An Assignment on

Pathophysiology and Drug

Therapy of Respiratory
Disorders.
m
By Shaik Shoaib. M
pharmacy First year
(pharmacology)Ht no:
10Y81S0-115
Contents
1 Pathophysiology And Drug Therapy of Bronchial Asthma.

2 Pathophysiology And Drug Therapy of COPD.

3 Pathophysiology And Drug Therapy of Cough.

Bronchial Asthma:
Asthma is a chronic inflammatory
disorder of the airways that causes
recurrent episodes of wheezing,
breathlessness, chest tightness, and cough,
particularly at night and/or early in the
morning(1).The clinical picture is caused by
repeated immediate hypersensitivity and late-phase
reactions in the lung that give rise to the triad of
intermittent & reversible airway obstruction,
chronic bronchial
inflammation with eosinophils , and
bronchial smooth muscle cell hypertrophy
& hyper reactivity.
Asthma is a heterogenous disease triggered
by a variety of inciting agents, there is no
universally accepted classification scheme.
About 70% of cases are said to be
³extrinsic´ or ³atopic´ and are due to IgE & TH
2 ±mediated immune responses to
environmental antigens. In the remaining
30% of patients, asthma is said to be
³intrinsic´ or ³non-atopic´ and is triggered
by non-immune mediated stimuli such as
aspirin; pulmonary infections, especially
those caused by viruses; cold;
Pathophysiology:
Allergic asthma is a disease characterized by
intermittent airway obstruction that causes
difficulty in breathing and, in the most severe
cases, death from asphyxiation. Ultimately,
airway obstruction is mediated by hyper
responsive bronchial smooth muscle, secreted
airway glycoprotein, and inflammatory debris
produced by airway goblet cells and other cells,
as well as edema or swelling of the airway wall.
Studies during the past 35 years have revealed 2
principal immune mechanisms that lead to airway
obstruction in the setting of allergic inflammation, both
of which ultimately depend on the presence in the lung
of a terminally differentiated subset of T helper cells,
the T helper cell type 2 (TH2 cell). The TH2 cells secrete
a highly characteristic cytokine repertoire that includes
interleukin-4 (IL-4), IL-5, IL-9, and IL-13, all of which
contribute to the various manifestations of allergic
inflammation and disease. The first TH2- dependent
mechanism leading to airway obstruction, the type 1 or
immediate hypersensitivity response, is mediated by
immunoglobulin E (IgE), an antibody isotype that is
produced by B cells activated by IL-4.
irculating IgE is captured by
immunoglobulin receptors (Fc receptor
I [Fc RI]) present on immune effector
cells such as mast cells/basophils ,
eosinophils , and other airway cells.
Subsequent encounters with antigen
induce Fc RI cross-linking, cellular
activation, degranulation , and release
of a variety of toxic inflammatory
molecules that ultimately elicit
obstruction.
There are many potentially toxic substances
released by degranulating eosinophils and
basophils/mast cells,
but of particular importance in asthma are the
leukotrienes, lipid mediators of inflammation
derived from arachidonic acid. These short-lived
small molecules exist in a variety of isoforms,
mostly as
distinct products of various arachidonic
acidmodifying enzymes. Acting through a variety
of G protein-coupled receptors, leukotrienes
induce or augment many features of asthma,
including airway hyperresponsiveness,
eosinophilia, and airway glycoprotein
hypersecretion.
A second TH2-dependent pathway underlying airway
obstruction, the type 4 hypersensitivity response, was
recognized through studies of
immunoglobulindeficientmice3 and is mediated
through the TH2cytokines IL-4 and IL-13.3,4 Both
cytokines, but predominantly IL-13, act directly on
airway smooth muscle and the epithelium to elicit
airway hyper reactivity, enhanced glycoprotein
production, and eosinophilia, the same features of
disease elicited by leukotrienes. Despite the strikingly
similar effect of IL-4 and IL-13 and leukotrienes on
airway disease, IL- 4 and IL-13 signal through an
entirely different receptor complex that includes the Į
chain of the IL-4 receptor,5±7
members of the Janus family of tyrosine
kinases, and signal transducer and activator of
transcription 6.8±10 Both IL-4 and IL-13 also
contribute indirectly to disease by participating in
type 1 immediate hypersensitivity reactions: IL-4
is required (together with IL-9) for mast cell
maturation11 and IgE secretion12±14 and signals
through Į chain of the IL-4
receptor, along with IL-5,15 mediate eosinophil
recruitment to the lung.3 Thus, the
pathophysiology of asthma reflects the coalescence
of transcriptional events coordinated through
multiple immune
receptors, including Fc RI, the leukotriene
receptors, and Į chain of the IL-4 receptor.
Bronchial Submucosal Glands:
Bronchial submucosal glands are increased in
size in individuals with asthma, but at some
stage, patients with chronic bronchitis also
show increased bronchial
submucosal glands, which is the basis for the
Reid index in chronic bronchitis.38±41 In fact,
increased bronchial submucosal glands
apparently are found in individuals with
recent onset of asthma rather than in
patients with long-standing asthma
Smooth Muscle:
Patients dying of status asthmaticus have a 2-fold to
3-fold increase in the amount of airway smooth
muscle, especially in the medium-sized bronchi.
This finding has been well documented by several
morphometric studies.43±45 Smooth muscle
thickness in asthmatic patients appears to increase
with age.46 It has been proposed that
myofibroblasts play a role in this smooth muscle
thickening and also in the reticular basement
membrane thickening because of the production
and deposition of fibronectin in the bronchial
mucosa.47 Presence of myofibroblasts has been
associated with local expression of TGF-ȕ produced
by eosinophils and fibroblasts48;
Some studies show that basal TGF-ȕ1
levels in the airways are elevated in
atopic asthma. The TGF-ȕ1 is up
regulated 24 hours after allergen
stimulation.49 It is thought that these
levels increase further in response to
allergen exposure. These findings are
consistent with the hypothesis that TGF-
ȕ1 plays an important role in airway wall
remodeling in asthmam
Signs & SymptomsO
-Dyspnea,wheezing, shortness
of breath,tightness of the
lungs, production of sputum
,cough. Are the major signs &
symptoms seen.
Management of AsthmaO
Management of asthma depends on the
type of asthma wither atopic, or non
atopic,occupational , or drug-induced .(1)
-In atopic asthma one way is the prevention of the
triggers like dusts & pollens(1).
-In non-atopic asthma taking drug
prophylaxis for viral infections(1).
-Patient education.(9)
-In Occupational asthma a simple way is to
change the position in the company or to
change the work(1).
-In drug-induced asthma by drug
Discontinuation(1).
Pharmacology Treatment O
-As we have said before that in asthma the
bronchi are usually constricted so one way
of treatment is to reduce this constriction
by using:
-B2- Adrenergic receptor Agonist as:
1-Short actingB2-receptor agonist:
Albuterol, Levalbuterol, Pirbuterol, and
Metaproterenol which are used specially in
the acute attack of asthma. -Long acting B2-receptor
agonist: Salmeterol(Serevent), and Formoterol
(Foradil) Also other B2- receptor agonist are used like
Terbutaline, Isoproterenol, Epinephrine, Ephedrine , but
they are with a large adverse effect.
2-Another method is by using
Methylxanthines like : Theophylline which
act as bronchodilator by the action on the
smooth muscles .
3-Leukotriene inhibitors like Zafirlukast,
montelukast, and Zileuton they act by
inhibiting the formation of leukotriene
which are mediators that are increased in asthma
leading to bronchospasm.
4-Anti-IgE antibody : like Omalizumab which
is only used in atopic asthma.
5-Mast cell desensitizers.
6-By using Glucocorticoids : like
beclomethasone they act by inhibition of
Phospholipase A2. It is only used in severe
cases like end-stage asthma.
Chronic Obstructive Pulmonary
Disorder (COPD) Case Study
OPD may include diseases that cause airflow
obstruction (e.g., Emphysema, chronic bronchitis)
or any combination of these disorders. Other
diseases as cystic fibrosis, bronchiectasis, and
asthma that were previously classified as types of
chronic obstructive lung disease are now classified
as chronic pulmonary
disorders. However, asthma is now considered as a
separate disorder and is classified as an abnormal
airway condition characterized primarily by
reversible inflammation. OPD can co-exist with
asthma. Both of these diseases have the same major
symptoms; however, symptoms are generally more
variable in asthma than in OPD.
PATHOPHYSIOLOGY
In OPD, the airflow limitation is both progressive and
associated with an abnormal inflammatory response
of the lungs to noxious particles or gases. The
inflammatory response occurs throughout the airways,
parenchyma, and pulmonary vasculature. Because of the
chronic inflammation and the body¶s attempts to repair it,
narrowing occurs in the small peripheral airways. Over
time, this injury-and-repair process causes scar tissue
formation and narrowing of the airway lumen. Airflow
obstruction may also be caused by
parenchymal destruction, as is seen with emphysema, a
disease of the alveoli or gas exchange units. In addition to
inflammation, processes related to imbalances of
proteinases and antiproteinases in the lung may be
responsible for airflow limitation.
ýhen activated by chronic inflammation,
proteiness and other substances may be
released, damaging the parenchyma of the
lung. The parenchymal changes may occur as
a consequence of inflammation or
environmental or genetic factors (eg. Alpha1-
antitrypsin deficiency). Early in the course of
OPD, the inflammatory response causes
pulmonary vasculature changes that are
characterized by thickening of the vessel wall.
These changes may result from exposure to
cigarette smoke, use of tobacco products, and
the release of inflammatory medicators.
HRONI BRONHITIS:
Lung damage and inflammation in the large airways
results in chronic bronchitis. hronic bronchitis is defined
in clinical terms as a cough with sputum production on
most days for 3 months of a year, for 2 consecutive years.
In the airways of the lung, the hallmark of chronic
bronchitris is an increased number (hyperplasia) and
increased size (hypertrophy) of the goblet cells and mucous
glands of the airway. As a result, there is more mucus than
usual in the airways, contributing to narrowing of the
airways and causing a cough with sputum. Inflammation is
followed by scarring and remodeling that thickens the
walls and also results in narrowing of the airways.
Emphysema is a chronic obstructive pulmonary disease
(OPD, as it is otherwise known, formerly termed
a chronic obstructive lung disease). It is often caused by
exposure to toxic chemicals, including long-term exposure
to tobacco smoke. Emphysema is characterized by loss of
elasticity (increased pulmonary compliance) of the lung
tissue caused by destruction of structures feeding the
alveoli, owing to the action of alpha 1 antitrypsin
deficiency. This causes the small airways to collapse during
forced exhalation, as alveolar collapsibility has decreased.
As a result, airflow is impeded and air becomes trapped in
the lungs, in the same way as other obstructive lung
diseases. Symptoms include shortness of breath on
exertion, and an expanded chest.
 TREATMENT
Bronchodilators:
Treating airway obstruction in OPD with
bronchodilators is similar but not identical to
treating bronchospasm in asthma. Bronchodilators
are medications that relax the muscles surrounding
the small airways thereby opening the
airways.Bronchodilators can be inhaled, taken
orally or administered intravenously. Metered dose
inhalers (MDIs) are used to deliver
bronchodilators. MDI is pressurized canister
containing a medication that is released when the
canister is compressed.
Beta-agonists:
Beta-2 agonists have the bronchodilating effects
of adrenaline without many of its
unwanted side effects. Beta-2 agonists can be
administered by MDI inhalers or orally
The action of beta-2 agonists starts within minutes
after inhalation and lasts for about 4 hours. Because
of their quick onset of action, beta-2 agonists
are especially helpful for patients who are acutely
short of breath. Because of their short duration of
action, these medications should be used for
symptoms as they develop rather than as
maintenance.
Examples of beta-2 agonists
include albuterol (Ventolin,
Proventil), metaproterenol
(Alupent), pirbuterol (Maxair),
terbutaline (Brethaire), and
isoetharine
(Bronkosol). Levalbuterol
(Xopenex) is a recently approved
Beta-2 agonist.
Corticosteroids:
When airway inflammation (which causes swelling)
contributes to airflow obstruction, antiinflammatory
medications (more specifically, corticosteroids) may be
beneficial. Examples of corticosteroids include Prednisone
and Prednisolone. Twenty to thirty percent of patients
with COPD show improvement in lung function when
given corticosteroids by mouth.
Corticosteroids also can be inhaled. Inhaled
corticosteroids have many fewer side effects than long
term oral corticosteroids. Examples of inhaled
corticosteroids include beclomethasone
dipropionate (Beclovent, Beconase, Vancenase, and
Vanceril), triamcinolone acetonide (Azmacort),
fluticasone (Flovent),
 cough
Pathophysiology:
A cough is a protective reflex in healthy individuals
which is influenced by psychological factors.The
cough reflex is initiated by stimulation of two
different classes of afferent nerves, namely the
myelinated rapidly adapting receptors, and
nonmyelinated -fibers with endings in the lungs.
However it is not certain that the stimulation of
nonmyelinated -fibers leads to cough with a reflex
as it's meant in physiology (with its own five
components): this stimulation may cause mast cells
degranulation (through an asso-assonic reflex.
Treatment:The most effective drugs in
this class are the opioids, such as
morphine, codeine or pholcodeine, but at
effective doses they have side-effects such
as drowsiness,nausea,constipation and
physical dependence. Investigations into
the cough reflex and into the potential
mechanisms of sensitised cough reflex
have uncovered several potential targets
for novel drugs. New opioids such as k-
and d-receptor agonists apart from m-
agonists have been developed .
Local anaesthetics, blockers of sodium-
dependent channels, and maxi-K CA2+-
dependent channel activators of afferent
nerves are inhibitors of the cough reflex. Some
of these novel agents may act centrally or
peripherally or at both sites as antitussives.
Large scale trials of these novel compounds
have not been tried in cough in man, but there
is a serious need for more effective
antitussives devoid of side-effects.
Reference:
1. www.scribd.com

2. Ran And Dale

3. www.wikipedia.com
The end