It covers the basic pharmacology of rugs acting on respiratory system.

1. Unit I
Pharmacology of Respiratory
System
Presented by:
Prof. Mirza Anwar Baig
Dept of Pharmacology
AIKTC, School of Pharmacy, New Panvel

2. Contents:
a. Anti -asthmatic drugs
b. Drugs used in the management of COPD
c. Expectorants and antitussives
d. Nasal decongestants
e. Respiratory stimulants

3. Course Outcome:
At the end of the topic students should be able to
1. understand the mechanism of drug action and its relevance in
the treatment of different infectious diseases
2. comprehend the principles of toxicology and treatment of
various poisonings and
3. appreciate correlation of pharmacology with related medical
sciences

4. What is Asthma?
 Asthma is the commonest chronic disease in children and adults.
 Inflammatory condition
 Recurrent (repeatable) reversible airways obstruction in response
to irritant stimuli.
 Causes wheeze, although the natural history of asthma includes
spontaneous remissions (disappearance)

5. CHARACTERISTICS OF ASTHMA
 Acute attacks are reversible, can progress in older patients to a chronic state
superficially resembling COPD.
 COPD, where the obstruction is either not reversible or at best incompletely
reversible by bronchodilators.
 Acute severe asthma (status asthmaticus) is not easily reversed and causes
hypoxaemia.
 Hospitalization is necessary
 Asthma is characterized by:
a. inflammation of the airways
b. bronchial hyper-reactivity
c. reversible airways obstruction.

6. PATHOGENESIS OF ASTHMA
• Asthmatics have activated T-helper (Th)2 followed by cytokine production
(might be activated by allergen).
The Th2 cytokines that are released do the following:
1. Attract eosinophils, to the mucosal surface.
2. Interleukin (IL)-5 and granulocyte–macrophage colony-stimulating factor
prime eosinophils to produce cysteinyl leukotrienes, and to release
granule proteins that damage the epithelium.
3. This damage is one cause of bronchial hyper-responsiveness.

7. 5. Promote IgE synthesis and responsiveness in some asthmatics
6. IL-4 and IL-13 ‘switch’ B cells to IgE synthesis and cause expression of
IgE receptors on mast cells and eosinophils; they also enhance adhesion
of eosinophils to endothelium.
7. Triggering degranulation with release of histamine and leukotriene B4
(powerful bronchoconstrictors )
8. The omalizumab (an anti-IgE antibody) serves to antiasthmatics.
8. Noxious gases (e.g. sulfur dioxide, ozone) and airway dehydration can
also cause mast cell degranulation.

8. The immediate phase of the asthmatic attack
(i.e. the initial response to allergen)
• Occurs abruptly and is mainly caused by spasm of the bronchial smooth
muscle.
• Causes release of histamine, leukotriene B4 and prostaglandin (PG) D2, IL-
4, IL-5, IL-13, macrophage inflammatory protein-1α and TNF-α.
• Attract leukocytes—particularly eosinophils and mononuclear cells—into
the area, setting the stage for the delayed phase.

9. Fig: T lymphocytes in allergic asthma.

10. The late phase
1. May be nocturnal
2. A progressing inflammatory reaction
3. The inflammatory cells include activated eosinophils.
4. These release cysteinyl leukotrienes, interleukins IL-3, IL-5 and IL-8, and
the toxic proteins, eosinophil cationic protein, major basic protein and
eosinophil-derived neurotoxin.
5. Toxic proteins causing damage and loss of epithelium

11. Fig. Immediate and late phases of asthma, with the actions of the
main drugs

12. DRUGS USED TO TREAT AND PREVENT ASTHMA
• There are two categories of antiasthma drugs: bronchodilators
and anti-inflammatory agents.
• Bronchodilators reverse the bronchospasm of the immediate phase;
antiinflammatory agents inhibit or prevent the inflammatory components of
both phases.
• Corticosteroids are the mainstay of therapy because they are the only
asthma drugs that potently inhibit T-cell activation,and thus the
inflammatory response, in the asthmatic airways.
• Cromoglicate has only a weak effect and is now seldom used.

13. 5 therapeutic steps to treat chronic asthma
Step 1: Very mild disease: short-acting bronchodilator alone.
Step 2: If patients need this more than once a day, a regular inhaled corticosteroid should be
added.
Step 3: If the asthma remains uncontrolled, add a long-acting bronchodilator
(salmeterol or formoterol); this minimises the need for increased doses of inhaled
corticosteroid .
Step 4: For symptomatic patient where the dose of inhaled corticosteroid to be increased
Corticosteroid-sparing agent to be added (Theophylline and leukotriene antagonists,
such as montelukast)
Step 5: If the patient’s condition is still poorly controlled, it may be necessary to add a
regular oral corticosteroid (e.g. Prednisolone).

14. CLASSIFICATION:
I. Bronchodilators
A. β2 Sympathomimetics: Salbutamol, Terbutaline, Bambuterol, Salmeterol,
Formoterol,Ephedrine.
B. Methylxanthines: Theophylline (anhydrous),Aminophylline, Choline theophyllinate,
Hydroxyethyl theophylline, Theophylline ethanolate of piperazine, Doxophylline.
C. Anticholinergics: Ipratropium bromide,Tiotropium bromide.
II. Leukotriene antagonists
Montelukast, Zafirlukast.
III. Mast cell stabilizers
Sodium cromoglycate, Ketotifen.
IV. Corticosteroids
A. Systemic: Hydrocortisone, Prednisolone and others.
B. Inhalational: Beclomethasone dipropionate,Budesonide, Fluticasone propionate,
Flunisolide, Ciclesonide.
V. Anti-IgE antibody
Omalizumab

15. A. SYMPATHOMIMETICS (β-Adrenoceptor agonists)
 Cause bronchodilatation through β2 receptor stimulation → increased
cAMP formation in bronchial muscle cell → relaxation.
 Increased cAMP in mast cells and other inflammatory cells decreases
mediator release.
 Since β2 receptors on inflammatory cells desensitize quickly, the
beneficial effect of β2 agonists is uncertain, and at best minimal.
 They are the most effective and fastest acting bronchodilators when
inhaled.
• Though adrenaline (β1+β2+α receptor agonist) and isoprenaline (β1+β2
agonist) are effective bronchodilators, it is the selective β2 agonists that
are now used in asthma to minimize cardiac side effects.

16. • Relax bronchial muscle
• Inhibit mediator release from mast cells and TNF-α release from
monocytes,
• Increase mucus clearance by an action on cilia.
Two categories of β2-adrenoceptor agonists are used in asthma.
1. Short-acting agents: (salbutamol and terbutaline). (duration 3-5 hrs)
 Inhalation
 Used on an ‘as needed’ basis to control symptoms.
2. Longer-acting agents: e.g. salmeterol and formoterol. (duration 8–12 h)
 Inhalation.
 Given regularly, twice daily
 Adjunctive therapy in patients whose asthma is inadequately controlled by
glucocorticoids.

17. METHYL XANTHINES
 Extensively used in asthma, but are not considered first line drugs.
 Often used in COPD.
 Methylated xanthine alkaloids are caffeine, theophylline and theobromine.
 Sources:

18. Pharmacological action:
• Theobromine is of no therapeutic importance.

19. Pharmacological actions
1. CNS:
• CNS stimulants, primarily affect the higher centres.
• Caffeine 150–250 mg produces a sense of wellbeing, alertness etc
• Caffeine is more active than theophylline in producing these effects.
• Higher doses cause nervousness, restlessness, panic, insomnia and
excitement. Still higher doses produce tremors, delirium and convulsions.
• Stimulate medullary vagal, respiratory and vasomotor centres. Vomiting at
high doses is due to both gastric irritation and CTZ stimulation.

20. 2. CVS :
 Methylxanthines directly stimulate the heart and increase force of myocardial
Contractions and decrease it by causing vagal stimulation—net effect is
variable.
 Tachycardia is more common with theophylline, but caffeine generally lowers
heart rate.
 At high doses cardiac arrhythmias may be produced.
 Dilate systemic blood vessels-- peripheral resistance is reduced.
 Cranial vessels are constricted, especially by caffeine; (use in migraine).
 Effect on BP is variable and unpredictable—
• Vasomotor centre and direct cardiac stimulation—tends to raise BP.
• Vagal stimulation and direct vasodilatation—tends to lower BP.
 Usually a rise in systolic and fall in diastolic BP is observed.

21. 3. Smooth muscles:
 All smooth muscles are relaxed, most prominent effect is exerted on
bronchi, especially in asthmatics.
 Theophylline is more potent than caffeine.
 Vital capacity is increased.
 Biliary spasm is relieved, but effect on intestines and urinary tract is
negligible.

22. 4. Kidney:
 Mild diuretics
 Act by inhibiting tubular reabsorption of Na+ and water as well as
increased renal blood flow and g.f.r.
 Theophylline is more potent, but action is brief.
5. Skeletal muscles:
 Contraction.
 Increases release of Ca2+ from sarcoplasmic reticulum by direct action.
 Increasing Ach release.
 Relieves fatigue and increases muscular work.
 Enhanced diaphragmatic contractility noted contributes to its beneficial
effects in dyspnoea and COPD.

23. 6. Stomach:
 Methylxanthines enhance secretion of acid and pepsin in stomach, even on
parenteral injection.
 They are also gastric irritants—theophylline more than caffeine.
7. Mast cells and inflammatory cells:
 Theophylline decreases release of histamine and other mediators from mast
cells and activated inflammatory cells.
 This may contribute to its therapeutic effect in bronchial asthma.

24. Mechanism of action
Three distinct cellular actions of methylxanthines have been defined—
(a) Release of Ca2+ from sarcoplasmic reticulum,especially in skeletal
and cardiac muscle.
(b) Inhibition of phosphodiesterase (PDE) which degrades cyclic
nucleotides intracellularly.
The concentration of cyclic nucleotides is increased.
Bronchodilatation, cardiac stimulation and vasodilatation occur when cAMP
level rises in the concerned cells.
(c) Blockade of adenosine receptors:
Adenosine acts as a local mediator in CNS, CVS and other organs—contracts
smooth muscles, especially bronchial; dilates cerebral blood vessels, depresses
cardiac pacemaker and inhibits gastric secretion.
Methylxanthines produce opposite effects.

25. Muscarinic receptor antagonists
Longer acting drug
 Block of M2 autoreceptors on the cholinergic nerves increases acetylcholine
release.
 Inhibits the mucus secretion that occurs in asthma and
 May increase the mucociliary clearance of bronchial secretions.
 Used in maintenance treatment of COPD.
Examples: ipratropium. Tiotropium
Cysteinyl leukotriene receptor antagonists
 The ‘lukast’ drugs (montelukast and zafirlukast) antagonise only CysLT1.
 Inhibit exercise-induced asthma
 Relax the airways in mild asthma
 Reduce sputum eosinophilia,.

26. Histamine H1-receptor antagonists
 Effective in the immediate phase of allergic asthma (Fig. 27.3) and in some
 Types of exercise-induced asthma
 Modestly effective in mild atopic asthma (precipitated by acute histamine
Release)
Anti-IgE treatment
 Humanised monoclonal anti-IgE antibody.
 Effective in allergic asthma and in allergic rhinitis.
 Expensive

27. B. Drugs used in the management of
COPD

28. Introduction:
• A major global health problem.
• Cigarette smoking and air pollution is the main cause.
• Received much less attention than asthma.
Clinical features.
 Attacks of morning cough during the winter
 Progresses to chronic cough with intermittent exacerbations (upper
respiratory infection).
 Progressive breathlessness.
 Pulmonary hypertension is a late complication
 Condition of patient may be complicated by respiratory failure
 Tracheostomy and artificial ventilation may prolong survival.
 https://www.youtube.com/watch?v=T1G9Rl65M-Q

29. Pathogenesis:
 There is small airways fibrosis, resulting in obstruction, and/or destruction of
alveoli (emphysema ) and of elastin fibres in the lung parenchyma.
 Caused by proteases, including elastase, released during the inflammatory
response.
 Chronic inflammation, (small airways and lung parenchyma), characterized by
increased numbers of macrophages, neutrophils and T lymphocytes.
 Lipid mediators, inflammatory peptides, reactive oxygen and nitrogen
species, chemokines, cytokines and growth factors are all involved.

30. Principles of treatment:
 Stopping smoking slows the progress of COPD.
 Patients should be immunised against influenza and Pneumococcus, because
superimposed infections with these organisms are potentially lethal.
 Glucocorticoids are generally ineffective, in contrast to asthma, but a trial of
glucocorticoid treatment is worthwhile because asthma may coexist with
COPD and have been overlooked.
 During asthma and COPD, multiple inflammatory genes are activated.
 HDAC activity is inhibited by smoking-related oxidative stress.
 Inflammatory gene causes acetylation of nuclear histones (DNA) is initiated
lead to synthesis of inflammatory proteins.

31.  Histone deacetylases (HDACs) are enzymes that catalyze the
removal of acetyl functional groups (deacetylation) from the
lysine residues of both histone and nonhistone proteins.
 Corticosteroids recruit HDAC to activated genes, reversing acetylation and
switching off inflammatory gene transcription.
 There is a link between the severity of COPD (but not of asthma) and
reduced HDAC activity in lung tissue.
 HDAC is a key molecule in suppressing production of proinflammatory
cytokines.

32. Long-acting bronchodilators
 Give modest benefit, but do not deal with the underlying inflammation.
 No currently licensed treatments reduce the progression of COPD or
suppress the inflammation in small airways and lung parenchyma.
 Some, such as chemokine antagonists, are directed against the influx of
inflammatory cells into the airways and lung parenchyma
 Phophodiesterase IV inhibitors (e.g. roflumilast) show some promise.
 Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-
activated protein kinase, nuclear factor κβ and phosphoinositide-3
kinase-γ.

33.  More specific approaches are to give antioxidants, inhibitors of inducible
NO synthase and leukotriene B4 antagonists (Leukotriene B4 induces
recruitment and activation of neutrophils, monocytes and eosinophils.)
 Other treatments have the potential to combat mucus hypersecretion, and
there is a search for serine protease and matrix metalloprotease inhibitors
to prevent lung destruction and the development of emphysema.

34. Specific aspects of treatment.
Short- and long-acting inhaled bronchodilators
 Shortacting drugs are ipratropium and salbutamol
 Long-acting drugs include tiotropium and salmeterol or formoterol
 Theophylline can be given, its respiratory stimulant effect may be useful
for patients who tend to retain CO2.
 Other respiratory stimulants (e.g. doxapram) are sometimes used briefly in
acute respiratory failure (e.g.postoperatively) but have largely been
replaced by ventilatory support.
 Long-term oxygen therapy administered at home prolongs life in patients
with severe disease and hypoxaemia

35. Acute exacerbations.
 Acute cases are treated with inhaled O2 in a concentration (initially, at least) of
only 24% O2, i.e. only just above atmospheric O2 concentration
(approximately 20%).
 The need for caution is because of the risk of precipitating CO2 retention as
a consequence of terminating the hypoxic drive to respiration.
 Blood gases and tissue oxygen saturation are monitored, and inspired O2
subsequently adjusted accordingly.
 Broad-spectrum antibiotics (e.g. cefuroxime), including activity against
Haemophilus influenzae, are used if there is evidence of infection.
 Inhaled bronchodilators may provide some symptomatic improvement

36.  A systemically active glucocorticoid (intravenous hydrocortisone
or oral prednisolone) is also administered routinely, although efficacy is
modest.
 Inhaled steroids do not influence the progressive decline in lung function in
patients with COPD, but do improve the quality of life, probably as a result
of a modest reduction in hospital admissions.

37. Expectorant and Anti-tussive

38. COUGH:
 A protective reflex that removes foreign material and secretions from the
bronchi and bronchioles.
 Occurs due to stimulation of mechano- or chemoreceptors in throat
respiratory passages or stretch receptors in the lungs
 Triggered by inflammation in the respiratory tract.
 Present in undiagnosed asthma or chronic reflux with aspiration, bronchial
carcinoma etc).
 Cough is common adverse effect of angiotensin-converting enzyme
inhibitors.
 Antitussive drugs are sometimes useful but can cause undesirable thickening
and retention of sputum and risk of respiratory depression.
• https://www.youtube.com/watch?v=dVac4G3e84Y

39. Treatment:
Apart from specific remedies (antibiotics, etc.), cough may be treated as a
Symptom (nonspecific therapy) with:
1. Pharyngeal demulcents:
Lozenges, cough drops, linctuses containing syrup, glycerine,liquorice.
2. Expectorants (Mucokinetics)
(a) Bronchial secretion enhancers:
Sodium or Potassium citrate, Potassium iodide, Guaiphenesin (Glyceryl
guaiacolate), balsum of Tolu, Vasaka, Ammonium chloride.
(b) Mucolytics:
Bromhexine, Ambroxol, Acetylcysteine, Carbocisteine
3. Antitussives (Cough centre suppressants)
(a) Opioids: Codeine, Ethylmorphine,Pholcodeine.
(b) Nonopioids: Noscapine, Dextromethorphan,Chlophedianol.
(c) Antihistamines: Chlorpheniramine, Diphenhydramine,Promethazine.
(d) Peripherally acting: Prenoxdiazine.
4. Adjuvant antitussives
Bronchodilators: Salbutamol, Terbutalin.

40. Specific treatment approaches:

41. Treatment:
• Pharyngeal demulcents - reduce afferent impulses from the
inflamed/irritated pharyngeal mucosa, thus provide symptomatic relief in
dry cough arising from throat.
• Expectorants (Mucokinetics) - increase bronchial secretion or reduce its
viscosity, facilitating its removal by coughing.
• Sodium and potassium citrate are considered to increase bronchial secretion
by salt action.
• Potassium iodide is secreted by bronchial glands and can irritate the airway
mucosa. Prolonged use can affect thyroid function and produce iodism. It is
not used now.
• Guaiphenesin, vasaka, tolu balsum are plant products which are supposed
to enhance bronchial secretion and mucociliary function while being
secreted by tracheobronchial glands.

42. • Ammonium salts are nauseating— reflexly increase respiratory secretions.
• The US-FDA has stopped marketing of all expectorants, except
guaiphenesin.
• Steam inhalation and proper hydration may be more helpful in clearing
airway mucus.

43. Antitussives:
 Suppress coughing (cough suppressants).
 All opioid analgesics are in clinical use which act by an ill-defined effect in
the brain stem, depressing an even more poorly defined ‘cough centre’.
 They suppress cough in doses below those required for pain relief.
 Those used as cough suppressants have minimal analgesic actions and
addictive properties.
 New opioid analogues that suppress cough by inhibiting release of excitatory
neuropeptides through an action on μ receptors on sensory nerves in the
bronchi are being assessed.

44. Codeine (methylmorphine):
 A weak opioid with considerably less addiction liability than the main opioids,
and is a mild cough suppressant.
 Decreases secretions in the bronchioles, which thickens sputum, and
inhibits ciliary activity.
 Constipation is common.
 Dextromethorphan and pholcodine have similar but possibly less intense
adverse effects.
 Respiratory depression is a risk with all drugs of this type.
 Morphine is used for palliative care in cases of lung cancer associated with
distressing cough.

45. d. Nasal Decongestants

46. What is nasal congestion?
 It is swelling of the nasal tissues.
 Blood vessels in nasal tissues become dilated, to get the immune
response cells to the nose to fight the virus that has entered the body.
Causes include:
• A Virus. The viruses entered through nose and begins to multiply.
The body’s response leads to inflammation that brings nasal
congestion.
• Allergies. Allergen, causes swelling of nasal tissues which leads to
nasal congestion.

47. What is nasal decongestants?
• α agonists, produce local vasoconstriction.
• The imidazoline compounds— naphazoline, xylometazoline and
oxymetazoline are relatively selective α2 agonist (like clonidine).
• They have a longer duration of action (12 hours) than ephedrine.
Side effects:
 After-congestion (less than that with ephedrine or phenylephrine).
 Stinging sensation (specially naphazoline).
 Impaired mucosal ciliary function (on long term use)
 Atrophic rhinitis and anosmia (due to persistent vasoconstriction).
 CNS depression and rise in BP (systemic effects).
 https://www.mountsinai.org/health-library/symptoms/stuffy-or-runny-nose-
adult

48. Nasal decongestants:
• Phenylephrine, Naphazoline
• Xylometazoline, Pseudoephedrine
• Oxymetazoline, Phenyl propanolamine

49. Phenylephrine:
• Selective α1 agonist, has negligible β action.
• It raises BP by causing vasoconstriction.
Therapeutic use:
• Nasal decongestant
• For producing mydriasis when cycloplegia is not required.
• To reduce intraocular tension by constricting ciliary body blood vessels.
• Constituent of orally administered nasal decongestant preparations

50. Pseudophedrine:
• A stereoisomer of ephedrine
• causes vasoconstriction, especially in mucosae and skin.
Therapeutic use:
• Oral decongestant of upper respiratory tract, nose and eustachian
tubes.
• Combined with antihistaminics, mucolytics,antitussives and
analgesics
• For symptomatic relief in common cold, allergic rhinitis, blocked
eustachian tubes and upper respiratory tract infections.
Side effects:
• rise in BP can occur, especially in hypertensives.

51. Phenylpropanolamine (PPA)
• Chemically and pharmacologically similar to ephedrine,
• Causes vasoconstriction and has some amphetamine like CNS effects,
including suppression of hunger.
Therapeutic Uses:
• Included in a large number of oral cold/decongestant combination remedies,
and in USA it was used as an appetite suppressant as well.
Side Effects/Adverse Effects:
 Can precipitate hemorrhagic stroke and behavioural/psychiatric disturbances
 Prohibited the sale of PPA containing medicines decades back in USA and
may countries.
 Lower amounts of PPA (25–50 mg) continued to be available over-the-
counter in India till recently.

52. II. ANALEPTICS (Respiratory stimulants)
 Have resuscitative value in coma or fainting.
 Stimulate respiration in subconvulsive doses.
 Margin of safety is narrow; the patient may get convulsions while still in
coma.
 Therapeutics use is very limited and dubious
 Mechanical support to respiration to improve circulation are more effective
and safe.

53. Situations in which they may be employed are:
(a) As a measure in hypnotic drug poisoning untill mechanical ventilation is
instituted.
(b) Suffocation on drowning, acute respiratory insufficiency.
(c) Apnoea in premature infant.
(d) Failure to ventilate spontaneously after general anaesthesia.

54. Doxapram
• It acts by promoting excitation of central neurones.
• At low doses it is more selective for the respiratory centre than other
analeptics.
• Respiration is stimulated through carotid and aortic body chemoreceptors
as well.
• Falling BP rises.
• Continuous i.v. infusion of doxapram may abolish episodes of apnoea in
premature infant not responding to theophylline.
.