Unit 1 respiratory system

Drugs acting on Respiratory system as PCI curriculum.

1. Unit I
Pharmacology of Respiratory
System
Presented by:
Prof. MirzaAnwar 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
reversibleby 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 eosinophilsto produce cysteinylleukotrienes, and to release
granule proteins that damage the epithelium.
3. This damage is one cause of bronchial hyper-responsiveness.

7. 5.Promote IgEsynthesis and responsiveness in some asthmatics
6.IL-4 and IL-13 ‘switch’ B cells to IgEsynthesis and cause expression of
IgEreceptors on mast cells and eosinophils; they also enhance adhesion
of eosinophilsto endothelium.
7.Triggering degranulationwith release of histamine and leukotrieneB4
(powerful bronchoconstrictors)
8.The omalizumab(an anti-IgEantibody) 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 spasmof the bronchial smooth
muscle.
•Causes release of histamine, leukotrieneB4 and prostaglandin (PG) D2, IL-
4, IL-5, IL-13, macrophage inflammatory protein-1α and TNF-α.
•Attract leukocytes—particularly eosinophilsand 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 cysteinylleukotrienes, interleukins IL-3, IL-5 and IL-8, and
the toxic proteins, eosinophilcationic 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.
•Bronchodilatorsreverse the bronchospasmof the immediate phase;
antiinflammatoryagents inhibit or prevent the inflammatory components of
both phases.
•Corticosteroidsare the mainstay of therapy because they are the only
asthma drugs that potently inhibit T-cell activation,andthus the
inflammatory response, in the asthmatic airways.
•Cromoglicatehas only a weak effect and is now seldom used.

13. 5 therapeutic steps to treat chronic asthma
Step1:Verymilddisease:short-actingbronchodilatoralone.
Step2:Ifpatientsneedthismorethanonceaday,aregularinhaledcorticosteroidshouldbe
added.
Step3:Iftheasthmaremainsuncontrolled,addalong-actingbronchodilator
(salmeterolorformoterol);thisminimisestheneedforincreaseddosesofinhaled
corticosteroid.
Step4:Forsymptomaticpatientwherethedoseofinhaledcorticosteroidtobeincreased
Corticosteroid-sparingagenttobeadded(Theophyllineandleukotrieneantagonists,
suchasmontelukast)
Step5:Ifthepatient’sconditionisstillpoorlycontrolled,itmaybenecessarytoadda
regularoralcorticosteroid(e.g.Prednisolone).

14. CLASSIFICATION:
I.Bronchodilators
A. β2 Sympathomimetics: Salbutamol, Terbutaline, Bambuterol, Salmeterol,
Formoterol,Ephedrine.
B. Methylxanthines: Theophylline(anhydrous),Aminophylline, Cholinetheophyllinate,
Hydroxyethyltheophylline, Theophyllineethanolateof piperazine, Doxophylline.
C. Anticholinergics:Ipratropiumbromide,Tiotropiumbromide.
II. Leukotrieneantagonists
Montelukast, Zafirlukast.
III. Mast cell stabilizers
Sodium cromoglycate, Ketotifen.
IV. Corticosteroids
A. Systemic: Hydrocortisone, Prednisoloneand others.
B. Inhalational: Beclomethasonedipropionate,Budesonide, Fluticasonepropionate,
Flunisolide, Ciclesonide.
V. Anti-IgEantibody
Omalizumab

15. A. SYMPATHOMIMETICS ( β-Adrenoceptoragonists)
Cause bronchodilatationthrough β2 receptor stimulation → increased
cAMPformation in bronchial muscle cell → relaxation.
Increased cAMPin 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: (salbutamoland terbutaline). (duration 3-5 hrs)
Inhalation
Used on an ‘as needed’ basis to control symptoms.
2. Longer-acting agents: e.g. salmeteroland 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.
Methylatedxanthinealkaloids are caffeine, theophyllineand theobromine.
Sources:

18. Pharmacological action:
•Theobromineis 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 theophyllinein producing these effects.
•Higher doses cause nervousness, restlessness, panic, insomnia and
excitement. Still higher dosesproduce tremors, delirium and convulsions.
•Stimulatemedullaryvagal, respiratory and vasomotor centres. Vomitingat
high doses is due to both gastric irritation and CTZ stimulation.

20. 2. CVS :
Methylxanthinesdirectly stimulate the heart and increase force of myocardial
Contractions and decrease it by causing vagalstimulation—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.
• Vagalstimulation 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.
Theophyllineis more potentthan caffeine.
Vital capacity is increased.
Biliaryspasm is relieved, but effect on intestines and urinary tract is
negligible.

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

23. 6. Stomach:
Methylxanthinesenhance secretion of acid and pepsin in stomach, even on
parenteralinjection.
They are also gastric irritants—theophyllinemore than caffeine.
7. Mast cells and inflammatory cells:
Theophyllinedecreases release of histamine and other mediators from mast
cells and activatedinflammatory cells.
This may contribute to its therapeutic effect in bronchial asthma.

24. Mechanism of action
Three distinct cellular actions of methylxanthineshave been defined—
(a) Release of Ca2
+
from sarcoplasmicreticulum,especiallyin 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.
Methylxanthinesproduce opposite effects.

25. Muscarinicreceptor antagonists
Longer acting drug
Block ofM2 autoreceptorson the cholinergic nerves increases acetylcholine
release.
Inhibits the mucus secretion that occurs in asthma and
May increase the mucociliaryclearance of bronchial secretions.
Used in maintenance treatment of COPD.
Examples: ipratropium. Tiotropium
Cysteinylleukotrienereceptor antagonists
The ‘lukast’ drugs (montelukastand zafirlukast) antagoniseonly 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-IgEtreatment
Humanisedmonoclonal anti-IgEantibody.
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.
Attacksof 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
Tracheostomyand 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 elastinfibresin 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, neutrophilsand 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 immunisedagainst influenza and Pneumococcus, because
superimposed infections with these organisms are potentially lethal.
Glucocorticoidsare generally ineffective, in contrast to asthma, but a trial of
glucocorticoidtreatment 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 acetylationof nuclear histones(DNA) is initiated
lead to synthesis of inflammatory proteins.

31. Histonedeacetylases(HDACs)are enzymes thatcatalyze the
removal of acetyl functional groups (deacetylation)from the
lysine residues of both histoneand nonhistoneproteins.
Corticosteroids recruit HDAC to activated genes, reversing acetylationand
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 chemokineantagonists, are directed against the influx of
inflammatory cellsinto the airways and lung parenchyma
PhophodiesteraseIV inhibitors (e.g. roflumilast) show some promise.
Other drugs that inhibit cell signallinginclude inhibitors of p38 mitogen-
activated protein kinase, nuclear factor κβand phosphoinositide-3
kinase-γ.

33. More specific approaches are to give antioxidants, inhibitors of inducible
NO synthaseand leukotrieneB4 antagonists (LeukotrieneB4induces
recruitment and activation of neutrophils, monocytesand eosinophils.)
Other treatments have the potential to combat mucus hypersecretion, and
there is a search for serine protease and matrix metalloproteaseinhibitors
to prevent lung destruction and the development of emphysema.

34. Specific aspects of treatment.
Short-and long-acting inhaled bronchodilators
Shortactingdrugs are ipratropiumand salbutamol
Long-acting drugs include tiotropiumand salmeterolor formoterol
Theophyllinecan 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 ventilatorysupport.
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
Haemophilusinfluenzae, 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 chemoreceptorsin throat
respiratory passages or stretch receptors in the lungs
Triggered by inflammationin 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.
Antitussivedrugs 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), balsumof Tolu, Vasaka, Ammonium chloride.
(b) Mucolytics:
Bromhexine, Ambroxol, Acetylcysteine, Carbocisteine
3. Antitussives (Coughcentre 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 iodideis 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, tolubalsumare plant products which are supposed
to enhance bronchial secretion and mucociliaryfunction while being
secreted by tracheobronchialglands.

42. •Ammonium salts are nauseating—reflexlyincrease 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 opioidanalgesics 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 opioidanalogues that suppress cough by inhibiting release of excitatory
neuropeptidesthrough an action on μ receptors on sensory nerves in the
bronchi are being assessed.

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

45. d. Nasal Decongestants

46. What is nasal congestion?
It is swellingof 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 enteredthrough nose and beginsto 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 imidazolinecompounds—naphazoline, xylometazolineand
oxymetazolineare 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 ciliaryfunction (on long term use)
Atrophic rhinitisand 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 mydriasiswhen cycloplegiais not required.
•To reduce intraocular tension by constricting ciliarybody blood vessels.
•Constituentof orally administered nasal decongestant preparations

50. Pseudophedrine:
•A stereoisomer of ephedrine
•causes vasoconstriction, especially in mucosaeand skin.
Therapeutic use:
•Oral decongestant of upper respiratory tract, nose and eustachian
tubes.
•Combinedwith antihistaminics, mucolytics,antitussivesand
analgesics
•For symptomatic relief in common cold, allergic rhinitis, blocked
eustachiantubes 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 subconvulsivedoses.
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 untillmechanical ventilation is
instituted.
(b) Suffocation on drowning, acute respiratory insufficiency.
(c) Apnoeain premature infant.
(d) Failure to ventilate spontaneously after general anaesthesia.

54. Doxapram
•It acts by promoting excitation of central neurones.
•At low dosesit 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. infusionof doxaprammay abolish episodes of apnoeain
premature infant not responding to theophylline.
.