CHAPTER

FIVE
DRUGS ACTING
THE
ON RESPIRATORY
SYSTEM
INTRODUCTION
 Respiratio
n:
Respiration
is the exchange of gases between
the tissue of the body and to
outside environment
process of air exchange
oxygen is obtained and carbon dioxide
is eliminated
gas exchange occurs in the alveoli
It
involves:
 breathing in of an air through
the respiratory tract
 uptake of oxygen from the lungs

 transport of oxygen through

the body in the blood stream
 utilization of oxygen in the
metabolic activities (cells) and
 removal of carbon dioxide from
the body
Respiratory Tract
nose, pharynx, larynx,
trachea, bronchi,
series of tubes that function
as airway passages
filters, warms and
humidifies incoming air
 Bronch
i that extend from the trachea to the
The bronchi are small air passages, composed of hyaline
cartilage,
bronchioles

There are two bronchi in the human body that branch

off from the trachea

The bronchi are lined with mucous membranes

that secrete mucus and cilia that sweep the mucus
and particles up and out of the airways
 Alveol
i thin membrane that
Have a very
allows rapid diffusion of oxygen and
carbon dioxide between capillary
blood and alveolar air spaces

Lined with surfactant to

prevent alveolar collapse
 Nervous System
Role system regulates the rate
Nervous
and depth of respirations

Medulla oblongata is the

respiratory control system of the
brain

Cough reflex is stimulated by

nervous system
Disorders of Respiratory System
Infections: pneumonia, tuberculosis

Allergic disorders

Inflammatory disorders

Obstructive airway

disorders
 Bronchial pulmonary dysplasia
– premature infants
 Asthma
 Chronic obstructive pulmonary
diseases (COPD)
Drugs for Asthma and Broncho-
constrictive Disorders
Asthma
Asthma is a chronic inflammatory disorder of the
airways in which many cells and cellular elements play
a role: in particular mast cells, eosinophils, T-
lymphocytes, macrophages, neutrophils, and epithelial
cells

characterized by:
 Hyper-reactivity to various stimuli - trigger
 Broncho-constriction
 Inflammation
Impairment of airflow in bronchial
asthma
is caused by three bronchial
abnormalities:
i. contraction of airway smooth muscles

ii.thickening of bronchial mucosa from

edema and cellular infiltration

iii.inspissation in the airway lumen

of abnormally thick, viscid plugs of
Here comes
asthma!
Clinical Manifestations –
Asthma
Dyspnea – difficulty
breathing Wheezing
Chest
tightness
Cough
Sputum
production
Precipitating Factors –
Triggers
Viral infections – especially with infants and
young children

Allergens

GERD – Gastro Esophageal Reflux

Disease Cigarette smoke

Smoggy air – smoke from fires

Windy weather – hot and dry Santa Ana winds,

cold air, ozone
 Pathophysiology
Acute reaction to some trigger
– reversible with treatment

Mast cells release substances that

cause inflammation and constriction

Broncho-constriction or
bronchospasm which is aggravated
by inflammation, mucosal edema
and excessive mucus
Inhaled allergen challenge
models contribute most to our
understanding of acute inflammation
in asthma
inhaled allergen challenge in allergic
patients leads to an early phase allergic
reaction that, in some cases, may be
followed by a late- phase reaction
the activation of cells bearing allergen-
specific IgE initiates the early phase
reaction
It is characterized primarily by the rapid
activation of airway mast cells and
macrophages

the activated cells rapidly release

proinflammatory mediators such as
histamine, eicosanoids, and reactive oxygen
species that induce contraction of airway
smooth muscle, mucus secretion, and
vasodilation
The late-phase inflammatory
reaction occurs 6 to 9 hours after
allergen provocation and involves
the recruitment and activation of
eosinophils, CD4+ T cells, basophils,
neutrophils, and macrophages
Types
There are two
types of bronchial
asthma
1. extrinsic and
2. intrinsic
 1. Extrinsic
asthma
 associated with
 history of
allergies in
childhood
 family history of
allergies
 hay fever, or
 2. Intrinsic
asthma
occurs in middle-
aged
subjects with no
family history of
allergies
negative skin
 PHARMACOTHERAPY OF
BRONCHIAL ASTHMA
Asthmatic bronchospasm results from a combination of
release of mediators and an exaggeration of
responsiveness to their effects

this predicts that asthma may be effectively treated

by drugs with different modes of action:
 reduce the amount of IgE bound to mast cells (anti-
IgE antibody)
 prevent mast cell degranulation (cromolyn or
nedocromil, sympathomimetic agents, calcium channel
blockers)
 block the action of the products
released (antihistamines and
leukotriene-receptor antagonists)
 inhibit the effect of acetylcholine released
from vagal motor nerves (muscarinic
antagonists) or
 directly relax airway smooth muscle
(sympathomimetic agents,
theophylline)

Drugs used in the treatment of

bronchial asthma can be grouped into
three main categories:-
 1.
Bronchodilators
a. β- Adrenergic agonists which
include:
 Non selective β-agonists e.g. adrenaline
 Selective β-agonists e.g. salbutamol

b. Methyl xanthines:
theophylline derivatives
c. Muscranic receptor antagonists
e.g. Ipratropium bromide
2. Mast cell stabilizers:
 cromolyn sodium
 nedocromil
 Ketotifen
3. Anti-inflammatory
agents:
 corticosteroids
 1.Bronchodilators
are drugs that expand pulmonary air
ways(bronchi) block the early response by
inhibiting immediate bronchoconstriction
some agents especially theophylline and
beta2 adrenergic agonists also inhibit late
response inflammation
In addition to relaxing smooth muscles and reducing
air way reactivity, bronchodilators reduce coughing,
wheezing and shortness of breath
are usually used when a persistent cough and
bronchial constriction are present
 A. β- ADRENERGIC AGONISTS
(SYMPATHOMIMETIC AGENTS)
a) Non- selective- β-
agonists Epinephrine,
ephedrine,
isoproterenol
b). Selective β-agonists
Salbutamol, terbutaline,
metaproterenol, salmeterol,
formaterol and etc
Mechanism of
Action
They have several pharmacological actions
important in the treatment of asthma:
 Relax smooth muscles

 Inhibit release of inflammatory mediator

or bronchoconstriction substances from mast
cells

 Inhibit microvasculature leakage

 Increase mucociliary transport

a. Non-selective β-
agonists
cause more cardiac
stimulation (mediated by a β1
receptor)

they should be reserved

for special situation
Epinephrine
very effective, rapidly
acting bronchodilator

especially preferable for the relief

of acute attack of bronchial
asthma

Maximal bronchodilation is
achieved 15 minutes after inhalation
and lasts 60–90 minutes
 Administration
 Administeredby inhalation
or subcutaneously
 Side
Occurseffects
due to its stimulatory effect
on alpha,beta-1 &2
 arrhythmia
 worsening of angina pectoris

 increase blood pressure

 tremors etc
Contraindicatio
nhypertension
arrhythmia
 Ephedrin
 was e in China
used for more
than 2000 years before its
introduction into Western
medicine in 1924
 compared to epinephrine, it
has longer duration of action
 more pronounced central effect
and lower potency
 It can be given orally
 b. Selective β2-
agonists
are the most widely used
sympathomimetics for treatment of the
bronchoconstriction of asthma at present
largely replaced non – selective β2-
agonists
are effective after inhaled or
oral administration
have longer duration of action
Commonly used drugs both by oral
and inhalation are:
 Salbutamol
 terbutaline
 metaproterenol
 pirbuterol and
 bitolterol
Albuterol, terbutaline,
metaproterenol, and
pirbuterol Albuterol
are available as metered-dose inhalers

Bronchodilation is maximal within 15–30

minutes and persists for 3–4 hours

Of these agents, only terbutaline is available

for subcutaneous injection (0.25 mg)

The indications for this route are similar to

those for subcutaneous epinephrine—severe
asthma requiring emergency treatment
when aerosolized therapy is not available or
has been ineffective
 Albuterol and terbutaline
are also available in tablet form
One tablet two or three times daily is the
usual regimen
the principal adverse effects of skeletal muscle
tremor, nervousness, and occasional weakness
may be reduced by starting the patient on
half- strength tablets for the first 2 weeks of
therapy
This route of administration presents no
advantage over inhaled treatment and is
thus rarely prescribed
 Salmeterol and
areformeterol
newer generation

long acting β2- selective agonists

(with duration of action 12 hrs or
more)

These drugs appear to interact with

inhaled corticosteroids to improve asthma
control

Because they have no anti-

inflammatory action, they are not
recommended as monotherapy for
Delivery of adrenoreceptor agonists through
inhalation results in the greatest local effect
Generally
on airway smooth muscle with least systemic
toxicity
Side effects
 tremors
 anxiety
 insomnia
 tachycardia
 headache
 hypertension and etc
Precautions:
 hypertension
 cardiac dysfunction
 hyperthyroidism
 glaucoma
 diabetes
 pregnancy
Contraindications
Sympathomimetics
are contraindicated in
patients with known
hypersensitivity to the
drugs
B. METHYLXANTHINES
are found in cola, tea and coffee

are bronchodilators that reduce

bronchial smooth muscle activity, most
likely by increasing intracellular cAMP
level

The three important methylxanthines

are:
 theophylline
 theobromine, and
 Mechanism of
3 main Action
mechanisms:
I . Competitively inhibit phosphodiesterase
(PDE) enzyme leading to increased cAMP
level
ii.They competitively inhibit the action of
adenosine on adenosine (A1 and A2)
receptors
Adenosine has been shown to cause contraction
of isolated airway smooth muscle and to
provoke histamine release from airway mast
cells
iii.Inhibit the release of histamines and
Other Organ system effects of
MXs
 Of the three natural
xanthines, agents theophylline
is most selective in its smooth
muscle effect, while caffeine
has the most marked central
effect
Theophyllin
e The theophylline
preparations most commonly
used for therapeutic purposes
is aminophylline

Theop Diethyl Aminoph

hylline amine ylline
 Clinical
useimproves long-term control of
Theophylline
asthma when taken as the sole
maintenance treatment or when added to
inhaled corticosteroids

is now largely reserved for patients in whom

symptoms remain poorly controlled despite
the combination of regular treatment with an
inhaled anti- inflammatory agents
 C. MUSCRANIC
RECEPTOR
ANTAGONISTS
Mechanism of Action
competitively inhibit the effect of acetylcholine
at muscarinic receptors

block the contraction of air way smooth

muscle se the secretion of mucus that occurs in
response to vagal activity
e.g. atropine sulfate
Antimuscranic antagonist drugs appear to
be slightly less effective than β- agonists
agents in reversing asthmatic
bronchospasm

They appear to be of significant value

in chronic obstructive pulmonary
diseasesperhaps more than asthma

They are useful as alternative therapies

for patients intolerant of β - agonists
 Ipratropium
bromide
is poorly absorbed

does not readily enter the central nervous system

-
-thus permits the delivery of high doses
to muscarinic receptor in the airways

hence, it can safely be used for bronchial

asthma
The addition of ipratropium enhances the
bronchodilation produced by nebulized
albuterol in acute sever asthma
Systemic adverse
effects
include:
 urinary retention
 tachycardia
 loss of accommodation and
agitation and
 local effects like excessive dryness
of mouth
This limits the quantity of atropine
used
2. ANTI-INFLAMMATORY AGENTS

CORTICOSTEROID
S
Are ant-inflammatory drugs similar to
natural corticosteroid hormones
produced by the adrenal cortex

Inhibit late phase asthmatic response

to antigen challenge

Used for both treatment and

prophylactic purposes
 Mechanism of
action
They are presumed to act by their broad
anti inflammatory efficacy mediated in part
by
 inhibition of production of
inflammatory mediators like cytokines
by eosinophils, monocytes, mast cells
and lymphocytes
 reducing number of mast cells lining the
surfaces of airway mucosal cells
 inhibiting chemotaxis and activation
of eosinophils
They also potentiate the effects of
Effects on
airway
 decrease bronchial reactivity
 increase airway caliber
decrease frequency of
asthma exacerbation and
severity of symptoms
Other Organ system effects
The corticosteroids
commonly used are:
hydrocortisone
predinisolone
beclomethasone
triamcinolone and
etc
 The drugs can be
taken by inhalation
as aerosol, oral, or
an IV
administration
 Clinical uses
in
bronchial
asthma
Urgent treatment
severe
of asthma
not improved
with
bronchodilators
IV, inhalation
Nocturnal
asthma
prevention
oral or
inhalation Chronic
asthma
Side
effects:
 Suppression of the
hypothalamic- pituitary-adrenal
axis
 Osteoporosis
 Sodium retention
and hypertension
 Cataract
 impairment of
growth in children
 Susceptibility to infection like
points 2b considered when using
Because of severe adverse effects when given
chronically, oral and parenteral
corticosteroids are reserved for patients
who need urgent treatment and those
who have not improved with
bronchodilators

Aerosol treatment is the most effective way

to decrease the systemic adverse effect of
corticosteroid therapy
Abrupt discontinuation should be
discouraged because of the fear of
adrenal insufficiency

Doses should be decreased

after improvement

Regular or controlled therapy is better

maintained with aerosol
corticosteroids
 3. MAST
CELL
STABILIZERS

e.g.
Cromolyn
sodium &
Mechanism of
action
Stabilize the mast cells so that
release of histamine and other
mediators is inhibited through
alteration in the function of delayed
chloride channel in cell membrane
These drugs have no role once
mediator is released and are used for
casual prophylaxis
Clinical
uses
 Exercise and
antigen induced
asthma

Occupational
asthma
Side effects
Poorly absorbed so
minimal side effect
 throat irritation
 cough
 drynessof mouth
 chest tightness
and wheezing
 LEUKOTRIENE PATHWAY
INHIBITORS
Leukotrienes result from the action of 5-lipoxygenase
on arachidonic acid
are synthesized by a variety of inflammatory cells in
the airways, including eosinophils, mast cells,
macrophages, and basophils
Leukotriene B4 (LTB4) is a potent neutrophil
chemoattractant
LTC4 and LTD4 exert many effects known to occur
in asthma, including bronchoconstriction, increased
bronchial reactivity, mucosal edema, and mucus
hypersecretion
 Mechanism of action
 Two approaches to interrupting the
leukotriene pathway have been pursued:
inhibition of 5-lipoxygenase, thereby
preventing leukotriene synthesis--
zileuton and
inhibition of the binding of LTs to their
receptors on target tissues, thereby
preventing their actions- zafirlukast and
montelukast
hydroperoxyeicosatetraenoic acids
All have been shown to improve asthma control and
to reduce the frequency of asthma exacerbations in
outpatient clinical trials
Their principal advantage is that they are taken orally
and
strong safety profile
as some patients—especially children—comply poorly
with inhaled therapies their popularity has been
increased for use in children
Montelukast is approved for children as young as 6 years
of age
LT antagonists also reduce Aspirin induced asthma,
a disorder affecting nearly 10% of cases of asthma
Anti-IgE Monoclonal
AntibodiesOmalizumab
An entirely new approach to
the treatment of asthma

targeted against the portion of IgE

that binds to its receptors (FC -R1
and FC -R2 receptors) on mast cells
and other inflammatory cells
Omalizumab (an anti-IgE monoclonal
antibody) inhibits the binding of IgE to mast and
thus does not provoke mast cell degranulation

It may also inhibit IgE synthesis by B lymphocytes

Its most important effect is reduction of the

frequency and severity of asthma
exacerbations, even while enabling a reduction
in corticosteroid requirements
TREATMENT OF STATUS
ASTHMATICS
Very severe and sustained
attack of asthma which
fails to respond to
treatment with usual
measures
Managemen
t  Administration of oxygen
Frequent or continuous
administration of
aerosolized ß2 agonists
like salbutamol
 Systemic corticosteroids
like methyl prednisolone or
hydrocortisone IV
 Aminophylline IV infusion
 Iv fluid to avoid
dehydration
 Antibiotics in the presence
of evidence of infection
 CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
COPD is characterized by airflow limitation
that is not fully reversible with bronchodilator
treatment
broncho-constriction and inflammation are
more constant and less reversible
changes have occurred over the years
the airflow limitation is usually progressive and
is believed to reflect an abnormal inflammatory
response of the lung to noxious particles or
gases
 The condition is most often a consequence of
prolonged habitual cigarette smoking, but
approximately 15% of cases occur in
nonsmokers may be due to:
 heredity
 second hand smoke
 exposure to air pollution and
 history of childhood
respiratory infections
It encompasses emphysema and
chronic
bronchiti
s
 Emphysema
causes irreversible lung damage by weakening and destroying air
sacs within the lungs, which reduces lung elasticity and causes air
way collapse and obstruction
Loss of elasticity of the lung tissue
Destruction of structures supporting the alveoli and
capillaries feeding the alveoli
Increased alveolar gas volume
 Chronic bronchitis
Is an inflammatory disease that begins in
smaller lung airways and advances gradually
to larger airways

Increased mucus in the airways and more

frequent bacterial infectionsin the
bronchi , which in turn impedes air flow
COPD - Clinical Manifestations
Dyspnea – difficulty
breathing Activity
intolerance
Cough and sputum production
Chest tightness
Progressive
Although asthma and COPD are both
characterized by
COP and
 airway inflammation
ASTHMA
 reduction in maximum expiratory
flow and
 episodic exacerbations of airflow
obstruction—most often triggered by
viral respiratory infection—they
differ in many important respects
Most important among their differences are:
 differences in the populations affected
 characteristics of airway inflammation
 reversibility of airflow obstruction
 responsiveness to corticosteroid treatment, and
course and prognosis
Compared with asthma, COPD:
 occurs in older patients
 is associated with neutrophilic rather than
eosinophilic inflammation
 is poorly responsive even to high-dose
inhaled corticosteroid therapy, and
 is associated with progressive, inexorable loss
of pulmonary function over time, especially
with continued cigarette smoking
Pharmacologic treatment- COPD
🞇 Despite these differences, the approaches to
treatment are similar for asthma and COPD,
although the benefits expected (and achieved)
are less for COPD than for asthma

Acute
inhalationsymptoms
of a short-acting agonist (e.g.
albuterol) anticholinergic drug (e.g. ipratropium
bromide) or the two in combination is usually
effective
 Persistent
symptoms
 Include exertional dyspnea and limitation
of activities
 regular use of a long-acting
bronchodilators, whether –
 long-acting agonist (e.g., salmeterol) or
 long-acting anticholinergic
(e.g., tiotropium) is indicated
For patients with severe airflow
obstruction or with a history of
exacerbations, regular use of an
inhaled corticosteroid reduces the
incidence of future exacerbations
Theophylline may have a particular place in
COPD, since it may improve contractile
function of the diaphragm, thus improving
ventilatory capacity
Continuous nasal oxygen may be required as
the disease progresses
The major difference in management of
exacerbations is in the routine use of
antibiotics, because exacerbations in COPD far
more often involve bacterial infection of the
lower airways than occurs in asthma
 ANTI-
COUGH
TUSSIVES
Is forceful release of air from the lungs
Is a sudden often involuntary reflex and a
major defense mechanism
is a protective reflex, which serves the purpose
of expelling sputum and other irritant materials
from the respiratory airway
Air way irritation activates the reflex by
stimulating the airways, which then activates
afferent nerves going from respiratory
passages through the vagal nerve to the
medulla
 Etiolog
y are due to viral illness
o Most coughs
– common cold
o Medication (particularly ACEIs)
(<1%)
o Postnasal drip -vagal irritation
o Post URI
o GERD (mediated via vagal
irritation)
o Asthma
Types:
a. Useful productive cough
Effectively expels secretions
and exudates
b. Useless cough
Non-productive chronic
cough Due to smoking and
local
irritants
Antitussives
…..drugs used to suppress the intensity
are
and frequency of coughing
Coughs triggered by drainage of mucus from
nasal passages into airways are treated with
these drugs

MOA--Suppress cough by depressing the

cough center of the medulla oblongata or
cough receptors in the throat

2 types-
 Central
 peripheral
1. Central
antitussives
Suppress the medullay cough
center and may be divided into
two groups:
 Opoid antitussive

e.g. codeine, hydrocodeine, etc

 Non opoid antitussives

e.g. dextromethorphan
2. Peripheral
 Decrease the input of stimuli from
antitussives
the cough receptor in the
respiratory passage
 Include:
Demulcents- coat the irritated
pharyngeal mucosa and exert a
mild analgesic effect locally
e.g. liquorices lozenges,
honey Local anesthetics
e.g. lidocaine aerosol
 CODEIN
E relatively less
is a narcotic
addicting drug and
central antitussive agent
it’s main side effects
are dryness of mouth,
constipation and
dependence
 DEXTROMETROPHAN
is non opoid
antitussive
synthetic
essentially free of
analgesic and addictive
properties the main side
effect is
respiratory depression
 DECONGESTANTS
are drugs that reduce congestion of nasal
passages, which in turn open clogged
nasal passages and enhance drainages of
the sinuses
e.g.
 phenylephrine
 oxymetazoline etc
Mechanism of
Action
Mucus membrane
decongestants are α1 agonists,
which produce localized
vasoconstriction on the small
blood vessels of the nasal
membrane
reduce congestion in
nasal passages
Classification:
1.Short acting decongestants administered
topically
 Phenylepherne
 Phenylpropanolamine

2. Long acting decongestants administered orally

 Ephedrine
 Pseudoephedrine
 Naphazoline

3. Long acting topical decongestants

 Xylometazoline
 oxymetazoline
Clinical
uses:
Used in congestion associated with :
hay fever
 allergic rhinitis and
to a lesser extent common

cold Drugs can be administered

nasally or orally for longer duration of
action
Side
effects:
1.Rebound nasal congestion
2. Ischemic changes in
mucus membranes
3. Nasal burning, stinging,
dryness
4. Tachycardia, arrhythmia,
nervousness, restlessness,
insomnia, blurred vision
Contraindications
Hypertension
 severe
coronary artery
disease