This document provides an overview of pharmacotherapy for chronic obstructive pulmonary disease (COPD). It discusses non-pharmacologic approaches like pulmonary rehabilitation and smoking cessation. Standard maintenance therapies include long-acting bronchodilators like tiotropium. Newer bronchodilators in development include once-daily long-acting beta-2 agonists. Anti-inflammatory treatments target mediators like leukotrienes, cytokines, proteases, and phosphodiesterase-4 inhibitors. Vaccines against influenza and pneumococcus are recommended to prevent exacerbations. Antibiotics are used to treat mild, moderate, and severe exacerbations based on risk factors.

1. Pharmacotherapy of Chronic Obstructive
Pulmonary Disease (COPD)
R.ARBIND KUMAR
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACOLOGY
IRT-PMC

2. COPD Overview
India

4. Therapeutic Pearls / Nonpharmacologic Approach FOR ALL PATIENTS
An estimated 50% of patients are
non‐adherent to COPD therapy and 50% of
patients cannot demonstrate proper inhaler
technique! Reassess at every visit
Pulmonary rehab has proven benefits in symptomatic and
recently hospitalized patients (NNT = 4 to prevent one
hospitalization in patients with recent exacerbation)
Encourage smoking cessation. Benefits (40%in both death
& rate of lung function decline) apparent even in severe
COPD ("never too late to quit!")
Annual influenza vaccinedeath by up to 50% and hospitalizations by up to 40%
 Pneumococcal vaccine recommended by guidelines (x1 dose, ?repeat in 5‐10 years in
severe COPD); however, only weak evidence of benefit available

6. Standard Maintenance Therapy
Morbidity & Mortality: 2009 Chart Book on Cardiovascular, Lung and Blood Diseases. 2009.

7. Targets for COPD therapy. PDE4: phosphodiesterase-4; p38 MAPK: p38 mitogen activated protein; IKK-2: inhibitor of nuclear factor-kB kinase; PI3K-c: phosphoinositide 3 inase-gamma; PPAR-
c: peroxisome proliferation activated receptor-c; TGF-b: transforming growth factor-b; CTG: connective tissue growth factor; IL-8: interleukin-8; CXC: cysteine-X-cysteine; LTB4: leukotriene
B4; TNF: tumour necrosis factor; NE: neutrophil elastase; MMP: matrix metalloproteinases; EGFR: epidermal growth factor receptors; CACC: calcium-activated chloride channe
New approaches to
COPD
Cigarette smoke
(and other irritants)
Alveolar wall destruction
(Emphysema)
Mucushypersecretion
(Chronic bronchitis)
Neutrophil
CD8+
lymphocyte
Alveolar macrophageEpithelial
cells
Fibrosis
(COB)
Fibroblast
TGF-
CTGF
Monocyte
PROTEASES
Chemotactic factors
Chemokine and
mediator antagonists
Smoking cessation
Nicotine antagonists
and vaccination
Anti-inflammatory
treatments
PDE4, IKK-2, p38 MAPK,
PI3K- / inhibitors
PPAR- agonists
Mucoregulators
EGFRantagonists
Retinoic acid
Stem cells
Anti-proteases
NEinhibitors
MMP-9 inhibitors
Anti-TGF-
PPAR- agonists
Fig. 1. Cigarette smoke (and other irritants) activates macro-
phages in the respiratory tract that release multiple chemotactic
may also be involved in alveolar wall destruction. TGF- and
connectivetissuegrowth factor (CTGF) released from inflamma-

9. Feldman et al; licensee BioMed Central Ltd. 2010
New Bronchodilators

10. New Bronchodilators
•Long-acting inhaled bronchodilators
(long-acting 𝛽2- agonists)
##Several once-daily inhaled 𝛽2- agonists, such as Indacaterol and Carmoterol, are
now in clinical development .
Indacaterol is a very effective dilator of small
human airways measured by Videomicroscopy
in a precision-cut lung slice preparation and has
a bronchodilator action of over 24 h in patients
with COPD with a fast onset of action and no
evidence of tolerance or significant side effects .

12. The once-daily inhaled
anticholinergic tiotropium
bromide has been an
important advance in
therapy and several other
long-acting inhaled
muscarinic antagonists,
ACLIDINIUM BROMIDE
and GLYCOPYRROLATE,
are now in development .
Combination inhalers with a long-
acting 𝛽2-agonists with a long-
acting inhaled muscarinic
antagonist are also in development
as there is an additive effect
between these two bronchodilator
classes .
GSK-961081

13. Blocking Inflammatory Mediators
Many mediators have been implicated
in the pathophysiology of COPD , but
as in asthma it seems unlikely that
these will prove to be very effective
therapies as there is considerable
redundancy in the effects of these
mediators.

14. Lipid Antagonists
Leukotriene B4 (LTB4) is increased in sputum and Broncho alveolar
lavage fluid of patients with COPD and is chemotactic for
neutrophils and lymphocytes.
Several antagonists of the major receptor BLT1 have been
developed , but so far clinical studies in COPD have been negative.
5 -Lipoxygenase inhibitors should also be beneficial by blocking the
production of endogenous LTB4, but it has been difficult to discover
5-lipoxygenase inhibitors without hepatic toxicity.

15. Cytokine Inhibitors uses stopped infliximab
• Tumour necrosis factor- (TNF- )
concentrations are increased in
sputum, particularly during
exacerbations, and this cytokine
amplifies inflammation and may
account not only for
neutrophilic inflammation in the
lungs but also some systemic
features such as skeletal muscle
wasting.
• However, blockade of TNF- with
a blocking antibody (infliximab)
has no beneficial clinical effects
in patients with COPD, using the
same doses which are effective
in rheumatoid arthritis .
Of particular concern was the finding that
more COPD patient treated with anti-TNF
developed respiratory cancers and severe
lung infections. Other cytokines that are
currently targeted for inhibition include
interleukin (IL)-1 , IL-6 and IL-17.
IL-6 is increased in sputum and in the
systemic circulation of COPD patients and
may account for the increase in
circulating C-reactive protein.

16. Antiproteases
• In COPD there is an imbalance between proteases that digest elastin
(and other structural proteins)
• Antiproteases that protect against this
inhibiting these proteolytic enzymes or
increasing endogenous antiproteases may
be beneficial and should prevent the
progression of emphysema
several proteases are implicated in COPD
so that blocking a single enzyme may not
have a major therapeutic effect.
Endogenous Antiproteases: ⍺1- antitrypsin, secretory leukoprotease inhibitor,
elafin, tissue inhibitors of MMP
MMP-9/MMP-12 Inhibitor & AZ11557272

17. Transforming Growth Factor- Inhibitors:
• Play a key role in the fibrosis of small airways, which is turning out to be a
major mechanism for progressive loss of FEV1 and reduced exercise
performance in COPD and may be activated by oxidative stress and
cigarette smoke
• TGF- -related genes show increased expression in small airways of COPD
patients
SD-280
Small-molecule inhibitors of TGF-receptor tyrosine kinase (activated receptor-like
kinase 5)

18. Peroxisome Proliferator-Activated Receptor Activators :
There is evidence that activation of PPAR- ⍺ and PPAR- 𝛅 may have anti-inflammatory and
immunomodulatory effects.
Milam JE, Keshamouni VG, et al PPAR-gamma agonists inhibit profibrotic phenotypes in human lung
fibroblasts and bleomycin- induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol
2008;294:L891–L901.
Remels AH, Schrauwen P, et al : Peroxisome proliferator-activated receptor expression is reduced in
skeletal muscle in COPD. Eur Respir J 2007;30:245–252.
SUGGESTING THAT THEY MAY HAVE ANTI-INFLAMMATORY
EFFECTS IN COPD
PPAR- agonists,
Troglitazone and Rosiglitazone,
@@@@@@ Inhibit the release of inflammatory cytokines
from monocytes and induce apoptosis of T lymphocytes.

19. Novel Pharmacotherapy
• Inflammatory cells such as
neutrophils, CD8 lymphocytes,
and macrophages, express
predominantly phosphodiesterase
(PDE) type 4.
PDE type 4 hydrolyzes cyclic adenosine
monophosphate (cAMP) in inflammatory cells.
By inhibiting PDE type 4, intracellular cAMP
concentrations increase which leads to activation of
protein kinase A, phosphorylation and inactivation of
target transcription factors, which ultimately result in
reduction of cellular inflammatory activity.
While theophylline is a nonspecific PDE inhibitor (thus with a large side-effect profile
including diarrhea, seizures and cardiac arrhythmias), several new drugs have been
tested that target PDE type 4 specifically, notably Cilomilast and Roflumilast

20. PDE-4

21. PDE-4 Inhibitors
•The safety and efficacy of Cilomilast (15 mg twice daily) was
evaluated in
• A double-blind placebo-controlled study
• Significant increase in FEV1 as well as fewer exacerbations over a 24-week period.
• Gastrointestinal side effects (nausea and diarrhea) were greater in the first 3
weeks of the study in the treatment arm.
• Cilomilast has been evaluated in three additional multicenter, randomized,
placebo-controlled phase III trials.
• The change of FEV1 (from 30–40 mL) compared to placebo was significant in only two of the four studies.
• Overall, these studies did not show as large of improvements in FEV1 as was
expected based on phase II trials.

22. New Anti-Inflammatory Treatments4
d
n
s
s
n
.
Table1. Somenew anti-inflammatory treatmentsin development
for COPD
Drug class Clinical development
LTB4 antagonists development stopped
Anti-TNF development stopped
CXCR2 antagonists in early clinical development
MMP-9 inhibitors in early clinical development
Neutrophil elastaseinhibitor in early clinical development
PDE4 inhibitors phaseIII trialsbut sideeffects
amajor limitation
p38 MAPK inhibitors phaseI studiesbut problems
with sideeffectsand toxicity
NF- B (IKK2) inhibitors pre-clinical but concernsabout
sideeffects
PI3K- / inhibitors early clinical development
PPAR- agonists already developed for diabetes,
clinical studiesin progress

26. Pharmacologic Therapy
Antibiotic Regimens
Definition Oral Treatment IV Treatment
Mild exacerbation: no risk factors for poor
outcome
Amoxicillin, doxycycline, TMP/SMX,
azithromycin, 3rd generation cephalosporin
—
Moderate exacerbation with risk factor(s)* for
poor outcome
Amoxicillin-clavulanate, levofloxacin,
moxifloxacin
Ampicillin-sulbactam, 3rd generation
cephalosporin, levofloxacin, moxifloxacin
Severe exacerbation with risk factors for
Pseudomonas aeruginosa
Ciprofloxacin, levofloxacin (high dose) Ciprofloxacin, levofloxacin (high dose), beta
lactam with P. aeruginosa activity
*—comorbid diseases, severe COPD, frequent exacerbations (> 3/year), antimicrobial use within past 3 months.
GOLD, 2009

27. Pharmacologic Therapy
Preventive therapy opportunities
• Vaccination
• Influenza
• Annually for all patients with COPD (SOR: A)
• Pneumococcal
• All patients < 65 years with COPD
• Anyone >65 years old
• All smokers
• Counseling for smoking cessation Rabe, 2007
GOLD, 2009

29. References - Continued
• Kerstjens HA, Bantje TA, Luursema PB, et al. Effects of short-acting
bronchodilators added to maintenance tiotropium therapy. Chest.
2007;132(5):1493-1499.
• Lee TA, Wilke C, Joo M, et al. Outcomes associated with tiotropium use in
patients with chronic obstructive pulmonary disease. Arch Intern Med.
2009;169(15):1403-1410.
• Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP. Cardiovascular
safety of tiotropium in patients with COPD. 2010;137(1):20-30.
• Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM, Rothberg MB.
Association of corticosteroid dose and route of administration with risk of
treatment failure in acute exacerbation of chronic obstructive pulmonary
disease. JAMA. 2010;303(23):2359-2367.

30. References - Continued
• Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular events associated with
ipratropium bromide in COPD. Chest. 2010;137(1):13-19.
• Peytremann-Bridevaux I, Staeger P, Bridevaux PO, Ghali WA, Burnand B. Effectiveness of
chronic obstructive pulmonary disease-management programs: systemic review and meta-
analysis. Am J Med. 2008;121(5):433-443.e4.
• Rabe KF, Hurd S, Anzueto A, et al., for the Global Initiative for Chronic Obstructive Lung
Disease. Global strategy for the diagnosis, management, and prevention of chronic
obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care
Med. 2007;176(6):532-555.
• Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW. Beta-blockers may reduce mortality
and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch
Intern Med. 2010;170(10):880-887.

31. References - Continued
• Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers for chronic
obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2005, Issue 4.
• Singh S, Loke YK, Furburg CD. Inhaled anticholinergics and risk of major adverse
cardiovascular events in patients with chronic obstructive pulmonary disease: a
systematic review and meta-analysis [published correction appears in JAMA.
2009;301(12):1227-1230]. JAMA. 2008;300(12):1439-1450.
• Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N
Engl J Med. 2004;350(26):2689-2697.
• Tashkin DP, Celli B, Senn S, et al., for the UPLIFT Study Investigators. A 4-year trial of
tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-
1554.
• Vijayasaratha K, Stockley RA. Reported and unreported exacerbations of COPD: analysis by
diary cards. Chest. 2008;133(1):34-41.