DRUGS ACTING ON RESPIRATORY SYSTEM

1. DRUGS ACTING ON RESPIRATORY SYSTEM

2. RESPIRATORY DISEASES • Asthma • Allergic rhinitis • Chronic obstructive pulmonary disease • Cough

3. ASTHMA • Asthma is characterized clinically by • Recurrent bouts of shortness of breath • Chest tightness • Wheezing Reversible narrowing of bronchial airways • Marked bronchial responsiveness to inhaled stimuli

4. PATHOPHSIOLOGY OF ASTHMA • Asthma is a chronic inflammatory disease of the airways that is characterized by activation of mast cells, infiltration of eosinophils, and T helper 2 (TH2) lymphocytes • Immediate cause of asthmatic bronchoconstriction is release of several mediators from the IgE sensitized mast cells • Chronic inflammation leads to marked bronchial hyper reactivity to various inhaled substances

5. Lymphocytic and eosinophilic inflammation of bronchial mucosa • Hyperplasia of secretary, vascular and smooth muscle cell • The Th2 cytokines that are released to promote immunoglobulin (Ig)E synthesis and responsiveness in some asthmatics. 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.

6. CLASSIFICATION OF DRUGS USED TO TREAT ASTHMA • Bronchodilators include • Beta2 Agonist • Muscarinic antagonist • Methylxanthines

7. Anti-inflammatory drugs • Steroids • Anti IgE antibodies Leukotriene Antagonist • Lipooxygenase inhibitors • Leukotirene Receptor inhibitors

8. STRATEGIES OF ASTHMA THERAPY • Acute asthmatic bronchospasm must be treated promptly with bronchodilators. Beta 2 agonist, muscarinic antagonist, and theophylline and its derivatives are available for this indication cells. • Long term preventive treatment requires control of inflammatory process in air ways. Most important anti inflammatory drugs are corticosteroids and drugs such as commonly and nedocromil that inhibit release of mediators from mast cells and inflammatory cells.

9. Long acting beta 2 agonist can improve the response to corticosteroids • Anti IgE antibodies also appear promising for chronic therapy (Omalizumab) • Leukotriene antagonists have effects on both bronchconstriction and inflammation but are used only for prophylaxis

10. BRONCHODILATORS • Drugs stimulating both alpha and beta receptors (adrenaline, ephedrine) • Drugs stimulating beta receptors (isoprenaline) • Selective beta 2 stimulants (salbutamol, terbutaline, salmeterol, formeterol)

11. EPINEPHRINE • Effective, rapid acting bronchodilator • Injected subcutaneously, 0.4m1 of 1:1000 solution • Inhaled as a micro aerosol, 320 mcg per puff • Max. bronchodilator achieved in 15 min after inhalation and lasts for 60-90 min • Used in anaphylaxis • Tachycardia's, arrhythmias, worsening of angina are troublesome effects

12. EPHEDRINE • Alkaloid obtained from ephedrine • Acts on both alpha and beta receptors • Has long duration of action • Produces mild stimulation of CNS • Now infrequently used for asthma because of better therapies

13. ISOPROTERENOL (ISOPRENALINE) • Acts on betal and 2 receptors • Potent bronchodilator when inhaled • 80-120 mcg produces max bronchodilator within 5 min • Has 60-90 min duration of action Causes cardiac arrhythmias

14. BETA2 ADRENERGIC AGONIST • Albuterol, terbutaline and metaproterenol are short acting drugs • Salmeterol and formoterol are long acting drugs Mechanism of action Beta adrenoceptor agonist stimulate adenylyl cyclase and increases cyclic adenosine monophosphate (cAMP) in smooth muscle cells

15. The molecular mechanisms by which agonists induce relaxation of airway smooth muscle include: • Lowering of concentration by active removal of Ca' from the cytosol into intracellular stores and out of the cell • Inhibition of myosin light chain kinase activation Activation of myosin light chain phosphates Opening of a large conductance Ca2+-activated K+ channel, which repolarizes the smooth muscle cell and may stimulate the sequestration of Ca' into intracellular stores.

16. Clinical use • Short – acting beta2 agonists are the bronchodilators of choice in treating acute severe asthma. • The nebulizer route of administration is easier and safer than intravenous administration and just as effective. • Inhalation is preferable to the oral administration because systemic side effects are less, and inhalation may be more effective. Their effect is maximal in 15 min and lasts for 4 hrs.

17. Long acting drugs are used for prophylaxis. The long- acting inhaled beta2 agonists salmeterol, formoterol, and arformoterol have proved to be a significant advance in asthma and COPD therapy. These drugs have a bronchodilator action of > 12 hours and also protect against brochoconstriction for a similar period. They improve asthma control compared with regular treatment with short- acting beta2 agonists. They are used in combination with corticosteroids to improve control.

18. ADVERSE EFFECTS • Muscle tremor due to stimulation of beta 2 receptors in skeletal muscle is the most common side effect. It may be more troublesome with elderly patients and so is a more frequent problem in COPD patients. • Tachycardia and palpitations are due to reflex cardiac stimulation secondary to peripheral vasodilatation, from direct stimulation of a trial beta 2 receptors. These side effects tend to disappear with continued use of the drug, reflecting the development of tolerance. • Hypokalemia is a potentially serious side effect. This is due to beta2 receptor stimulation of potassium entry into skeletal muscle, which may be secondary to a rise in insulin secretion.

19. TOLERANCE • Continuous treatment with an agonist often leads to tolerance (desensitization, sub sensitivity), which may be due to down-regulation of the receptor . • Tolerance of non-airway 2 receptor—mediated responses, such as tremor and cardiovascular and metabolic responses, is readily induced in normal and asthmatic subjects.

20. METHYLXANTHINES Methylxanthines are purine derivatives Theophylline found in tea is the only member used in the treatment of asthma Mechanism of action Theophylline inhibits phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP and thus increase cAMP It also block adenosine receptors in CNS and inhibit sleepiness inducing adenosine

21. Effects on gene transcription. Theophylline prevents the translocation of the pro-inflammatory transcription factor NF-kappa B into the nucleus, potentially reducing the expression of inflammatory genes in asthma and COPD. Inhibition of NF-kappa B appears to be due to a protective effect against the degradation of the inhibitory protein. However, these effects are seen at high concentrations and may be mediated by inhibition of PDE.

22. Pharmacokinetics • Theophylline is distributed in the extracellular fluid, in the placenta, in the mother's milk and in the central nervous system. • The volume of distribution is 0.5 L/kg. • The protein binding is 40%. • The volume of distribution may increase in neonates and those suffering from cirrhosis or malnutrition, whereas the volume of distribution may decrease in those who are obese. Theophylline is metabolized extensively in the liver (up to 70%). It undergoes demethylation via cytochromeP450 • Theophylline is excreted unchanged in the urine (up to 10%).

23. Aminophylline: • It is water soluble but highly irritant. It can be administered orally. Aminophylline is less potent and shorter-acting than theophylline. Its most common use is in the treatment of bronchial asthma. • Causes bronchodilatation, dieresis, CNS and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenine monophosphate (cAMP) which in turn promotes catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis and induces release of epinephrine from adrenal medulla cells • Toxicity • CNS: restlessness, insomnia, headache, tremors • GIT: nausea, vomiting, gastritis • Heart: tachycardia, palpitation, hypotension

24. ANTICHOLINERGICS • These drugs are now rarely used in bronchial asthma as they often have unpleasant side effects. Some of the drugs are ipratropium bromide and tiotropium bromide. These are atropine substitutes. • They selectively block the effects of acetylcholine in bronchial smooth muscle and cause bronchodilatation. They have slow onset of action and less effective than sympathomimetic drugs in bronchial asthma.

25. LEUKOTRIENE ANTAGONISTS • Leukotrienes result from action of lipooxygenase on arachidonic acid. LTC4 and LTD4 exert many effects known to occur in bronchial asthma including bronchoconstriction, increased bronchial reactivity, mucosal edema and mucus hyper secretion. Leukotriene antagonists are used to treat these diseases by inhibiting the production or activity of leukotrienes. These drugs competitively block the effects leukotrienes.

26. Two approaches have been pursued • Inhibition of lipooxygenase, thereby preventing leukotriene synthesis like zileuton. • Inhibition of binding of leukotiene to its receptor on montelukast and zafirlukast

27. Montelukast • Montelukast is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is usually administered orally. Montelukast is a CysLT, antagonist; that is it blocks the action of leukotrienes (and secondary legends LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT, in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene and results in less inflammation.

28. Clinical uses • Montelukast is used for the treatment of asthma and seasonal allergic rhinitis. Montelukast begins working after 3 to 14 days of therapy. Therefore, it should not be used for the treatment of an acute asthmatic attack. • Side effects • The most common side effects with montelukast are headache, dizziness, abdominal pain, sore throat, and rhinitis (inflammation of the inner lining of the nose). These side effects occur in 1 in 50 to 1 in 7 persons who take montelukast. Rarely, patients may experience nose bleeds.

29. Zafirlukast • Zafirlukast is an oral leukotriene receptor antagonist (LTD4) for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. It is available as a tablet and is usually dosed twice daily. • Zafirlukast blocks the action of the cysteinyl leukotrienes on the CysLT1 receptors, thus reducing constriction of the airways, build-up of mucus in the lungs and inflammation of the breathing passages. • A single oral dose of 40 mg of zafirlukast attaining peak plasma concentrations of about 607 pg/L at 3.4 hours. The elimination half-life ranged from 12 to 20 hours.

30. Clinical uses • Zileuton is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with zileuton can be continued during acute exacerbations of asthma. • The recommended dose of 600 mg tablet, four times per day. The tablets may be split in half to make them easier to swallow. The recommended dose extended-release tablets is 2400 mg twice daily. • Research on mice suggests that Zileuton used alone or in combination with imatinib may inhibit chronic myeloid leukaemia (CML).

31. Side effects • The most common adverse reactions reported by patients treated with zileuton were sinusitis and nausea • The most serious side effect zileuton is potential elevation of liver enzymes (in 2% of patients). Therefore, zileuton is contraindicated in patients with active liver disease or persistent hepatic function enzymes elevations • Neuropsychiatric events, including sleep disorders and behavioral changes, may occur.

32. Drug interactions • Zileuton is a weak inhibitor of cytochrome P450 and thus has three clinically important drug interactions, which include increasing warfarin, theophylline, and propranolol levels. • It has been shown to lower theophylline clearance significantly, doubling the AUC and prolonging half-life by nearly 25%. • Warfarin metabolism and clearance is mainly affected by zileuton. This can lead to an increase in prothrombin time.

33. CORTICOSTEROIDS • All corticosteroids are potentially beneficial in severe asthma; however, because of their toxicity systemic (oral) corticosteroids are used chronically only when other therapies are unsuccessful. • Local aerosol administration of corticosteroids (e.g beclomathasone, dexamethasone, fluticasone, mometasone) is relatively safe, and inhaled corticosteroids have become first line therapy for individuals with moderate to severe asthma. • Important intravenous corticosteroids for status asthamaticus include prednisolone and hydrocortisone.

34. Mechanism of action • Corticosteroids reduce the synthesis of arachidonic acid by phospholipase A2, and inhibit the expression of COX -2. It has been suggested that corticosteroids increase the responsiveness of beta adrenoceptors in the airway. • Effects • Glucocorticoids bind to intracellular receptors and activate glucocorticoid response elements in the nucleus, resulting in the synthesis of substances that prevent the full expression of inflammation and allergy. Reduced activity of phospholipase A0 is thought to be particularly important in asthma because the leukotrienes that result from eicosanoid synthesis are extremely potent bronchoconstrictiors and may also participate in the inflammatory response

35. Clinical uses • Inhaled glucocorticoids are now considered appropriate (even for children) in most cases of moderate asthma that are not fully responsive to aerosol R agonists. • In cases of severe asthma, patients are usually hospitalized and stabilized on daily systemic prednisone and then switched to inhaled or alternate- day oral therapy before discharge. • In status asthmatic us parenteral steroids are lifesaving and apparently act more promptly than in ordinary asthma • Intravenous steroids are indicated in acute asthma if lung function is <30% predicted and in patients who show no significant improvement with nebulized z agonist. Hydrocortisone is the steroid of choice because it has the most rapid onset (5-6 hours after administration).

36. Toxicity • Life threatening toxicities include metabolic effects (diabetes, osteoporosis), salt retention and psychosis. • Changes in or pharyngeal flora result in candidacies • Frequent aerosol administration can cause a very small degree of adrenal suppression. In case of oral therapy adrenal suppression can be reduced by using alternate-day therapy. • Inhaled corticosteroids may have local side effects due to the deposition of inhaled steroid in the oropharynx. The most common problem is hoarseness and weakness of the voice (dysphonia) due to atrophy of the vocal cords following laryngeal deposition of steroid

37. CROMOLYN AND NEDOCROMIL (MAST CELL STABILIZERS) Cromolyn (disodium cromoglycate) and nedocromil are unusually insoluble chemicals. They are given by aerosol for asthma. Cromolyn is the prototype of this group. Mechanism of action It involves a decrease in the release of mediators (such as leukotrienes and histamine) from the mast cells. The drugs do not have bronchodilator action but can prevent bronchoconstriction caused by antigen to which the patient is allergic

38. Effects • They are not absorbed from the site of administration, cromolyn and nedocromil have only local effects. • When administered orally, cromolyn has some efficacy in preventing food allergy. • Similar actions were noted after local application in conjunctiva and nasopharynx for allergic IgE mediated reactions in these tissues.

39. Clinical uses • It is used in asthma especially in children • Nasal and eye drop formulations are available for hay fever • Oral formulation is used for food allergy • Toxicity • Cromolyn and nedocromil may cause cough and irritation of the airway when given by aerosol. • Rare instances of drug allergy have been reported.

40. ANTI- IGE ANTIBODY • Omalizumab • It is a recombinant DNA- derived monoclonal antibody that selectively binds to human IgE. It binds to the IgE on sensitized mast cells and prevents activation by asthma triggers and subsequent release of inflammatory mediators. • Omalizumab may be particularly useful for the treatment of moderate to severe allergic asthma in patients who are poorly controlled with conventional therapy. • It was approved in 2003 for the prophylactic management of asthma. It is very expensive and must be administered parent rally.

41. DRUGS USED TO TREART CHRONIC OBSTRUCTIVE PULMONARY DISEASE • Chronic obstructive pulmonary disease (COPD) is a chronic, irreversible obstruction of air flow. Smoking is the greatest risk factor for COPD and is directly linked to the progressive decline of the lung function. • In COPD, there is a predominance of neutrophils, macrophages, and cytotoxic T-lymphocytes (Tcl cells). The inflammation predominantly affects small airways, resulting in progressive small airway narrowing and fibrosis (chronic obstructive bronchiolitis) and destruction of the lung parenchyma with destruction of the alveolar walls (emphysema)

42. Emphysema is a pathological condition sometimes associated with COPD, in which lung parenchyma is destroyed and replaced by air spaces that coalesce to form bullae-blister-like air-filled spaces in the lung tissue. • These pathological changes result in airway closure on expiration, leading to air trapping and hyperinflation. This accounts for shortness of breath on exertion and exercise limitation that are characteristic symptoms of COPD.

43. Inhaled bronchodilators, such as anticholinergic agents (ipratropium and tiotropium) and beta2 adrenergic agonists are the foundation of therapy for COPD. • Longer acting drugs such as salmeterol and tiotropium have the advantage of less frequent dosing and together provide synergistic effect. They improve the lung function and provide a better relief in COPD.

44. Theophylline can be given by mouth but is of uncertain benefit. 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 ventilator support

45. SURFACTANTS • Pulmonary surfactants act as a result of their physicochemical properties within the airways rather than by binding to specific receptors. They are effective in the prophylaxis and management of respiratory distress syndrome in newborn babies, especially if premature. Examples include beractant and poractant alpha which are derivatives of the physiological pulmonary surfactant protein. They are administered directly into the tracheobronchial tree via an end tracheal tube

46. ALLERGIC RHINITIS • Hay fever; Nasal allergies • Rhinitis is characterized by sneezing, itchy nose/eyes, watery rhinorrhea and nasal congestion • Allergic rhinitis is a group of symptoms affecting the nose. These symptoms occur when you breathe in something you are allergic to, such as dust, dander, insect venom, or pollen. • When a person with allergic rhinitis breathes in an allergen such as pollen or dust, the body releases chemicals, including histamine. This causes allergy symptoms. • Hay fever involves an allergic reaction to pollen. A similar reaction occurs with allergy to mold, animal dander, dust, and other allergens that you breathe in.

47. Symptoms that occur shortly after you come into contact with the substance you are allergic to may include: • Itchy nose, mouth, eyes, throat, skin, or any area • Problems with smell o Runny nose o Sneezing • Symptoms that may develop later include: • Stuffy nose (nasal congestion) • Coughing • Clogged ears and decreased sense of smell • Sore throat • Dark circles under the eyes • Puffiness under the eyes • Fatigue and irritability • Headache

48. Antihistamines • Over-the-counter antihistamines - Include diphenhydramine, chlorpheniramine, clemastine. These older antihistamines can cause sleepiness. Loratadine, cetrizine, and fexofenadine do not cause as much drowsiness as older antihistamines. • Long acting drugs: These medications are longer-acting than over-the-counter antihistamines and are usually taken once a day. They include desloratadine

49. H1 receptor blockers have major application in allergies of the immediate type. These conditions include hay fever and urticaria. The side effects include dry mouth/ eyes, difficult urinating and defecating. These effects are transient and may resolve in 7 -10 days

50. Corticosteroids • These prescription sprays reduce inflammation of the nose and help relieve sneezing, itching, and runny nose. It may take a few days to a week to see improvement in symptoms. • Beclomethasone • Fluticasone • Mometasone • Triacinolone