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January - March 2009: 
Volume 22, Issue 1

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Pulmonary toxicity from cardiovascular drugs
Abstract
SUMMARY. A large number of medicinal drugs used in cardiology have been related to a variety of side effects in the lungs. The list of such drugs has increased as new drugs have been introduced in recent years. Lung disease due to medication may appear as parenchymal disease, angeitis, or mediastinal disease. Airway injury may be caused by medication, giving rise to cough, bronchospasm, and obstructive bronchiolitis. In addition, systemic reactions such as lupus erythematosus are commonly observed in conjunction with lung injury. In this review, the side effects on the respiratory system of cardiovascular medications are described, with an emphasis on the nosological entities that are most frequently observed. Pneumon 2009; 22(1):–
Full text

Introduction

Lung disease due to the side effects of pharmaceutical drugs may appear as a variety of clinical entities, which have been correlated with more than 300 drugs. The diagnosis of drug related pulmonary disease is usually made by exclusion of other lung diseases, taking into consideration the absence of specific signs, symptoms or laboratory findings. A detailed history of recent or long term administration of certain drugs is indispensible for orientation towards the diagnosis. Pulmonary injury may occur from within minutes of, to many years after, administration of the medication. Its presentation involves a variety of mechanisms, including: 1) production of free oxygen radicals (oxidative stress), 2) direct hypersensitivity, 3) hypersensitivity due to haptene formation, and 4) direct cellular toxicity. Although the pulmonary complications of most drugs subside, provided they are diagnosed early and handled promptly, some patients die from the complications of certain drugs. The progress of pulmonary disease due to drugs must be avoided by stopping or changing the medication 1,2. The aim of this review is to summarize the side effects of cardiovascular (CV) drugs on the respiratory system, with emphasis on the nosological entities that are most frequently observed.

CLINICAL FORMS OF PULMONARY TOXICITY DUE TO CARDIOVASCULAR DRUGS (Table 1)

1. Cough

ACE inhibitors are drugs widely used for the treatment of arterial hypertension and cardiac failure. ACE inhibitors may be the cause of persistent dry cough3, related to bradikinine release, in 10-20% of patients. The cough may start a few days after the beginning of the treatment, but usually appears after 1-2 months, and total remission is observed within a few days of cessation of the drug. Asthma is not a contraindication to the use of ACE inhibitors. Patients with asthma are at the same degree of risk as the rest of the population, and persistent non-controlled asthma or asthmatic crises due to ACE inhibitors have rarely been described3. Some antagonists of angiotensin II-receptors, such as losartane, have also been implicated in the production of chronic cough4.

2. Bronchospasm

The drugs most often responsible for drug induced bronchospasm are aspirin5 and non steroid anti-inflammatory drugs (NSAIDs) and b-blockers. The term ‘worsening' is considered to be more accurate than the term ‘provocation', because in the majority of cases the drug induced attack is not the first episode of bronchospasm, but an exacerbation of previously existing bronchial asthma or chronic obstructive pulmonary disease (COPD). Only rarely are the above mentioned drugs the inducers of the first paroxysm of bronchospasm. Aspirin can cause bronchospasm in a percentage of 0.3% of normal people and 4-20% of people with a history of chronic bronchial asthma or COPD. The pathogenetic mechanism appears to be related to the metabolism of the prostaglandins, but is not fully understood. Typically, the appearance of an asthmatic crisis after aspirin administration occurs mainly in patients with coexistent nasal polyps. The administration of b-blockers, either per os, intravenously (i.v.) or as eye drops, may cause persistent bronchospasm. Propanalol and timolol are the medications most commonly implicated, while atenolol and metoprolol appear to have less effect on the airways. The result of b-blockers may be either overt bronchospasm or reduction of the bronchodilatory effect of medication administrated to the patients for coexistent pulmonary diseases. The drug-induced bronchospasm appears within a few minutes or hours of administration of the drug; it is severe and difficult to treat. Other drugs have also been implicated in the provocation of bronchospasm (Table 2). Cases have been described of intense bronchospasm after i.v. administration of adenosine6, which is used for treatment of hyperventricular arrhythmia. Another complication which is, however, rare, is bronchospasm after a-MEA administration. This complication may appear 10-15 days after the beginning of treatment. The underlying pathogenetic mechanism is not well understood7. Two cases have described in the literature of bronchospasm after amiodarone administration. Both patients had bronchial asthma as a coexisting disease, but they were free of symptoms before the beginning of antiarrhythmic medication with amiodarone. The bronchospasm resolved completely after interruption of amiodarone treatment8. Two cases of asthma exacerbation after administration of dipiridamole have been described9-13. The treatment of drug induced bronchospasm due to CV drugs includes administration of inhaled bronchodilators and discontinuation of the implicated drug.

Table 1. Signs of pulmonary toxicity due to cardiovascular drugs

  • Cough
  • Bronchospasm
  • Interstitial lung disease
  • Non cardiogenic pulmonary oedema
  • Pulmonary alveolar haemorrhage
  • Mediastinal disease
  • Drug induced lupus erythematosous
  • Thromboembolic disease
  • Pulmonary hypertension
  • Hilar and mediastinal lymphadenopathy
  • Mediastinal haemorrhage
  • Chest pain

Table 2. Cardiovascular drugs that can cause bronchospasm

Antiarrhythmic drugs

1. Adenosine

2. Amiodarone

3. Lidocaine

4. Propapheanone
-blockers

ACE inhibitors

Blockers of the receptors of angiotensin II

1. Losartane

Antiplatelet factors

1. Aspirin

2. Dipiridamole

Thrombolitic drugs

1. Urokinase

2. Streptokinase

Table 3. Clinical forms of interstitial lung disease induced by cardiovascular drugs

  • Acute interstitial pneumonitis (alveolitis)
  • Pulmonary fibrosis
  • Drug induced eosinophilic lung disease
  • Bronchiolitis obliterans organizing pneumonia (BOOP)
  • Pulmonary nodules
  • Hypersensitivity pneumonitis

Table 4. Cardiovascular drugs causing acute interstitial pneumonitis

  • Diuretics

1. Hydrochlorothiazine

  • Antiarrhythmic drugs

2. Disopyramide

3. Procainamide

4. Amiodarone

5. Phenytoin

  • b-Adrenergic blockers

1. Atenolol

2. Carvedilol

3. Nadolol

4. Oxprenolol

  • ACE inhibitors

1. Captoprile

  • Antagonists of the receptors of angiotensin II

2. Valsartane

  • Vasodilator drugs

Dihydrallazine/hydrallazine

  • Antilipidaemic factors

Simvastatin

 

 

3. Chest pain

Atypical chest pain may appear in some patients after specific CV drug administration1,2,14,15. The diagnosis of chest pain due to CV drugs is made by exclusion of other causes of thoracic pain.7,6 Adenosine, methyldopa, pravastatin and simvastatin are drugs that may cause chest pain. The pathogenetic mechanism is only partially known14,15.

4. Interstitial lung disease (ILD)

Many CV drugs have been implicated in the presentation of interstitial lung disease (ILD). Drug induced ILD may appear as in a variety of forms, as described below.

a. Acute interstitial pneumonia and pulmonary fibrosis

Drugs that may cause acute interstitial pneumonia are shown in Table 41,2,16-19. The clinical appearance of acute interstitial pneumonia is progressive dyspnoea, fever and persistent dry cough1,2,16,18. Pulmonary fibrosis is the end stage disease of drug induced pulmonary toxicity. Irreversible lesions of pulmonary fibrosis have rarely been observed and these were caused by amiodarone1,2. Some b-adrenergic blockers, such as lavetamol, pindolol, and practolol, have also been implicated in lung fibrosis16-19. The disease follows a pattern of gradual invasion. Patients present months to years after the beginning of treatment with fatigue and progressive dyspnoea on exercise, dry cough, and chest tightness. Sometimes weight loss may be a feature. Clinical examination reveals mid-inspiratory and end-inspiratory crackles especially in the lower pulmonary zones, similar similar to those of UIP. Chest X-ray examination shows bilateral diffuse reticular and alveolar infiltrates with lung volume diminution. Chest computerized tomography (CT) shows bilateral patchy alveolar infiltrates and ‘ground glass' appearance (Figure 1). Other CT findings include traction bronchiectasis, honeycomb appearance, subpleural fibrosis and atelectasis. Perfusion scanning (PFT) usually shows reduced diffusing capacity and a restrictive pattern on spirometric examination. The treatment of acute interstitial pneumonia and pulmonary fibrosis includes discontinuation of the drug and corticosteroid administration16-19.

b. Drug induced eosinophilic lung disease

CV drugs implicated in the development of eosinophilic pulmonary infiltrates are shown in Table 520. Patients are usually asymptomatic but dry cough, dyspnoea, wheezing, rash, joint pain, fatigue, fever may occur, with blood evidence of eosinophilia. Eosinophilia is usually detected in the bronchoalveolar lavage (BAL) fluid20. The interval between the beginning of administration of the drug and the appearance of lung disease varies. A photographic negative of cardiac pulmonary oedema is observed on X-ray and CT examination (Figure 2). The persistence or reappearance of pulmonary infiltrates after drug interruption, in the absence of other causative factors, supports the diagnosis of chronic eosinophilic pneumonia20-26. Drug induced eosinophilic pneumonia generally has a good prognosis and the remission of symptoms is observed a few days after stopping the drug and starting corticosteroid treatment21,22,25.

Table 5. Cardiovascular drugs which induce eosinophilic lung disease

Diuretics

1. Hydrochlorothiazine

Antiarrhythmic drugs

1. Amiodarone

1. Phenytoin

β-adrenergic blockers

1. Lavitalol

1. Propanoloe

ACE inhibitors

1. Captoprile

2. Peridronprile

3. Posinoprile

Antiplatelet factors

Aspirin

Antilipidaemic factors

Clofibrate

 

c. Bronchiolitis obliterans organizing pneumonia (BOOP)

Bronchiolitis obliterans organizing pneumonia (BOOP) is a histological diagnosis characterized by the formation of granulomatous tissue in the small airways and fibrosis of the alveoli. CV drugs that may induce BOOP are shown in Table 627,28. Dyspnoea on exertion, dry cough, fever and chest pain are common presenting symptoms. Chest X-ray reveals bilateral, asymmetrical, migratory alveolar opacities27,28. The treatment consists of drug interruption and administration of corticosteroids27,28.

d. Pulmonary nodules

Drug induced pulmonary nodules usually present as incidental radiological findings in asymptomatic patients (Figure 3), and more rarely with persistent dry cough and dyspnoea29. Amiodarone29, phenytoin30,31 and tiklopidine32 are associated with pulmonary nodules. Pulmonary nodules after amiodarone administration may sometimes be cavitated. Findings of granulomatous disease on lung biopsy confirm the diagnosis. Complete remission of the nodules is observed after stopping the implicated drug and initiation of corticosteroids1,2,30,32.

e. Hypersensitivity pneumonia

Hypersensitivity pneumonia may have an acute or subacute onset33,34. Fever, fatigue and muscle and joint pain may be present. The pulmonary symptoms are also non-specific and include dry cough and dyspnoea, which usually start after the onset of the generalized symptoms33,34. Blood eosinophilia is observed in a percentage of 20-40% of cases. Chest X-ray shows focal, lobar or diffuse alveolar shadows, usually in a peripheral location1,2,33,34. The drugs mainly implicated in the appearance of hypersensitivity pneumonia are the β-blockers33,34.

Table 6. Cardiovascular drugs that can cause bronchiolitis obliterans organizing pneumonia (BOOP)

  • Antiarrhythmic drugs
    Amiodarone
    Phenytoin
  • b-adrenergic blockers
    Asevoutalol
    Betaxolol
    Sotalol
  • Vasodilator drugs
    Hydrallazine
  • Antilipidaemic factors
    Simvastatin
    Pravastatin
  • Antiplatelet factors
    Ticlopidine

 

 

f. Non-cardiac pulmonary oedema (NCPE)

Non-cardiac pulmonary oedema (NCPE) has been observed after the intake of various drugs. CV drugs that may cause NCPE are aspirin, diltiazeme, xylocaine, and hydrochlorothiazide35-38. This type of oedema is due to increased permeability of the alveolar-capillary membrane and appears hours or days after the administration and results in acute respiratory failure with intense dyspnoea and foamy sputum production. Chest X-ray reveals patchy alveolar infiltrations similar to those of cardiac pulmonary oedema, but the cardiothoracic index is normal and no pleural effusion is observed (Figure 4). Short term mechanical ventilation is sometimes necessary due to the severity of the respiratory insufficiency. The prognosis is in general good with supportive care in parallel with drug interruption35-38.

6. Drug induced systemic lupus erythematosus (DISLE)

Patients with drug induced systemic lupus erythematosus (DISLE) present with joint pain, myalgia, fever, pleuritis and skin lesions39-41. Renal and nervous system involvement is rare in DISLE but respiratory manifestations are frequently observed. CV drugs that provoke DISLE are shown in table 742-49. Serum antinuclear antibodies (ANA) may be elevated, but disappear a few weeks after drug cessation. Pulmonary thromboembolic disease may be a feature of DISLE. Response to treatment is satisfactory after drug interruption, with remission of symptoms after weeks or months in some patients46,50.

g. Alveolar haemorrhage

Independent of the mode of administration (per os, i.v., etc) anticoagulant and fibrinolytic factors may cause alveolar haemorrhage51-55. Other CV drugs are more rarely implicated in pulmonary haemorrhage Table 8). The most commonly observed respiratory manifestations are dyspnoea, haemoptysis and hypoxaemia. Alveolar opacities are observed on the chest X-ray and CT (Figure 5). It is important to recognize that haemoptysis does not always occur in alveolar haemorrhage (>30% of patients) and this can lead to misdiagnosis51-55.

Table 7. Cardiovascular drugs that can induce the syndrome of systemic lupus erythematosis (SLE)

Antiarrhythmic medications

1. Amiodarone

2. Phenytoin

3. Procainamide

4. Quinidine
    -adrenergic blockers

5. Lavitalol

6. Betaxolol

7. Pindolol

8. Propranolol

ACE inhibitors

Captoprile

Antihypertensive drugs with central action

1. Clonidine

2. Methyldopa

Vasodilator drugs

- Dihydrallazine/hydrallazine

Antilipidaemic factors

- Simvastatin

- Pravastatin

- Clofibrate

 

h. Pleural disease

Pleural effusion with or without eosinophils in the pleural fluid can be observed after the administration of several drugs. The pleural fluid in drug induced pleuritis, has no specific characteristics, which makes it difficult to identify the causative factor. Pleural fibrosis is a rare complication associated with the use of amiodarone and procainamide56. The administration of statins has been implicated in the production of chylothorax57. CV drugs that have been associated with pleural disease are shown in Table 914,58,59.

Table 8. Cardiovascular drugs and alveolar haemorrhage

Antiarrhythmic medications

5. Amiodarone

6. Phenytoin

7. Quinidine

Anticoagulants

- Warfarin

Aniplatelet factors

- Aspirin

- Clopidogrele

Thrombolytics

- Urokinase

- Streptokinase

i. Pulmonary hypertension

CV drugs implicated in pulmonary hypertension are shown in Table 1060,61. Protamine administration is a leading causative factor of pulmonary hypertension62. The clinical features of secondary pulmonary hypertension are similar to those of primary hypertension. The symptoms at the onset of the disease are dyspnoea and retrosternal pain during exercise. Unfortunately, even after discontinuation of the implicated drugs, irreversible pulmonary hypertension may persist, with features similar to those of primary pulmonary hypertension and the same prognosis60,61.

Table 9. Cardiovascular drugs associated with mediastinal disease.

Antiarrhythmic medications

8. Amiodarone (mediastinal fibrosis)

9. Procainamide (mediastinal fibrosis)

Phenytoin
-adrenergic blockers

Betaxolol

9. Carvedilol

10. Oxprenolol

ACE-inhibitors

Imidaprile

Vasodilator drugs

Dihydrallazine

Anticoagulant

Warfarin

Asenokoumarol

Antiplatelet factors

Ticlopidine

Antilipidaemic factors

Statins

Table 10. Cardiovascular drugs that can cause pulmonary hypertension

  • b-adrenergic blockers
    vasodilators

Dihydrallazine
antiplatelet

Protamine

 

 

j. Pulmonary thromboembolic disease (PTD)

Two CV drugs, procainamide and phenyntoin, have been associated with pulmonary thromboembolic disease (PTD)62,63. This may be not a separate clinical entity but a systemic respiratory manifestation of DISLE63. Anti-cardiolipin and ANA may be present in the serum of these patients. PFT of the lungs may reveal findings of pulmonary embolism63.

k. Hilar and mediastinal lymphadenopathy

Only phenyntoin of the CV drugs has been implicated in hilar (Figure 6) and mediastinal lymphadenopathy64.

THE DIAGNOSTIC APPROACH TO DRUG INDUCED LUNG DISEASE DUE
TO CARDIOVASCULAR DRUGS

Drug induced lung disease is difficult to confirm, and the diagnostic approach is dependent on the analytical history regarding medication and the interval between the administration of the drug and the onset of symptoms1,2,69.

The main basic question is whether an administered drug could be implicated in pulmonary toxicity1,2,69. In order for a drug to be considered responsible for lung injury, all other diagnoses which can produce similar respiratory symptoms must be excluded. The differential diagnosis should be oriented primarily towards the exclusion of respiratory infections and pulmonary complications of the CV diseases for which the patient received the specific drug1,2,69.

Definite exposure to the specific drug must have occurred before the onset of the respiratory symptoms2,69. Other pharmaceutical agents administered to the patient after the presentation of the respiratory symptoms can be excluded from the list of possible causative factors1,2,69. A full history of administration of drugs in the past is necessary, taking into consideration that the onset of respiratory symptoms can occur even years after from the administration1,2,69. Differential diagnosis is very difficult if the patient is receiving combined therapy with two or more CV drugs known to cause lung toxicity1,2,69.

In order to attribute pulmonary disease to an administered drug it is absolutely necessary to confirm improvement of respiratory symptoms after discontinuation of that drug. The exception to this principle is amiodarone, which continues to maintain high lung tissue concentrations for a long time (several months) after the end of treatment1,2,69. Relapse of symptoms after readministration of the implicated CV drug confirms the diagnosis, but it is not recommended for a drug to be given for diagnostic reasons and readministration must be reserved only for patients for whom there is no alternative drug1,2,69.

The imaging findings (X-ray, CT and HRCT) are non-specific for drug induced lung disease1,2,69.

Patients who are candidates for histological examination must be assessed separately. If differential diagnosis is difficult, transbronchial or open lung biopsy may be necessary for the exclusion of other lung diseases and the confirmation of pulmonary drug toxicity1,2,69.

In the clinical setting, a low degree of suspicion of such a diagnosis is commonly observed. Drug induced pulmonary diseases are rare in routine clinical practice and other lung diseases are more probable. However, drug induced lung diseases must always be kept in mind for CV patients presenting with respiratory symptoms, particularly when the cardiac disease was under control and the clinical state stable at the time of onset of pulmonary disease1,2,69.

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