1. Review on Respiratory System Disorders and Management
Jamaluddin Shaikh, Ph.D.
Good morning everybody. Today I am going to discuss about …….
School of Pharmacy, University of Nizwa

2. Respiratory System Disorders
Asthma
Chronic Obstructive Pulmonary Disease
Allergic Rhinitis
Cough

3. Asthma
Asthma is a chronic disease characterized by the inflammation of the airway wall
Asthma is characterized by:
inflammation of the airways
bronchial hyper-reactivity
reversible airways obstruction

4. Risk Factors that Lead to Asthma Development
Host Factors:
Genetic predisposition
Airway hyperresponsiveness
Gender
Race/Thnicity
Environmental Factors:
Indoor/Outdoor allergens
Tobacco smoke
Respiratory infections
Parasitic infections
Socioeconomic conditions
Diet and drugs

5. Asthma Management
Educate people to develop a partnership in asthma management
Assess and monitor asthma severity with symptoms reports and measure of lung function as much as possible
Avoid exposure of risk factors
Establish medication plans for chronic management for children and adults
Establish individual plans for managing exacerbations
Provide regular follow-up care

6. Drugs Used to Treat Asthma
Two categories of antiasthma drugs:
Bronchodilators
Anti-inflammatory agents

7. Bronchodilators
Bronchodilators reduce the work of breathing, relieve asthmatic symptoms, and improve ventilation
Bronchodilators produce a substantial increase in pulmonary function by relaxing bronchial smooth muscle, thus dilating the airways
Types of Bronchodilators:
β2-Adrenergic agonists
Xanthines
cysteinyl leukotriene receptor antagonists
muscarinic receptor antagonists
Omalizumab

8. β2-Adrenergic Agonists: Mechanisms of Action
Primary effect in asthma is to dilate the bronchi by a direct action on the β2-adrenoceptors on the smooth muscle
Being physiological antagonists of bronchoconstrictors, they relax bronchial muscle
They inhibit mediator release from mast cells and TNF-α release from monocytes, and increase mucus clearance

9. β2-Adrenergic Agonists: Uses
They are delivered directly to the airways via inhalation
They are classified as short- or long-acting agonists
Short-acting agonists:
used only for symptomatic relief of asthma
maximum effect occurs within 30 minutes and the duration of action is 3-5 hours
used on an 'as needed' basis to control symptoms
long-acting agonists:
used in the treatment of the disease
duration of action is 8-12 hours
not used 'as needed' but are given regularly, twice daily

10. β2-Adrenergic Agonists: Adverse Effects
The common adverse effect is tremor
Other unwanted effect is tachycardia

11. Xanthine Drugs
There are three pharmacologically active, naturally occurring methylxanthines:
Theophylline
Theobromine
Caffeine

12. Xanthine Drugs: Mechanisms of Action
The relaxant effect on smooth muscle has been attributed to inhibition of the phosphodiesterase (PDE) isoenzymes, with resultant increase in cAMP and/or cGMP
Competitive antagonism of adenosine at adenosine A1 and A2 receptors may contribute in bronchodilation
Type IV PDE is implicated in inflammatory cells, and non-specific methylxanthines may have some anti- inflammatory effect

13. Xanthine Drugs: Pharmacokinetics
Methylxanthines are given orally
Well absorbed from the gastrointestinal tract
Metabolised by the CYP450 system in the liver
Elimination half-life is about 8 hours
The half-life is increased in liver disease, cardiac failure and viral infections, and is decreased in heavy cigarette smokers and drinkers

14. Xanthine Drugs: Adverse Effects
When theophylline is used in asthma, unwanted side effects occur in CNS, cardiovascular, and gastrointestinal
Therapeutic plasma concentration range is μmol/l, and adverse effects are common with concentrations greater than 110μmol/l. Serious cardiovascular and CNS effects can occur when the plasma concentration exceeds 200μmol/l.
Seizures can occur with theophylline concentrations at or slightly above the upper limit of the therapeutic range

15. Cysteinyl Leukotriene Receptor Antagonist: Pharmacological Action
They inhibit exercise-induced asthma and decrease both early and late responses to inhaled allergen
They relax the airways in mild asthma
Their action is additive with β2-adrenoceptor agonists

16. Cysteinyl Leukotriene Receptor Antagonists: Pharmacokinetics
Drugs are given orally

17. Cysteinyl Leukotriene Receptor Antagonist: Adverse Effects
Headache and gastrointestinal disturbances

18. Muscarinic Receptor Antagonists: Uses
Used on a regular basis in asthma
It does not discriminate between muscarinic receptor subtypes, and it is possible that its blockade of M2 autoreceptors on the cholinergic nerves increases acetylcholine release and reduces the effectiveness of its antagonism at the M3 receptors on the smooth muscle
It has no effect on the late inflammatory phase of asthma.

19. Muscarinic Receptor Antagonists: Pharmacokinetics
It is given by aerosol inhalation
The maximum effect occurs after approximately 30 minutes and persists for 3-5 hours

20. Omalizumab
Omalizumab is a monoclonal antibody that selectively binds to human IgE. This leads to decreased binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils. Reduction in surface-bound IgE limits the degree of release of mediators of the allergic response
Omalizumab is useful for treatment of moderate to severe allergic asthma in patients who are poorly controlled with conventional therapy

21. Role of Inflammation in Asthma
Airflow obstruction in asthma is due to bronchoconstriction that results from contraction of bronchial smooth muscle, inflammation of the bronchial wall, and increased mucous secretion
Asthmatic attacks may be related to recent exposure to allergens or inhaled irritants, leading to bronchial hyperactivity and inflammation of the airway mucosa
The symptoms of asthma may be effectively treated by several drugs

22. Anti-Inflammatory Agents
The main drugs used for their anti-inflammatory action in asthma are the glucocorticoids
Cromoglicate also has some anti-inflammatory action
Glucocorticoids are not bronchodilators, but prevent the progression of chronic asthma and are effective in acute severe asthma

23. Glucocorticoids: Mechanism of Action
They decrease the formation of cytokines and activate eosinophils and are responsible for promoting the production of IgE and the expression of IgE receptors
Glucocorticoids inhibit the generation of vasodilators PGE2 and PGI2, by inhibiting induction of COX-2
Glucocorticoids up-regulate β2 adrenoceptors, decrease microvascular permeability, and indirectly reduce mediator release from eosinophils by inhibiting the production of cytokines

24. Glucocorticoids: Route of Administration
The development of inhaled glucocorticoid has markedly reduced the need for systemic corticosteroid treatment to achieve asthma control
Appropriate inhalation technique is critical to the success of therapy
Patients with severe exacerbation of asthma may require intravenous administration

25. Glucocorticoids: Unwanted Effects
Serious unwanted effects are uncommon with inhaled steroids. Sore throat and croaky voice can occur
Regular high doses can produce some adrenal suppression, particularly in children

26. Cromoglicate: Drug of Action
Cromoglicate is not bronchodilators; it do not has any direct effects on smooth muscle, nor do it inhibits the actions of any of the known smooth muscle stimulants
Rather, it can reduce both the immediate and the late-phase asthmatic responses and reduce bronchial hyper-reactivity

27. Cromoglicate: Mechanism of Action
Cromoglicate was originally thought to act as a 'mast cell stabiliser', preventing histamine release from mast cells. However, although it has this effect it is clearly not the basis of its action in asthma
There is evidence that cromoglicate depresses the exaggerated neuronal reflexes; it suppresses the response of sensory C fibres to the irritant capsaicin and inhibit the release of preformed T cell cytokines

28. Cromoglicate: Pharmacokinetics
Cromoglicate is poorly absorbed from the gastrointestinal tract
Given by inhalation as an aerosol, as a nebulised solution or in powder form; about 10% is absorbed into the circulation when it is given in this way
It is excreted unchanged: 50% in the bile and 50% in the urine
Its half-life in the plasma is 90 minutes

29. Cromoglicate: Unwanted Effects
Unwanted effects are few and consist mostly of the effects of irritation in the upper respiratory tract
Hypersensitivity reactions have been reported, but are rare

30. Treatment of Asthma: Summary
Classifica-tion
Broncocos-tructive Episode
Results of Peak Flow
Long-term Control
Quick Relief of Symptoms
Mild Intermittent
Less than two per week
Near normal
No daily medication
Short acting β2-agonist
Mild Persistent
More than two per week
Low-dose inhaled corticosteroids
Moderate Persistent
Daily
60 to 80 percent of normal
Low- to medium-dose inhaled corticosteroids and a long acting β2-agonist
Severe Persistent
Continual
Less than 60 percent of normal
High-dose inhaled corticosteroids and a long acting β2-agonist

31. Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) consists of
Chronic bronchitis
Emphysema

32. Chronic Bronchitis
Chronic bronchitis is inflammation of the bronchi and bronchioles
Caused by air pollution but is more usually associated with cigarette smoking
Symptoms are cough in the early stages and in the later stages productive cough, and breathlessness owing to airflow limitation
Smoking cessation and/or continued avoidance should be recommended
Inhaled bronchodilators, such as anticholinergic agents and β2-adrenergic agonists, are the foundation of therapy for COPD

33. Emphysema
Emphysema is distension and damage of lung tissue beyond the respiratory bronchioles
The airflow limitation is partially reversible in the early stages
Emphysema can be prevented or its progression slowed if the patient stops smoking
Drug treatment is palliative, the main drug being ipratropium bromide. Salbutamol is also used and corticosteroids (inhaled or oral) can be of value in some cases

34. COPD: Summary Stage Characteristics Long-term control Mild COPD
Forced Expiratory Volume in 1 seconds (FEV1) greater than 80% predicted
Short-acting bronchodilator when needed
Moderate COPD
FEV1 50 to 80% predicted
Regular treatment with one or more bronchodilators
Inhaled corticosteroids
Severe COPD
FEV1 less than 30% predicted
Long-term oxygen therapy

35. Allergic Rhinitis
Rhinitis is an inflammation of the mucous membranes of the nose and is characterized by sneezing, itchy nose/eyes, and nasal congestion
Attack may be more by inhalation of an allergen
Mast cells release mediators, such as histamine, leukotrienes, and chemotactic factors, that promote bronchiolar spasm and mucosal thickening
Combinations of oral antihistamines with decongestants are the first-line therapies for allergic rhinitis

36. Allergic Rhenitis: Treatments
Types of treatment available
Antihistamine
β-Adrenergic agonists
Corticosteroids
Cromolyn

37. Allergic Rhenitis: Treatment with Antihistamine
Antihistamines are the most frequently used agents in the treatment of allergic rhinitis
H1-histamine receptor blockers are useful in treating the allergic rhinitis
Ocular and nasal antihistamine delivery devices are available
Combinations of antihistamines with decongestants are effective when congestion is a feature of rhinitis

38. Allergic Rhenitis: Treatment with β-Adrenergic agonists
Short-acting β-adrenergic agonists constrict dilated arterioles in the nasal mucosa and reduce airway resistance
When administered as an aerosol, these drugs have a rapid onset of action, with few effects
Oral administration results in longer duration of action but also increased systemic effects
Combinations of these agents with antihistamines are frequently used
Should be used no longer than several days due to the risk of rebound nasal congestion

39. Allergic Rhenitis: Treatment with Corticosteroids
Corticosteroids are effective when administered as nasal sprays
Topical steroids may be more effective than systemic antihistamines in relieving the nasal symptoms of allergic rhinitis
Treatment of chronic rhinitis may not result in improvement until 1 to 2 weeks after starting therapy

40. Allergic Rhenitis: Treatment with Cromolyn
Intranasal cromolyn is useful, particularly when administered before contact with an allergen
To optimize the therapeutic effect of cromolyn, dosing should occur at least 1 to 2 weeks prior to allergen exposure
Due to a short duration of action, cromolyn requires multiple daily dosing, which may impact therapeutic efficacy

41. Cough
Cough is a protective reflex mechanism that removes foreign material and secretions from the bronchi and bronchioles
It can be inappropriately stimulated by inflammation in the respiratory tract
For treatment, antitussive (or cough suppressant) drugs are sometimes used
In cough associated with chronic bronchitis, antitussive drugs can cause harmful sputum thickening and retention. They should not be used for the cough associated with asthma

42. Drugs Used for Cough
Antitussive drugs act by an ill-defined effect in the brainstem, depressing an even more poorly defined 'cough centre‘
The narcotic analgesics have effective antitussive action in doses below those required for pain relief, and various isomers of these agents, are also effective against cough.
New opioid analogues that suppress cough by inhibiting release of excitatory neuropeptides are useful

43. Few Antitussive Drugs Codeine: Dextromethorphan: Pholcodine:
An opiate, is an effective cough suppressant.
It decreases secretions in the bronchioles, this reduces clearance of the thickened sputum.
Dextromethorphan:
Its antitussive potency is equivalent to that of codeine
it produces only marginally less constipation and inhibition of mucociliary clearance
Pholcodine:
A non-analgesic opiate, has an antitusive potency

44. Summary of Drugs Affecting Respiratory System
Drugs used to treat Asthma:
β2-Adrenergic agonists
Short acting: Salbutamol, terbutaline, albuterol
Long acting: Salmeterol, formoterol
Corticosteroids (Beclomethasone, Budesomide, Fluticasone)
Cromoglicate (Cromolyn, nedocromil)
Muscarinic receptor antagonists (Ipratropium, tiotropium)
Leukotriene antagonists (Monteleukast, zafirlukast, zileutron)
Omalizumab
Xanthine (Theophylline, theobromine, caffiene)

45. Summary of Drugs Affecting Respiratory System
Drug used to treat COPD:
β2-Adrenergic agonists
Short acting: (Salbutamol, albuterol, terbutaline)
Long acting: (Salmeterol, formoterol)
Corticosteroids (Beclomethasone, Budesomide, Fluticasone)
Muscarinic receptor antagonists (Ipratropium, tiotropium)

46. Summary of Drugs Affecting Respiratory System, continued……….
Drug used to treat Allergic Rhinitis:
α-Adrenergic agonists
Short-acting: Phenylephrine
Long-acting: Oxymetazoline
Antihistamines (Diphenhydramine, loratadine)
Corticosteroids (Beclomethasone, Budesomide, Fluticasone)
Cromoglicate (Cromolyn)
Drugs used to treat Cough:
Codeine
Dextromethorphan
Opiate

47. Case Study 1: A 12-year-old girl with a childhood history of asthma complained of cough, dyspnea, and wheezing after visiting a riding stable. Her symptoms became so severe that her parents brought her to the emergency room. Physical examination revealed diaphoresis, dyspnea, tachycardia, and tachypnea. Her respiratory rate was 42 breaths per minute, pulse rate 110 beats per minute, and blood pressure 132/65 mm Hg. Which of the following is the most appropriate drug to rapidly reverse her bronchoconstriction?
A. Inhaled cromolyn.
B. Inhaled beclomethasone.
C. Inhaled albuterol.
D. Intravenous propranolol. Correct answer = C. Inhalation of a rapid-acting β2 agonist, such as albuterol, usually provides immediate bronchodilation. An acute asthmatic crisis often requires intravenous corticosteroids, often methylprednisolone. Inhaled beclomethasone will not deliver enough steroid to fully combat airway inflammation. Propranolol is a β-blocker and would aggravate the patient's bronchoconstriction. Cromolyn can be used prophylactically to reduce the inflammatory response but is ineffective in relieving acute symptoms.

48. Case Study 2: A 9-year-old girl has severe asthma, which required three hospitalizations in the last year. She is now receiving therapy that has greatly reduced the frequency of these severe attacks. Which of the following therapies is most likely responsible for this benefit?
A. Albuterol by aerosol.
B. Cromolyn by inhaler.
C. Fluticasone by aerosol.
D. Theophylline orally.
E. Zafirlukast orally. Correct answer = C. Administration of a corticosteroid directly to the lung significantly reduces the frequency of severe asthma attacks. This benefit is accomplished with minimal risk of the severe systemic adverse effects of corticosteroid therapy. Albuterol is only used to treat acute asthmatic episodes. The other agents may reduce the severity of attacks but not to the same degree or consistency as fluticasone (or other corticosteroids).