drugs acting in respiratory diseases

1. PHARMACOLOGY OF
RESPIRATORY SYSTEM
By
Dr. Abeer Mohamed Rashad

2. Bronchial asthma is a chronic inflammatory disorder of the
airways characterized clinically by recurrent episodes of
wheezing, breathlessness, chest tightness, dyspnea and
cough.
• The bronchi show multiple pathological lesions including
inflammatory cell infiltration with eosinophils, neutrophils,
and lymphocytes, plugging of small airways with thick
mucus, hypertrophy of bronchial smooth muscle, mast cell
activation and airway edema. All these pathological lesions
lead at the end to bronchospasm.

3. • The strongest predisposing factor for the development of
asthma is allergy. When the sensitive patient is exposed to
certain allergens e.g. by inhalation, and sometimes drugs like
aspirin, the airway inflammation and hyperresponsiveness
increase, and symptoms of airway obstruction appear.
• In this allergic type of asthma, the allergen interacts with
immunoglobulin IgE on mast cell  liberating inflammatory
mediators that produce the airway inflammation and bronchial
hyperreactivity. Parasympathetic tone to inflamed bronchi may
increase causing the bronchoconstriction

4. FIGURE .1 COMPARISON OF BRONCHI OF NORMAL AND ASTHMATIC
INDIVIDUALS.

5. FIGURE.2 HYPERSENSITIVITY REACTIONS MEDIATED BY
IMMUNOGLOBULIN E (IGE) MOLECULES CAN CAUSE ASTHMA.

6. • Nonspecific precipitants of asthma in atopic patients include
exercise (exercise-induced asthma), upper respiratory tract
infection, sinusitis, gastroesophageal reflux, stress and change
in the weather.

7. Antiasthmatic drugs can be classified as follows:
1- Selective β2-adrenergic agonists
2- Anticholinergic drugs
3- Phosphodiesterase inhibitors (Methylxanthines)
4- Antiinflammatory which include:
a) Cromolyn sodium
b) Corticosteroids
c) Leukotriene antagonists
d) Anti-IgE therapy (biological drugs)

8. • Nonspecific precipitants of asthma in atopic patients include
exercise (exercise-induced asthma), upper respiratory tract
infection, sinusitis, gastroesophageal reflux, stress and change
in the weather.

9. 1- Selective β2-adrenergic agonists:
a) Short acting: e.g. Salbutamol and terbutaline:
 These drugs stimulate 2 adrenergic receptors in the
bronchi  bronchodilatation.
 They can be given by inhalation and orally.
 They have rapid onset and short duration of action (3-6
hours). Therefore, they are the preferred treatment for
rapid symptomatic relief of dyspnea associated with
asthmatic bronchoconstriction i.e. they can be used on
an as-needed basis (acute asthma).

10. b) Long acting: e.g. salmeterol and formoterol:
 They are similar action to short acting group on bronchi, but
their broncodilator effect has a slow onset and longer
duration of action (up to 12 hours).
 They are indicated as a maintenance treatment of asthma but
not for acute cases and they are given usually by inhalation.
 Chronic treatment with a receptor agonist  receptor
desensitization and diminution of effect.
 To avoid occurrence of this phenomenon, these drugs are
better given in combination with corticosteroids in patients
with resistant asthma.

11. 2- Anticholinergic drugs:
Example is ipratropium which is a quaternary derivative of
atropine, free of atropine side effects.
Mechanism of action: it reverses cholinergic mediated
bronchospasm especially if associated with chronic bronchitis
or emphysema where cholinergic tone is high. It also
decreases mucus gland hypersecretion seen in asthma.
The bronchodilator effect is slowly developing and lasts for 4-
6 hours, but it is less intense than that produced by adrenergic
agonists.

12. • The drug is given by inhalation usually in asthmatic patients
intolerant to β2 adrenergic agonists and in β-blockers induced
bronchospasm.
• Tiotropium is similar to ipratropium but of longer duration
of action (24 hours) as it dissociates from muscarinic
receptors much more slowly than ipratropium. Therefore, it is
administered usually once daily by inhalation.

13. 3- Phosphodiesterase inhibitors (Methylxanthines)
•Example is theophylline.
•Mechanism of action: Inhibition of phosphodiesterase enzyme
 blocking of the breakdown of both cAMP and cGMP 
increase levels in bronchial smooth muscle  bronchodilatation.
• Theophylline has also a moderate anti-inflammatory effect that
may be also attributed to its phosphodiesterase inhibitory action.
Furthermore, theophylline inhibits adenosine receptors, and
adenosine in asthmatics can cause bronchoconstriction..

14. •It has different pharmacological actions other than the
bronchodilator effects e.g. CNS stimulation, increase of heart rate
and cardiac output, weak diuretic effect, and increase of gastric
secretion.
• Theophylline is metabolized in the liver by CYP 1A2 and 3A4.
It has a narrow therapeutic range in the blood and its
administration needs follow up of its plasma concentration to
avoid toxicity.

15. • Hepatic cirrhosis and congestive heart failure delay its
metabolism  drug may accumulate.
• Cimetidine and erythromycin (CYP inhibitors)  elevate its
plasma concentration as they delay its metabolism. While
smoking (CYP inducer)  accelerates its metabolism and dose of
the drug may need to be increased.

16. • Therapeutic uses: Because of its side effects, it has not been
considered as a prior selection in treatment of asthma.
1- Moderate and severe persistent asthma and they are used as an
adjuvant therapy. Sustained release theophylline preparations are
effective in controlling nocturnal asthma.
2- Premature infants with prolonged apnea to guard against
occurrence of hypoxia and neurological damage in infant.

17. • Side effects of theophylline are dose related.
• In therapeutic dose  GIT discomforts, insomnia & palpitation.
•At higher doses  seizures, hypotension and arrhythmia (may
be fatal if the drug in given rapidly I.V. So, theophylline should
be given slowly I.V.

19. 4- Antiinflammatory agents:
a) Cromolyn sodium and nedocromil:
•Mechanism of action: stabilization of bronchial mast cell on
exposure to allergens  preventing the release of
bronchoconstrictor chemical mediators (e.g. histamine,
bradykinin and slow reacting substances of anaphylaxis) as a
consequence of IgE mediated allergic response.
• They have no bronchodilator effect. They are not useful in
managing an acute asthma attack.
• They can be effective when taken before exposure to allergens
or exercise but do not relieve asthmatic symptoms once present.

20. • Therapeutic uses:
1- As a prophylactic treatment to guard against occurrence of new
asthmatic attacks. They are given by inhalation and their effect
may need several weeks until improvement occurs
2- As a nasal spray in treatment of allergic rhinitis, and topically
as eye drops in treatment of allergic conjunctivitis.

21. b) Corticosteroids:
•Mechanism of action: the anti-inflammatory effects of
corticosteroids in asthma are mediated through inhibition of
cytokines & eicosanoid production, inhibition of basophil and
eosinophil accumulation in lung tissue and decrease vascular
permeability.
• These effects make corticosteroids significantly effective either
alone or combined with other antiasthmatic agents in the
treatment of asthma.
* They may be given by inhalation or systemically.

22. * Inhaled corticosteroids:
(i) They are preferred as first line agents for patients with
persistent asthma.
(ii) Twice daily dosing of inhaled corticosteroids (most
frequently beclomethasone, triamcinolone and budesonide) is
usually adequate for control of asthma. Higher doses are used if
symptoms persist. The dose then should be reduced once
symptoms have improved.
(iii) Maximum response from inhaled corticosteroids may not be
observed for months.

23. (iv) Oropharyngeal candidiasis are common side effects at higher
doses of inhaled corticosteroids. These side effects can be
minimized if the patient uses a large volume spacer device and
washes his mouth with water after inhalation. Hoarseness of
voice may be another side effect from continued inhalation
procedure of the drug.

24. FIG. 3 PHARMACOKINETICS OF INHALED GLUCOCORTICOIDS.

25. •Systemic corticosteroids (oral or parenteral):
• Oral corticosteroids (e.g. prednisone) should only be used if
symptom control can not be achieved with maximum doses of
inhaled bronchodilators and steroids.
• I.V. route (e.g. methylprednisolone) achieves prompt control
of severe symptoms as in status asthmaticus where the attack
is severe, prolonged and refractory to other conventional
bronchodilators.

26. (ii) Once the patient has improved, it is preferred to reduce the
dose of the drug gradually for discontinuance within 1-2
weeks. Rapid discontinuation of systemic corticosteroids after
chronic use may precipitate adrenal insufficiency. However,
short courses of oral prednisone are not enough to suppress
hypothalamo-pituitary-adrenocortical axis and gradual drug
withdrawal is not necessary.
(iii) Different side effects related to systemic prolonged use of
steroids are expected like osteoporosis, gastritis, edema, etc.

27. c) Leukotriene antagonists:
* Leukotrienes are biochemical mediators that are produced as a
part of inflammatory cascade from arachidonic acid through the
5-lipoxygenase pathway. 5-lipoxygenase is found in mast cells,
basophils, eosinophils and neutrophils.
•Leukotriene (LT) B4 is a product that acts as a chemo-attractant
to inflammatory cells particularly neutrophils and eosinophils.
• Cysteinyl leukotrienes (e.g. LTC4, LTD4 and LTE4) are other
leukotriene products that contribute in obstruction of airways and
asthma symptoms by causing contraction of bronchial smooth
muscle, increasing mucus secretion and vascular permeability.

28. FIGURE .4 SITES OF ACTION OF LEUKOTRIENE MODIFYING DRUGS.

29. * There are two types of oral drugs attenuating the effect of
leukotrienes in asthma:
1- Zileuton: it is 5-lipoxygenase inhibitor preventing formation of
both LTB4 and the cysteinyl leukotrienes.
2- Zafirlukast & montelukast: they are selective and reversible
inhibitors of the cysteinyl leukotriene receptors blocking the
effect of cysteinyl leukotrienes.

31. Their role in treatment of asthma can be summarized as follows:
(i) Prophylactic treatment of mild asthma. They are alternatives to
low dose inhaled steroids for control of mild chronic asthma.
(ii) They are not effective in acute attacks of athma.
(iii) Their use in asthmatic patients may reduce moderately the
doses required of β2-agonists and corticosteroids.
(iv) They are of value as a prophylaxis against aspirin-induced
asthma  aspirin inhibits COX pathway of arachidonic acid 
increase lipoxygenase activity which will be suppressed by
antileukotrienes.

32. Side effects:
1- Elevation of plasma level of aminotransferase liver enzyme.
Monitoring of liver enzymes is required during therapy.
2- Eosinophilic vasculitis (Churg-Strauss syndrome especially
when concomitant corticosteroid therapy is withdrawn.

33. d) Anti-IgE therapy (biological drugs)
Example is omalizumab.
Mechanism of action: It is a recombinant humanized monoclonal
antibody targeted against IgE immunoglobulin. IgE bound to
omalizumab cannot bind to IgE receptors on mast cells and
basophils, preventing the allergic reaction at a very early step in
the process.

34. Therapeutic use : Moderate to severe persistent asthma in patients
older than 12 years. It may reduce the frequency of attacks as
well as dependence on corticosteroid therapy.
• The high cost of the drug in addition to limitation of available
clinical trial data (especially for possible development of
malignancy during its use) make it not used as first line therapy in
asthma.

35. Treatment of acute exacerbations of bronchial asthma:
# Mild acute attack: (dyspnea only with activity, peak expiratory
flow rate [PEF] > 70%), give inhaled short acting β2 agonist
alone which may need to be continued every 3-4 hours for one to
two days. If patient already taking inhaled corticosteroids, a 7-
day course of oral corticosteroids may be necessary.
# Moderate acute attack: (dyspnea interferes with usual activities,
PFF 40-69%), give inhaled short acting β2 agonist continuously
plus early administration of systemic corticosteroids.

36. # Severe acute attack and status asthmaticus: (dyspnea at rest that
interferes with ability of conversation, PEF<40%), patient is
hospitalized and should receive oxygen to avoid fatal asphyxia,
high dose of inhaled short acting β2 agonist and systemic
corticosteroids (I.V.).
• Addition of ipratropium by inhalation can reduce the rate of
hospital admission. Theophylline I.V. may be added. The patient
usually improves. If not, tracheal intubation and mechanical
ventilation may be needed.

37. • Cough is a reflex action that serves to clear the respiratory
passages of foreign material and excess secretions. The cough
reflex is complex and involves the central and peripheral nervous
systems as well as the smooth muscle of the bronchial tree.
Anticough drugs
• Cough may be productive (associated with mucus secretion) or
nonproductive (dry cough).
Cough may be the first or only symptom in bronchial asthma or
allergy, and in such cases, bronchodilators e.g. β2-adrenergic
agonists reduce cough.

38. Centrally acting antitussives include:
a) Codeine: it is an opioid analgesic with low affinity to opioid
receptors. As an antitussive, the drug binds to distinct receptors
concerning codeine itself. It inhibits cough at a dose ineffective to
produce analgesia.
b) Dextromethorphan: it is the d-isomer of codeine analog with
no analgesic or addictive properties. The drug acts centrally to
elevate the threshold for coughing but not through binding to
opioid receptors (naloxone which is an opioid antagonist does not
inhibit the antitussive effect of dextromethorphan but it does for
codeine) .

39. c) Pholcodine: it is structurally related to opioids but has no
opioid like action. It is at least as effective as codeine as an
antitussive with long half-life that allows once or twice daily
administration.