-1 inhibitorColchicine (overdose)  
AzathioprineSulfasalazine - anakinra   
Sulfasalazine  Methotrexate   
Chlorambucil  Corticosteroids   

It is recommended to rule out tuberculosis requiring treatment before starting treatment for TNF blockade

It is recommended to rule out tuberculosis requiring treatment before starting treatment for TNF blockade

. Then the examination for a latent tuberculosis infection should be carried out, most likely by testing according to Mendel-Mantoux. If the test result is positive (> 5 mm or> 10 mm in diameter), the relevant recommendations for the treatment of latent tuberculosis must be taken into account.

Cardiovascular drugs

Several drugs used to treat cardiovascular diseases have the potential to cause pneumotoxicity [5].

Angiotensin Converting Enzyme (ACE) inhibitors

All active substances in this group can cause a dry, persistent, especially nocturnal cough (incidence 3–20%). The causes discussed are: reduced breakdown of irritating, bronchoconstrictive mediators such as bradykinin and substance P; Increase in sensitivity to irritants; genetic predisposition (differences in ACE genes). In terms of differential diagnosis, it is important that the cough can also be a symptom of congestive heart disease. If the ACE inhibitor-induced cough persists, the therapy must be discontinued

If the ACE inhibitor-induced cough persists, the therapy must be discontinued

. Angiotensin II receptor antagonists are available as therapeutic alternatives, for which an increased incidence of cough has not been described [5].

β-adrenoceptor blockers

The so-called β-blockers do not induce pulmonary parenchyma disease, but can lead to exacerbation of diseases of the respiratory tract such as asthma or COPD and of the pulmonary vessels such as portopulmonary hypertension

β-blockers can lead to exacerbation of diseases of the respiratory tract and pulmonary vessels

. In addition to β-blockers, other drugs can also cause bronchospasm (Tab. (Tab. 55).

β-adrenoceptor blockers (β-blockers)
Acetylsalicylic acid (ASA)
Amphotericin B
ACE inhibitors
Interferon-α, -β
Nonsteroidal Anti-Inflammatory Drugs / Anti-Inflammatory Drugs (NSAIDs)
X-ray contrast media

The problem of β-blocker therapy for obstructive airway diseases is well known. Because of safety considerations, patients with asthma or COPD were usually excluded from the large studies on β-blocker therapy, e.g. B. coronary artery disease excluded. This fact explains the limited data available on β-blocker therapy in pulmonary comorbidity. In a Cochrane analysis of 20 randomized studies, no difference was found in the lung function values ​​of COPD patients on β-blocker therapy compared with placebo [20].

In terms of evidence-based practice, the following recommendations can be made


submit [5]:

  • In each individual case, the benefit of β-blocker therapy must be weighed against its risk.

  • Patients with asthma or bronchial hyperreactivity should not be treated with a β-blocker.

  • Patients with stable COPD and partially reversible or irreversible airway obstruction can, if necessary, with a β1-selective drugs such as metoprolol, bisoprolol etc. are treated.

  • Β-blocker therapy should not be initiated during an exacerbation of obstructive airways disease.

  • If clinically justifiable, β-blocker therapy should be started at a low dose, and further dose increases should be carried out under appropriate close monitoring.

It must also be taken into account that β1-Blockers can improve the survival of patients with congestive heart disease

β1-Blockers can improve the survival of patients with congestive heart disease

. The decision not to use these drugs because of a suspected or proven obstructive airway disease must be made after careful consideration [5, 24].

β-blockers are used to prevent variceal bleeding in cirrhosis of the liver with portal hypertension. The physical performance of the patient can be reduced by the β-blocker-induced increase in pulmonary vascular resistance [18].


From this group of drugs, procainamide - more rarely quinidine - can typically cause the clinical picture of lupus erythematosus

Lupus erythematosus

("Drug induced LE") induce [5]. Approximately 50-90% of patients have a positive ANA titer. Symptoms of PE appear in around 10–20% of patients.

Two forms of manifestation are possible in the area of ​​the respiratory tract:

  • Pleurisy associated with pleural effusion and pleural pain,

  • diffuse pulmonary parenchyma disease.

The examination of the pleural fluid reveals the detection of LE cells, an ANA titer ≥160 and a quotient ANA titer pleural fluid / serum ≥1.0. With these parameters it is not possible to differentiate it from systemic or spontaneous lupus (SLE). In contrast to SLE, the absence of renal and central nervous symptoms, the absence of anti-double-stranded DNA antibodies and hypocomplementemia suggest drug-induced lupus erythematosus.

AK detection against the histone complex H2A-H2B is a serological parameter with a positive predictive value for drug-induced lupus

Histone complex H2A-H2B

[23]. The absence of these AKs almost excludes drug-induced PE. Conversely, since detection is successful in approx. 20% of SLE patients, no differentiation between SLE and drug PE is possible based on the AK detection.

Antiarrhythmics such as flecainide and mexiletine can induce pneumonitis. The administration of sotalol can induce bronchoconstriction. The same applies to adenosine, which can characteristically cause bronchospasm through a mediator release from mast cells in the presence of asthma / CODP.


It is a highly effective drug for the therapy of supraventricular and ventricular tachyarrhythmias. Pulmonary toxicity is the most important undesirable effect of the antiarrhythmic drug. Their incidence is 2–3%, up to a maximum of 5% [10]. Pulmonary manifestations are:

  • chronic interstitial pneumonitis,

  • organizing pneumonia, possibly with BOOP,

  • acute respiratory distress syndrome (ARDS),

  • solitary pulmonary tumor (“mass”).

A direct cytotoxic effect and a hypersensitivity reaction are discussed as pathomechanisms [6].

Risk constellations

Risk constellations

for the occurrence of amiodarone-induced pulmonary toxicity are:

  • high cumulative dose,

  • Daily doses ≥400 mg,

  • Duration of therapy> 2 months,

  • older age,

  • pre-existing structural lung disease such as COPD,

  • thoracic / extrathoracic surgery,

  • Pulmonary angiography.

Pulmonary toxicities can also occur at low daily doses of 150–300 mg, albeit with a lower incidence.

There is no predictor of amiodarone pulmonary toxicity. In this respect, serial measurements of lung function and diffusion capacity are also not indicated. The diagnosis of amiodarone-induced lung damage is made by exclusion

The diagnosis of amiodarone-induced lung damage is made by exclusion

. In the differential diagnosis, left ventricular failure, pathogen-related pneumonia, pulmonary artery embolism, and a malignancy such as bronchoalveolar carcinoma (BAC) must be taken into account.

The presence of at least 3 of the following changes is indicative of amiodarone-induced pneumotoxicity [16]:

  • new or worsening symptoms,

  • new changes in the x-ray of the lungs,

  • Decrease in total lung capacity (≥15%) or diffusion capacity (> 20%),

  • Phospholipidosis in lung cells,

  • pronounced CD8 + lymphocytosis in the BAL,

  • Lung biopsy with diffuse alveolar damage, organizing pneumonia, interstitial pneumonitis, or fibrosis,

  • Improvement in pulmonary findings after discontinuation of amiodarone (with or without corticosteroid therapy).

The serum concentrations of amiodarone are usually in the normal range. The determination of KL-6 is possibly groundbreaking


in serum, a glycoprotein secreted by type II pneumocytes. In the case of amiodarone-induced pneumotoxicity, its serum concentration is increased approx. 4 to 6 times [8].

The symptoms and the results from functional examinations and from imaging correspond to those described for other pulmonary toxic drugs. The BAL in amiodarone-induced pneumonitis gives z. B. lymphocytosis, neutrophilia, eosinophilia or a normal cell distribution. The detection of phospholipid-containing lamellar inclusion bodies in alveolar macrophages confirms exposure to amiodarone, but not its toxicity. Conversely, in the absence of these cells, amiodaron toxicity can be ruled out.

Treatment consists of discontinuing amiodarone therapy (caution: elimination half-life of 45 days) and initiating corticosteroid therapy

Treatment consists of stopping amiodarone therapy and initiating corticosteroid therapy

(40–60 mg per day, dose reduction over 2–6 months).Because of the long half-life, the pulmonary disease can initially still be progressive even after discontinuation of amiodarone.

The prognosis is usually good. The mortality from amiodarone-induced lung damage is significantly lower than 10% (but up to 50% possible in ARDS).


Concluding remarks on the drug-induced lung changes are summarized in Tab. Tab. 66.

“Think about it” - especially with lung changes that are difficult to diagnose / classify
Review of medication
In-depth medical history / consideration of risk factors
Lung function test and determination of diffusion capacity, arterial blood gas analysis
"High-resolution CT"
Bronchoscopy including BAL + if necessary TBB (transbronchial biopsy) → differential diagnosis
In dubio discontinuation of potential pneumotoxic drugs
Attempted therapy with a systemic glucocorticoid with significant functional impairment

CME questionnaire

Which statement about drug-induced lung diseases is correct?

More than 1000 drugs are known triggers.

A certain drug can only induce a defined pulmonary toxicity.

Hospital treatment for drug-induced lung damage often implies a lethal outcome.

The majority of drug-induced lung diseases are systematically recorded across Europe.

The frequency of drug-induced lung diseases is only estimated.

Which symptom often occurs as the initial sign in drug-induced lung diseases?



Dyspnea, especially during exertion.


Purulent expectoration.

Which diagnostic measure belongs Not standard procedures for suspected drug-induced lung disease?

Determination of the diffusion capacity.

Open lung biopsy.


Bronchoscopy with BAL.

Drug history.

In the case of drug-induced lung changes, which assignment is "type of change ↔ drug prototype" Not applicable?

Granulomatous interstitial pneumonia ↔ methotrexate.

Fibrosing alveolitis ↔ amiodarone.

Eosinophilic pneumonia ↔ NSAIDs.

Organizing pneumonia ↔ bleomycin.

Diffuse alveolar damage ↔ β-blockers.

No Risk factor for methotrexate-induced pulmonary toxicity is:


Pulmonary Involvement in Rheumatoid Arthritis.

Diabetes mellitus.

Young age.

Older age.

Antagonists of tumor necrosis factor-α (TNF-α) for the treatment of rheumatoid arthritis / chronic inflammatory bowel diseases have characteristically increased infections due to:

Helicobacter pylori.

Stenotrophomonas maltophilia.

Methicillin-resistant Staphylococcus aureus.

M. tuberculosis.

Enterococcus faecalis.

Bronchospasm is common Not caused by:






As part of drug-induced lung damage, a dry cough is common Not observed after administration of:

ACE inhibitor.


AT-II receptor antagonist.



A risk factor for the occurrence of amiodarone-induced lung disease is Not:

Daily doses ≥400 mg.

Older age.

Duration of therapy> 2 months.

Pre-existing structural lung disease.

EF <30%.

Which statement about the β-blocker therapy of a heart disease with concomitant obstructive ventilation disorders such as asthma or COPD is correct?

β-blockers are responsible for most of the deaths in acute asthma attacks.

Any obstructive ventilation disorder is an absolute contraindication for therapy with β-blockers.

Patients with stable COPD without evidence of bronchial hyperreactivity can be treated with a β1-selective blockers are treated.

β-blockers have a bronchodilator effect by blocking presynaptic autoreceptors.

Inhaled corticosteroids can reduce the bronchial effects of β1-Blockers antagonize.

Conflict of interest

There is no conflict of interest. The corresponding author assures that there are no connections with a company whose product is named in the article or a company that sells a competing product. The presentation of the topic is independent and the presentation of the content is product-neutral.