Transcript leukotriene pathway inhibitors

DRUGS FOR THE
RESPIRATORY
SYSTEM
Dr. Henri O. de la Cruz, M.D.
G lobal
INitiative for
A Sthma, 2008
update
GOLD, 2008
Four Components of COPD
Management
1. Assess and monitor
disease
2. Reduce risk factors
3. Manage stable COPD

Education

Pharmacologic

Non-pharmacologic
4. Manage exacerbations
Rank 1990
Percent of Total
DALYs
Rank 2020
Percent of Total
DALYs
Lower respiratory
infections
Diarrheal diseases
Perinatal period
conditions
Unipolar major
depression
Ischemic heart disease
1
8.2
6
3.1
2
3
7.2
6.7
9
11
2.7
2.5
4
3.7
2
5.7
5
3.4
1
5.9
Cerebrovascular disease
6
2.8
4
4.4
Tuberculosis
Measles
Road traffic accidents
7
8
9
2.8
2.6
2.5
7
25
3
3.1
1.1
5.1
Congenital anomalies
10
2.4
13
2.2
Malaria
COPD
Trachea, bronchus, lung
cancer
11
12
33
2.3
2.1
0.6
19
5
15
1.5
4.1
1.8
Disease or Injury
Excerpted with permission from Murray and Lopez.
Am. J. Respir. Crit. Care Med., Volume 163, Number
5, April 2001, 1256-1276
Which aspect of Airflow obstruction can be addressed by
drug therapy?
prolonged expiratory
phase & wheezing
 mucus secretion
 smooth muscle
constriction
 airway inflammation
 interstitial edema
 inflammatory
cascade
Goals of therapy?
RELIEVERS
Direct relaxation of airway smooth muscle
Sympathomimetic drugs
Theophylline
Reduction of cholinergic influence from vagal motor
nerves
 Antimuscarinic agents
PREVENTERS
Reduction of inflammatory mediator release
Corticosteroids
LT receptor antagonists
Long acting Sympathomimetic drugs
Anti IgE and PDE4
Reduction of mast cell degranulation
Cromolyn / nedrocromil
Commonly Used Medications
Relievers =Bronchodilators
Short-acting
beta-agonists
Fenoterol
Salbutamol (albuterol)
Terbutaline
inhaled/oral
inhaled/oral
inhaled/oral
Long-acting
beta-agonists
Formoterol
Salmeterol
inhaled
inhaled
Short-acting
anticholinergics
Ipratropium
Oxitropium
inhaled
inhaled
Long-acting
anticholinergic
Tiotropium
inhaled
Methylxanthines
Aminophylline
Theophylline
oral
oral
Combination
inhalers
Fenoterol/Ipratropium
Salbutamol/Ipratropium
inhaled
inhaled
Control of airway diameter
RELIEVER MEDICATIONS
SYMPATHOMIMETIC AGENTS
Non-selective :
epinephrine / ethylnorepinephrine
ephedrine
Selective B2 adrenergic agonists
Salbutamol (Ventolin)
Terbutaline (Bricanyl)
Levalbuterol
Pirbuterol
Bitolterol
Isoproterenol
Less-selective Beta1 & 2 adrenergic
agents
Metaproterenol
Isoetharine
BRONCHODILATORS
Beta adrenergic drugs
• MOA: Stimulates adenylyl cyclase
=  cAMP = smooth muscle
relaxation
• Benefits of Beta receptor agonism
• Relaxation of airway smooth muscle
• Inhibits mediator release
• May increase mucociliary transport
– increase ciliary beat frequency, enhance
mucus secretion, and stimulate chlorideion secretion toward the lumen, suggesting
enhanced water secretion onto the airway
surface.
• May inhibit microvascular leakage
Classification of beta agonists
Mixed Beta agonists:
• isoproterenol HCl
(Isuprel)
• epinephrine chloride
(Adrenalin)
Beta1 agonist activity:
• norepinephrine
(Levophed)
• dobutamine (Dobutrex)
• dopamine HCl (Intropin;
Dopastat)
Beta2 agonists:
• albuterol sulfate
(Proventil;ventolin)
• metaproterenol sulfate
(Metaprel)
• terbutaline sulfate (Bricanyl;
Brethine)
• ritodrine HCl (Yutopar)
R isomer (levalbuterol)
• GOLD 2008:
• Albuterol is a racemic mixture : equal
parts of R and S albuterol,
• The S isomer may have some
proinflammatory effects and binds to the
ß2-receptor weakly, but for a longer
period. S-isomer pharmacologically
inert; may increase airway
hyperreactivity, inc. in eosinophil activity
and histamine production
– There appears to be no
advantage of single
dose as needed
levalbuterol over other
short acting
bronchodilators.
Meta-analysis (2007)
large multicenter trials are
needed to prove its
therapeutic superiority
and cost-effectiveness
in long term.
• The R isomer, or levalbuterol, is more
active and produces greater
bronchodilation over a longer period in Donohue, J. F. Chest 2004;126:125Sboth adults and children in long-term–
137S
dosing studies
J Pediatr. 2007 Feb;74(2):161-7.
Levalbuterol
• Selective R-isomer
activity responsible for
cAMP activation
– Cumulative effect:
diminishing effect and
shorter intervals
between treatment
Controversies on prolonged b2 agonist
Con
Regular Use Of Asthma Drugs Poses
Respiratory, Cardiac Dangers
ScienceDaily (June 18, 2004) —
ITHACA, N.Y. -- Physicians who
prescribe the regular use of beta-agonist
drugs for asthma could be endangering
their patients, two new studies by
researchers at Cornell and Stanford
universities find.
One study compiles previously
published clinical trials to conclude that
patients could both develop a tolerance
for beta-agonists and be at increased
risk for asthma attacks, compared with
those who do not use the drug at all.
The second study shows that
beta-agonist use increases cardiac risks,
such as heart attacks, by more than twofold, compared with the use of a
Pro
• Previous literature indicates that
confounding by poor asthma control
may explain the apparent deleterious
effects of inhaled beta2-agonists.
•
Tolerance to nonbronchodilator effects
of beta2-agonists may account for the
increase in reactivity to indirect
bronchoconstrictor challenges and
explain why some studies have
demonstrated enhanced
bronchoconstriction in patients with
asthma after regular beta 2-agonist
therapy.
• despite all of the concerns raised by the
SMART, inhaled beta2-agonists remain
the most effective bronchodilators
available for the immediate relief of
asthma symptoms and, as such, remain
an important component of asthma
management.
J Asthma. 2008 Jan-Feb;45(1):9-18.
Ther Adv Respir Dis. 2007 Oct;1(1):35-46.
2 - Adrenoreceptor Polymorphism
• 13 polymorphisms identified
– Expression
-receptor
– Down Regulation
– G-protein coupling
The Arg16 polymorphism of the B 2adrenergic receptor is associated with
enhanced agonist-mediated
desensitization in the vasculature =
increased asthma severity, reduced
bronchodilator response,
• the Glu27 polymorphism is associated
with increased agonist-mediated
responsiveness.
NEJM 2001;345:1030-5.
Mechanisms of action
• decreased plasma
exudation
• as well as inhibition of
mediator release from
smooth muscle cells,
mast cells,
eosinophils,
monocytes,1 and
lymphocytes.
• inhibition of smooth
muscle cell and
fibroblast
proliferationby ß2
agonists.
Beta agonist and steroid interactions
• Receptor cross-talk:
– cAMP response binding
element (CREB)
 ↓CBP  ↓ GR function
• ↑cAMP  + GC receptor  +
transcription of GCR
• cAMP can activate protein kinase
A which is able to phosphorylate
an important nuclear transcription
factor called cAMP response
element binding protein (CREB).
Phosphorylated CREB is able to
bind to segments of DNA and can
thus influence gene transcription,
Mechanisms of action
• PKA by beta agonist =
Gs  sarcplasmic ret.:
Ca –calmodulin
interaction =MLCK
• Lungs: β-arrestin in
agonist-promoted
internalization of the M2
mAChR
•
J. Biol. Chem., Vol. 276, Issue 45, 42509-42513,
November 9, 2001
Mechanisms of action
• beta 2-adrenoceptor agonists inhibit
production of ET-1 from airway EpCs =
increase cyclic AMP levels in the cells
• ET-1 production was shown to be elevated
in asthmatic subjects and in patients
suffering from other inflammatory lung
disorders
• arterial oxygen tension may decrease after
beta-agonist use
Inflammation. 2007 Jul 10
Pharmacokinetics
Short Acting Beta Agonist (SABA) is the primary
treatment for bronchospasm & should be
administered by inhalation repetitively or by
continuous administration
 Onset of action <5min & repetitive administration
produces incremental bronchodilation
 2/3 of asthmatics respond well enough to albuterol
to be discharged from ED after three 2.5mg doses of
nebulized albuterol every 20minutes
– Strauss & et al
BRONCHODILATORS
Beta adrenergic drugs
ORAL INHALED
• Peak effect
2-3 h
0.5-2 h
• Duration
4-6 h
3-4 h
• Half life
3.8 h
3.8-5 h
• Metabolism:
sulfide
liver conversion to inactive
Pharmacogenomic considerations in beta agonist
use
• Asthma Clinical Research Network has shown
that persons with the arg/arg mutation at position
16 of the ß-receptor gene who regularly use
SABAs such as albuterol have a decrease in lung
function further exacerbated by withdrawal of the
drug.
• patients with the B16-Arg/Arg polymorphism may
be at risk for adverse effects, or less of a salutary
effect, when using -agonists regularly.
Am J Respir Crit Care Med 2000;162,75-80
SALBUTAMOL
BRONCHODILATORS
Adverse effects
TERBUTALINE
> 10%
> 10%
tachycardia, palpitations,
nervousness, restlessness, trembling
GI upset nausea
1-10 %
1- 10 %
tachycardia, hypertension, dizziness,
drowsiness h/a insomnia;
flushing of face, hpn,
hypotn
nervousness, CNS stimulation,
hyperactivity, insomnia, dizziness
muscle cramps, weakness
xerostomia, N/V, bad taste; diaphoresis
lightheadedness, drowsiness, h/a;
tremors; weakness; muscle cramping
<1%
coughing; dysuria; diaphoresis;
paradoxical bronchospasm;
< 1%
hypokalemia
chest pain; loss of appetite; paradoxical
bronchospasm; hypokalemia
chest pain; loss of appetite;
BRONCHODILATORS
Beta adrenergic drugs
• Drug interactions
 effects: TCAs; MAO inh.; sympathomimetics
 effects: Beta adrenergic blockers
• Pregnancy risk factor C (risk cannot be ruled
out)
• Tolerance
• downregulation of beta 2 receptors on
chronic use; more on
oral route
• Duration of action more affected than peak effect
Systemic beta agonists
 No advantage to subcutaneous epinephrine or
terbutaline over inhaled albuterol in initial treatment of
SAE
Indications:

Inability to comply with inhaled therapy because of
altered mental status or near arrest situation

Poor response to several hours of inhaled therapy,
subcutaneous epinephrine maybe helpful
 Coronary artery disease relative contraindication
 IV administration is not recommended
 Combination of inhaled & parenteral treatment have
not been adequately evaluated
BRONCHODILATORS
Beta adrenergic drugs Dose Preparations
Salbutamol
Aerosol 100 mcg/dose
(200 doses)
Rotacaps 200 mcg
Terbutaline
Injectable
Aerosol 0.2 mg/dose
Solution, inh.: 5 mg/ml
Turbohaler 500mcg
Syrup 2mg/ 5ml
Tab 2.5, 5 mg
Tab
2, 4 mg
Tab, ext release 4, 8 mg
BRONCHODILATORS
Anticholinergics: IPRATROPIUM
 MOA: quaternary nitrogen blocks Ach at
parasympathetic sites in bronchial
smooth muscle causing bronchodilation
Anticholinergic Mechanism of
Bronchodilation
•
Competitive block of the M3 receptor
subtype inhibits Gs protein, that in
turn inhibits phospholipase C (PLC).
– PLC causes a breakdown of
phosphoinositides into inositol
triphosphate (IP3) and diacyl
glycerol (DAG).
– This leads to an increase in
cytoplasmic [Ca++] and smooth
muscle contraction and
glandular secretion.
• Blockade of M1 receptors prevents
transmission of nervous impulse to
neuroeffector site.
Responses to albuterol sulfate and ipratropium bromide
Donohue, J. F. Chest 2004;126:125S-137S
 Clinical data supports
adding ipratropium
bromide to albuterol in the
initial treatment of
SAE
 Rodrigo & Rodrigo
demonstrated combination
albuterol & ipratropium had
a 20.5%-48%
improvement in FEV1 &
PEF
 Rate of hospitalizations
decreased significantly
from 39% alone to 20%
combination
 Clinical benefits
 May be sl. less effective than
beta-agonist drugs in
reversing bronchospasm
 Probably equally effective for
COPD pts.
 In acute severe asthma:
enhances effect of salbutamol
 Valuable in pts. Intolerant of
inhaled beta-agonist drugs
 NIH: esp. effective in
management of asthma in the
elderly
 Treatment of choice for betablocker induced
bronchospasm
BRONCHODILATORS
Anticholinergics: TIOTROPIUM
• MOA: subtype-selective
competitive binding of Ach
receptors = antagonist of
Ach; M3 & M1> M2
• Out of M1-M5 receptors in
the body only M1-M3 are
found in the lung
• M3: mediate bronchoconstrictor and
mucus secretory
response to Ach
IPRATROPIUM, TIOTROPIUM VS. LABA
In head-to-head comparisons, short-acting
anticholinergics such as ipratropium are less potent
than LABAs and long-acting anticholinergics such as
tiotropium.56 Anticholinergics in COPD are useful when
combined with SABAs and/or theophyllines.
Anticholinergics, particularly when administered by
nebulized solution or by metered-dose inhaler and
spacer in higher doses such as four puffs every 4 h,
are useful in acute attacks of asthma and COPD. The
longer-acting agents such as tiotropium are effective in
stable patients with COPD for up to 24 h.
In COPD, it appears that the longer-acting
anticholinergic agents are superior to salmeterol,
ipratropium, or placebo. In asthma, tiotropium
bronchoprotects for up to 48 h.
BRONCHODILATORS
Anticholinergics: IPRATROPIUM
Adverse effects
 10 %
Nervousness, dizziness, fatigue h/a
Nausea, xerostomia, stomach upset
 1-10 %
Palpitations, hypotension, insomnia, trembling, blurred vision
Urinary retention, nasal congestion
 <1%
Rash, urticaria, stomatitis
Pregnancy risk Factor B ( no evidence of risk in
humans)
BRONCHODILATORS
Anticholinergics: IPRATROPIUM
• Onset: 1-3 min after administration
• Peak: 1.5-2 hrs
• Duration: 4-6 hrs
• Prep:
inh 18 mcg/actuation
nasal spray 0.03%, 0.06%
nebulizing: 0.02 % / 2.5 ml
BRONCHODILATORS
Anticholinergics: TIOTROPIUM
Adverse effects
3%
dry mouth, dyspepsia, vomiting, abdominal pain, myalagia,
pharyngitis, rhinitis, URTI; UTI; rash
 1- 3 %
allergic reaction leg pain, dysphonia, paresthesia, GERD,
stomatitis, hypercholesterolemia, hyperglycemia, skeletal pain,
angina, depression, laryngitis, cataract
 < 1%
AF, SVT, angioedema
BRONCHODILATORS
Anticholinergics: TIOTROPIUM
• Peak: 1.5 – 2 hrs
• Duration: 540 hrs
• Poorly absorbed thru GIT
• Prep:
Handihaler 18 ug/dose OD - BID
BRONCHODILATORS
THEOPHYLLINE
MOA:
- ?blocks phosphodiesterase 
inc. cAMP  enhanced calcium
influx = epi release 
bronchodilatation / gastric acid
secretion / cardiac stimulation
- low doses: inc. catecholamine
release secondary to inhibition of
presynaptic adenosine receptors
 prevents mooth muscle
contraction & histamine release
fr. Lung cells
- anti-inflammatory action: low
dose theophylline inhibits late
response to antigenic challenge
cAMP
ATP
Adenylyl Cyclase
+
Gs
Gi
AMP
Phosphodiesterase
-
Theophylline
Theophylline
BRONCHODILATORS
THEOPHYLLINE
 Adverse effects:
15 – 25 mcg/ml: GI upset, diarrhea, N/V, abdominal pain, nervousness,
h/a,
insomnia, agitation, dizziness, muscle cramp, tremor
25 – 35 mcg/ml: tachycardia, occasional PVC
> 35 mcg : Vtach; frequent PVC, seizures
Others: weak diuretic effect; unknown mechanism + reduced blood
viscosity (e.g. pentoxifylline)
 Meta-analysis of 15 adult studies did not
result in any additional bronchodilation
compared with standard care with beta
agonist
 Pregnancy risk factor C (risk cannot be ruled out)
BRONCHODILATORS
THEOPHYLLINE
Drug interactions
 levels (induction of microsomal enzymes):
barbiturates, carbamazepine, charcoal,
high protein / low carbohydrate diet,
hydantoins, isoniazid, rifamipicin, smoking,
sympathomimetics, ketoconazole
 levels:
allopurinol, beta blockers, calcium channel
blockers, CS, hepatic cirrhosis, ciprofloxacin, cor pulmonale,
macrolides, isoniazid, oral
contraceptives,
thyroid hormones
BRONCHODILATORS
THEOPHYLLINE
• Preparations:
• Aminophylline (IV): may be added after the first hr. if
with no relief with beta blocker
• Immediate release theophylline 100 mg, 200 mg
• Timed release
– 8-24 hrs (Theodur) 100 mg, 200 mg, 300 mg, 450 mg
– 24 hrs (Unidur) 400 mg, 600 mg
• Dietary precautions
• Avoid caffeine containing food or beverages
• Avoid extremes of dietary protein, carbohydrate,
charcoal intake
• Adm. with water 1 hr before or 2 hrs after meals
Bronchodilators
Epinephrine & Ephedrine
• Epinephrine
• Rapidly acting
bronchodilator:
SQ / IV / inhalation,
intratracheal
• Useful in asthma
emergencies
• Side-effects: B1 and
B2 receptor activation:
- tachycardia
- other arrythmias
- exacerbate angina
• Ephedrine
• Relative to Epi:
- longer duration
- orally active
- more CNS effects
- low potency
• Infrequently used
Risk Factors for Fatal or Near Fatal
Asthma
Frequent ED visits
 Frequent
hospitalizations
 Intensive Care
admissions
 Prior Intubation
 Hypercapnia
 Barotrauma
 Psychiatric Illness
 Medical Noncompliance
 Illicit drug use
 Low socioeconomic
status
 Inadequate access to
medical care
 Use of > 2 canisters of
SABA/month
 Poor perception of
airflow
obstruction
 Comorbidities such as
coronary artery disease
PREVENTER MEDICATIONS
PREVENTERS
Corticosteroids
Anti-leukotrienes
Prednisolone, Betamethasone
Montelukast, Zafirlukast
Beclomethasone, Budesonide
Fluticasone
Xanthines
Theophylline SR
Long acting 2 agonists
Mast cell stabilisers
Bambuterol,
Sodium cromoglycate
Salmeterol
Formoterol
COMBINATIONS
Salmeterol/Fluticasone
Formoterol/Budesonide
Salbutamol/Beclomethasone
Asthma Inflammation: Cells and Mediators
Source: Peter J. Barnes, MD
Cigarette smoke
Biomass particles
Particulates
Pathogenesis of
COPD
Host factors
Amplifying mechanisms
LUNG INFLAMMATION
Anti-oxidants
Oxidative
stress
Anti-proteinases
Proteinases
Repair
mechanisms
COPD PATHOLOGY
Source: Peter J. Barnes, MD
Oxidative Stress in COPD
Macrophage Neutrophil
Anti-proteases
SLPI 1-AT
NF-B
Proteolysis
IL-8
↓ HDAC2
O2-, H202
OH., ONOO-
↑Inflammation
Steroid
resistance
Isoprostanes
Plasma leak
TNF-
Neutrophil
recruitment
Bronchoconstriction
 Mucus secretion
Source: Peter J. Barnes, MD
Asthma Pathways
Environment
Normal Airway
Function
Remodeling
Genetic
Predisposition
Asthma
Origins
Epithelial Injury
Injury
Matrix Deposition
Repair
Angiogenesis
Remission, Persistence
Predisposition
Progression or Regression?Genetic
for Remodeling
Smooth Muscle
Hypertrophy/Hyperplasia
Lazaar AL, Panettieri R. Am J Med. 2003;115:652-659.
Models of Disease Progression
from Childhood to Adulthood
100
A. Normal: remains
normal
FEV1 (% Predicted)
90
A
B
80
C
70
D
C. Begins normal: rapid
decline early on
resulting in severe
obstruction
60
50
40
0
B. Begins normal: steep
slope resulting in
severe obstruction
over time
5 10 15 20 30 40 50 60 70
Age (Years)
Szefler SJ. J Allergy Clin Immunol. 2005;115:685-688.
D. Begins with low values
and continues with low
lung function
Inflammatory mechanisms in COPD
Barnes, P. J. Chest 2000;117:10S-14S
Levels of Asthma Control
Characteristic
Daytime symptoms
Controlled
Partly controlled
(All of the following)
(Any present in any week)
None (2 or less /
week)
More than
twice / week
Limitations of
activities
None
Any
Nocturnal symptoms
/ awakening
None
Any
Need for rescue /
“reliever” treatment
None (2 or less /
week)
More than
twice / week
Lung function
(PEF or FEV1)
Normal
< 80% predicted or
personal best (if
known) on any day
Exacerbation
None
One or more / year
Uncontrolled
3 or more
features of
partly
controlled
asthma
present in any
week
1 in any week
REDUCE
LEVEL OF CONTROL
TREATMENT OF ACTION
maintain and find lowest
controlling step
partly controlled
consider stepping up to
gain control
INCREASE
controlled
uncontrolled
exacerbation
step up until controlled
treat as exacerbation
REDUCE
INCREASE
TREATMENT STEPS
STEP
STEP
STEP
STEP
STEP
1
2
3
4
5
Therapy at Each Stage of COPD
I: Mild
II: Moderate
III: Severe
IV: Very Severe
 FEV1/FVC < 70%
 FEV1/FVC < 70%
 FEV1 > 80% predicted
 FEV1/FVC < 70%
 50% < FEV1 < 80%
predicted
 FEV1/FVC < 70%
 30% < FEV1 < 50%
predicted
 FEV1 < 30% predicted
or FEV1 < 50% predicted
plus chronic respiratory
failure
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting
bronchodilators (when needed); Add rehabilitation
Add inhaled glucocorticosteroids if
repeated exacerbations
Add long term oxygen
if chronic respiratory
failure. Consider
surgical treatments
Improving Asthma Control
Goals of long-term control therapy
Prevent symptoms
Improve pulmonary function
Reduce inflammation
Resolve and prevent progression
Airway inflammation
Mast cells – Classic Model
- IgA Ab bind to mucosal mast cells
a. Ag-Ab interaction on mast
cell surface
b. release of mediators = early
reaction
Histamine
Trytase / other neutral proteases
Leukotrienes C4 and D4
PAF
PG D2
RELIEVER MEDICATIONS
CROMOLYN Na / Nedocromil
Adverse effects:
 10 % unpleasant taste; hoarseness; coughing
 1-10% angioedema; xerostomia; dysuria; sneezing;
nasal congestion
 < 1% dizziness, h/a, rash, urticaria, n/v, diarrhea,
arthralgia, ocular stinging, lacrimation, wheezing, throat
irritation, eosinophilic pneumonia, pulmonaryinfiltrates,
nasal burning, anaphylactic reactions
Pregnancy risk factor B (no evidence of risk in humans)
Airway inflammation
• Eosinophils
• Impt. in infiltrative component
• MBP and ECP: destroy airway epithelium cells
• Lymphocytes
• TH1 cytokines: IL-2 + IF   B cell activation
• TH2 cytokines: IL-4 and IL-5

eosinophil attraction & act.
 IgE production by B cells
• IL-5 = eosinophil proliferation
basophil granule release
Airway inflammation
Other cells:
Neutrophils
Macrophages
Endothelial cells
Epithelial cells
Mediators (histamine; bradykinin; LT
C, D, E; PAF; PGE2, PGF2a;
PGD2):
Bronchoconstriction
Vascular congestion
Edema
 mucus production / impaired mucociliary
transport
Reversible airflow limitation in COPD
• Accumulation of inflammatory cells, mucus and plasma
exudate
• Smooth muscle contraction in peripheral and central
airways
• Dynamic hyperinflammation
RELIEVER MEDICATIONS
CORTICOSTEROIDS (CS) Mechanisms
1o Anti-inflammatory effect: prevents migration of
eosinophils, PMN, fibroblasts
Inh. of cytokine production
Lysosomal stabilization at the cellular level
Reverses capillary permeability
2o enhancement of beta-receptor agonist effects
RELIEVER MEDICATIONS
CORTICOSTEROIDS (CS)
• BENEFICIAL EFFECTS
• Diminish bronchial reactivity; Increase airway diameter in
acutely ill pts.
• In asthma
- Reduced frequency of asthmatic exacerbations;
- pts not adequately maintained or worsening on
bronchodilator therapy
• in COPD:
- inhaled CS for symptomatic pts. with a documented
spirometric response or with an FEV1 < 50% predicted
with repeated exacerbations req. tx with oral steroids
(Evidence B, GOLD)
- chronic tx with systemic CS should be avoided because
of an unfavorable risk-to-benefit ratio (Evidence A, GOLD)
RELIEVER MEDICATIONS
CORTICOSTEROIDS (CS)
• In vitro effects of corticosteroids on remodelling processes
• Decreased smooth muscle proliferation88–91
• Increased or decreased smooth muscle fibronectin production,
depending on steroid92
• Decreased smooth muscle cytokine synthesis93,94
• Decreased fibroblast TGFß expression95
• Decreased fibroblast collagen gene expression96,97
Advantages of steroids in acute exacerbations
• use of corticosteroids within 1 hr of arrival to ED
reduces the need for hospitalization & benefits are
greatest in pts with the more severe asthma &
those not taking corticosteroids
• Decrease the number of relapses in first 710days & number of asthma deaths
• Speeds rate of recovery in hospitalized patients
RELIEVER MEDICATIONS
CORTICOSTEROIDS (CS)
• Increased or decreased fibroblast proliferation98–104
• Increased expression of SLPI (secretory leukocyte protease
inhibitor) by epithelial cells105
• Decreased VEGF expression by epithelial cells106
• Reduced adhesion molecule expression by endothelial cells,
fibroblasts, and epithelial cells107–109
• Reconstitution of epithelial structure110
• Decreased mucus production111
• Decreased expression of cytokines and chemokines by a
variety of cells87
IV vs. ORAL vs. INHALED
 NIH recommends 40-80 mg/day of either prednisone,
methylprednisolone or prednisolone in 1 or 2 divided doses
until PEF reaches 70% of personal best
 No known advantage for higher doses of corticosteroids in
SAE, nor is there any advantage for IV over oral therapy
provided GI absorption is not impaired
 Total course of corticosteriods for an asthma
exacerbation may last from 3-10 days
 Corticosteroid courses < 1week, there is no
need to taper the dose
 Slightly longer course (3-10 days) probably
does not need to taper, especially if patient is
taking ICS
 ICS can be started any point in treatment
Estimate Comparative Daily Dosages for
Inhaled Glucocorticosteroids by Age
Drug
Low Daily Dose (g)
> 5 y Age < 5 y
Medium Daily Dose (g)
> 5 y Age < 5 y
Beclomethasone
200-500
100-200
>500-1000
>200-400
Budesonide
200-600
100-200
600-1000
>200-400
Budesonide-Neb
Inhalation Suspension
Ciclesonide
250-500
80 – 160
High Daily Dose (g)
> 5 y Age < 5 y
>1000
>1000
>500-1000
>400
>400
>1000
80-160
>160-320
>160-320
>320-1280
>320
Flunisolide
500-1000
500-750
>1000-2000
>750-1250
>2000
>1250
Fluticasone
100-250
100-200
>250-500
>200-500
>500
>500
Mometasone furoate
200-400
100-200
> 400-800
>200-400
>800-1200
Triamcinolone acetonide
400-1000
400-800
>1000-2000
>800-1200
>2000
>400
>1200
Drug
Equivalent
Pharmalogic
dose (mg)
Biological Half
life (hrs)
Hydrocortisone
(solucortef)
20 mg
8-12 hr
Cortisone
25 mg
8-12 hr
Prednisone
5 mg
24-36 hr
Solumedrol
methylprednislone
4 mg
24-36 hr
Dexamethasone
(decadron)
0.75 mg
36-54 hr
Therapy at Each Stage of COPD
I: Mild
II: Moderate
III: Severe
IV: Very Severe
 FEV1/FVC < 70%
 FEV1/FVC < 70%
 FEV1 > 80% predicted
 FEV1/FVC < 70%
 50% < FEV1 < 80%
predicted
 FEV1/FVC < 70%
 30% < FEV1 < 50%
predicted
 FEV1 < 30% predicted
or FEV1 < 50% predicted
plus chronic respiratory
failure
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting
bronchodilators (when needed); Add rehabilitation
Add inhaled glucocorticosteroids if
repeated exacerbations
Add long term oxygen
if chronic respiratory
failure. Consider
surgical treatments
RELIEVER MEDICATIONS
CORTICOSTEROIDS (CS)
• Advantages of inhaled CS
- reduces / eliminates need
for oral CS
- improvement in
pulmonary fcn in pts with
mild to severe asthma
- reduced bronchiole
reactivity
*- reduced risk of adrenal
suppression & reduced risk
of adverse effects
RELIEVER MEDICATIONS
CS Adverse effects
>10%
respiratory infection, rhinitis
1-10%
Resp: bronchitis, bronchospasm, cough,
epistaxis, nasal irritation, sinusitis, stridor;
GI: oral candidiasis; taste perversion, weight gain, abdominal
pain, anorexia, diarrhea, dry mouth, dyspepsia; bruising,
Skin: c.dermatitis, eczema, pruritus, rash,
CNS: insomnia, migraine, nervousness,
emotional
lability, migraine, back and chest
pain, headache;
Others: allergic rxn; flu-like syndrome; infection;
voice
alteration; cervical lymphadenopathy; arthralgia,
fracture, hypertonia
RELIEVER MEDICATIONS
CORTICOSTEROIDS (CS)
< 1% facial swelling, palpitations, aggressive reactions,
anxiety, depression, irritability, angioedema,
avascular necorsis of the femoral head, dyspnea,
reduced sense of smell, hoarseness, osteoporosis,
cataract formation
May cause adrenal suppression: oral doses should
be tapered
May cause a reduction in growth velocity in pediatric
pts.
Immunosuppression risk shld be considered esp. in
pts. with systemic infection
Pregnancy category C (risk cannot be ruled out)
ATS copd guidelines
Chemical Structures
Formoterol
O
HN
O
HO
N
H
OH
Salmeterol
HO
HO
O
N
H
OH
BRONCHODILATORS
Beta adrenergic drugs
Formoterol
• a long-acting beta-agonist with a shorter onset of
action than salmeterol (3-5 minutes vs. 10-20
minutes).
• The duration of action of formoterol is 12 hours.
INDACATEROL:
ultra-long acting beta agonist
Eur Respir J. 2007 May;29(5):871-8. Epub 2007 Jan 24.
β2 Receptor Binding for Formoterol and
Salmeterol
• Both molecules bind to the β2 adrenergic receptor
active site, however
– Prolonged salmeterol activity depends on binding with
an exosite
– Prolonged activity of formoterol is independent of
exosite binding
• Mutation in the exosite region (Ile 164) could
affect duration of action of salmeterol
Green SA, et al. J Biol Chem. 1996;271:24029-24035.
Long acting beta agonists
• Meta-analysis of 9 studies comparing salmeterol
with doubling the dose of inhaled steroid showed
that salmeterol improved symptoms and lessened
the need for rescue medication.
• Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose
of inhaled steroid or addition of salmeterol in symptomatic asthma.
BMJ 2000;320:1360-73.
“Patients with moderate to severe symptoms of
COPD require combination of
bronchodilators”
“Combining bronchodilators with different
mechanisms and durations of actions may
increase the degree of bronchodilation for
equivalent or lesser side effects’’
GOLD Report 2008
Algorithm for the management of COPD
Mild
assess with symptoms and spirometry
Short acting bronchodilator – as required
Tiotropium
Long acting beta agonist
LABA + tiotropium
Tiotropium+LABA
Severe
Add
-Inhaled steroids
-Theophylline
LEUKOTRIENE
PATHWAY INHIBITORS
Factors involved in the pathophysiology of
Salvi, S. S. et al. Chest 2001;119:1533-1546
Asthma Pathology
Allergen
Macrophage/
dendritic cell
Th2 cell
Mast cell
Leukotrienes
C4, D4 & E4
Neutrophil
Eosinophil
Mucus plug
Nerve activation
Epithelial shedding
Subepithelial
fibrosis
Plasma leak
Oedema
Mucus
hypersecretion
Hyperplasia
Barnes PJ
Vasodilatation
New vessels
Sensory nerve
activation
Cholinergic
reflex
Bronchoconstriction
Hypertrophy/hyperplasia
RELIEVER MEDICATIONS
LEUKOTRIENE PATHWAY INHIBITORS
Leukotriene mediators:
 Synthesized by
inflammatory cells found in
the airway: eosinophils
macrophages
mast cells
basophils
 Effects of LT B4, C4 and
D4:
• Bronchoconstriction
• mucosal edema
• mucus hypersecretion
• increase bronchial
hyperreactivity
Phospholipid
Corticosteroids
Phospholipase A2
5-lipoxyenase
Arachidonic
acid Cyclooxygenase
(PGI2)
Leukotriene
PGE2
PGH2
PGF2
Diagrammatic representation of the steps involved
Salvi, S. S. et al. Chest 2001;119:1533-1546
RELIEVER MEDICATIONS
LEUKOTRIENE PATHWAY INHIBITORS
• 5-Lipoxygenase inhibitors
– Zileuton
• Inhibitor of LT-D4 receptor binding
– Zafirlukast
– Montelukast
– Pranlukast
• pranlukast may inhibit NF-kappaB activation and MUC2 gene transcription
through pathways distinct from cysLT(1) receptor antagonism in cultured
human epithelial cells. (Pharmacology. 2005 Feb;73(2):89-96.)
ZAFIRLUKAST
MONTELUKAST
PRANLUKAST
RELIEVER MEDICATIONS
LEUKOTRIENE PATHWAY INHIBITORS
ZILEUTON
 5 lipoxygenase inhibitor
 Use: prophylaxis and chronic tx of asthma in
adults & pts > or = 12 yrs of age
 Not indicated for reversal of bronchospasm in
acute exacerbations of asthma
 Peak: 1-2 hrs
 Half life: 2.5 hrs
 dose: 600 mg qid with meals and at bedtime
RELIEVER MEDICATIONS
LEUKOTRIENE PATHWAY INHIBITORS
MONTELUKAST (Singulaire)
inh. of LTD4 receptor binding
Use: modestly effective for maintenance tx of
adults & children with intermittent / persistent
asthma; no use in acute exacerbations of
asthma
Less effective than inhaled steroids
May be added to oral / inh. CS to improve
asthma pts with aspirin intolerant asthma
Only LT drug approved for use in children 6 –
12 yrs old
RELIEVER MEDICATIONS
LEUKOTRIENE PATHWAY INHIBITORS
• Adverse effects
> 10 %
headache
1 – 10%
dizziness, fatigue, fever; rash;
Dyspepsia, dental pain, gastroenteritis; abd pain
Weakness; Cough; Flu-like S/S
Churg Strauss vasculitis
• Pregnancy category B (no evidence of risk in
humans
What is the clinical efficacy of
LEUKOTRIENE PATHWAY INHIBITORS
• No evidence of benefit in COPD.
GOLD 2008
• Alternative treatment for mild persistent asthma
• Effect is generally less than that of low dose
inhaled CS; Cannot be substituted for low dose CS
therapy for those on inhaled CS therapy;
• Requires monitoring for hepatic toxicity
• Adverse effects:
>10 %
h/a; inc. ALT
1- 10% chest pain, dizziness, fever, insomnia, malaise,
nervousness,dyspepsia, nausea, abd. pain, constipation,
flatulence, myalgia, arthralgia, weakness, conjunctivitis,
low white blood cell count
RELIEVER MEDICATIONS
CROMOLYN Na / Nedocromil
• MOA: mast cell stabilizers by altering fcn of delayed
chloride channels
• Cl-mediated channel effects:
- inhibition of cough
- inhibition of early response to antigens
(mast cells)
- inhibition of late response to antigens (eos)
RELIEVER MEDICATIONS
CROMOLYN Na / Nedocromil
Use: - prophylaxis with chronic tx
= reduces need for bronchodilators in
pts with perennial asthma
= effective in reducing symptoms of
allergic rhinitis/asthma & hay fever
= prevention of exercise-induced asthma
No direct effect on airway muscles; will not reverse
bronchospasm
Blocks bronchoconstriction due to Ag inhalatation or
aspirin ingestion
Anti-IgE antibodies
Omalizumab
• Addition of anti-IgE treatment to other controller medications
improves control of allergic asthma when control has not been
achieved on other medications (Evidence A)
• Mech: inhibits the binding of IgE to the high-affinity IgE receptor
(FceRI) on the surface of mast cells, basophils, and dendritic cells.
– it cannot interact with IgE that is already bound to cell surfaces and thus
cannot induce degranulation of mast cells or basophils.8,13 Instead,
omalizumab binds to circulating IgE, regardless of allergen specificity, forming
small, biologically inert IgE–anti-IgE complexes without activating the
complement cascade.8,12,14
– An 89 to 99 percent reduction in free serum IgE (i.e., IgE not bound to
omalizumab) occurs soon after the administration of omalizumab, and low
levels persist throughout treatment with appropriate doses
Anti-IgE antibodies
Omalizumab
• Indication: moderate-to-severe, persistent allergic
asthma even with inhaled steroids
• injectable dosage form, every 2 to 4 weeks
• $4 000 to $20 000 per year (ave $12 000.00)
Omaluzimab: Efficacy
• Among patients in a clinical trial who had had a response to
omalizumab by 16 weeks, 87 percent had done so by 12 weeks.
• ¾ RCT trials, treatment with omalizumab as compared with placebo
was associated with significantly fewer exacerbations of asthma per
patient, and a significantly lower percentage of patients had an
exacerbation. In addition, the dose of inhaled corticosteroids required
to control symptoms was significantly less among patients treated with
omalizumab than among those who received placebo.
• no significant effect on the frequency of exacerbations was seen,
although the dose of inhaled corticosteroids required to control
symptoms was significantly lower among patients treated with
omalizumab.
• there is considerable variability of response to omalizumab therapy
Strunk, NEJM, 2006Volume 354:2689-2695
Anti-IgE antibodies
Omalizumab
• Adverse effects: injection site reaction
(45%), viral infections (23%), upper
respiratory tract
• infection (20%), sinusitis (16%), headache
(15%), and pharyngitis (11%).
• an increased (0.5%) malignancies of
various types, compared with patients who
received the placebo drug (0.2%), possible
induction of Churg-Strauss syndrome,
nasal polyps and adrenal insufficiency
Phosphodiesterase4 inhibitors
Roflumilast
• 4 form (PDE4). Inhibition of this
enzyme prevents cAMP breakdown
and thereby increases its intracellular
concentration.
• increased cAMP in smooth muscle
causes relaxation
• predominant isoenzyme in the
majority of inflammatory cells, with
the exception of platelets, implicated
in inflammatory airways disease. It is
expressed in the airways smooth
muscle, brain and cardiovascular
tissues
Phosphodiesterase4 inhibitors
• asthma, COPD, allergic rhinitis, psoriasis, multiple
sclerosis, depression, Alzheimer's disease and
schizophrenia.
• roflumilast is equivalent to taking inhaled
beclomethasone diproprionate in the treatment of
mild to moderate asthma, suggesting that such
drugs may prove to be a viable alternative therapy
to inhaled glucocorticosteroids (reviewed by
Lipworth, 2005).
• ventricular arrhythmias in about 12% of patients,
some of which may be life-threatening.
Headaches and hypotension occur in about 3% of
patients.
Allergen-specific Immunotherapy

The role of specific immunotherapy in asthma is
limited

Specific immunotherapy should be considered
only after strict environmental avoidance and
pharmacologic intervention, including inhaled
glucocorticosteroids, have failed to control
asthma

Perform only by trained physician
Component 1: Develop Patient/Doctor Partnership
Key factors to facilitate communication:
 Friendly demeanor
 Interactive dialogue
 Encouragement and praise
 Provide appropriate information
 Feedback and review
Component 2: Identify and Reduce Exposure to Risk
Factors
 Measures to prevent the
development of asthma, and
asthma exacerbations by avoiding
or reducing exposure to risk
factors should be implemented
wherever possible.
 Asthma exacerbations may be
caused by a variety of risk factors
– allergens, viral infections,
pollutants and drugs.
 Reducing exposure to some
categories of risk factors
improves the control of asthma
and reduces medications needs.
SUMMARY
 Bronchoconstriction may be due
to
- direct mediator effects
- activation of neuronal / humoral
pathways
 The reversible components of
COPD may respond to therapy
BUT none of these will alter the
long-term decline in lung function
(Evidence A, GOLD)
Pharmacological approaches must
have multiple mechanisms
In the pipeline …
In the pipeline
Mediator antagonists
 Leukotriene B4 (LTB4) antagonists: LY29311, SC-53228, CP105696, SB 201146, BIIL284
 5'-lipoxygenase inhibitors: zileuton, Bay x1005
 Chemokine inhibitors
 Interleukin-8 antagonists: CXCR2 antagonists, e.g. SB225002
 Monocyte chemotactic protein (MCP) antagonists (CCR2
antagonists)

Tumour necrosis factor (TNF) inhibitors: monoclonal antibodies,
soluble receptors, TNF- converting enzyme inhibitors
 Antioxidants: e.g. stable glutathione analogues
 Inducible nitric oxide synthase (iNOS) inhibitors: e.g. L-N6-(1imminoethyl)lysine (L-NIL)
The inflammatory cascade in asthma
Salvi, S. S. et al. Chest 2001;119:1533-1546
Oxygen
 Low flow oxygen by nasal
cannula is recommended
to maintain arterial oxygen
saturation >90%
– >95% in pregnant women
&
coexistent heart disease
 Improves oxygen delivery
to peripheral tissues,
reverses hypoxic
pulmonary
vasoconstriction & may
stimulate bronchodilation
Antibiotics are not generally recommended
for the treatment of acute asthma
exacerbations
 Reserved for patients who have fever &
purulent sputum & have strong evidence of
pneumonia
 Presence of bacterial sinusitis
 Bacterial infections usually do not contribute to
asthma exacerbations
“The aim of (pulmo-active) therapy is to maintain
control with the least amount of medication and
hence minimal risk for adverse effects.”
NHBLI Guidelines
• Most men die of their remedies, not of their
illnesses. - Moliere