Transcript Asthma, COPD, and Allergic Rhinitis

+
Asthma,
COPD, and
Allergic Rhinitis
Jennifer Toy, PharmD
UW Medicine Harborview
Family Medicine Clinic
January 2015
+
ASTHMA CASE 1
GD is a 56 yo male who comes to clinic c/o dyspnea and
coughing that have progressively worsened over the past
2 days. Recently diagnosed with asthma ~ 1 mo ago.
Reports inhaler is “not working.”

Physical exam reveals audible wheezes, occasional
coughing.

Medications:
 Albuterol HFA inhaler 1-2 puffs q4-6h prn shortness of
breath or cough
 Your evaluation should consist of … ?
+
3 Point Evaluation – “3 T’s”
 Appropriate Therapy?
 Change
– increase or decrease dose
 Initiate new therapy
 Stop/discontinue therapy
 Appropriate Technique?
 Tolerability?
+
Proper Inhaler Technique
 10-25%
of expelled medication will reach
pulmonary system
 Remainder is deposited on the mouth, pharynx,
esophagus, and stomach
 40%
of persons are NOT able to demonstrate
proper inhaler technique
+
Proper Inhaler Technique

Majority of medication accumulates on the throat and
contributes to systemic side effects

Use of proper technique or Aerochamber improves
lung deposition and reduces systemic side effects
 Aerochamber improves lung deposition by 25%
+
Spacer vs Suspending Chamber
+
CASE 1 (continued)
 So
how do we know the patient is using
appropriate technique?
+ Proper Metered Dose Inhaler (MDI)
Technique

When using MDI for first time:
 Shake the inhaler for 5 seconds

Prime the inhaler by pressing down the canister with the
index finger to release the medication

Press canister down again 3 times

After an inhaler is used for the first time, no need to prime
again UNLESS patient has not used for 2 weeks or more
+ Proper MDI Technique

Shake canister vigorously for 5 seconds

Uncap mouthpiece and check for loose objects in the device

Breathe out normally

Hold MDI upright

Close lips around spacer OR if no spacer is available, close lips
around mouthpiece or position it about 4 cm from the mouth
 Keep tongue away from the spacer opening or mouthpiece

Exhale completely before MDI actuation

Press down the top of the medication canister with the index
finger to release the medication

Slow deep inhalation (3-5 sec) until the lungs are completely
filled
+ MDI Inhaler Technique Pearls

One puff per inhalation

Wait 60 seconds between puffs, or long enough to perform
the next inhalation properly

Shake canister again before use

Recap mouthpiece

Rinse mouth after using an ICS, and spit the water out rather
than swallow it
+
MDI vs. Dry Powder Inhaler (DPI)

DPI in response to CFC ban

Powder requires different technique:
 Requires sufficient inspiratory effort for powder to reach
lungs
 Does not require coordination
 Contains smaller particles
 Possibly improved lung deposition of medications
 Persons are unable to determine if they received the
medication (no taste, no tactile sensation)
+ Dry Powder Inhaler (DPI)
Technique

For single-use devices, load a capsule into the device as
directed

Breath out slowly and completely (not into the mouthpiece)

Place mouthpiece between the front teeth and seal lips
around it

Breathe in through the mouth quickly and deeply over 2-3
seconds

Remove inhaler from mouth

Hold breath for as long as possible ~10 seconds

Breathe out slowly
+
Short-Acting Beta Agonists
(SABAs or Rescue Inhalers)

Beta-2 agonist
 Bronchodilator

Increases cAMP, decreases intracellular calcium

Produces smooth muscle relaxation

Stabilizes mast-cells (minimal effect)
+Inhaled SABAs
Short-Acting Beta Agonist
Duration
Onset
Albuterol
Metaproterenol (no longer
available)
Terbutaline
3-6 hrs
4 hrs
1.5-4 hrs
5 mins
5-30 mins
5-30 mins
1-3 hrs
1-3 hrs
2-5 mins
1-5 mins
Nonselective B-agonist:
Isoproterenol
Epinephrine
+
Inhaled Beta-Agonists

PRN vs scheduled
 Asthma management vs exercise induced
bronchospasm

Monitor utilization of beta-agonist
 Improper technique
 Proper technique – relief indicates severity of asthma
 Use of SABA helps determine when to initiate inhaled
steroids
+
CASE 2 – Asthma
 SM
is 40 yo female with asthma presents to clinic
with increasing SOB over the past few days. She is
unable to complete sentences.
 What
is your treatment of choice?
 What
formulation?
+
MDI vs Nebulizer
Outcomes
Nebulizer
Group
Spacer Group P value
Severity score improvement %
80.9
79.4
0.79
Final PEFR, % Predicted
79
76
0.61
Final Oxygen Saturation %
97
97
0.67
Mean # of Treatments
2.5
2.3
0.55
Steroid Administration %
44
54
0.26
Admission Rate %
6.2
5.6
0.89
Mean Treatment Time (mins)
103
66
<0.001
Vomiting %
20
8
<0.05
Mean increase in Heart Rate
15
5
<0.001
+
MDI vs Nebulizer

Albuterol Dose
 MDI 90 mcg/dose
 Neb 2.5mg/ampule
 MDI 2-4 puffs = 2.5mg Neb

MDI + Spacer/Aerochamber is a MORE efficient
delivery system than Nebulizer
+
Albuterol vs Levalbuterol

Racemic Albuterol (S and R) and Levalbuterol (R-albuterol)

Pediatric exacerbations randomized to nebulized Albuterol
vs Levalbuterol
 83% African American children
 Significantly lower hospitalization rate with levalbuterol
 LOS not significantly different
 Similar rates of side effects: HR, RR, and nausea
Carl. J Ped 2003; 143:731-6.
+
SABAs
Short-Acting Agonist
Dosage Forms
Strengths
Cost
Albuterol
(Proventil,
Ventolin,
AccuNeb)
Neb
MDI
0.63 mg/3 ml
1.25 mg/3 ml
2.5 mg/3 ml
5 mg/ml
Neb #25 = $17-40
MDI = $30-$78
90 mcg/puff
Levalbuterol
(Xopenex)
Tabs
Syrup
2 mg, 4 mg
2 mg/ 5 ml
Tab #30 = $5 (cash $115-161)
#120 ml = $14
Neb
MDI
0.31 mg/neb
0.63 mg/neb
1.25 mg/neb
Neb #24 = $147-173
Neb #24 = $147-173
Neb #24 = $147-173
45 mcg/puff
MDI = $71-81
Short-Acting
-Agonist
Brands
Dosing*
Adults &
Children  12
years
Dosing*
Children 5-11
years
Dosing*
Children 0-4
years
Pearls
Albuterol HFA
Proventil
Ventolin
ProAir
AccuNeb
2 puffs every 46 hours
2 puffs 5 min
prior to
exercise
1.25-5 mg neb
every 4-6 hours
2 puffs every 46 hours
2 puffs 5 min
prior to
exercise
1.2-5 mg neb
every 4-6 hours
2 puffs every 46 hours
1-2 puffs 5 min
prior to
exercise
0.63-2.5 mg
neb every 4-6
hours
Contains
EtOH and
Oleic Acid
No
Excipients
Levalbuterol
HFA*
Xopenex
2 puffs every 46 hours
2 puffs 5 min
prior to
exercise
0.63-1.25 mg
neb 3 times a
day
2 puffs every 46 hours
(Dose for 4-11
years)
0.31-0.63 mg
neb 3 times a
day
MDI safety and
efficacy not
established
0.31-1.25 mg
neb every 4-6
hours
Contains
EtOH and
Oleic Acid
*Prime 4
times before
use
*Usually
used in
COPD
Pirbuterol
Maxair
2 puff every 4-6
hours
2 puffs 5 min
prior to
exercise
Safety and
efficacy not
established
Safety and
efficacy not
established
No longer
available –
phased out
d/t CFC ban
+
+
Acute Asthma Exacerbations
 Albuterol
vs Albuterol + Ipratropium
 Efficacy: Pediatric
and Adult studies demonstrate
variable results and do not consistently show
benefit
 Combination
of Albuterol + Ipratropium may
benefit patients with severe obstruction or FEV1
<50%
+ Albuterol and Ipratropium
MDI or Nebulizer
Strength
Cost
Albuterol HFA
90 mcg/puff
MDI = $30-78
Ipratropium HFA
(Atrovent)
18 mcg/puff
MDI = $40-51
Albuterol/Ipratropium
(Combivent)
103 mcg – 18 mcg/puff
MDI = $320-375
Albuterol Neb
2.5 mg/3 ml
Neb #24 = $16-40
Ipratropium Neb
0.2 mg/ml
Neb #25 = $13-38
Albuterol/Ipratropium
Neb (DuoNeb)
0.5mg-2.5mg/3 ml
Neb #30 = $49-76
+ Albuterol and Ipratropium
MDI or Nebulizer
Dosing*Adults
and Children 
12 years
Dosing*Childr
en 5-11 years
Dosing*
Children 0-4
years
Albuterol HFA
2 puffs every 4-6
hours
2 puffs every 4-6
hours
2 puffs every 4-6
hours
Ipratropium HFA
(Atrovent)
2-4 puffs every 6
hours
Safety and efficacy
not established
Safety and efficacy
not established
Safety and efficacy
2 puffs every 6 hours not established
Safety and efficacy
not established
Albuterol Neb
1.25-5 mg neb
every 4 hours
1.25-5 mg neb every
4 hours
0.63-2.5 mg neb
every 4-6 hours
Ipratropium Neb
500 mcg every 20
minutes, then as
needed
Safety and efficacy
not established
Safety and efficacy
not established
Albuterol/Ipratropium
Neb (Duoneb)
3 ml every 4-6 hours
Safety and efficacy
not established
Safety and efficacy
not established
Albuterol/Ipratropium
(Combivent)
+
Home Acute Asthma Exacerbation
Peak Flow (PF) < 50% Predicted
Albuterol MDI 2-4 puffs every 20 mins
OR
Single nebulizer treatment
PEF > 80%
PEF 50-80%
-Continue Albuterol every 3-4 hrs x 2-4 days -Continue Albuterol every 20-60 mins
-Double inhaled steroid x 7-10 days
-Oral steroid burst
PEF < 50 %
-Continue Albuterol every 20 mins
-Oral steroid burst, call provider, or go to ED
+ ER Acute Asthma Exacerbation
FEV1 or PEF > 50%
-Albuterol MDI or Neb x 2 in the 1st hr
-O2 to achieve O2 sat ≥ 90%
-Oral steroids if no immediate response
FEV1 or PEF < 50%
-Albuterol MDI or Neb every 20 mins or continuously for 1 hr
-O2 to achieve O2 sat ≥ 90%
-Then Levalbuterol OR Albuterol AND Anticholinergic every 20
mins for 1 hr
-Oral steroids
Impending or actual respiratory arrest
-Intubation or medical ventilation with 100% O2
-Nebulized Albuterol AND anticholinergic
-IV steroid
+ CASE 3 – Acute Asthma
Exacerbation
 You
are about to prescribe prednisone for an acute
exacerbation.
 How
would you prescribe prednisone?
 Dose?
 Taper
or no taper?
+
Steroid Bursts
(Taper vs Non-Taper)
 Taper
prednisone 10mg
 Take 4 tabs daily x 3 days
 Take 3 tabs daily x 3 days
 Take 2 tabs daily x 3 days
 Take 1 tab daily x 3 days then stop
 Non-Taper
prednisone 20mg
 Take 2 tabs daily for 5-7 days or
 Take 3 tabs daily x 3 days then take 2 tabs daily
x 3days then stop
+
CASE 4-Step Up Therapy
JZ 25 yo male returns to the clinic after being prescribed
albuterol
 He
states the albuterol helps relieve his shortness of
breath but it does not last long
 State
requiring the albuterol at night about 3 times in the
last month
+ Inhaled Corticosteroids (ICS)
+ Inhaled Corticosteroids (ICS)
Inhaled Corticosteroids
Brand
Strengths
Cost
Budesonide DPI
Pulmicort
90 mcg/puff
180 mcg/puff
$161-194
$222-298
Beclomethasone MDI
QVAR
40 mcg/puff
80 mcg/puff
$176-188
$209-241
Flunisolide MDI
Aerospan
AeroBid (d/c-ed)
80 mcg/puff
$201-225
Fluticasone
Flovent HFA
44 mcg/puff
110 mcg/puff
220 mcg/puff
50 mcg, 100mcg,
250mcg/blister
$181-194
$230-250
$363-382
$163-185
Flovent DPI
Mometasone DPI
Asmanex
110 mcg/puff
220 mcg/puff
$194-230
$236-251
Ciclesonide MDI
Alvesco
80 mcg/puff
160 mcg/puff
$227-263
$227-262
Inhaled
Corticosteroids
Dosing* Adults and
Children  12 years
Dosing* Children 5-11 years
Dosing*
Children 04 years
Budesonide
(Pulmicort)
Low Dose (180-600 mcg)/day
Medium Dose (>600-1200
mcg)/day
High Dose (>1200 mcg)/day
Low Dose (180-400 mcg)/day
Medium Dose (>400-800
mcg)/day
High Dose (>800 mcg)
*Can use Pulmicort Respules
NA
*Can use
Pulmicort
Respules
Beclomethasone
MDI (QVAR)
Low Dose (80-240 mcg)/day
Medium Dose (>240-480
mcg)/day
High Dose (>480 mcg)/day
Low Dose (80-160 mcg)/day
Medium Dose (>240-320
mcg)/day
High Dose (>320 mcg)/day
NA
Flunisolide MDI
(AeroBid)
Low Dose (500-1000 mcg)/day
Medium Dose (>1000-2000
mcg)/day
High Dose (>2000 mcg)/day
Low Dose (500-750 mcg)/day
Medium Dose (>1000-1250
mcg)/day
High Dose (>1250 mcg)/day
NA
Fluticasone MDI
(Flovent)
Low Dose (88-264 mcg)/day
Medium Dose (>264-440
mcg)/day
High Dose (>440 mcg)/day
Low Dose (88-176 mcg)/day
Medium Dose (>176-352
mcg)/day
High Dose (>352 mcg)/day
Approved for 4 years and older
NA
Mometasone DPI
(Asmanex)
Low Dose (220 mcg)/day
Medium Dose (440 mcg)/day
High Dose (>440 mcg)/day
Dose (110 mcg)/day
Approved for 4 years and older
NA
Ciclesonide
MDI
Low Dose (160 mcg)
Medium Dose (320 mcg)
High Dose (640 mcg)
NA
NA
+
+
Comparative ICS Potency
Relative Topical Potencies
1200
1000
800
600
400
200
0
Aerobid
Azmacort Belcovent Pulmicort
Flovent
+
Summary:
Comparative ICS Potency
 Potency
is not related to efficacy
 Potency
equates to # of puffs required
 Differences
between inhaled steroids
 # of puffs required per day
 Bioavailability (1st pass effect)
 Receptor affinity and half-life
+
+
Side Effects of ICS

Effects of local deposition: dysphonia, topical
candidiasis, contact hypersensitivity

Systemic ADRs:
 Adrenal suppression
 Lung infection
 Ocular effects
 Skeletal effects
 Other Concerns
+
ICS: Adrenal Suppression?

Mixed results

Dependent on dose, duration, frequency, and timing
glucocorticoid administration

Effects of ICS on HPA axis appear infrequent and
clinically insignificant
+
ICS: Lung Infection?

Mixed results

Some studies found small increase in risk for bacterial
lung infection

No increased mortality
+
ICS: Ocular Effects?

Intraocular pressure

Cataracts
 Limited data demonstrate no relationship between
glaucoma or increased intraocular pressure and
inhaled steroids
 Lifetime doses of >2000mg may increase prevalence
of cataracts
+ ICS: Growth Deceleration?

Childhood Asthma Management Program (CAMP)
• N=1041, age 5-12, randomized to inhaled budesonide
or nedocromil
• Results:
• Year 1: reduction of growth velocity in budesonide
group
• End of study: no difference in growth results

CAMP Follow-Up Study
 N=943, age 24.9± 2.7 yrs
 Results:
 Mean adult height was 1.2 cm lower in budesonide
group vs placebo compared to growth difference of
1.1 cm at time of trial
+
ICS: Osteoporosis?

Mixed results – clinical significance is unclear

No strong evidence that low-med dose inhaled steroids
reduce bone mineral density

May affect bone health in certain populations eg postmenopausal women, pts taking higher doses, men with
COPD
+
ICS: Drug-Drug Interactions

Ritonavir and Fluticasone propionate
 Ritonavir – strong CYP3A4 inhibitor  increased
serum concentration of fluticasone propionate 
increased serum concentrations and increased
systemic effects

Ketoconazole and Fluticasone furoate/vilanterol
 Ketoconazole – strong CYP3A4 inhibitor  serum
concentration fluticasone furoate  increased serum
concentrations and increased systemic effects
+
Long-Acting Beta Agonists (LABAs)
+ Stepping Up Therapy
+ LABAs
LABAs
Onset
Peak
Duration
Binding
Affinity
Formoterol
2-3 mins
1-3
hours
8-12 hours
+++
Salmetorol
10-20 mins
10-12 hours
++
40-56 hours
+++
26 hours
+++
2-3
hours
Indacaterol
*COPD
5 mins
15 min
Arformoterol 7-20 mins
*COPD
1-3
+ LABAs
Long-Acting -Agonist
Dosage
Forms
Strengths
Cost
Formoterol (Foradil)
*Must be used with ICS
in asthma
Powder
Caps
12 mcg/cap
#60 caps = $264-297
Formoterol Neb
(Perforomist)
*COPD
Neb
20 mcg/2 ml
#30 vials = $368
Arformoterol Neb
(Brovana)
*COPD
Neb
15 mcg/2 ml
#30 vials = $356-415
Salmeterol (Serevent)
*Must be used with ICS
in asthma
Diskus
50 mcg/dose
DPI = $266-319
+ LABAs
LongActing Agonist
Brands
Dosing*Adults
& Children 
12 yeas
Dosing*
Children 5-11
years
Dosing*
Children 0-4
years
Formoterol
Foradil
1 cap BID
1 cap BID
Safety and
efficacy not
established
Salmeterol
Serevent 1 blister BID
1 blister BID
(Dose for 4-11
years)
Safety and
efficacy not
established
+
LABA Controversies
 Differences
between salmeterol and formoterol
 Salmeterol may attenuate response to SABAs
 Slight benefit of formoterol but probably
clinically equivalent
 Safety
of LABAs used alone in asthma patients
+
Should LABAs be used as
controller medications in Asthma?
 Salmeterol
Multi-center Asthma Research Trial
(SMART)
 Salmeterol
BID vs Placebo
 Interim results demonstrated no significant
differences in primary endpoints
 Non-significant higher asthma related events in
patients receiving Salmeterol
 Study discontinued 2002
+ SMART Trial

47% of patients received inhaled steroids
 50% Caucasian
 38% African-American

No differences in endpts in pts receiving inhaled steroids

Patients without inhaled steroids experienced higher rates of
asthma-related deaths compared to placebo

Long acting B-agonists are NOT controller medications for asthma

Long acting B-agonists are not substitutes for inhaled steroids and
should NOT be used as monotherapy

Inhaled steroid should not be discontinued
+ Black Box Warning

Data from a large placebo controlled study compared
Salmeterol or placebo + usual care
Results
showed a small but significant increase in
asthma related death in patients receiving Salmeterol
 13 deaths /13,174 ~ 0.098% treated versus
 4 deaths/13,179 ~ 0.03% placebo for 28 wks

Subgroup analysis suggest the risk may be greater in
African-American patients compared to Caucasians
+ Fluticasone + Salmeterol
Inhaled Steroid +
Long acting agonist
Brands
Strengths
Dosing
Cost
Fluticasone +
Salmeterol
Advair
(DPI)
Fluticasone 100 mcg
Salmeterol 50 mcg
Adult and Child
 12 years:
1 puffs BID
$288-310
Fluticasone 250 mcg
Salmeterol 50 mcg
Fluticasone 500 mcg
Salmeterol 50 mcg
Advair
(HFA)
Fluticasone 45 mcg
Salmeterol 21 mcg
$343-386
Children 4-11
years:
1 puff of
(100/50) BID
Adult and Child
 12 years:
1 puffs BID
$444-492
$272-308
Fluticasone 115 mcg
Salmeterol 21 mcg
$346-384
Fluticasone 230 mcg
Salmeterol 21 mcg
$443-501
+ Budesonide + Formoterol
Inhaled
Steroid +
Long-Acting
-agonist
Brands
Strengths
Dosing
Budesonide +
Formoterol
Symbicort
Budesonide 80 mcg Adults and
+
Children  12
Formoterol 4.5 mcg years:
1-2 puffs BID
Children 5-11
years:
2 puffs (80/4.5)
BID
Budesonide 160
mcg +
Fomoterol 4.5 mcg
Cost
$272$300
$318$335
+
+ Leukotriene Receptor Antagonists &
Mast Cell Stabilizers
Leukotriene Receptor
Antagonists (LTRAs)
Brand
Strengths
Dosing
Cost
Montelukast
Singulair
4 mg
5 mg
10 mg
Adults and Children  15 years: 10 mg
daily
$30170/mo
Children 6-23 months: 4 mg daily
Children 2-5 years: 4 mg daily
Children 6-14 years: 5 mg daily
Mast Cell Stabilizers
Brand
Strengths
Dosing
Cost
Cromolyn Sodium
NA
Neb 20
mg/amp
Adults and Children  12 years:
1 amp 4 times daily
$60170/mo
Children 5-11 years:
1 amp 4 times daily
Children 2-4 years: 1 amp 4 times
daily
+ Theophylline

MOA: Phosphodiesterase inhibitor, results in increased
cAMP and decreases cGMP to produce bronchodilation,
also increases muscle contraction of diaphragm
Drug
Brand
Strengths
Dosing
Cost
Theophylline
Theo-24 Hr
100 mg, 200 mg,
300 mg, 400 mg
$30-$44
Theochron-ER-12 Hr
100 mg, 200 mg,
300 mg
Doses should be
individualized, based
on peak serum
concentrations, and
should be based on
ideal body weight.
Theophylline ER-24
Hr
400 mg, 600 mg
The elimination half-life
is highly variable based
on age, liver function,
lung disease, and
smoking history.
Monitor Serum Peak
Levels: Asthma: 5-12
mcg/ml
$44-$50
$30-$60
+
Theophylline

Side effects: tachycardia, nausea, GI upset,
hyperkalemia, hyperglycemia, SEIZURES

Maintain concentration 5-12 mcg/ml

The following INCREASE theophylline levels:
 Erythromycin, ciprofloxacin, carbamazepine, CHF,
cimetidine, disulfiram, hepatic disease, isoniazid,
mexiletine, thiazolidinedione
+
Omalizumab

Pts with Serum Ig-E level of 30-700IU/ml

Pts uncontrolled on High dose inhaled steroids and Long
acting beta-agonist and Oral steroids (max 20mg/day)
Omalizumab Placebo
p-value
ER visit
24%
44%
0.038
Hospitalization
6.2%
11%
0.117
+Management of Asthma
in Pregnancy

Albuterol preferred SABA

Budesonide preferred ICS

Salmeterol is preferred LABA

Leukotriene receptor antagonists alternative but NOT
preferred

Treatment for acute exacerbations including systemic
glucocorticoids – key is to monitor mother and fetus
+ Monitoring

Symptoms (use of rescue inhaler, exacerbations,
nocturnal symptoms)

Side effects

Inhaler technique

Barriers or difficulties with therapy

Review home care plan with patient/caregivers

Review proper use of medications with
patient/caregivers
+
Chronic Obstructive Pulmonary
Disease (COPD)
+
Pharmacotherapy

Bronchodilator therapy
 Beta-agonists
 Anticholinergics
 Methylxanthines

Provides symptomatic relief

No benefit in mortality
 Goal: Reduction of symptoms
+
Recommended Therapy
for Stable COPD
Stage I: Mild
[FEV1: FVC < 70%, FEV1  80% ± symptoms]

Smoking cessation

Influenza vaccine + pneumococcal vaccine

Short-acting bronchodilator
+
Recommended Therapy
for Stable COPD
Stage II: Moderate
[FEV1: FVC < 70%, 50% < FEV1 < 80% ± symptoms]

Smoking cessation

Influenza vaccine + pneumococcal vaccine

Short-acting bronchodilator + long-acting bronchodilator +
rehabilitation
+
Recommended Therapy
for Stable COPD
Stage III: Severe
[FEV1: FVC < 70%, 30% < FEV1 < 50% ± symptoms]

Smoking cessation

Influenza vaccine + pneumococcal vaccine

Short-acting bronchodilator + long-acting bronchodilator +
rehabilitation

Add inhaled corticosteroids if repeat exacerbations
+
Recommended Therapy
for Stable COPD
Stage IV: Severe
[FEV1: FVC<70%, FEV1<30% ± symptoms]

Smoking cessation

Influenza vaccine + pneumococcal vaccine

Short-acting bronchodilator + long-acting
bronchodilator + rehabilitation

Add inhaled corticosteroids if repeat exacerbations

Add long-term oxygen if chronic respiratory failure
+
Short-Acting Bronchodilators:
Albuterol vs Ipratropium
Short-acting
bronchodilators
Onset
Peak Onset
Albuterol
5 mins
15-30 mins
Ipratropium
15 mins
30-60 mins
+
Short-Acting Anticholinergic
Ipratropium

Ipratropium MOA
 Ipratropium decreases ↓ cGMP
 cGMP causes contraction of airway
smooth muscles, bronchoconstriction and
enhances inflammation by indirectly
stimulating release of mast cell contents
 May reduce mucus gland secretion

Side effects: Dry mouth, anxiety,
palpitations, nausea, blurred vision,
headaches
+
Ipratropium
 Ipratropium
reduces the volume of sputum without
altering its viscosity
 Ipratropium
can block Vagal mediated reflex
preventing bronchoconstriction triggered by dusts,
fumes and cigarette smoke
+
Albuterol or Ipratropium?
 Approximately
70% of patients who were initially
unresponsive to albuterol demonstrated
responsiveness after subsequent administration
 Albuterol
and Ipratropium are equally efficacious
in the treatment of acute exacerbations of COPD
 Neither
other
medication potentiates the action of the
+ COPD
Short-Acting Bronchodilators
Drug
Brand
Strength
*Adult Dosing
Cost
Albuterol
ProAir HFA
Proventil HFA
Ventolin HFA
90 mcg/puff
1-2 puffs every 4-6 hours
$30-78
Levalbuterol
Xopenex
45 mcg/puff
2 puffs every 4-6 hours
$71-81
Ipratropium
Atrovent HFA
18 mcg/puff
2-4 puff 3 to 4 times daily
$281-342
Albuterol +
Ipratropium
Combivent
Respimat
Ipratropium
bromide 20
mcg/albuterol
base 100 mcg
1 puffs every 6 hours
$320-375
+ Combivent Respimat
Drug
Brand
Strength
Ipratropium/
Albuterol
Combivent 18 mcg/103
Respimat
mcg
*Adult Dosing
Cost
1 puff every 4 hours
$320$375
+Long-Acting Anticholinergic
Tiotropium
Drug
Brand
Strength
*Adult Dosing
Tiotropium DPI Spiriva 18 mcg/puff 1 cap inhaled daily
Cost
$340$385
+
Long-Acting Anticholinergic
Aclindinium bromide
Drug
Brand
Strength
*Adult
Dosing
Aclindinium
bromide
Tudorza
Pressair
400mcg/pu 1 puff BID
ff
Cost
$315-346
+
Long-Acting Beta-Agonists
Salmeterol and Formoterol
Long-Acting - Brand
agonist
Strengths
* Adult
Dosing
Cost
Formoterol
Foradil
12 mcg/cap
1 cap BID
#60 caps =
$264-297
Salmeterol
Serevent
50
mcg/dose
1 puff BID
#1 inh
=$266-319
+
Long-Acting Beta-Agonist
Indacterol and Olodaterol
Long-Acting agonist
Brand
Strengths
* Adult Dosing
Cost
Indacaterol
Arcapta
Neohaler
*COPD
Powder Caps
75mcg/dose
1 cap inhaled
daily
#30 caps =
$220-240
Striverdi
Respimat
*COPD
2.5
mcg/actuatio
n
2 oral
inhalations (5
mcg) once
daily at same
time every
day
#1 inhaler
per month
FDA Approval
Date: July 1, 2011
Olodaterol
FDA Approval
Date: August 1,
2014
$$$ (?)
+ LABA + ICS Combination Inhaler
Long-Acting - Brand
agonist + ICS
Strengths
Fluticasone +
salmeterol
Advair
Diskus
250mcg/salm 1 inhalation
eterol 50 mcg twice daily
$343-384
Fluticasone
furoate +
vilanterol
Breo
Ellipta
100mcg/25m
cg per
inhalation
$302-328
FDA Approval
Date: 2013
Adult
Dosing
1 inhalation
once daily
Cost
+
Tiotropium vs Salmeterol
 Included
persons with COPD and FEV1 39% of
predicted
 Randomized
to tiotropium daily or salmeterol BID x6
mos
Brausasco. Thorax 2003;58:399–404
+
Tiotropium vs Salmeterol
2
1.5
Tiotropium
1
Salmeterol
Placebo
0.5
0
Hosp
LOS
Brausasco. Thorax 2003;58:399–404
Office
visits
All Hosp
+
Tiotropium vs Salmeterol
(POET-COPD)
 7376
patients with moderate-to-severe COPD
1
year randomized, double-blind, parallel-group
trial

Tiotropium 18mcg/day vs. Salmeterol 50mcg BID
 Tiotropium
increased the time to first exacerbation
compared with Salmeterol
•
187 days vs. 145 days; HR 0.83 (95% CI 0.77 to 0.90; P< 0.001)
 Tiotropium
also reduced the annual number of
moderate or severe COPD exacerbations
compared to Salmeterol

0.64 vs. 0.72; RR 0.89 (95% CI 0.83 to 0.96; P = 0.002); NNT=25
Vogelmeier V, Hederer B, Glaab T, et al. NEJM 2011; 364:1093.
+ Salmeterol/Fluticasone vs
Tiotropium (INSPIRE)

1323 patients with severe COPD
• High-dose Salmeterol/Fluticasone (Advair) 50/500mcg vs. Tiotropium
(Spiriva) 18mcg/day

Exacerbation rate did not differ between treatment groups (P=0.656)
In exacerbations…
• Salmeterol/Fluticasone patients needed an antibiotic
• Tiotropium patients needed an oral corticosteroid
 Mortality was lower in the Salmeterol/Fluticasone group than in the
Tiotropium group (3% vs 6%, p=0.032)


Pneumonia was more frequent in the Salmeterol/Fluticasone group (HR
1.94, 95% CI 1.19 to 3.17; p=0.008)
Wedzicha JA, Calverley PMA, Seemungal TA, et al. Am J RespirCrit Care Med 2008; 177:19-26.
+ Towards A Revolution in COPD
Health (TORCH)

6112 patients, mostly severe COPD, randomized to treatment for 3 years
• - Salmeterol 50mcg BID
• - Fluticasone 500mcg BID
• - Salmeterol + Fluticasone combination
• - Placebo

There was no significant mortality difference between combination therapy and
Salmeterol

Patients treated with combination therapy were less likely to die than those treated
with Fluticasone alone (HR 0.774, 95% CI 0.641 to 0.934; P=0.007)

Fewer exacerbations in those receiving Salmeterol + Fluticasone compared to either
agent alone or placebo; NNT = 4 (Combination vs. Placebo)

However, any group that received treatment with an ICS had increased reports of
pneumonia – 19.6% combination therapy , 18.3% fluticasone group vs. placebo 12.3%
(p<0.001)
Calverley et al. NEJM 2007;356:75-89.
+ Evidence to Support
Triple Inhaler Therapy
•
In patients with severe COPD, triple therapy with a LABA, ICS,
and LAAC is often used
•
UPLIFT TRIAL
•
•
•
•
•
6000 patients
2/3 LABA + ICS + LAAC (Tiotropium)
1/3 LABA + ICS
Addition of Tiotropium to LABA + ICS significantly
improved airflow, reduced exacerbations, and improved
health related quality of life
Several retrospective cohorts have also found that the
combination of LABA + ICS + Tiotropium is associated with ↓
mortality, ↓ exacerbations, and ↓ hospitalizations
+ Theophylline

MOA: directly relax bronchial and pulmonary blood
vessel smooth muscle, central respiratory stimulant, and
more

Therapeutic levels: 8-12 mcg/ml

Side effects:
 Common: Nausea, vomiting, insomnia, restlessness,
anxiety, anorexia, palpitations
 Serious: Seizures, arrhythmias

Place in therapy?
+
Theophylline Drug-Drug
Interactions
Increase Metabolism
Decrease Metabolism
Cigarette smoking
High protein diet
Hyperthyroidism
Marijuana smoking
Carbamazepine
Barbiturates
Rifampin
Phenytoin
Age >60 years
Severe hypoxemia (arterial Po2 <45 mmHg)
CHF
Viral infections
Allopurinol
Cimetidine
Erythromycin
Quinolone
Verapamil
+ Acute COPD Exacerbations:
Cortiscosteroids

Leuppi et al (2013)
Treatment for 5 vs 14 days prednisone 40mg daily
 N=314 pts
 No sig diff in primary outcome treatment relapse
 No sig diff in lung function or in any subjective
outcomes
+ Acute Exacerbations: Antibiotics

Coverage: Haemophilus, Streptococcus, and Moraxella

Indicated for treating infectious exacerbations of COPD and
other bacterial infections

Tx options:
trimethoprim-sulfamethoxazole
 Doxycycline
 beta-lactamase stable PCNs
 2nd or 3rd gene cephalosporins
 extended spectrum macrolides
 antipneumococcal FQs

+ Azithromycin Daily?

8 studies have evaluated whether macrolide antibiotics
DECREASE the risk of acute exacerbations of COPD
 Mixed results

Albert et al (2011)
 Azithromcyin 250mg po qday vs placebo for one year
 No significant difference though fewer
hospitalizations for any cause, fewer hospitalizations
related to COPD, fewer emergency dept or urgent
care visits
+ Vitamin D in COPD?
 No
definitive evidence demonstrating benefit in
patients with pulmonary disease
 Slight
improvements may be observed in patients
who are already vitamin D deficient –
supplementation gets them back to normal levels
+
Summary of Step-Wise Therapy
 Bronchodilator Therapy
 Beta-agonist
(short-acting) or Ipratropium
 Ipratropium + Beta agonist (Combined)
 Tiotropium
 Inhaled
steroid (may reduce exacerbations, but
increase RISK of pneumonia)
 Consider
addition of Theophylline
+
ALLERGIC RHINITIS
+
Allergic Response
 Allergic
response: IgE
 Production
 IgE
of IgE antibodies
bound mast cells interacts with allergen
 Release
of inflammatory mediators
 Response
 Immediate: Histamines, leukotrienes, prostaglandin,
bradykininis
 Late: eosinophils, monocytes, macrophage, basophil,
lymphocyte
+
Allergies
 Immunologic
IgE mediated reaction
 Degranulation
of mast cells and immediate release
of histamine, leukotriene, prostaglandin, and kinins
Vasodilation, Increased vascular permeability
Rhinorrhea, Sneezing, Itchy eyes
+
Rhinitis
 Infectious
 Viral
 Bacterial
 Non-Infectious
 Allergy
(immune mediated)
 Non-allergic (vasomotor)
+
Non-Pharmacologic Treatment
 Allergen
avoidance
 Exposure
 HEPA
reduction
vacuums (poor evidence)
 Encase
bedding (poor evidence)
 Dehumidifier
evidence)
supposed to limit mold (poor
+
Pharmacologic Treatment
 Antihistamines: oral
 Inhaled
or nasal or ophthalmic
steroids
 Antihistamines
+ inhaled steroids
 Other:
 Mast
cell stabilizers
 Leukotriene modifiers
 Ipratropium (anti-cholinergic)
 Decongestants
+
Antihistamines
+
Antihistamines:
H1 Receptor Blockers
 MOA: blocks
H1 receptors, no effect on
leukotrienes, prostaglandins, bradykinins
 Reduces
nasal itching, sneezing, rhinorrhea (NOT
as effective at reducing nasal congestion)
 Limited
 When
effectiveness
should patients administer?
+ Antihistamines
Class
1st Generation
2nd Generation
Alkylamines
Brompheniramine
Chlorpheniramine
Pheniramine
Triprolidine
Acrivastine
Ethanolamines
Clemastine (Tavist)
Diphenhydramine (Benadryl)
Doxylamine
Piperazines
Hydroxyzine (Vistaril)
Meclizine (Bonine, Antivert)
Cetirizine (Zyrtec)
Levocetirizine (Xyzal)
Piperidine
Azatadine
Cyproheptadine
Astemizole
Loratadine (Claritin)
Desloratadine (Clarinex)
Phenothiazines
Promethazine
Fexofenadine (Allegra)
Olopatadine
Terfenadine
Other
Doxepin
Azelastine
Emedastine
+ Antihistamines
 Active
metabolite of Hydroxyzine
 Cetirizine (Zyrtec)
 Levocetirizine (Xyzal)*
 Active
metabolite of Terfenadine
 Fexofenadine (Allegra)*
 Loratadine
(Claritin)
 Desloratadine (Clarinex)*
+
How long do Antihistamines take to
work?
 1st
Generation
 Onset of effect: 15-60 minutes
 Duration of effect: 4-8 hours
 Half-life: 3-8 hours
 2nd
Generation
 Onset of effect: 1-3 hours
 Duration of effect: 12-24 hours
 Half-life: 12-15 hours
+
1st Generation Antihistamines
 Crosses
blood brain barrier, lipophilic
 Anti-cholinergic
 Anti-serotonergic
 Anti-alpha-adrenergic
 Sedative
effects minimized if initiated at bedtime
+ Adverse Effects
 Anti-cholinergic
(muscarinic)
 Dry mouth, urinary retention, constipation,
tachycardia
 Anti-serotonergic
 Increased
appetite
 Anti-alpha-adrenergic
 Hypotension, dizziness, tachycardia
 Cardiac-ion
channels
 Prolong QT interval
+ Considerations in Kids & Elderly
 Kids
 Impaired
school performance
 Paradoxical agitation
 Elderly
more susceptible to anti-cholinergic effects
 Dyskinesia
 Urinary hesitancy
 Confusion
+
2nd Generation Antihistamines
 MOA: bind
more specifically to peripheral H-
receptors
 Do NOT cross blood-brain barrier, less lipophilic
 This
means LESS sedation, dizziness, fatigue,
insomnia, irritability, nervousness, urinary
retention
+
2nd Generation:
Comparisons

Sedation: Cetirizine, Levocetirizine

Onset of action:
 Levocetirizine < Cetirizine, fexofenadine <
Loratadine

Lack of evidence of superiority between 2nd
generation antihistamines

No evidence one antihistamine will be effective
after failing a previous antihistamine
+ Comparative Efficacy
 2nd
generation are LESS effective in relieving nasal
congestion compared to 1st generation
antihistamines
 Both
1st and 2nd generation antihistamines are LESS
effective vs intranasal steroids
+
2nd Generation Antihistamines:
Sedation-Free?
Cetirizine
Fexofenadine
Loratadine
Dizziness
2%
-
-
Drowsiness
13.7%
1.3%
8%
Fatigue
5.9%
1.3%
4%
+
2nd Generation Antihistamines:
Safety Concerns

Prolongation of QTc interval

Astemizole and Terfendadine removed from market

No reports with current 2nd generation anti-histamines
+
Pregnancy and Lactation
 Category
B
 Chlorpheniramine, Diphenhydramine
 Cetirizine, Loratadine
 Inhaled steroids
 Category
C
 Hydroxyzine, Ketotifen
 Azelastine, Desloratadine, Fexofenadine,
Olopatadine
+
Antihistamines: OTC vs Rx
 Over
the counter (OTC)
 1st generation
 2nd generation
 Loratadine (Claritin)
 Cetirizine (Zyrtec)
 Fexofenadine (Allegra)
 Prescription
(Rx)
 Levocetirizine (Xyzal)
 Desloratadine (Clarinex)
+ Current Antihistamines
Drug
*Adult Dosing
*Child Dosing
Generic OTC or Rx
Chlorpheniramine
(Chlor-Trimeton)
4 mg every 4-6 hours or 2-6 years: 1 mg every 4-6
SR 8-12 mg every 8-12
hours NTE 6 mg in 24 hours
hours ; NTE 24 mg/day
Yes
OTC
$12.99
Clemastine fumurate
(Tavist)
1.34 mg every 8 hours
6-12 years: 0.67 mg every 12
hours
Yes
OTC
$18.00
Diphenhyramine HCl
(Benadryl)
25-50 mg every 8 hours
5 mg/kg per day divided every
8 hours
Yes
OTC
$4.00
Loratadine
(Claritin)
10 mg daily
2-5 years: 5 mg once daily
Yes
OTC
$21.99
Cetirizine
(Zyrtec)
5-10 mg daily
6-12 mo: 2.5 mg daily
12 mo - < 2 years: 2.5 mg
every 12 hours
Yes
OTC
$29.99
Levocetirizine
(Xyzal)
2.5-5 mg daily
6 mo-5 years: 1.25 mg daily
6-11 years: 2.5 mg daily
No
Rx
$99.00
Desloratadine
(Clarinex)
5 mg daily
6-11 mo: 1 mg daily
12 mo-5 years: 1.25 mg daily
6-11 years: 2.5 mg daily
No
Rx
$147.00
Fexofenadine
(Allegra)
60 mg every 12 hours
or 180 mg daily
6 mo-< 2 years: 15 mg every
12 hours
2-11 years: 30 mg twice daily
Yes
OTC
$15.00
+ Antihistamines: Intranasal
Drug
*Adult
Dosing
*Child
Dosing
Azelastine
(Astelin)
(AH)
1 to 2 sprays
in each
nostril
BID
Ages 5 to 11 Yes
years:
1 spray in
each nostril
BID
$77-156
Not
approved
for ages
less than 12
years
$198-273
Olopatadine 2 sprays in
(Patanase)
each nostril
(AH)
BID
Generic
No
Cost
+ Antihistamines: Ophthalmic

Useful for allergic conjunctivitis

Azelastine (Optivar)

Emedastine (Emadine)

Levocabastine (Livostin)

Olopatadine (Patanol)

Epinastine (Elestat)

Ketotifen (Zaditor) (Zyrtec)



OTC - antihistamine / mast cell stabilizer
Study suggesting more effective compared to olopatadine
Naphazoline/pheniramine (Naphcon-A, Opcon-A, Visine-A)

OTC - can cause rebound symptoms – AVOID use >3
days
+
Nasal Corticosteroids
+ Nasal Corticosteroids
 Blocks
inflammatory response
 Reduces
symptoms of
 Nasal congestion
 Rhinorrhea
 Sneezing, Nasal itching
 Conjunctivitis
 Generally
MORE effective than antihistamines,
decongestants, leukotriene antagonist and mast
cell stabilizers
+ Nasal Corticosteroids
Drug
*Adult Dosing
*Child Dosing
Generic
Cost
Beclomethasone
(Beconase AQ)
(S)
1 to 2 sprays
in each nostril BID
Ages 6 to 12 years:
1 to 2 sprays in each nostril BID
No
$149.99
Budesonide
(Rhinocort Aqua)
(S)
1 to 4 sprays
in each nostril
daily
Ages 6 to 11 years:
1 to 2 sprays in each nostril daily
No
$111.96
Ciclesonide
(Omnaris)
(S)
2 sprays in
each nostril daily
Ages 6 to 11 (seasonal allergic
rhinitis indication only):
2 sprays in each nostril daily
No
$105.99
Flunisolide
(Nasarel)
(S)
2 sprays in
each nostril BID to
TID
(max 8 sprays in
each nostril per
day)
Ages 6 to 14 years:
2 sprays in each nostril BID
or
1 spray in each nostril TID
(max 4 sprays in each nostril per
day)
Yes
$45.99
Fluticasone furoate
(Veramyst)
(S)
1 to 2 sprays
in each nostril
daily
Ages 2 to 11 years:
1 to 2 sprays in each nostril daily
No
$105.61
Fluticasone propionate
(Flonase)
(S)
1 to 2 sprays
in each nostril
daily
Ages 4 to 17 years:
1 to 2 sprays in each nostril daily
Yes
$55.99 (generic)
$85.98 (brand)
Mometasone
(Nasonex)
(S)
2 sprays in
each nostril daily
Ages 2 to 11 years:
1 spray in each nostril daily
No
$116.82
Triamcinolone
(Nasacort AQ)
(S)
1 to 2 sprays
in each nostril
daily
Ages 6 to 11 years:
1 to 2 sprays in each nostril daily
No
$113.08
+ Evidence for Intranasal
Corticosteroids vs Antihistamines
Percent %
Rinne. J All Clin Imm 2002;109(3):426
+ Combination Therapy:
Antihistamines + Inhaled Steroids

Limited studies

Little to minimal benefit

Unfortunately minimal benefit at twice the cost
+
Decongestants
+
Decongestants
 Short-term
benefit
 Efficacy: topical
 Oral
> oral
decongestants; longer duration, increased
systemic side effects
+
Decongestants Side Effects
 Topical
 Rebound
congestion (rhinitis medicamentosa)
 Do NOT use > 3-5 days
 Systemic
 HTN, urinary
retention, mydriasis, tachycardia,
restlessness, agitation, nervousness
+
Decongestants
 Phenylpropanolamine, Ephedrine
were removed
due to observational association with stroke
 Ephedrine
(Ephedra, Ma Huang)
 Associated with stroke
 Avoid chronic use
 Pseudoephedrine, Phenylephrine
 Available
 Avoid
chronic use
+ Efficacy:
Pseudoephedrine vs Phenylephrine
 “A
placebo-controlled study of the nasal
decongestant effect of phenylephrine and
pseudoephedrine in the Vienna Challenge
Chamber”
 Authors conclude that during 6 hr observation
period, single dose of PSE but not PE resulted in
significant improvement in measures of nasal
congestion
+
Drug-Drug Interactions
 MAO-Inhibitors
 Ergotamines
(vasoconstrictors)
 SSRIs
 Diet
pills, St. John’s Wort, Methamphetamines
 Linezolid
+
Decongestants: Precautions
•
Precautions
• Uncontrolled Hypertension
• History of cardiovascular disease
• History of stroke
• Glaucoma
• Arrhythmia
• Hyperthyroidism
• Prostatic hypertrophy
• Renal insufficiency
+
Management of Allergic Rhinitis in
Pregnancy
 Intranasal
corticosteroids most effective and when
used at prescribed doses low risk
 Montelukast
okay but minimal data
 Antihistamines
 Avoid
loratadine and cetirizine okay
oral decongestants; use nasal dilator, shortterm topical oxymetazoline
+ Summary
 Inhaled
steroids are more efficacious compared to:
 Oral antihistamines (1st and 2nd generation)
 Inhaled antihistamines
 Montelukast
 Montelukast + oral antihistamines
 Cromolyn sodium
 Ipratropium
 Inhaled
steroids are similar in efficacy compared to
oral antihistamine + pseudoephedrine
 Antihistamine
ophthalmic agents
 Combination Inhaled steroids + ophthalmic
antihistamine is slightly more effective than
Inhaled steroids + oral antihistamine
 EXPENSIVE
+
Step Wise Therapy
•
Oral 1st generation Antihistamine
•
Inhaled Steroid (1st line therapy) OR 2nd generation
antihistamines (not as effective as inhaled steroids)
•
Inhaled nasal steroids + oral antihistamines
(minimal benefit with increased cost)
•
Montelukast (not as effective as inhaled steroids)
•
Oral Prednisone
•
Immunotherapy
+ References

Kelly W, Sorkness CA. Asthma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR,
Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th
ed. McGraw Hill; 2010; 463-493.

Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and
Management of Asthma. Report commissioned by the National Asthma
Education and Prevention Program (NAEPP) Coordinating Committee (CC),
coordinated by the National Heart, Lung, and Blood Institute (NHLBI) of the
National Institutes of Health. 2007. Available from:
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

Williams DM, Bourdet SV. Chronic obstructive pulmonary disease. In: DiPiro
JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy:
A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008: 495517.

Global Strategy for the Diagnosis, Management and Prevention of COPD,
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014.
Available from: http://www.goldcopd.org.
+ References

Carl J, et al. Comparison of racemic albuterol and levalbuterol for the treatment of acute
asthma. J Pediatr 2003;143:731-6.

Brambilla C, Le Gros V, Bourdeix I; Efficacy of Foradil in Asthma (EFORA) French Study Group.
Formoterol 12 μg BID administered via single-dose dry powder inhaler in adults with asthma
suboptimally controlled with salmeterol or on-demand salbutamol: A multicenter, randomized,
open-label, parallel-group study. Clin Ther. 2003 Jul;25 (7):2022-36.

Au DH, Lemaitre RN, Curtis JR, Smith NL, Psaty BM.The risk of myocardial infarction associated
with inhaled beta-adrenoceptor agonists. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):82730.

Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following
treatment for six months with once daily tiotropium compared with twice daily salmeterol in
patients with COPD. Thorax. 2003 May;58(5):399-404. Erratum in: Thorax. 2005 Feb;60(2):105.

Advair (salmeterol/fluticasone) vs Spiriva (tiotropium) for COPD. Pharmacist's Letter/Prescriber's
Letter 2008;24(3):240308.

Albert RK, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med
2011;365:689-98.

LeuppiJD,SchuetzP,BingisserR,etal.Short-termvsconventionalglucocor- ticoid therapy in acute
exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial
[published online May 21, 2013]. JAMA. 2013; 309(21):2223-2231.
+
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