KAMPALA INTERNATIONAL UNIVERSITY W-

CAMPUS

ASTHMA AND COPD PHARMACOLOGY

BY.

1
NIWAMANYA NICODEMUS.
 BRONCHIAL ASTHMA

 Asthma is a condition that is characterised by recurrent 'reversible' obstruction of

the airflow in the airways in response to stimuli.

The classification of asthma

Asthma may be chronic or acute.
 In chronic asthma,
➢ the individual has irregular attacks of difficulty in breathing,
➢ wheezing,
➢ coughing.
 Acute severe asthma (also known as status asthmaticus) is not easily reversed. It
can be fatal and requires aggressive treatment. Hospitalisation may also be 2

necessary.
Characteristic features of most cases of asthma are:
 Inflammatory changes in the airways associated with
bronchial hyper-reactivity

The term bronchial hyper-reactivity (or hyper-

responsiveness) refers to abnormal sensitivity to a wide range
of stimuli such as irritant chemicals, cold air, stimulant
drugs, etc., all of which can result in bronchoconstriction.

Causes of Asthmatic attacks

 Allergens (in sensitised individuals), (pollen, animal hair
etc)
 Exercise (in which the stimulus may be cold air)
 Respiratory infections
 Atmospheric pollutants such as sulfurdioxide.
 The NSAIDs, especially aspirin, can precipitate asthma in 3

sensitive individuals.
TYPES OF ASTHMA
A. Extrinsic Asthma (Allergic asthma)
 Asthma associated with specific allergic reactions. E.G.
Exercise – Induced asthma
 This type is the commonest and occurs in patients who
develop allergy to inhaled antigenic substances. Allergen
avoidance is particularly relevant to management of this
type of Asthma.
 Occurs most in children over age of 3 years and in most
young adults.

B. Intrinsic asthma
 Some patients exhibit wheeze and breathlessness in the
absence of any obvious allergen. They are considered to
have an intrinsic asthma because they lack an identifiable
allergen. Allergen avoidance has no place in its
management. 4
PATHOPHYSIOLOGY OF ALLERGIC ASTHMA

 Antigens (foreign materials) such as proteins from house dust, mites,

cockroaches, cat dander, molds, and pollen, sensitize individuals by
eliciting the production of antibodies of the immunoglobulin (Ig) E
and induce expression of IgE receptors.

 Once produced, IgE antibodies bind to receptors on the surface of

mast cells in the airway mucosa. The system thus becomes sensitized
so that subsequent re-exposure to the relevant allergen will cause an
asthmatic attack.

 This is followed by two phases:

5
1. Immediate phase

2. Late Phase
The immediate phase of the asthmatic attack

 In allergic asthma, the immediate phase (i.e. the initial response to

allergen provocation) occurs abruptly and is mainly caused by
spasm of the bronchial smooth muscle. Allergen interaction with
mast cell-fixed IgE causes release of several spasmogens: histamine,
the leukotrienes (LTC4 and LTD4) and prostaglandin D2 (PGD2),
which diffuse through the airway mucosa triggering the muscle
contraction and vascular leakage responsible for the acute
bronchoconstriction of the "early asthmatic response.

Most exercise-induced asthma appears to involve mainly6the

phenomena of this first phase.
The late phase
 The early phase is often followed in 4–6 hours by a second, more sustained phase
of bronchoconstriction, the "late asthmatic response," which is associated with an
influx of inflammatory cells into the bronchial mucosa and with an increase in
bronchial responsiveness that may last for several weeks after a single inhalation of
allergen.

 The mediators responsible for this late response are thought to be cytokines
produced by lymphocytes which stimulate the release of cytokines; especially
interleukins 3, 5, 9 and the toxic proteins. The cytokines are thought to attract and
activate eosinophils, stimulate IgE production by B lymphocytes, and directly
stimulate mucus production by bronchial epithelial cells.

 The toxic proteins causing damage and loss of epithelium.

7


.

8
 AIRWAY OBSTRUCTION
 Three factors contribute to airway obstruction in
asthma:
➢ Contraction of the smooth muscle that surrounds the
airways
➢ Excessive secretion of mucus and in some, secretion of
thick mucus that adheres to the walls of the airways
➢ Edema of the respiratory mucosa.
o Spasm of the bronchial smooth muscle can occur
rapidly in response to a provocative stimulus and
likewise can be reversed rapidly by drug therapy.
o In contrast, respiratory mucus accumulation and
edema formation are likely to require more time to
develop and are only slowly reversible 9
AIRWAY INFLAMMATION
 In this model, antigens, such as pollen or house dust
and animal hair sensitize individuals by eliciting the
production of antibodies of the immunoglobulin (Ig) E
type.
 These antibodies attach themselves to the surface of
mast cells and basophils.
 If the individual is re-exposed to the same antigen
days to months later, the resulting antigen–antibody
reaction on lung mast cells will trigger the release of
histamine and other spasmogens that produce
bronchoconstriction, mucus secretion, and pulmonary
edema.
 Ultimately, repeated exposure to antigen establishes a
chronic inflammatory state in the asthmatic airway. 10
GOALS OF MANAGEMENT OF ASTHMA
 Prevent chronic and troublesome symptoms
 Maintain (near) normal pulmonary function

 Prevent recurrent asthma asthmatic attacks and minimize

the need for emergency department visits or
hospitalizations
 Provide optimal pharmacotherapy with minimal adverse
effects

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NB
 In addition to drug therapy, all asthmatic patients
must be educated about the three key behaviors:
✓ The appropriate use of medications to control
symptoms (e.g., proper technique for use of metered-
dose inhalers)
✓ Recognition of the signs of a deteriorating disease
status (e.g., a progressive increase in the use of
bronchodilators)
✓ Prevention strategies (e.g., avoidance of antigenic
material and other agents the individual may be
sensitive to)

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 DRUGS USED IN TREATMENT ASTHMA
 Classified into three:
A. Bronchodilators ( also called the relievers)
B. Anti-inflammatory agents (also called the
controllers)
C. Alternative therapies

N.B:
 Bronchodilators are effective in reversing the
bronchospasm of the immediate phase while anti-
inflammatory agents are effective in inhibiting or
preventing the inflammatory components of both phases.
 But note that these two categories are not mutually
exclusive: some drugs classified as bronchodilators may
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also have some effect on inflammatory cells.
 BRONCHODILATORS
Drugs used as bronchodilators include
A. β2 - adrenoceptor agonists

Short acting e.g. Salbutamol

Long acting e.g. Salmeterol

B. Non selective adrenergic agonist e.g. Adrenaline

C. Xanthines e.g. Aminophylline
D. Muscarinic receptor antagonists e.g. Ipratropium

14
 THE Β2 -ADRENOCEPTOR AGONISTS

Further subdivided into two:

 Short-acting agents e.g. Salbutamol,
terbutaline,isoproterenol, metaproterenol, and pirbuterol

 Long- acting agents e.g. Salmeterol, formoterol,

fenoterol, and reprotelol.

15
General MOA:
 Their primary effect in asthma is to dilate the bronchi by a
direct action on the β2-adrenoceptors on the smooth muscle.
a. Being physiological agonists, they relax the
bronchial muscle irrespective of the spasmogens
involved.

b. They also inhibit mediator release from mast

cells
Preparation:
 These drugs are usually given by inhalation of aerosol,
powder or nebulised solution, but some may be given orally
or by injection.
16
 PK of Short acting agents:
 They are given by inhalation, orally and
subcutaneously(severe asthma requiring
emergency treatment in absence of
aerosolized therapy or has been
ineffective).
 Maximum effect occurs within 30 minutes
and the duration of action is 4-6 hours

17
PK of Longer-acting agents
 Administered by inhalation
 The duration of action is 12 hours.
 Given regularly, twice daily, as adjunctive therapy in patients
whose asthma is inadequately controlled by glucocorticoids alone

Clinical uses
 Used in acute asthmatic attacks
 Used to improve respiratory function in chronic obstructive
lung disease
 Used to arrest premature labour

Tolerance
 There is some evidence that β2-agonist tolerance can occur
in asthmatic airways and that steroids can reduce the
development of tolerance because they inhibit β2- 18
adrenoceptor down regulation.
Side effects
• Muscle tremor, which results from a direct
stimulation of β2-adrenoceptors in skeletal
muscle.
• β2-Agonists also cause tachycardia and
palpitations in some patients because of
their effect on the heart through β1.
N.B:
 The β2-adrenoceptor antagonists, such as propranolol,
though having no effect on airway function in normal
individuals, cause wheezing in asthmatics and can
precipitate a potentially serious acute asthmatic attack.
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 XANTHINES
Prototype: Theophylline (aka aminophylline)
Others: Bamifylline, elixophylline, theobromine and caffeine

 Caffeine and theophylline are constituents of coffee and

tea, and theobromine is a constituent of cocoa.
 Theophylline has bronchodilator action, though it is rather
less effective than the β2-adrenoceptor agonists

20
,

21
MOA
 Xanthines inhibit phosphodiesterase (PDE) enzymes which
inactivates cAMP, a second messengers that mediate
bronchial smooth muscle relaxation. This results in an
increase in cAMP; with smooth muscle relaxation and
bronchodilation.

PK
 Administered orally and by slow intravenous injection of a
loading dose followed by intravenous infusion.
 Well absorbed from GIT, metabolised in the liver and has
a half-life of about 8 hours.
 Its half-life is increased in liver disease and is decreased in
heavy cigarette smokers and drinkers.
22
Clinical uses:
• As a second-line drug, in addition to steroids, in patients
whose asthma does not respond adequately to β2-
adrenoceptor agonists.
• Administered I.V in acute severe asthma to reduce
symptoms
• To relieve dyspnea associated with pulmonary edema that
develops from Congestive heart failure

Side effects
• GIT effects: anorexia, nausea, vomiting and abdominal
discomfort
 CNS : headache, nervousness, and seizures

23
Drug interactions
 Its plasma concentration is decreased by drugs CYP450
enzymes inducers, such as rifampicin, phenobarbital and
phenytoin
 The concentration is increased by CYP450 enzyme
inhibitors such as oral contraceptives, erythromycin,
ciprofloxacin, calcium-channel blockers, fluconazole and
zileuton

N.B
 Xanthines have a very narrow therapeutic window.

 Xanthines can be given as a slow intravenous infusion with

a loading dose for acute severe asthma.
 For treatment of nocturnal asthma the medication should
be given before bed time. 24
 MUSCARINIC RECEPTOR ANTAGONISTS
Prototype: Ipratropium
Others: Oxitropium

MOA
 Ipratropium competitively relieves bronchoconstriction by
reducing the effects of acetylcholine in the bronchioles
 Through blocking muscarinic receptors in the lungs and the
decrease in secretion of mucus that occurs in response to
vagal activity in allergic asthma and may increase the
mucociliary clearance of bronchial secretions.

25
N.B:
 Ipratropium is not particularly effective against allergen
challenge but it inhibits the augmentation of mucus
secretion that occurs in asthma.
Clinical use
• As an adjunct to β2-adrenoceptor agonists and
steroids when these on their own do not control
asthma.
• As a bronchodilator in some patients with chronic
bronchitis, and in bronchospasm precipitated by
β2-adrenoceptor antagonists.

Adverse Effects
• Dry mouth, headache, nervousness, dizziness,
nausea, and cough. 26
ANTI-INFLAMMATORY AGENTS
Classified into three
A. THE GLUCOCORTICOIDS
B. LEUKOTRIENE RECEPTOR ANTAGONISTS
C. CROMOGLICATE

27
 THE GLUCOCORTICOIDS
E.g. Prednisolone, beclomethasone, budesonide and
fluticasone

 They are main anti-inflammatory drugs used in treatment

of asthma.
 They are effective in the management of chronic asthma
and their effects take several hours to days to develop, so
they cannot be used for quick relief of acute episodes of
bronchospasm.

28
 MOA of Glucocorticoid in Asthma
 Decrease formation of cytokines that recruit and activate
eosinophils and are responsible for promoting the production of
IgE (which leads to release of histamine, the cysteinyl-
leukotrienes (LTC4 and LTD4; and prostaglandin D2 (PGD2)
from mast cells when the allergens interact with IgE receptors on
them).
 Inhibit the generation of prostaglandins (PGE2 and PGI2), the
vasodilators; by inhibiting induction of cyclooxygenase-2.

 By virtue of inducing lipocortin, an enzyme which inhibits the

synthesis of arachidonic acid from plasma lipids which is a
precursor for Leukotrienes, they inhibit production of the LTC4
and LTD4, LTB4 and platelet-activating factor, thus reducing
recruitment and activation of inflammatory cells.

29
• Glucocorticoids can upregulate β2-adrenoceptors, decrease
microvascular permeability and reduce mediator release from
eosinophils.
• The reduction in the synthesis of IL-3 (the cytokine that regulates
mast cell production) may explain why long-term steroid treatment
eventually reduces the early-phase response to allergens and
prevents exercise-induced asthma.

Clinical use of glucocorticoids in asthma

 Used prophylactically to control asthma rather than acutely
to reverse asthma symptoms

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 Unwanted effects
 Oropharyngeal candidiasis, can occur, as
can dysphonia (voice problems), but these
are less likely to occur if 'spacing' devices
are used, which decrease oropharyngeal
deposition of the drug and increase
airway deposition.
 Regular large doses can produce adrenal
suppression, particularly in children
 Suppression of response to infections

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LEUKOTRIENE RECEPTOR ANTAGONISTS
 Leukotrienes result from the action of 5-lipoxygenase on
arachidonic acid and are synthesized by a variety of
inflammatory cells in the airways.
 Leukotriene B4 (LTB4) is a potent neutrophil
chemoattractant, and LTC4 and LTD4 exert many effects
known to occur in asthma, including bronchoconstriction,
increased bronchial reactivity, mucosal edema, and mucus
hypersecretion.

Two approaches to interrupting the leukotriene

pathway:
1. Inhibition of 5-lipoxygenase, thereby preventing
leukotriene synthesis .
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2. Inhibition of the binding of LTD4 to its receptor on target
tissues, thereby preventing its action.
Thus leukotriene receptor antagonists are classified into two:
 Lipoxygenase enzyme Inhibitors e.g. zileuton

 Leukotriene receptor blockers e.g. montelucast and

zafirlukast

Lipoxygenase enzyme Inhibitors MOA

 Zileuton suppresses synthesis of the leukotrienes by
inhibiting 5-lipoxygenase, a key enzyme in conversion of
arachidonic acid to the leukotrienes.

Leukotriene receptor antagonists MOA

 Montelukast and zafirlukast suppress biological actions of
leukotrienes by competitively blocking leukotriene
receptors .
33
.

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Clinical uses
 Prevent aspirin-sensitive asthma
 Inhibit exercise-induced asthma and decrease both early and late
responses to inhaled allergen.
 They relax the airways in mild asthma, their action is additive
with β2-adrenoceptor agonists.
 They also increase mucocillary clearance

Unwanted effects
 Mainly headache and gastrointestinal disturbances

Drug interactions
 Zileuton decreases the clearance of theophylline and
warfarin, substantially increasing their plasma
concentrations.

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CROMOGLICATE
E.gs: Cromolyn and nedocromil
 Are chemically related drugs called chromones.

Clinical uses:
 May be useful in patients whose symptoms occur seasonally
or after clear-cut inciting stimuli.
 In patients whose symptoms are continuous or occur
without an obvious inciting stimulus.

N.B:
 Their effect is established only with a therapeutic trial of
inhaled drug four times a day for 4 weeks.

36
MOA.

 inhibits degranulation of mast cells, subsequently

preventing the release of histamine and slow-reacting
substance of anaphylaxis (SRS-A), mediators of type I
allergic reactions.

 Cromoglicate also may reduce the release of inflammatory

leukotrienes.

 Cromoglicate may act by inhibiting calcium influx

 They block the bronchoconstriction caused by allergen
inhalation, by exercise, sulfur dioxide, and by other causes
of occupational asthma.
37
 Children are more likely to respond than adults.
Pharmacokinetic
 Cromoglicate is extremely poorly absorbed from the
gastrointestinal tract.
 Given by inhalation as an aerosol, as a nebulised
solution or in powder form; about 10% is absorbed into
the circulation when it is given in this way.
 Excreted unchanged: 50% in the bile and 50% in the
urine
 Half-life in the plasma is 90 minutes.
 Nedocromil is also given by inhalation and is rather
better absorbed.
Unwanted effects
 Unwanted effects are few and consist mostly of the effects
of irritation in the upper respiratory tract.
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 Hypersensitivity reactions have been reported (urticaria,
anaphylaxis), but are rare.
OTHERS
 ANTI-IgE MONOCLONAL ANTIBODY
Prototype: Omalizumab
 Treatment with omalizumab is reserved for patients with
chronic severe asthma inadequately controlled by high-
dose inhaled corticosteroid plus long-acting -agonist
combination treatment.
Mechanism of action
 This treatment reduces lymphocytic, eosinophilic bronchial
inflammation and effectively reduces the frequency and
severity of asthmatic attacks.
Clinical indication
 It is reserved for patients with severe asthma which may
not be controlled by other drugs.
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STATUS ASTHMATICUS
 This is an acute life threatening exacerbation of
asthmatic symptoms that is unresponsive to
standard therapy
 It must be treated very aggressively and
hospitalization may be necessary
 Factors like prolonged exposure to allergens or
respiratory infections can lead to status
asthmaticus
 Treatment includes oxygen therapy, inhaled
short acting beta two agonists and oral or
parenteral corticosteroids
40
CONT ………………
 Subcutaneous beta agonists can be given to
patients who respond poorly to inhaled
adrenomimetics
 Inhaled ipratropium may be effective in some
patients

41
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)

 the symptoms. This is a chronic irreversible

obstruction of air flow.

 Smoking is the greatest risk factor of COPD.

 Bronchodilators like anticholinergic agents, beta

adrenergic agonists and theophylline are used to
relieve COPD respiratory symptoms.

 Treatment does not cure the disease but only

reduces the symptoms. 42
CONT…
 COPD refers to the chronic bronchitis and
emphysema, a pair of two commonly co existing
diseases of the lungs in which the airways
become narrowed.
 This leads to a limitation of the flow of air to and
from the lungs causing shortness of breath.
 The airway and the air sac loose their elastic
quality.
 The walls between many air sacs are destroyed

 The walls of the airways become thick and

inflamed
 The airways make more mucus than usual, which
tends to clog them
43
PATHOPHYSIOLOGY
 Abnormal inflammatory response of the lungs
due to toxic gases

 response occurs in the airways, parenchyma, and

pulmonary vasculature

 Narrowing of the airways takes place

 Destruction of the parenchyma leads to

emphysema

44
CONT…
Causes
➢ Smoking
➢ Occupational exposure e.g work place dust,
chemicals, toxic fumes
➢ Air pollution
➢ Bronchial hyper-responsiveness due to existing
diseases like asthma
➢ Certain carcinogens

45
TREATMENT
 Currently there is no cure for COPD, but
treatment can help slow the progression of the
condition and control the symptoms
❖ Stopping smoking

❖ Inhalers and tablets to ease breathing

❖ Pulmonary rehabilitation ..a specialized

programme and of exercise and education
❖ Surgery or lung transplant although this is only
an option for the small number of people

46
CONT…
 Short acting bronchodilator inhalers, B 2 agonist
inhalers(salbutamol, terbutaline), antimuscarinic
inhalers (ipratropium)
 Long acting bronchodilator inhalers

B2 agonist inhalers like salmeterol, formoterol,

indacaterol
ant muscarinic inhalers, tiotropium,
glycopyronium, aclidinium
 Steroids are also used especially inhalers

 theophylline tablets or capsule,

 adverse effects; headaches, insomnia,

palpitations.
 Mucolytics, eg, carbocisteine
47
CONT.,

48
Introduction to
.

cough

49
❖ Cough is a protective reflex whose purpose is to
.
expel respiratory secretions or foreign particles
from lungs or upper air way passages
❖ Cough may be classified as;
 Productive/ wet (useful)

 Non productive/ dry(useless)

50
 TYPES

❖ Cough can be classified basing on duration as

follows;

 Acute sudden onset (less than 3 weeks

 Sub acute 3-8 weeks

 Chronic more than 8 weeks

51
  MECHANISM OF COUGH
❖ The cough reflex is complex, involving the central and peripheral
nervous systems as well as the smooth muscle of the bronchial
.

tree.

❖ Chemical or mechanical irritation of the epithelium within

bronchial mucosa causes bronchoconstriction, which in turn
stimulates cough receptors located within the tracheobronchial
tree.

❖ Afferent conduction from these receptors occurs via the vagus

nerve to the medulla.

52
❖ Following inspiration to near total lung capacity, closure of the
glottis and contraction of the abdominal wall muscles, the glottis
.

is suddenly opened resulting in upward movement of the

diaphragm and expulsion of air at velocities of up to 600 miles per
hour (950 km/h).

❖ The abdominal muscles involved in developing the driving

pressures necessary for cough include the external oblique
(efferent nerves T7–T12), the internal oblique (T7–L1), and the
rectus abdominis (T6–T12).

❖ Weakness of the abdominal muscles can significantly reduce the

53

effectiveness of the cough in clearing the airway of foreign

 TREATMENT FOR COUGH
❖ Treatment of cough is classified as;
.

 Specific

 nonspecific

Nonspecific therapy.

1. Pharyngeal demulcents;

Lozenges, cough drops, linctus-containing syrups, glycerin liquorice

2. Expectorants (mucokinetics)

A. Bronchial secretion enhancer

Sodium or potassium citrate, potassium iodide, guaifenesin, (glyceryl

guainacolate, ammonium chloride, vasaka, etc
54
B) mucolytics

 Bromhexine, carbocisten, acetylcysteine, ambroxol

.

3. Antitussives ( cough center suppressants)

a) Opioids ( codeine, ethyl morphine, pholcodine)

b) Non opioids (noscapine, dextromethorphan, chlophedianol)

c) Antihistamines (chlorpheniramine, diphenhydramine,

promethazine)

d) Peripherally acting agents(prenoxdiazine)

Adjuvant antitutives

▪ Salbutamol 55

▪ terbutaline
 ASSIGNMENT

 Read the pk and pd of each drug in each class of

anticough agents,

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.

Good luck

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