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

Respiratory System Disorders Asthma Chronic Obstructive Pulmonary Disease Allergic Rhinitis Cough

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

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

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

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

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

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

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

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

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

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

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

Xanthine Drugs: Adverse Effects When theophylline is used in asthma, unwanted side effects occur in CNS, cardiovascular, and gastrointestinal Therapeutic plasma concentration range is 30-100μmol/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

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

Cysteinyl Leukotriene Receptor Antagonists: Pharmacokinetics Drugs are given orally

Cysteinyl Leukotriene Receptor Antagonist: Adverse Effects Headache and gastrointestinal disturbances

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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)

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

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.

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).