PHARMACOTHERAPY OF

ASTHMA
AND CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
ASTHMA
Asthma (from the Greek ,
sthma, "panting") is a common
chronic inflammatory disease of
the airways characterized by
variable and recurring symptoms,
reversible airflow obstruction and
bronchospasm. Common
symptoms include wheezing,
coughing, chest tightness, and
shortness of breath.
 PHARMACOLOGICAL APPROACH

BRONCHODILATOR DRUGS
Beta2-agonists
Methylxanthines
Muscarinic antagonists

ANTI-INFLAMMATORY OR IMMUNOMODULATOR
DRUGS
Corticosteroids
Leukotriene receptor antagonists
Anti-IgE monoclonal antibodies
PHARMACODINAMICS OF
BRONCHODILATORS

Katsungetal,BasicandClinicalPharmacology12thedition
PHARMACODINAMICS OF
BRONCHODILATORS
PHARMACODINAMICS OF
BRONCHODILATORS

M3

M3
 BETA2-AGONISTS
Noradrenaline
Modifications of the amine chain
of catecholamines
Adrenaline determine the beta2-receptor
selectivity
IsopreterenoI/
Isoprenaline

Salbutamol

Salmeterol

Formoterol

GoodmanandGillman,12thedition
 DIRECT BRONCHODILATOR
EFFECTS
Adenylate Beta2-AR
cyclase

+
Gs
cAMP ATP

o Opening of K+ channels with

PKA hyperpolarization
phosphorylates o Closing of voltage-dependent [Ca++ ]
target
channels
substrates in
o Inhibition of PLC-IP-Ca++ pathway
bronchial
smooth muscle o Increased Na + /Ca ++ exchange
cells o Increased Ca ++ ATPase activity
ModifiedfromRosenbaumatal,Nature2009
 INDIRECT BRONCHODILATOR
EFFECTS
o Inhibition of bronchoconstrictor mediator release
by inflammatory cells, such as macrophages and
mast cells
o Reduction of acetylcholine release via pre-
synaptic beta2-receptors activation
Inhibition of
cholinergic broncho-obstructive reflex
o Increase of mucociliary clearance
 SHORT-ACTING BETA2-AGONISTS
(SABA)
SALBUTAMOL - TERBUTALINE - FENOTEROL []
Onset of action: 5 minutes
Duration: 3-4 hours
Inhalatory formulations (metered-dose inhaler or
hand-held nebulizer) are the most commonly
used reduction of systemic side
effects
Available also in tablet form (salbutamol,
terbutaline) or as subcutaneous injection
(terbutaline 0,25 mg)

Reliever drugs in acute asthma

 LONG-ACTING BETA2-AGONISTS
(LABA)
SALMETEROL - FORMOTEROL - ARMOFOTEROL []
Salmeterol: partial agonist
Formoterol: full agonist
Onset: 20-30 minutes
Duration: up to 12 hours
Twice a day administration
Inhalatory formulations (metered-dose inhaler or
hand-held nebulizer) in association with
corticosteroids are the most commonly used

Controller drugs in asthma

- Long-term improvement of symptoms
- Prevention of reacutizations
 SIDE EFFECTS

Headache
Restlessness
Anxiety
Insomnia
Tremor of skeletal muscles
Tachyarrhythmias
Hypokaliemia
Hypossiemia and paradox bronchospasm
 METHYLXANTHINES

Theophylline,
Caffeine and
Theobromine, derive
from tea, coffee and
cocoa, respectively

3,7-dimethylxanthine A theophylline
preparation commonly
used for therapeutic
purpose is
Aminophylline, a
theophylline-
ethylenediamine
complex
1,3,7-trimethylxanthine 1,3-dimethylxanthine

Katsungetal,BasicandClinicalPharmacology12thedition
 THEOPHYLLINE:
MAIN MECHANISMS OF ACTION
Non-selective inhibition of phosphodiesterase (PDE) enzyme,
resulting in higher concentrations of intracellular cAMP and
cGMP
PDE4 is the most involved in regulation of airway smooth muscle
relaxation and inhibition of cytokines and chemokines release from
inflammatory cells

Inhibition of cell surface receptors for adenosine (A1A, A2A,

A2B)
Adenosine has been shown to provoke contraction of isolated airway
smooth muscle and histamine release from airway mast cells

Inhibition of nuclear translocation of NF-KB, pro-inflammatory

transcription factor, and activation of histone deacetylase
Block of inflammatory gene transcription
Synergic effect with corticosteroids
INFLAMMATORY CELLS STRUCTURAL CELLS

GoodmanandGillman,12thedition
 PHARMACOKINETICS AND
CLINICAL USE
Low doses of theophylline are used for long-term control
of moderate-severe asthma, as the sole maintenance
treatment or in addiction to inhaled corticosteroids

Oral administration (200 mg x 4 daily - 400 mg x 3 daily)

Intravenous administration (slow infusion; maximum
velocity 25 mg/min)
Available formulations for intramuscular and rectal use
Drug-plasmatic proteins bond: 60%
Hepatic metabolism (CYP1A2 and CYP2E1 are involved)
Half-life: 3,5-9 hours
 SIDE EFFECTS

Gastric symptoms, nausea, emesis

Headache PDE4 INHIBITION
CNS stimulation, irritability, insomnia
Epileptic crisis A1
Diuresis RECEPTOR
ANTAGONIS
Cardiac arrhytmias M
PDE3 INHIBITION
Peripheral vasodilation, hypotension
MUSCARINIC ANTAGONISTS

Observation of the use of

leaves from Datura
stramonium for asthma
treatment in India led to the
discovery of Atropine, the
prototypical competitive
inhibitor of acetylcholine at
postganglionic muscarinic
receptors, as a bronchodilator

Synthetic quaternary
ammonium compounds,
Ipratropium bromide,
Tiotropium bromide and
Ossitropium bromide, are
commonly used in clinics as
 MECHANISMS OF ACTION

Muscarinic antagonists competitively inhibit

the effect of acetylcholine at muscarinic
receptors in the airways

Muscarinic antagonists block the contraction of airway

smooth muscle and the increase in secretion of mucus
that occurs in response to vagal activity

The selectivity of muscarinic antagonists limits their

usefulness in preventing bronchospasm they inhibit
only that portion of the response mediated by
muscarinic receptors, which varies by stimulus, and
which further appears to vary among individual
 REGULATORY ROLE OF
ACETYLCHOLINE IN INFLAMMATORY
CELL ACTIVATION

Soler,CurrAllergyAsthmaRep(2014)
 TIOTROPIUM BROMIDE
Indicated by soft-inhaler as
controller of bronchoconstriction in
severe asthma, in addiction to
corticosteroids and antileukotriene
drugs
Inhalatory use
Slow onset of action: 30-
60 minutes
Long duration: 24 hours (LAMA)
One daily administration

Mundyandal.,NatureRevDrugDiscovery2004
 SIDE EFFECTS

Xerostomia
Tachycardia
Constipation
Difficulties of urination
Tachycardia Increasing
doses of the
Mydriasis
drug
Blurred vision
Confusion and memory deficit
Agitation
Hallucination
Delirium
 CORTICOSTEROIDS

HYDROCORTISONE BECLOMETHASO BUDESONIDE

NE
DIPROPIONATE

FLUTICASON FLUNISOLIDE TRIAMCINOLONE ACETONIDE

E
PROPIONATE GoodmanandGillman,12thedition
 ANTI-INFLAMMATORY ACTIONS

Corticosteroids enter the cell, bind to the glucocorticoid

receptor (GR) in the cytoplasm and translocate to the
nucleus
Through transactivation, binding of the activated
glucocorticoid receptor homodimer to a
glucocorticosteroid response elements (GRE) in the
promoter region of steroid-sensitive genes leads to the
transcription of genes encoding anti-inflammatory
mediators such as annexin1, secretory leukoprotease
inhibitor, IL10 and the inhibitor of nuclear factorB

Through transrepression, the glucocorticoid receptor-

corticosteroid complex interacts with large co-activator
molecules with intrinsic histone acetyltransferase (HAT)
activity (such as cAMP response element binding
protein), which are activated by proinflammatory
transcription factors, such as NFB, thus switching off
Holgateetal,NatRevImmunol.2008
ANTI-INFLAMMATORY ACTIONS

Holgateetal,NatRevImmunol.2008
 EFFECTS IN THE AIRWAYS

INFLAMMATORY CELLS
o Increase of eosinophils apoptosis
o Reduction of mast cells and dendritic cells number
o Inhibition of cytokines release by T-lymphocytes and
macrophages

STRUCTURAL CELLS
o Reduction of mucous secretion
o Increase of beta2-receptor responsivity in the smooth
muscle
o Inhibition of cytokines and mediators release by
epitelial cells
o Inhibition of extravasation
 CLINICAL USE OF
CORTICOSTEROIDS
Inhalatory corticosteroids are used as first-choice controller drugs

Inhaled corticosteroid Total daily dose (mcg)

Low Medium High

Beclometasone dipropionate >500

200500 >1000
(CFC) 1000
Beclometasone dipropionate
100200 >200400 >400
(HFA)
Budesonide (DPI) 200400 >400800 >800
Ciclesonide (HFA) 80160 >160320 >320
Fluticasone propionate (DPI
100250 >250500 >500
or HFA)
Mometasone
Most of thefuroate
clinical benefit from110220
ICS is seen>220440
at low doses >440
High doses are arbitrary, but for most ICS are >1000
those that, with
Triamcinolone acetonide 4001000 >2000
prolonged use, are associated with increased 2000
risk of systemic side-
effects

Globalinitiativeforasthma(GINA)2015
 SIDE EFFECTS
LOCAL
Dysphonia
Oropharyngeal candidiasis
Cough

SYSTEMIC - at high doses -

Adrenal insufficiency
Growth delay in children
Osteoporosis
Glaucoma, cataract
Metabolic disturbances (glucose, insulin,
triglycerides)
Euphoria, mood deflection
Respiratory infections
 ANTILEUKOTRIENE DRUGS
LEUKOTRIENES IN ASTHMA
Leukotrienes (LT) result from the action of 5-lipoxygenase on
arachidonic acid and they are synthesized by inflammatory
cells in the airways, including eosinophils, mast cells,
macrophages, basophils

Main effects
Neutrophil chemoattraction (LTB4)
Bronchoconstriction (LTC4 - LTD 4)
Increased bronchial reactivity (LTC4 - LTD4)
Mucosal oedema (LTC4 - LTD 4)
Mucus hypersecretion (LTC4 - LTD4)
 PHARMACODYNAMIC PROPERTIES
LTD 4-
receptor
Antagonis
ts

5-
lipoxygenas
e
Inhibitor
Katsungetal,BasicandClinicalPharmacology12thedition
 PHARMACOKINETICS AND
CLINICAL USE
Long-term control of moderate-severe asthma, as
the sole maintenance treatment or in addiction to
inhaled corticosteroids

Oral administration
Drug-plasmatic proteins bond: 70-90%
Hepatic metabolism (CYP2C9 CYP3A4)
Half-life
- Zafirlukast: 10 hours
- Montelukast: 3-6 hours
- Zileuton: 2-3 hours
 SIDE EFFECTS

Headache

Nausea, diarrhoea

Skin hypersensitivity

Churg-Strauss syndrome, characterized by systemic

vasculitis, eosinophilia, sinusitis and rhinitis rare side
effect

Hepatic dysfunction associated with haematic parameters

alterations (zafirlukast)

Anxiety, mood deflection (montelukast)

 ANTI-IGE MONOCLONAL
ANTIBODIES
OMALIZUMAB
It is a biological engineered, humanized recombinant monoclonal
anti-IgE antibody
It is reserved for patients with demonstrated IgE-mediated
sensitivity by positive skin test or radioallergosorbent test (RAST)
to common allergens and an IgE level within a range (clinical
benefits are reduced in patients with IgE level < 76 UI/ml)
The recommended dose of 600 mg must be administered twice-
weekly by subcutaneous injection

CLINICAL USE
Add-on therapy in patients with severe persistent asthma who are
inadequately controlled, despite best available therapy
MECHANISM OF ACTION

Holgateetal,NatRevImmunol.2008
 MENAGEMENT OF
MANAGEMENT OF ASTHMA

ASTHMA STEP 5

STEP 4
STEP 3
PREFERRED STEP 1 STEP 2 Refer
ONTROLLER for add-
Med/high on
CHOICE treatme
Low dose ICS/LABA nt
Low dose ICS ICS/LABA* e.g.
anti-IgE
Add
Other Consider Leukotriene receptor antagonists (LTRA) Med/high dose Add
tiotropium# tiotropiu
controller low dose Low dose theophylline* ICS High dose ICS m#
ICS Low dose
options As-needed short-acting beta2-agonist ICS+LTRA
+ LTRA Add low
(or + theoph*) dose OCS
RELIEVE (or +As-needed
theoph*) SABA or
R (SABA) low dose ICS/formoterol**

*For children 6-11 years, theophylline is not recommended, and

preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol
maintenance and reliever therapy
# Tiotropium by soft-mist inhaler is indicated as add-on treatment for
patients with a history of exacerbations; it is not indicated in children
<18 years Globalinitiativeforasthma(GINA)2015
 ACUTE ASTHMA

MILD or MODERATE SEVERE

Talks in phrases
Prefers sitting to lying
Not agitated
Respiratory rate increased
Accessory muscles not used
Pulse rate 100120 bpm
O2 saturation (on air) 9095%
PEF >50% predicted or best
Talks in words
Sits hunched forwards
Agitated
Respiratory rate >30/min
Accessory muscles being used
Pulse rate >120 bpm
O2 saturation (on air) < 90%
PEF 50% predicted or best

Short-acting beta2-agonists Short-acting beta2-agonists

Consider ipratropium bromide Ipratropium bromide
Controlled O2 to maintain Controlled O2 to maintain
saturation 9395% (children 94-98%) saturation 9395% (children 94-98%)
Oral corticosteroids Oral or IV corticosteroids
Consider IV magnesium
Consider high dose ICS

Globalinitiativeforasthma(GINA)2015
 CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
(COPD)
Chronic obstructive pulmonary disease (COPD), also known as
chronic obstructive lung disease (COLD), and chronic obstructive
airway disease (COAD), among others, is a type of obstructive lung
disease characterized by chronically poor airflow. It typically
worsens over time. The main symptoms include shortness of
breath, cough, and sputum production. Most people with chronic
bronchitis have COPD.

Tobacco smoking is the most common cause of COPD, with a

number of other factors such as air pollution and genetics playing a
smaller role. Long-term exposure to these irritants causes an
inflammatory response in the lungs resulting in narrowing of the
small airways and breakdown of lung tissue known as emphysema.
Male

Female
 Global Strategy for Diagnosis, Management and
Prevention of COPD
COPD MEDICATIONS
BETA2-AGONISTS
Short-acting beta2-agonists
Long-acting beta2-agonists
ANTICHOLINERGICS
Short-acting anticholinergics
Long-acting anticholinergics
Combination short-acting beta2-agonists +
anticholinergic in one inhaler
Combination long-acting beta2-agonist + anticholinergic
in one inhaler
METHYLXANTHINES
INHALED CORTICOSTEROIDS
Combination long-acting beta2-agonists +
corticosteroids in one inhaler
PHOSPHODIESTERASE-4
2015
INHIBITORS
Global Initiative for Chronic Obstructive Lung Disease
2015GlobalInitiativeforChronicObstructiveLungDisease
 BRONCHODILATORS

Bronchodilator medications are central to the

symptomatic management of COPD
They are prescribed on an as-needed or on a
regular basis to prevent or reduce symptoms
The principal bronchodilator treatments are
BETA2-AGONISTS, ANTICHOLINERGICS,
THEOPHYLLINE or combination therapy
The choice of treatment depends on the
availability of medications and each patients
individual response in terms of symptom relief and
side effects

2015GlobalInitiativeforChronicObstructiveLungDisease
 BRONCHODILATORS

LONG-ACTING INHALED BRONCHODILATORS

are convenient and more effective for symptom
relief than SHORT-ACTING
BRONCHODILATORS, because they reduce
exacerbations and related hospitalizations and
improve symptoms and health status
Combining bronchodilators of different
pharmacological classes may improve efficacy
and decrease the risk of side effects compared
to increasing the dose of a single bronchodilator

2015GlobalInitiativeforChronicObstructiveLungDisease
 INHALED CORTICOSTEROIDS

Regular treatment with inhaled

corticosteroids improves symptoms, lung
function and quality of life and reduces
frequency of exacerbations for COPD patients
with an FEV1 < 60% predicted
Inhaled corticosteroid therapy is associated
with an increased risk of pneumonia
Withdrawal from treatment with inhaled
corticosteroids may lead to exacerbations in
some patients

2015GlobalInitiativeforChronicObstructiveLungDisease
 COMBINATION THERAPY

An inhaled corticosteroid combined with a long-

acting beta2-agonist is more effective than the
individual components in improving lung function
and health status and reducing exacerbations in
moderate to very severe COPD.
Combination therapy is associated with an
increased risk of pneumonia.
Addition of a long-acting beta2-agonist/inhaled
glucorticosteroid combination to an
anticholinergic (tiotropium) appears to provide
additional benefits

2015GlobalInitiativeforChronicObstructiveLungDisease
 PHOSPHODIESTERASE-4
INHIBITORS
In patients with severe and very severe COPD
(GOLD 3 and 4) and a history of
exacerbations and chronic bronchitis, the
PDE-4 inhibitor, ROFLUMILAST, reduces
exacerbations treated with oral
corticosteroids

2015GlobalInitiativeforChronicObstructiveLungDisease
 THEOPHYLLINE

Theophylline is less effective and less well

tolerated than inhaled long-acting
bronchodilators

It is not recommended if previous drugs are

available and affordable

Addition of theophylline to salmeterol

produces a greater increase in FEV1 and
breathlessness than salmeterol alone

Low dose theophylline reduces exacerbations

but does not improve post-bronchodilator
2015GlobalInitiativeforChronicObstructiveLungDisease
 OTHER PHARMACOLOGIC
TREATMENTS
INFLUENZA VACCINES can reduce serious illness
PNEUMOCOCCAL POLYSACCHARIDE VACCINE is
recommended for COPD patients 65 years and older
and for COPD patients younger than age 65 with an
FEV1 < 40% predicted
MUCOLYTICS: patients with viscous sputum may
benefit from mucolytics; overall benefits are very small

THE USE OF ANTIBIOTICS, OTHER THAN FOR TREATING

INFECTIOUS EXACERBATIONS OF COPD AND OTHER
BACTERIAL INFECTIONS, IS CURRENTLY NOT INDICATED

2015GlobalInitiativeforChronicObstructiveLungDisease