1. RESPIRATORY(PULMONARY) PHARMACOLOGY.pptx

THE PHARMACOLOGY OF RESPIRATORY SYSTEM.

1. RESPIRATORY PHARMACOLOGY 1

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3. FUNCTIONS OF RESPIRATION Supply of oxygen Remove carbon dioxide 3

4. REGULATION OF RESPIRATION Respiration is controlled by spontaneous rhythmic discharges from the respiratory center in the medulla Modulated by input from pontine and higher centers of the central nervous system Vagal afferent from the lungs 4

5. REGULATION OF RESPIRATION Chemical factors that affect the respiratory center Partial pressure of CO 2 in arterial blood (P ACO 2 ) by an action on medullary chemoreceptors partial pressure of O 2 (P AO 2 ) by action on chemoreceptors in the carotid bodies 5

6. muscarinic receptors targeted M 1 receptors- ganglia and postsynaptic cells Fascilitate nicotinic neurotransmission M 2 receptors- inhibitory autoreceptors Mediate negative feedback on acetlycholine released by postganglionic cholinergic nerves M 3 receptors- pharmacologically important located on bronchial smooth muscle and glands Mediate bronchoconstriction and mucus secretion 6

7. DISORDERS OF THE RESPIRATORY SYSTEM Main disorders of the respiratory system Bronchial Asthma Chronic bronchitis Drug induced respiratory depression Cough 7

8. BRONCHIAL ASTHMA Definition: Recurrent reversible airway obstruction, with attacks of wheeze, shortness of breath and often nocturnal cough. Severe attacks cause hypoxaemia and are life-threatening. commonest chronic disease in children common in adults. 8

9. BRONCHIAL ASTHMA cont Characteristics of asthma; Intermittent attacks of wheezing, shortness of breath, difficulty in breathing out and cough Acute attack (reversible) Asthma is characterised by; Inflammation of the airways Bronchial hyperactivity (stimuli) Reversible airways obstruction 9

10. Bronchial hyper-reactivity (or hyper-responsiveness) Refers to abnormal sensitivity to a wide range of stimuli, such as irritant chemicals, cold air, and stimulant drugs, all of which can result in bronchoconstriction. once established asthma attacks can be triggered by various stimuli such as viral infection, exercise (in which the stimulus may be cold air and/or drying of the airways), and atmospheric pollutants such as sulfur dioxide Numerous cells and mediators play a part in the pathogenesis of asthma. 10

11. Pathogenesis of asthma Genetic Environmental Aspirin sensitive asthma (NSAIDS) Abnormal leukotriene ( cysteinyl leukotriene) production and sensitivity 11

12. Pathogenesis of asthma cont. Pathogenesis involves exposure of genetically disposed individuals to allergens. Activation of Th2 lymphocytes and cytokine generation promote; differentiation and activation of eosinophils IgE production and release expression of IgE receptors on mast cells and eosinophils . Important mediators include leukotriene B 4 and cysteinyl leukotrienes (C 4 and D 4 ); interleukins IL-4, IL-5, IL-13; and tissue-damaging eosinophil proteins 12

13. Pathogenesis of asthma cont. 13

14. Pathogenesis of asthma cont. 14

15. Significance of Th2 cytokines Th2 cytokines; Promote IgE synthesis and responsiveness (some asthmatics) IL-4 and IL-13 ‘switch’ B cells to IgE synthesis and cause expression of IgE receptors on mast cells and eosinophils . MAJOR cause of bronchial hyper-responsiveness. 15

16. Aspirin sensitive asthma (NSAIDS) Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin can precipitate asthma in sensitive individuals. Individuals sensitive to one NSAID are usually also sensitive to other chemically unrelated cyclo-oxygenase (COX) inhibitors like paracetamol . 16

17. Aspirin sensitive asthma (NSAIDS ) cont. Abnormal leukotriene production and sensitivity are implicated. Patients with aspirin-sensitive asthma produce more cysteinyl leukotriene and have greater airway hyper-responsiveness to inhaled cysteinyl leukotrienes than aspirin-tolerant asthmatics. Down-regulated by aspirin de- sensitisation 17

18. TYPES OF BRONCHIAL ASTHMA Allergic: Atopic or 'extrinsic' asthma Non-allergic: Non-atopic or 'intrinsic' asthma 18

19. Phases of bronchial asthma Phases of Asthmatic attack; Early (immediate ) phase Late (delayed) phase 19

20. Immediate phase of the asthmatic attack The initial response to allergen provocation Occurs abruptly and is mainly caused by spasm of the bronchial smooth muscle. Allergen interaction with mast cell-fixed IgE causes release of several spasmogens : histamine, leukotriene B4 and prostaglandin (PG) D2. Other mediators released include IL-4, IL-5, IL-13, macrophage inflammatory protein-1α and T umour N ecrosis F actor (TNF)-α. 20

21. Late phase (inflammatory) Delayed response. May be nocturnal. The influx of Th2 lymphocytes as a result of progressing inflammatory reaction and initiation which occurred during the first phase. Releases cysteinyl leukotrienes ; interleukins IL-3, IL-5 and IL-8 ; and the toxic proteins , eosinophil cationic protein, major basic protein and eosinophil-derived neurotoxin. The toxic proteins cause damage and loss of epithelium. Other putative mediators of the inflammatory process in the delayed phase are adenosine , induced NO and the neuropeptides . 21

22. TREATMENT BRONCHIAL ASTHMA ( DRUGS) 22

23. Categories of antiasthma drugs There are two categories of antiasthma drugs: Bronchodilators : reverse the bronchospasm of the immediate phase. Anti-inflammatory agents: inhibit or prevent the inflammatory components of both phases. NB : some drugs classified as bronchodilators also have some anti-inflammatory effect. 23

24. Bronchodilators β2- adrenoceptor agonists (main drugs used) Xanthine Muscarinic receptor antagonists Cysteinyl leukotriene receptor antagonists 24

25. β2 agonists - Bronchodilators cont. Two (2) main categories Short -acting agents e.g. salbutamol, terbutaline Inhalation (max. effect 30minutes, duration 3-5hours) PRN USE to control symptoms Longer- acting agents e.g. salmeterol , formoterol Given regularly by Inhalation (duration – 8-12hrs) Given 2x daily as an adjunct therapy in patients not adequately controlled by glucocorticoids. 25

26. β2 agonists - Bronchodilators cont. Administered by; I nhalation of aerosol, powder or nebulized solution Orally Intravenously 26

27. β2- agonists - Bronchodilators cont. Primary effect Dilate bronchi airway by direct action on β2 adrenoceptors on smooth muscle. They act as physiological antagonists of the spasmogenic mediators. Inhibit mediator release from mast cells Inhibit TNF- α from monocytes Increase mucus clearance by cilliary action. 27

28. β2 agonists - Bronchodilators cont. Clinical use: Short- acting: prevent or treat wheezing (reversible obstructive airways disease ) Long acting drugs: prevent bronchospasm (night or exercise) in patient requiring long-term bronchodilator therapy 28

29. β2 agonists - Bronchodilators cont. Unwanted effects include: F ine tremor (particularly in the hands ) Cardiac dysrhythmia Tachycardia Nervous tension , H eadache , M uscle cramps 29

30. Xanthine Drugs – Bronchodilators cont. There are Three (3) pharmacologically active, naturally acting methyl- xanthines : Theophylline Theobromine Caffeine 30

31. Xanthine Drugs – Bronchodilators cont. Eg . Aminophylline (Theophylline + ethylenediamine ) Main therapeutic drug in this group Bronchodilator action likely to cause more side effects compared to the β2- adrenoceptor agonists. Narrow therapeutic index. 31

32. Xanthine Drugs – Bronchodilators cont. Mechanism of action of xanthines Relaxant effect on smooth muscles through inhibition of phosphodiesterase (PDE) isoenzymes with resultant increase in cAMP and/or cGMP . 32

33. Xanthine Drugs – Bronchodilators cont. Pharmacokinetics Methylxanthines Orally (sustained- release preparations) Aminophylline Slow intravenous injection of a loading dose followed by intravenous infusion. Theophylline Well absorbed in the GIT Metabolised by P450 enzymes in liver Elimination T 1/2 is about 8hrs. NB: increases liver disease, cardiac failure and viral infections T 1/2 is decreased in heavy cigarette smokers and drinkers 33

34. Xanthine Drugs – Bronchodilators cont. Unwanted effects CNS, cardiovascular, GIT and diuretic effects Caution Therapeutic plasma concentration, 30-100 μ mol/l Adverse effects are common with concentrations > 110 μ mol/l Measurement of plasma concentration is useful to optimise the dosage of aminophylline Serious CV and CNS effects at concentration > 200 μ mol/l Dysrhythmia (fatal) and seizures (fatal) in patients with impaired respiration due to severe asthma. 34

35. Xanthine Drugs – Bronchodilators cont. Drug interactions of xanthines Plasma concentration is decreased by drugs that induce P450 enzymes (e.g. rifampicin, phenobarbital, phenytoin, carbamazepine) Plasma concentration is increased by drugs that inhibit P450 enzymes (e.g. erythromycin, clarithromycin, ciprofloxacin, diltiazem , fluconazole). Clarithromycin treatment is started with hospitalised patient due to anticipated chest infection. 35

36. Muscarinic receptor antagonists (Bronchodilators) e.g . ipatropium , tiotropium It is given by aerosol inhalation. Not used on regular basis Useful for cough caused by irritant stimuli A non-specific blocker of muscarinic receptors M ₂ receptor blockade can reduce the effectiveness of its antagonism on M3 receptors 36

37. Muscarinic receptor antagonists (Bronchodilators) It is not particularly effective against allergen challenge But it inhibits the augmentation of mucus secretion May increase the muco-ciliary clearance of bronchial secretions. It has no effect on the late inflammatory phase of asthma. 37

38. Muscarinic receptor antagonists (Bronchodilators) Pharmacokinetics Highly polar - hence poorly absorbed. Action is mainly on muscarinic receptors on bronchi. The maximum effect occurs after approximately 30 minutes and persists for 3-5 hours. 38

39. Muscarinic receptor antagonists (Bronchodilators) Clinical uses: For asthma, as an adjunct to β2- adrenoceptor antagonists and steroids. For some patients with chronic obstructive pulmonary disease (COPD), especially long-acting drugs (e.g. tiotropium ). For bronchospasm precipitated by β2- adrenoceptor antagonists. NB: Safe and well tolerated. It can be used with β 2 -adrenoceptor agonists 39

40. Muscarinic receptor antagonists (Bronchodilators) Side-effects Dry mouth is the most common side effect. Gastrointestinal motility disorder (including constipation and diarrhoea ), Cough Headache 40

41. Cysteinyl leukotriene receptor antagonists (Bronchodilators) Eg . Lukast ’ drugs: ( Montelukast , Zafirlucast ) MOA Blocks the action of leukotriene C4, D4, & E4 on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene, and results in less inflammation. 41

42. Cysteinyl leukotriene receptor antagonists (Bronchodilators) Clinical Uses: Maintenance treatment of asthma Relieve symptoms of seasonal allergic rhinitis. Reduce acute reaction to aspirin in sensitive patients. Inhibit exercise induced asthma Decrease both early and late response to inhaled allergen Relax airway in mild asthma (less effect than salbutamol) Additive action with β2 receptor agonists Reduce sputum eosinophilia NB: Not useful for the treatment of acute asthma attacks . 42

43. Cysteinyl leukotriene receptor antagonists (Bronchodilators) Pharmacokinetics Orally, Montelukast once daily Zafirlukast twice daily Unwanted effects Headache, GIT, Churg -Strauss syndrome 43

44. ANTI-INFLAMMATORY AGENTS ( CORTICOCORTICOIDS) Considered the preferred long-term control therapy for persistent asthma in all patients. The only therapy that reduces the risk of dying from asthma More effective than either cromolyn , nedocromil , theophylline , or the leukotriene antagonists in long-term control. Available as oral, parenteral , and Inhaled corticosteroids (ICS). 44

45. ANTI-INFLAMMATORY AGENTS ( ICSs vrs Systemic CORTICOCORTICOIDS ) ICSs Budesonide Flunisolide Fluticasone Mometasone Triamcinolone Beclomethasone Systemic admin Predinisolone - oral Hydrocortisone – I.V Dexamethasone – oral/I.V 1

46. ANTI-INFLAMMATORY AGENTS (SYSTEMIC CORTICOCORTICOIDS ) Local adverse effects from ICSs Oropharyngeal candidiasis and Dysphonia that are dose-dependent The dysphonia appears to be due to a local corticosteroid-induced myopathy of the vocal cords The use of a spacer device can decrease oropharyngeal deposition and thus decrease the incidence and severity of local side effects The risks of these adverse effects are all dose-dependent Principal advantage of ICSs High topical potency to reduce inflammation in the lung and low systemic activity. 1

47. ANTI-INFLAMMATORY AGENTS (CORTICOCORTICOIDS) 1

48. ANTI-INFLAMMATORY AGENTS (CORTICOCORTICOIDS) Actions useful in treating asthma Increasing the number of β2-adrenergic receptors and improving the receptor responsiveness to β2-adrenergic stimulation, Reducing mucus production and hypersecretion , Reducing increased hyper-responsiveness Preventing and reversing airway remodeling. 1

49. ANTI-INFLAMMATORY AGENTS (CORTICOCORTICOIDS) Mechanism of action Glucocorticoids decrease formation of cytokines, in particular the Th2 cytokines that recruit and activate eosinophils . They are responsible for; Promoting the production of IgE and the expression of IgE receptors. They also inhibit the generation of the vasodilators PGE₂ and PGI₂, by inhibiting induction of COX-2. They Induce annexin to inhibit the production of leukotrienes . 1

50. ANTI-INFLAMMATORY AGENTS (CORTICOCORTICOIDS) Clinical uses Prophylaxis of asthma A 'rescue course' of oral prednisolone may be needed at any stage of severity if the clinical condition is deteriorating rapidly. Prolonged treatment with oral prednisolone, in addition to inhaled bronchodilators and steroids, is needed by a few severely asthmatic patients. 50

51. ANTI-INFLAMMATORY AGENTS (SYSTEMIC CORTICOCORTICOIDS ) Systemic corticosteroids are indicated in all patients with acute severe asthma not responding completely to initial inhaled β2-agonist administration (every 20 minutes for three to four doses). I.V therapy offers no therapeutic advantage over oral administration. Systemic corticosteroids are necessary for those individuals not controlled on ICSs 1

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53. ANTI-INFLAMMATORY AGENTS (SYSTEMIC CORTICOCORTICOIDS) Note The inflammatory response of asthma has been shown to inhibit steroid-receptor binding. This provides strong theoretical evidence for initially beginning patients on higher and more frequent doses and then tapering down once control has been achieved. 1

54. ANTI-INFLAMMATORY AGENTS (SYSTEMIC CORTICOCORTICOIDS) Glucocorticoid resistance Ineffective even in high doses Number of glucocorticoid receptors reduced activity of histone deacetylase (HDAC) in cigarette smokers Drug interactions Cytochrome P450 inducers Estrogens, oral contraceptives, itraconazole , macrolide antibiotics may reduce glucocortociod clearance Cyclosporine may increase plasma concentration Potassium deleting diuretics and related drugs cause enhanced hypokalemia 54

55. Cromoglicate and Nedocromil Eg , Cromolyn sodium and nedocromil sodium are non- steriodal drugs Anti-inflammatory properties Less effective than inhaled corticosteriods Excellent safety profile Good use in children. 55

56. Cromoglicate and Nedocromil Therapeutic effects Prevent early and late phase response to asthma ( prophylactically ) Suppress nonspecific airway reactivity (maintenance therapy for asthma) Effective in antigen-induced, exercise-induced and irritant-induced asthma 56

57. Cromoglicate and Nedocromil Mechanism of action Stabilize mast cells locally Inhibits mast cell degranulation Administration MDI and a neublizer solution ( cromolyn sodium) MDI ( nedocromil sodium) Prophylaxis in EIB administer 1hour before exercise Initial improvement is seen within 1-2 weeks 57

58. Cromoglicate and Nedocromil Precautions Not effective during an acute asthma exacerbation Useful as maintenance therapy of persistent asthma Prevention of EIB Unwanted effects Paradoxical bronchospasm Wheezing Coughing Nasal congestion Irritation or dryness of throat 58

59. SEVERE ACUTE ASTHMA (STATUS ASTHMATICUS) Medical emergency and require hospitalisation Treatment Oxygen Inhalation of salbutamol in oxygen given by nebuliser IV hydrocortisone Course of oral prednisolone Nebulised Ipratropium , IV sabutamol or aminophyline Antibiotics if bacterial infection is present 59

60. Histamine H 1 - receptor antagonist Eg . Cetirizine, loratadine, piriton Not routine in therapy Effective (modestly) in atopic asthma precipitated by acute histamine release in patients with concomitant allergy such as hay fever. 60

61. Analeptics ( Respiratory Stimulants) Used to antagonize respiratory depression caused by overdosage with CNS depressants; eg . Doxapram Act on respiratory center in the brain stem as well as on peripheral carotid chemoreceptors to increase the depth and rate of respiration 61

62. THANK YOU 62