BLOK RESPIRASI, FK UMI, 13 April 2021

Drugs for Respiratory Tract Disorders

(Asthma, COPD and Antitussives)
Prof. DR. dr. Hadyanto Lim, M.Kes, SpFK, FESC, FIBA, FAHA
Department of Pharmacology and Pharmacy, FK UMI- Medan
Asthma
• A chronic disease of the airways that is
characterized by airway inflammation
and hyperresponsiveness to stimuli
that produce bronchoconstriction.

• The stimuli include cold air, exercise, a

wide variety of allergens, and
emotional stress.

• The symptoms of asthma include

dyspnea and wheezing as well as
mucus production and cough,
particularly at night.
Chapman DG, et al. Clin Exp Allergy. 2015 April ; 45(4): 706–719.
 Asthma
⦁ Both as an obstructive lung disease and
an inflammatory disease.

• The obstructive component is characterized

by bronchoconstriction, whereas the
inflammatory component is marked by
airway edema, goblet cell hyperplasia, mucus
secretion, and infiltration and cytokine
release by immune and inflammatory cells.

⦁ Although the airway obstruction is generally

reversible, asthma, may overtime, cause airway Airway remodeling occur throughout the bronchial tree.
remodeling and permanent deterioration in Airway wall thickness is increased by between 50 and 230%
pulmonary function. compared to normal controls n fatal asthma, while in nonfatal
asthma, the increase ranges from 25–150%
Shifren A, et al. Journal of Allergy 2012
Pathophysiology of Asthma
Glucocorticoids (corticosteroids) inhibit
numerous steps in this process, including
T-cell activation, cytokine production,
eosinophil recruitment and activation,
and mast cell migration.

Glucocorticoids, cromolyn sodium,

and other cromolyn-related drugs all
inhibit the release of mediators from
mast cells and eosinophils.

Cromolyn and related drugs also inhibit

eosinophil chemotaxis induced by
cytokines and other mediators.

Leukotriene inhibitors either block leukotriene

receptors or inhibit leukotriene synthesis.

IgE, Immunoglobulin E.

Brenner and Stevens’ Pharmacology, Elsevier 2018

Anti-Inflammatory Drugs

• Glucocorticoid

• Mast Cell Stabilizers

• Leukotriene Inhibitors
Glucocorticoids (Corticosteroids)

• Are available for oral, parenteral, topical, and inhalational

administration.

• Although glucocorticoids are the most efficacious anti-

inflammatory drugs available for the treatment of both
asthma and allergic rhinitis, they have the potential to cause
the greatest number of adverse effects.

• The incidence of adverse effects is markedly reduced when

these dugs are given by inhalation.
Glucocorticoids (Corticosteroids)

• Among the glucocorticoids available as metered-dose inhalers are

beclomethasone, budesonide, fluticasone, and triamcinolone.
⦁ Beclomethasone and triamcinolone are usually
administered
three or four times a day, whereas fluticasone and
budesonide need to be administered only twice a day.
 Glucocorticoids (MDI)
•The proper use of metered-dose inhalers (MDI) requires considerable
skill and the utilization of a spacer device between the mouth and the
inhaler.

⦁ The spacer decreases the amount of drug that is deposited in the mouth
and upper airway and facilitates the delivery of the drug to the
bronchioles.
Glucocorticoids (Corticosteroids)

• Glucocorticoids are primarily used on a long-term

basis to prevent asthmatic attacks, rather than to
treat acute bronchospasm.

• The maximal response to glucocorticoids usually

requires up to 8 weeks to develop.

• Glucocorticoids can reduce the number and severity

of symptoms and decrease the need for 𝛃2-adrenergic
receptor agonists and other bronchodilators.
 Mast cell stabilizers
• Cromolyn sodium
- Cromolyn sodium and related compounds are nonsteroidal
compound that stabilize the plasma membrane of mast cells and
eosinophils, thereby prevent degranulation and release of
histamine, leukotrienes, and other mediators of
allergic reactions that lead to airway inflammation.
Therefore, these drugs are often called mast cell stabilizers.

- Minimal systemic absorption occurs following their oral

administration.
- Most of the drug is swallowed following inhalation, and about 98%
of it is excreted in the feces.
Cromolyn sodium
• Cromolyn is administered by inhalation to treat asthma or
allergic rhinitis and is available in an ophthalmic solution to
treat vernal (seasonal) conjunctivitis.

• Cromolyn and related compounds are primarily used for

the long-term prophylaxis of asthmatic bronchoconstriction
and allergic reactions. They have no role in the treatment
of acute bronchospasm.

• Improvement can require several weeks, and then the

dosage can be reduced to the lowest effective level.
Adverse effects

• Cromolyn and other related mast cell stabilizers are

markedly nontoxic, partly because of their low solubility
and systemic absorption.

• However, in some patients, cromolyn inhalation can irritate

the throat and cause cough and bronchospasm.
Nedocromil and Lodoxamide

• Nedocromil has properties that are similar to those of

cromolyn.

• However, nedocromil is only available as an aerosol for the

prevention of bronchospasm in patients with asthma.

• Lodoxamide is formulated as an ophthalmic solution to

treat ocular allergies, including vernal keratitis and vernal
conjunctivitis.
 Leukotriene Inhibitors
• Leukotriene are a group of arachidonic acid metabolites formed via the 5-lipoxygenase pathway.

⦁ The formation of leukotriene A4 (LTA4) is inhibited by zileuton by inhibiting 5-lipoxygenase enzyme .

⦁ LTA4 is converted to leukotriene B4, which activates B leukotriene receptors, such as BLT1, and also
converted to the cysteinyl leukotrienes C4, D4, and E4, which activate cysteinyl leukotriene receptors, suc
as CysLT1.
⦁ These receptors are blocked by montelukast and zafirlukast. Leukotriene receptors are coupled with Gq and
Gi, leading to increased intracellular calcium, decreased cAMP, activation of protein kinases, and biologic
effects.
Zafirlukast and Montelukast
• Leukotrienes serve as mediators in the inflammatory events that contribute to
bronchospasm in patients with asthma.

⦁ Two leukotriene receptor antagonists, Zafirlukast (Accolade, 20 mg) and

Montelukast (Singulair, 10 mg), are available. Zileuton is a leukotriene
synthesis inhibitor.
Zafirlukast and Montelukast

• Zafirlukast and Montelukast are administered orally and are well

absorbed from the gut.

• The half life of zafirlukast is about 10 hours, whereas that of

Montelukast is only about 4 hours.

• Montelukast is administered as a single daily dose in the

evening, whereas zafirlukast is usually given twice a day.
The biologic activity of Montelukast persists longer that
serum levels of the drug.
Zafirlukast and Montelukast
• The receptor antagonists improve pulmonary function, control
symptoms, and can significantly reduce the incidence of asthmatic
attacks.

• The beneficial effects require several weeks to months of therapy.

• Their main benefit seems to be a reduction in airway inflammation, but

they also produce significant bronchodilation within 1 hour after
administration.
Zafirlukast and Montelukast

• The leukotriene receptor antagonists are relatively free

of serious adverse effects. However, some patients can
develop allergic granulomatous angiitis (Churg-Strauss
syndrome) who were being withdrawn from
glucocorticoid therapy while receiving zafirlukast.

• Zafirlukast inhibits the CYP2C9 and CYP3A4 isozymes of

cytochrome P450 and may thereby interfere with the
metabolism of phenytoin and warfarin (drugs
metabolized by CYP2C9) and of felodipine, lovastatin,
and triazolam (drugs metabolized by CYP3A4).
Zafirlukast and Montelukast

• Montelukast does not inhibit these isozymes or

exhibit significant drug interactions. Hence, its
use may be preferred in patients receiving
concomitant drug therapy.
Bronchodilators

• Selective 𝛃2-adrenergic receptor agonists

• Muscarinic receptor antagonists
• Theophylline
Bronchodilators
• All of these drugs relax bronchial smooth muscle and prevent or
relieve bronchospasm.
• The selective 𝛃2-adrenergic receptor agonists are the only type
of bronchodilator used to counteract an acute asthmatic attack.
• Muscarinic antagonists are less useful in asthma, but are
primarily used to treat patients with COPD (chronic obstructive
pulmonary disease).
• Theophylline can be administered to prevent
bronchoconstriction in either asthma or empyema in the long-
term basis.
 Mechanisms of Action
Selective 𝛃2 -adrenergic receptor agonists, theophylline, and muscarinic
receptor antagonists
• By activating 𝛃2 –receptors, these drugs increase cyclic adenosine monophosphate (cAMP)
concentration in smooth muscle and thereby cause the muscle to relax.
Mechanisms of Action
Selective 𝛃2 -adrenergic receptor agonists, theophylline, and
muscarinic receptor antagonists

• Theophylline inhibits phosphodiesterase isozymes and

blocks the degradation of cAMP to 5’-AMP

• Ipratropium and tiopropium block the stimulation of

muscarinic receptors by acethylcholine (Ach) released
from the vagus nerve and thereby attenuate reflex
bronchoconstriction.
 Selective 𝛃2 -adrenergic receptor agonists
• The selective 𝛃2 receptor agonists relax bronchial smooth muscle without producing
as much cardiac stimulation as do their nonselective counterparts (isoproterenol),
which also activate 𝛃1 in the heart.

However, higher doses of selective 𝛃2 receptor agonists can activate cardiac 𝛃1

receptors and thereby increase heart rate and contractility.
Selective 𝛃2 -adrenergic receptor agonists
• Rapid acting 𝛃2 -adrenergic receptor
agonists (e.g., albuterol, levabuterol,
fenoterol, pirbuterol, and terbutaline) are
usually given by inhalational route to
prevent or treat acute bronchospasm.

• Although oral formulations of albuterol (=

salbutamol, VentolinR ) and terbutaline
are available for children or adults who
are unable to use a metered-dose inhaler,
the oral formulations have a slower onset
of action and can cause more systemic
side effects.
Pharmacologic Properties of Selected β-Adrenoceptor Agonists Administered by Inhalation

ONSET OF DURATION OF
DRUG ACTION ACTION DOSAGE
(MINUTES) (HOURS)
2 puffs every
Albuterol 5 3–8
4–6 hours

1 inhalation
Formoterol 5 12
every 12 hours

1 inhalation
Indacaterol 15 >24
every 24 hours

2 puffs every
Salmeterol 20 12
12 hours
2 puffs every
Terbutaline 5–15 3–6
4–6 hours
Selective 𝛃2 -adrenergic receptor agonists
• Salmeterol and formoterol are slower and longer 𝛃2
receptor agonists that are given twice daily by
inhalation for long-term treatment of asthma.
LABA (Long Acting Beta-Adrenoceptor Agonists)

• Salmeterol and formoterol are LABAs given twice

daily by inhalation for the long-term treatment of
asthma and emphysema.
• They are particularly useful in preventing nocturnal
asthmatic attacks, which are sometimes life-
threatening.
• These drugs are not indicated for the treatment of
acute bronchospasm, for which a rapid-acting β2-
agonist should be used.
Indacaterol
• Indacaterol is an ultralong-acting β2-receptor agonist that has
recently been approved for the treatment of airflow obstruction
in patients with COPD.

• It is the only once-daily β2-receptor agonist bronchodilator

available for this purpose.
LABAs Warning
• A black-box warning has been added to products
containing LABAs, stating that these drugs may
increase the risk of asthma-related death. 

• However, the two studies on which this warning was

based were criticized as not being well controlled.

• Asthma treatment guidelines still recommend use of

LABAs in combination with corticosteroids for persons
with moderate to severe asthma not controlled by
corticosteroids alone.