Therapeutics II

Fall Semester, 2024/2025

Respiratory Disorders
Chronic Asthma

Professor Wesam Ammari

PhD in Clinical Pharmacy, University of Bradford, UK

Pharmacy - Faculty of Health Sciences

American University of Madaba (AUM)
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 Chronic Asthma

“A chronic inflammatory disorder of the airways in

susceptible individuals. The inflammatory
symptoms are usually associated with a
widespread but variable airflow obstruction and
an increase in airway response to a variety of
stimuli”.

Airflow obstruction is often reversible, either

spontaneously or with treatment”.
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 Pathophysiology of Asthma
Asthma is primarily classified into two types;
atopic (allergic) and non-atopic asthma.

Atopic asthma:
- The immune response at the surface of the
involved airways is regulated in a way that it
recognizes certain environmental stimuli
(allergens); thus initiating multicellular
inflammatory processes.

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- These environmental irritants may include cigarette
smoke, dust, air pollution, pollens and fungal
spores.

- Dendritic cells distributed in the epithelial lining of

the airways uptake (internalize) the inhaled
allergens; consequently acting as antigen-
presenting cells to the T-lymphocytes (Th2-Type
cells).

- This allergen internalization is promoted and

enhanced by the immunoglobulin E (IgE) bound to
the surface of the dendritic cells.
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 Once the antigen peptide is presented to the T-
cells.

Sensitization of the immune response is initiated.

under the influence of the chemokines, T-cells (Th2-

Type) proliferate at the site of antigen presentation
on the airways’ surface and start producing a wide
range of cytokines.

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 Attract secondary effector cells (eosinophils,
basophiles and macrophages) to the inflammation
site and activate them to secrete their inflammatory
mediators

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IgE binding to their receptors on mast cells surface
→ initiates the EAR through their main mediators:
- leukotriene (LT)D4, - tryptase
- prostaglandin (PG)D2, - heparin
- histamine, - cytokines

inflammatory features

bronchoconstriction, increase in microvascular

permeability and thus cellular infiltration,
fibrogenesis and smooth muscle remodelling (airway
thickening)

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The inflammatory processes of asthma impair
mucociliary transport and increase the size and
number of the goblet cells.

↑ mucus secretion & viscosity

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 In more severe asthma conditions, the Th1-
Type T lymphocytes are also involved in the
inflammation process causing tissue damaging
through the secretion of the tumor necrosis
factor (TNF)-α and interferon (INF)-γ.

Mast cells have also a major role in both:

1. The early asthmatic reaction (EAR) (immediate
and lasts 30-60 min).
2. The late asthmatic reaction (LAR) starting 4-6
hours later.

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Eosinophil leukocytes contribute to the
inflammatory responses through their various
mediators Tissue remodelling by the
production of the transforming growth factor
(TGF)-ß1.

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 Non-atopic Asthma:
- underlying pathophysiology is not very clear
yet.
- Features are related to Non-IgE dependent
provocation caused by:

1. Occupational chemicals.
2. Viral and bacterial infections.
3. Exercise-induced bronchoconstriction

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Atopic asthma is more life-threatening than
non-atopic asthma.

A) True B) False

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 Clinical Presentation
Patients may complain of episodes of:
- dyspnea,
- chest tightness,
- coughing,
- wheezing (whistling sound when breathing).

Symptoms tend to be worse at night or early

morning.

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 Asthma can vary from chronic daily symptoms to
only intermittent symptoms.

Severity classification is determined by:

- Lung function test,
- Symptoms’ frequency,
- Night time awakenings,
- Interference with normal activity prior to therapy.

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 Lung Function Test
Lung function evaluation is important to confirm
or exclude the diagnosis of many respiratory
diseases as well as to assess/follow up on any
related medical intervention.

A spirometer → gives many outcome measures

that are compared to normal predicted values
based on the subject’s age, sex, race and
height.

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 Spirometric parameters
Peak expiratory flow (PEF) (litre/minute):

- The subject is asked to inhale to their total lung

capacity (TLC) and then to breathe out as hard
and fast as possible to the residual volume (RV).

- The PEF is normally used to monitor respiratory

diseases (especially asthma) once the diagnosis
has been made.

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 Spirometric Parameters
Forced Vital Capacity (FVC) (litres):
The volume of air exhaled during a forced
expiratory manoeuvre starting from a maximal
inspiration.

Forced Expiratory Volume in one second (FEV1)

(litres):
The volume of air expelled during the first
second of a FVC manoeuvre. It is very important
as it is reproducible and correlates well with lung
function and disease prognosis.

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 Spirometric Parameters
PEF, FEV1 and FVC can be read off the
spirometric plots; however, modern spirometry
instruments automatically provide these
parameters along with the normal predicted
values for the subject. → plot

Spirometric parameters can be used to confirm

the disease diagnosis, severity level
classification and follow up/prognosis.

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 Diagnosis of Asthma

Diagnosis is primarily made by the clinical

history of recurrent symptoms:

(The patient may have a family history of allergy or

asthma or have symptoms of allergic rhinitis. A history
of exercise or cold air precipitating dyspnea or
increased symptoms during specific allergen seasons
also suggests asthma).

▪ Diagnosis is confirmed by spirometry.

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Spirometry demonstrates obstruction →
FEV1/FVC ratio less than 80% with reversibility
after inhaled β2-agonist administration (at least
a 12% improvement in FEV1).

If baseline spirometry is normal, challenge

testing with exercise, histamine, or methacholine
can be used to elicit BHR.

Severity classification of asthma (GINA) →

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Management of Chronic Asthma
Desired Outcome/Goals:
Reducing impairment:
(1) Prevent or ↓ chronic and troublesome
symptoms.
(2) ↓ the need for frequent use (≤2 days/wk) of
inhaled short-acting β2-agonist for quick relief
of symptoms.
(3) Maintain (near-) normal pulmonary function.
(4) Maintain normal activity levels (including
exercise and attendance at work or school)

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 Reducing risk:
(1) prevent recurrent exacerbations and minimize
the need for ER visits or hospitalizations.

(2) prevent loss of lung function; for children

prevent reduced lung growth.

(3) minimal or no adverse effects of therapy.

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 Non-Pharmacological Rx
Patient education and teaching of self-
management skills:

- Counselling/training on correct inhaler

technique.

- Avoidance of known allergenic triggers:

(can improve symptoms, reduce medication
use, and decrease BHR).
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Pharmacotherapy: Bronchodilators
1) β2-Agonists:

β2-Adrenergic receptor stimulation activates

adenyl cyclase, which produces an increase in
intracellular cyclic adenosine monophosphate.

→ This results in smooth muscle relaxation &

mast cell membrane stabilization.

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 Depending on their onset and duration of
action:-

1. Short-acting ß2-agonists (SABA), e.g.

salbutamol (albuterol), terbutaline and
fenoterol, are used as rescue (reliever)
bronchodilators on “as- and when-needed”
administration basis.

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 Lec 3: Asthma

Albuterol and other inhaled short-acting

selective β2-agonists are indicated for treatment
of intermittent symptoms of bronchospasm.

SABA provide complete protection for at least 2

hours after inhalation (~ 4 hours).

Regular treatment (four times daily) does not

improve symptom control over as-needed use.

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2. Long-acting ß2-agonists (LABA), e.g.
Formoterol and salmeterol (LABA): indicated
as adjunctive long-term control for patients
with symptoms who are already on inhaled
corticosteroids.

LABA are ineffective for acute asthma

symptoms because it can take up to 20
minutes for onset. However, Formoterol has
been shown to have both short and long acting
effects.
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LABA provide significant protection for 8 to 12
hours initially (allows twice a day administration).

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 2) Anticholinergics
Ipratropium bromide and oxitropium bromide
(S.A.) are competitive inhibitors of muscarinic
receptors; they produce bronchodilation only in
cholinergic-mediated bronchoconstriction.

A.C. attenuate, but do not block, allergen- or

exercise-induced asthma in a dose-dependent
fashion.

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 Anticholinergics are effective bronchodilators but
are not as potent as β2-agonists.
→ The time to reach maximum bronchodilation
from aerosolized ipratropium is longer than from
aerosolized short-acting β2-agonists
(30 to 60 minutes vs. 5 to 10 minutes).

Ipratropium & oxitrop. have a duration of action

of 4 to 8 hours.

Tiotropium bromide.

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 3) Methylxanthines
E.g.: Theophylline
Act mainly as bronchodilators: by inhibiting
phosphodiesterases.

This also results in some extra anti-inflammatory

benefit through:
- ↓ mast cell mediator release.
- ↓ eosinophil basic protein release.
- ↓ T-lymphocyte proliferation & cytokine
release.
- ↓ plasma exudation. 39
 Theophyllines are administered orally (SR) or
parentally (IV).
Elimination:
- Hepatic metabolism (90%): primarily CYP1A2
and CYP3A4.
- Renal excretion (10% unchanged).

Clinically significant reductions in clearance can

result from cotherapy (e.g. cimetidine,
erythromycin, clarithromycin, allopurinol, etc.).
Other drugs can enhance clearance (e.g.
rifampin, carbamazepine, phenobarbital, etc)
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Due to high inter-patient variability in
theophylline clearance
→ routine monitoring of serum theophylline
concentrations is essential for safe and effective
use (TI: 5 to 15 mcg/mL).

Adverse effects include nausea, vomiting,

tachycardia, nervousness and difficulty sleeping.

More severe toxicities include cardiac tachy-

arrhythmias and seizures.

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Pharmacotherapy of Chronic Asthma:
Inhaled Corticosteroids
Advantages:

- ↓ mucus production and hypersecretion.

- ↓ BHR.

- ↓ airway edema and exudation.

- Increase the β2-adrenergic receptors’

responsiveness to β2-adrenergic stimulation
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Inhaled corticosteroids are the recommended
long-term preventer therapy for persistent
asthma in all patients.

Most patients with moderate disease can be

controlled with twice-daily dosing.

Asthmatics should be started on higher and

more frequent doses than the daily maintenance
doses and then stepped down once control has
been achieved. (inflammatory response of
asthma inhibits steroid receptor binding).
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The response to inhaled corticosteroids is
delayed:

→ symptoms improve within the first 1 to 2

weeks.

→ maximum improvement (including lung

function) in 4 to 8 weeks.

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 Systemic toxicity of inhaled corticosteroids is
minimal with low to moderate inhaled doses.
The risk of systemic effects increases with high
doses → Local AE: oropharyngeal candidiasis
and dysphonia.

Systemic (oral) corticosteroids are indicated in

all patients with severe asthma not responding
completely to initial inhaled combination Rx. (1-2
weeks to ↓ toxicities)
(e.g. Hydrocortisone, prednisone,
methylprednisolone)

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Pharmacotherapy of Chronic Asthma:
Mast Cell Stabilizers
E.g.: Cromolyn sodium, and nedocromil sodium.

Cause stabilization of mast cell membranes →

inhibit the response to allergen challenge.

Do not cause bronchodilation.

Both agents are effective only by inhalation

(available as MDIs).
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Cromolyn and nedocromil are less effective than
ICS and inhaled LABA → add-on therapy.

A.E. (mild):
- Cough and wheezing have been reported
(both).
- Nedocromil: bad taste and headache.

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 Pharmacotherapy of Chronic Asthma:
Leukotriene Modifiers
A) Oral leukotriene receptor antagonists
E.g : Zafirlukast and montelukast.

They:
- reduce the proinflammatory (increased
microvascular permeability and airway edema)
and bronchoconstriction effects of leukotriene
D4.
- improve pulmonary function tests.
- decrease nocturnal awakenings.
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Dosing:
Zafirlukast:
Adults: 20 mg twice daily, taken at least 1 hour
before or 2 hours after meals.
children (5-11 years): 10 mg twice daily.

Montelukast
Adults:10 mg once daily, taken in the evening
without regard to food.
Children (6-14 years): one 5-mg chewable tablet
daily in the evening.

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 Zileuton:
- An inhibitor of leukotriene synthesis.
- The dose of zileuton tablets is 600 mg four times
daily with meals and at bedtime.

Use of zileuton is limited due to:

- Potential for elevated hepatic enzymes
(especially in the first 3 months)

- Inhibition of the metabolism of some drugs

metabolized by CYP3A4 (e.g., theophylline,
warfarin)
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Pharmacotherapy of Chronic Asthma:
Omalizumab
An anti-IgE antibody.

Only indicated for patients who have difficult to treat,

severe allergic asthma with high serum IgE that is
inadequately controlled with the combination of
high-dose inhaled corticosteroids and LABA.

Doses range from 150 to 375 mg (SC) at either 2- or

4-week intervals.
Disadv: anaphylaxis (0.1%), cost.

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Pharmacotherapy of Chronic Asthma:
Mepolizumab
U.S. FDA approval: 04/11/2015.
A humanized interleukin-5 antagonist monoclonal
antibody produced by recombinant DNA technology.
→ Reduces the levels of blood eosinophils.

Only indicated for patients (≥ 12 yrs) who have

severe recurrent asthma attacks (exacerbations) -
as add-on option.

Given SC every 4-weeks.

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Pharmacotherapy of Chronic Asthma:
Reslizumab
U.S. FDA approval: 23/03/2016.
A humanized interleukin-5 antagonist monoclonal
antibody produced by recombinant DNA technology.
→ Reduces the levels of blood eosinophils.

Only indicated for patients (≥18 yrs) who have

severe recurrent asthma attacks (exacerbations) -
as add-on option.

Given IV infusion every 4-weeks.

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 Goals of asthma treatment

§ Few asthma symptoms

§ No sleep disturbance
Symptom control (e.g. ACT, ACQ)
§ No exercise limitation
§ Maintain normal lung function
§ Prevent flare-ups (exacerbations)
Risk reduction
§ Prevent asthma deaths
§ Minimize medication side-effects (including OCS)

§ The patient’s goals may be different

§ Symptom control and risk may be discordant
§ Patients with few symptoms can still have severe exacerbations

ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; OCS: oral corticosteroids
© Global Initiative for Asthma, www.ginasthma.org
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*Anti-inflammatory reliever (AIR) Box 3-12 © Global Initiative for Asthma, www.ginasthma.org
 GINA 2023 – Adults and adolescents
Track 2

*An anti-inflammatory reliever

(Steps 3–5)

Box 3-12 (3/4) Track 2 © Global Initiative for Asthma, www.ginasthma.org

Evaluation of Therapeutic Outcomes
Control of asthma is the ultimate goal ( reducing
both impairment and risk).

Assessment include:
- symptoms.
- night-time awakenings.
- interference with normal activities & QoL.
- pulmonary function. -,
- exacerbations.
- adherence to treatment & related AE.

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Spirometric tests are recommended at initial
assessment, after treatment is initiated, and then
every 1 to 2 years.
Peak flow monitoring is recommended in
moderate to severe persistent asthma.

All patients on inhaled drugs should have their

inhalation technique evaluated monthly initially
and then every 3 to 6 months.

Validated instruments (ACT & ACQ) are

recommended (poor vs. well controlled asthma).

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