Topic: Drug Induced Pulmonary Disease (PharmD 2nd Year - Pharmacotherapeutics) -Pulmonary Eosinophilia - Oxygen Toxicity - Drug Induced Pulmonary Fibrosis Reference: Dipero

1. DRUG INDUCED
PULMONARY
DISEASE
AVANI SUNIL PATEL
PHARMD. 2ND YEAR (2022-23)
PHARMACOTHERAPEUTICS-1

2. TOPICS TO BE COVERED
1. PULMONARY EOSINOPHILIA
2. OXYGEN TOXICITY
3. DRUG INDUCED PULMONARY FIBROSIS
 BONE MARROW TRANSPLANTATION
 PARAQUAT
 FURANS (NITROFURANTOIN)
 ANTINEOPLASTICS
 NITROSOUREAS
 BLEOMYCIN
 MITOMYCIN
 ALKYLATING AGENTS
 ANTIMETAOLITES
 NONCYTOTOXIC DRUGS
 AMIADARONE

3. PULMONARY
EOSINOPHILIA
Infiltration of eosinophils into the lung compartments
constituting airways, interstitium, and alveoli
01
Various infections, drugs, parasites, autoimmune
processes, malignancies, and obstructive lung diseases
have been associated with increased eosinophils in the
lungs.

5. FEVER
DYSPNEA
CLINICAL PRESENTATION
NON-PRODUCTIVE
COUGH
BILATERAL
PULMONARY
FILTRATES
EOSINOPHILIA
IN BLOOD
CYANOSIS

6. NITROFURANTOIN INDUCED INFILTRATES
Posteroanterior and lateral chest X-ray revealing bilateral reticular
infiltrates seen more significantly in the lower lung zones.
(NSAID INDUCED PULMONARY EOSINOPHILIA
IMAGE SOURCE:
https://casereports.bmj.com/content/2013/bcr-2013-009299
IMAGE SOURCE:
https://www.hindawi.com/journals/crj/2016/4287270/fig1/

7. Sulfonamides
para -
Aminosalicylic acid
sulfasalazine
Cromolyn
First reported as causative agents in users
of sulfanilamide vaginal cream
Frequently produced the syndrome in tuberculosis
patients being treated with this agent
Nine reported cases associated with
sulfasalazine use in inflammatory bowel disease.
Few cases of pulmonary eosinophilia have been reported
in asthmatics treated with cromolyn

8. Nitrofurantoi
n
Phenytoin &
carbamazepin
e therapy
● drug associated most frequently with this syndrome.
● Nitrofurantoin-induced lung disorders appear to be more
common in postmenopausal women.
● Most cases occur within 1 month of therapy.
● Typical symptoms include fever, tachypnea, dyspnea, dry
cough, and, less commonly, pleuritic chest pain.
● Radiographic findings include bilateral interstitial
infiltrates, predominant in the bases and pleural effusions
25% of the time.
● Complete recovery usually occurs within 15 days of
withdrawal.
● Cases of acute pneumonitis and eosinophilia have been
reported.
● Patients have had other symptoms of hypersensitivity,
including fever and rashes.The
● symptoms of dyspnea and cough subside following
discontinuation of the drug.

9. OXYGEN
TOXICITY
An iatrogenic illness caused by a high partial pressure of
inspired oxygen during the course of oxygen therapy.
02
Oxygen toxicity due to high levels of supplemental oxygen
markedly increases the production of reactive oxygen species
(ROS), which overwhelm host antioxidant defense mechanisms
in the immature lung and thus cause adverse molecular,
biochemical, histologic, and anatomic effects.

10. Earliest Manifestation: Substernal Pleuritic Pain from
tracheobronchitis
Onset of toxicity: follows an asymptomatic period and
presents as cough, chest pain, and dyspnea
Physiologic change:
• (first noted) decrease in pulmonary compliance
caused by reversible atelectasis
• decreases in vital capacity occur, followed by
progressive abnormalities in carbon monoxide
diffusing capacity
• Decreased inspiratory flow rates, reflected in the
need for high inspiratory pressures in ventilator-
dependent patients, occur as the fractional
concentration of inspired oxygen requirement
increases
• lungs become progressively stiffer as the ability to
oxygenate becomes more compromised.

11. FRACTION OF
INSPIRED
OXYGEN
DURATION OF
EXPOSURE
both important determinants
of the severity of lung damage
DURATION REQUIRED ∝
𝟏
𝐅𝐑𝐀𝐂𝐓𝐈𝐎𝐍 𝐎𝐅 𝐈𝐍𝐒𝐏𝐈𝐑𝐄𝐃 𝐎𝐗𝐘𝐆𝐄𝐍
*Underlying disease states may alter this relationship

12. Normal human
volunteers
- can tolerate
100% oxygen at
sea level
-for 24 to 48 hours
-with minimal to
no damage
Oxygen
concentrations
of less than
50% are well
tolerated even
for extended
periods.
Inspired oxygen
concentrations
between 50%
and 100%
carry a
substantial risk
of lung damage
*Lung damage may not be lasting and may
improve months to years after the exposure.

13. OXYGEN- INDUCED LUNG DAMAGE
Acute exudative phase
Subacute or chronic
proliferative phase
• perivascular,peribronchiolar,
interstitial, and alveolar edema
• with alveolar hemorrhage
• necrosis of pulmonary
endothelium and type I
epithelial cells.
• resorption of the exudates
• hyperplasia of interstitial and
type II alveolar lining cells.
• Collagen and elastin
deposition in the interstitium
of alveolar walls
• then leads to thickening of the
gas-exchange area and the
fibrosis.

15. https://www.thelancet.com/journals/lancet/article/PII
S0140-6736%2816%2900578-X/fulltext

16. Biochemical
Mechanism

17. HYPEROXIA CONDITION
increased production of highly reactive, partially
reduced oxygen metabolites (include the
superoxide anion, hydrogen peroxide, the hydroxyl
radical, singlet oxygen, and hypochlorous acid)
produce toxicity through destructive redox
reactions with protein sulfhydryl groups,
membrane lipids, and nucleic acids
Bleomycin
Cyclophosphamide
Nitrofurantoin
Paraquat
Drugs that
increases
production
of oxidants Carmustine
Cyclophosphamide
Nitrofurantoin
Drugs that
inhibit the
antioxidant
system
The oxidants are products of normal cellular respiration
that are normally counterbalanced by an antioxidant
defense system that prevents tissue destruction.
The antioxidants include superoxide
dismutase, catalase, glutathione peroxidase,
ceruloplasmin, and α -tocopherol (vitamin E).
Hyperoxia produces toxicity by overwhelming the
antioxidant system

18. DRUG-INDUCED
PULMONARY
FIBROSIS
03
Pulmonary fibrosis (PF) is a process that causes lung scarring,
in which fibrotic tissue blocks the movement of oxygen from
inside the tiny air sacs in the lungs into the bloodstream.

19. A large number of drugs are
associated with chronic
pulmonary fibrosis with or
without a preceding acute
pneumonitis
( Table 36–6 ).
The cancer chemotherapeutic
agents make up the
largest group and have been
the subject of numerous reviews

20. • Clinically, the development of pulmonary inflammation and fibrosis after bone
marrow transplantation in the absence of identifiable infectious agents has been
termed idiopathic pneumonia syndrome (IPS)
• IPS accounts for more than 40% of deaths related to bone marrow transplantation.
• Causes of IPS:
- radiation or chemotherapy regimens prior to transplantation,
- graft-versus-host disease
- unrecognized infections
- other inflammation-related lung injuries
• Clinical Presentation:
- Dyspnea
- Hypoxemia
- Non-Productive Cough
- Diffuse alveolar damage*
- Interstitial pneumonitis*
BONE MARROW TRANSPLANTATION
https://casesjournal.biomedcentral.com/articles/10.1186/1757-1626-1-234

21. • The lung damage following ingestion of the contact
herbicide paraquat classically resembles hyperoxic lung
damage.
• Hyperoxia accelerates the lung damage induced by
paraquat.
• MECHANISM: Paraquat readily accepts an electron from
reduced nicotinamide-adenine dinucleotide phosphate
and then is reoxidized rapidly, forming superoxide and
other oxygen radicals.
• The toxicity may be a result of nicotinamide-adenine
dinucleotide phosphate depletion and/or excess oxygen
free radical generation with lipid peroxidation.
• Treatment: exogenous superoxide dismutase
PARAQUAT
https://www.mjdrdypu.org/article.asp?issn=0975-2870;year=2014;volume=7;issue=4;spage=482;epage=485;aulast=Dhadwad

22. ADDITIONAL
INFO:

23. • Occasionally, patients with acute nitrofurantoin lung toxicity will progress to a chronic
reaction leading to fibrosis
• MECHANISM: nitrofurantoin undergoes cyclic reduction and reoxidation that may
produce superoxide radicals or deplete nicotinamide-adenine dinucleotide
phosphate.
• In addition, nitrofurantoin inhibits glutathione reductase, an enzyme involved in the
glutathione antioxidant system
FURANS (NITROFURANTOIN)

24. • six predisposing factors for the development of cytotoxic drug—induced pulmonary
disease were described:
(a) cumulative dose (b) increased age
(c) concurrent or previous radiotherapy (d) oxygen therapy
(e) other cytotoxic drug therapy (f) preexisting pulmonary disease.
• Older patients appear to be more susceptible, possibly as a result of a decrease in the
antioxidant defense system.
ANTINEOPLASTICS

25. • BCNU is associated with the highest incidence of pulmonary toxicity (20% to 30%)
• BCNU preferentially inhibits glutathione reductase, the enzyme required to regenerate
glutathione, thus reducing glutathione tissue stores.
• Patients present with dyspnea, tachypnea, and nonproductive cough
• Most patients receiving BCNU develop fibrosis that may remain asymptomatic or
become symptomatic any time up to 17 years after therapy.
• Cumulative dose has ranged from 580 to 2,100 mg/m2
• The disease is usually slowly progressive with a mortality rate from 15% to greater
than 90% depending on the study and period of follow-up.
• Female risk > Male
• Corticosteroids do not appear to be effective in reducing damage.
NITROSOUREAS

26. • Because of its lack of bone marrow suppression, pulmonary toxicity is the dose-limiting toxicity of
bleomycin therapy.
• Incidence of bleomycin lung toxicity is approximately 4%
• Risk factors:
- bleomycin cumulative dose (450-500 Units)
-age (<7 yrs more risk)
-high concentration of inspired oxygen
-radiation therapy
-multidrug regimens, particularly those with cyclophosphamide
• MECHANISM: -generates superoxide anions (lung toxicity is increased by radiation and hyperoxia)
-oxidizes arachidonic acid, which may account for the marked inflammation.
-affect collagen deposition by its stimulation of fibroblast growth
BLEOMYCIN

27. Clinical patterns of
bleomycin pulmonary
toxicity
Acute hypersensitivity
reactions
- OCCURS
INFREQUENTLY
Chronic progressive
fibrosis
- MORE COMMON
CLINICAL PRESENTATION:
• Cough
• Dyspnea
First physiologic abnormality seen:
• decreased diffusing capacity of carbon
monoxide
Chest radiographs
• bibasilar reticular pattern
Gallium scans
• marked uptake in the involved lung
Mortality rate is approximately 25%
Treatment: Corticosteroid therapy

28. • Alkylating antibiotic
• Produces pulmonary fibrosis at a frequency of 3% to 12%
• Unknown Mechanism
• But oxygen and radiation therapy appear to enhance the development of toxicity.
• Clinical presentation and symptoms are the same as for bleomycin
• Mortality rate is approximately 50%
• Treatment:
- Early withdrawal of drug
- Corticosteroids
MITOMYCIN

29. ALKYLATING AGENTS
Incidence of clinical toxicity - 4%
MECHANISM: epithelial cell damage that triggers the arachidonic acid inflammatory cascade
may be the initiating event
CLINICAL PRESENTATION:
• low-grade fever
• weight loss
• weakness
• dyspnea
• cough
• rales
PULMONARY FUNCTION TEST:
• abnormal diffusion capacity
• followed by a restrictive pattern (low vital
capacity)
HISTOPATHOLOGIC FINDINGS:
• non-specific

30. CYCLOPHOSPHOAMIDE (20 REPORTED CASES)
CLINICAL PRESENTATION:
• dyspnea on exertion
• cough
• fever
RADIOGRAPHIC CHANGES:
• Inspiratory crackles
• bibasilar reticular pattern
HISTOPATHOLOGIC FINDINGS:
• non-specific
• Approximately 60% of patients recover
• Corticosteroid therapy has been reported to be beneficial
Chlorambucil, melphalan, and uracil mustard are also associated with pulmonary fibrosis.
Of the alkylating agents, only nitrogen mustard and thiotepa have not been reported to
cause fibrotic pulmonary toxicity

31. • Methotrexate was first reported to induce pulmonary toxicity in 1969.
• most commonly appears to result from hypersensitivity
ANTIMETABOLITES
CLINICAL
PRESENTATION
Most common clinical
manifestations:
• Reductions in diffusing
capacity of carbon
monoxide and lung
volumes
• Pulmonary edema and
eosinophilia are common
• fibrosis occurs in only 10%
of the patients who develop
acute pneumonitis
Systemic symptoms:
chills, fever, and malaise
are common before the
onset of dyspnea, cough, and
acute pleuritic chest pain
• also associated with
granuloma formation

32. • Pulmonary fibrosis associated with the ganglionic-blocking agent hexamethonium was first
reported in 1954.
• Patients developed extreme dyspnea after several months on the drug.
• Pathological findings were consistent with bronchiectasis, bronchiolectasis, and fibrosis
NON-CYTOTOXIC DRUGS
Gold salts (sodium aurothiomalate)
-used in the treatment of rheumatoid arthritis
CLINICAL PRESENTATION:
• dyspnea
• cough
• Pleuritic Pain
• Eosinophilia
PULMONARY FUNCTION TEST:
• Restrictive Defect

33. • used for supraventricular and ventricular arrhythmias
• Estimated incidence is 1 in 1,000 to 2,000 treated patients per
year.
• The clinical course is variable, ranging from acute onset of
dyspnea with rapid progression into severe respiratory
failure and death caused by slowly developing exertional
dyspnea over a few months.
• The majority of patients develop reactions while taking
maintenance doses greater than 400 mg daily for more than 2
months or smaller doses for more than 2 years
• The risk of amiodarone pulmonary toxicity is higher during the
first 12 months of therapy even at a low dosage
• Carbon monoxide diffusing capacity studies are sensitive
indicators of amiodarone pulmonary toxicity but have only a 21%
positive predictive value
AMIODARONE
https://radiopaedia.org/cases/amiodarone-induced-pulmonary-fibrosis-1

34. CLINICAL FINDINGS:
• exertional dyspnea
• nonproductive cough
• weight loss
• occasionally low grade fever
RADIOGRAPHIC CHANGES:
(Non-diagnostic)
• diffuse bilateral interstitial changes
consistent with a pneumonitis
PULMONARY FUNCTION ABNORMALITIES:
• hypoxia
• restrictive changes
• diffusion abnormalities
mechanism of
amiodarone-induced
pulmonary toxicity
DIRECT cytotoxic process
INDIRECT
immunologic
reactions

36. THANK YOU!
REFERNCE:
PHARMACOTHERAPY- A
PATHOPHYSIOLOGIC APPROACH
8TH EDITION (JOSEPH T. DIPIRO)