Asthma/COPD. Asthma synopsis. chronic inflammation of bronchial airways bronchi lining bronchi muscles mucus

Transcription

1 1 Asthma & COPD

2 Asthma synopsis chronic inflammation of bronchial airways bronchi lining bronchi muscles mucus 2

3 Asthma synopsis chest tightness tachypnea wheezing acute broncho-constriction cough shortness of breath resolution? 3

4 Asthma synopsis generally not progressive remitting-relapsing M vs. M goals of therapy: - relieving symptoms - preventing recurrence - preventing bronchial remodeling - decreasing morbidity and related costs 4

5 oral vs. inhaled inhalation Tx: main advantage - main disadvantage - 5

6 oral vs. inhaled 6

7 corticosteroids β 2 -adrenergic agonists theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 7

8 corticosteroids β 2 -adrenergic agonists theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 8

9 Corticosteroids inhaled corticosteroids (ICS) - 1 st -line for: 9 persistent asthma + rescue SABAs required> 2/wk ICS improve asthma control more effectively in both children and adults than any other single, long-term control medication do. [NHLBI guidelines 2007] ICS are currently the most effective antiinflammatory medications for the treatment of persistent asthma [GINA report 2010]

10 ICS budesonide (Budicort ) fluticasone (Flixotide ) beclomethasone (Qvar ) 10

11 ICS - Mechanism: anti-inflammatory effect airway smooth muscle dilation 11

12 ICS - PK: proper inhalation reduces systemic exposure fate of non-inhaled drug? hepatic metabolism? 12

13 ICS - PK: poor inhaling technique PREVENTION: good inhaling technique 13 use of spacer

14 Spacer use Shake the inhaler well before use (3-4 shakes) 2. Remove the cap from your inhaler, and from your spacer, if it has one 3. Put the inhaler into the spacer 4. Breathe out, away from the spacer 5. Bring the spacer to your mouth, put the mouthpiece between your teeth and close your lips around it 6. Press the top of your inhaler once 7. Breathe in very slowly until you have taken a full breath. If you hear a whistle sound, you are breathing in too fast.slowly breath in. 8. Hold your breath for about ten seconds, then breath out.

15 ICS - benefits chronic use: the most effective Tx for long-term control of asthma in children and adults reduces airway hyper-responsiveness to various bronchial stimulators oral-corticosteroids sparing 15

16 Systemic corticosteroids IV/PO: may be required in acute, severe exacerbations ( status asthmaticus ) upon improvement - tapering off over 1-2wk refractory cases may need PO support for certain periods long-term PO use rarely required (persistent-severe uncontrolled asthma) 16

17 Corticosteroids - general short-term ADEs increase appetite insomnia nervousness anxiety adrenal suppression growth retardation (children) Cushing s syndrome 17

18 Corticosteroids - general long-term ADEs osteoporosis peptic ulcers diabetes weight gain adrenal suppression growth retardation (children) hypokalemia HTN skin thinning immuno-suppression triglycerides, cholesterol infection masking Cushing s syndrome more.. 18

19 ICS - general ADEs overall, ADEs risk significantly reduced with ICS local infections in mouth and pharynx importance of cough long-term high-dose ICS: - cataract (monitor) - osteoporosis (monitor, consider Ca ++ +vit. D) 19 - easy bruising

20 Corticosteroids - DDIs by CYP-450 inducers (phenytoin, phenobarbital, rifampin) / anticoagulant effect antacids ( oral absorption) estrogen ( clearance) live-attenuated vaccines (immuno-suppression) hypokalemic drugs, digoxin generally insignificant with ICS 20

21 corticosteroids β 2 -adrenergic agonists theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 21

22 β 2 -adrenergic agonists bronchodilation? anti-inflammatory? 22

23 β 2 -adrenergic agonists short acting (SABAs): salbutamol=albuterol (Ventolin ) terbutaline (Bricalin, Terbulin ) drugs of choice for mild asthma 23

24 β 2 -adrenergic agonists short acting (SABAs): rapid peak effect (0.5-2hr) moderate duration (3-6hr) suitable for.... proper inhalation technique minimizes ADEs ADEs: tachycardia, hyperglycemia, hypokalemia, tremor 24

25 β 2 -adrenergic agonists long acting (LABAs): salmeterol (Serevent ) formoterol (Foradil, Oxis ) 25

26 β 2 -adrenergic agonists long acting: delayed peak effect (3-4hr) long duration (12hr) acute vs. chronic use? ADEs generally similar to those of short-acting 26

27 β 2 -adrenergic agonists Long-term safety concerns Controversy has surrounded the use of beta-agonists in asthma patients ever since their introduction over 50 years ago. Numerous studies over many years have shown regular use of beta-agonists are associated with worsening of disease control. Observational studies have consistently shown that the risk of life threatening and fatal asthma attacks increase with the use of these medications. 27

28 β 2 -adrenergic agonists Long-term safety concerns SMART, Chest 2006;129:

29 β 2 -adrenergic agonists Long-term safety concerns - SMART 28 weeks >6,100 centers >26,000 patients (of 60,000 intended) early termination 29

30 β 2 -adrenergic agonists Long-term safety concerns - SMART 30

31 β 2 -adrenergic agonists Long-term safety concerns - conflicting meta-analyses, management: use LABAs in accordance with guidelines: - not 1 st -line! - not as monotherapy! - not for mild asthma! - consider patient characteristics! (adherence, follow-up) 31

32 β 2 -adrenergic agonists LABAs: June 2 nd 2010 Use of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated (absolutely advised against) in the treatment of asthma. LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. 32

33 33 β 2 -adrenergic agonists LABAs: June 2 nd 2010 LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an ICS. Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an ICS.

34 Inhaled LABA-CS combinations - salmeterol/fluticasone (Seretide ) - formoterol/budesonide (Symbicort ) for patients requiring both classes adherence promotion 34

35 corticosteroids β 2 -adrenergic agonists theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 35

36 Theophylline (Theotrim, Theotard ) methylxanthine derivative structurally-related to caffeine originally isolated from tea (1888) administered orally (sustained release) 36

37 Theophylline - mechanism A number of proposed mechanisms 1. bronchodilator (higher dose, >10mg/kg/d): - phosphodiesterase inhibitor ( camp ) - adenosine receptor antagonist? (adenosine histamine and leukotriene release) 37

38 Theophylline - mechanism A number of proposed mechanisms 2. anti-inflammatory (lower dose): active inflammatory gene transcription site corticosteroids recruitment histone deacetylase inhibition acetylated core histones 38 increased activity low-dose theophylline inflammatory gene transcription inflammatory process

39 Theophylline - PK near-complete absorption significant hepatic metabolism mainly hepatic elimination (varies due to multiple effects) T 1/2 : adults - 8hr, smokers - 5hr, elderly - 12hr 39

40 Theophylline - ADEs narrow therapeutic index: target of mcg/ml ADEs generally concentration-dependent: serum concentration mcg/l mcg/l >35 mcg/l adverse reactions GI nausea, vomiting, pain, CNS insomnia, headache, agitation, tremor, nervousness CV tahcycardia, occasional PVBs VT, frequent PVBs, seizures 40 TDM: 2hr post-oral dose

41 Theophylline - DDIs theophylline effect cimetidine, corticosteroids, macrolides (erythromycin), quinolones (ciprofloxacin), CCBs, BBs, loop diuretics, more theophylline effect antacids (absorption), phenytoin, phenobarbital, rifampin, cigarette smoke, ritonavir, ketoconazole, more.. 41

42 Theophylline - place in therapy decreasing use (ADEs, DDIs, better options); 3 rd -line combination with ICS (steroid-sparing) refractory cases possible comeback as low-dose practice (anti-inflammatory)? 42

43 corticosteroids β 2 -adrenergic agonists theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 43

44 Cromolyn/nedocromil mast-cell stabilizers 44

45 Cromolyn/nedocromil mast-cell stabilizers block mast-cell calcium channels mast cell degranulation histamine (+ leukotriene) release inflammatory response 45

46 Cromolyn/nedocromil mast-cell stabilizers for acute asthma attacks: 46

47 Cromolyn/nedocromil only effective as prophylaxis (ineffective for acute episodes) given as inhalation minimal systemic effects (local: irritation, bitter taste, dry mouth) useful in prevention of allergen-induced asthma safe in children, pregnancy 47

48 corticosteroids β 2 -adrenergic agonists theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 48

49 Ipratropium (Atrovent ) anticholinergic agent (atropine derivative) blocks vagally-mediated contraction of smooth muscle peak effect: 1.5-2hr duration of effect: 4-6hr negligible ADEs (does not penetrate BBB) for preventive Tx rarely used for asthma 49

50 β 2 -adrenergic agonists corticosteroids theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 50

51 Leukotriene receptor antagonists (LTRAs) cysteinyl leukotrienes 51

52 Leukotriene receptor antagonists (LTRAs) montelukast (Singulair ) selective, reversible antagonist of cysteinyl-1 receptor for long-term control once-daily (evening) oral administration (chewable) extensive hepatic metabolism fecal excretion 52

53 Leukotriene receptor antagonists (LTRAs) montelukast (Singulair ) selective, reversible antagonist of cysteinyl-1 receptor once-daily (evening) oral administration (chewable) extensive hepatic metabolism fecal excretion ADEs: headache (18%), impaired LFTs, dyspepsia, cough DDIs: 40% by phenobarbital (rifampin?) 53

54 LTRAs montelukast (Singulair ) for long-term control LABA/ICS sparing additional indication: prophylaxis of exercise-induced bronchospasm 54

55 corticosteroids β 2 -adrenergic agonists theophylline cromolyn/nedocromil ipratropium leukotriene modifiers omalizumab 55

56 Omalizumab (Xolair ) recombinant DNA-derived selective IgE monoclonal antibody USA 2003 data: 60% of asthma allergen-induced 56

57 Omalizumab (Xolair ) recombinant DNA-derived selective IgE monoclonal antibody SC administration every 2 or 4 weeks peak serum concentrations after 7-8 days tissue elimination (intracellular) T 1/2-26 days anaphylactic reactions in 0.2% cancer? 57

58 Omalizumab (Xolair ) indicated for children over 12 and adults with: poorly controlled moderate-severe persistent asthma year-round allergies (proven allergic reaction) inadequate control despite routine ICS use in these patients: free circulating IgE reduced by 96% decreased incidence of asthma exacerbations 58

59 Asthma classification episode frequency spirometry (FEV 1 ) acute Tx long-term Tx mild-intermittent 2/week >80% SABA none mild-persistent >2/week >80% SABA low-dose ICS moderatepersistent daily 60-80% SABA Low/medium dose ICS + LABA severe-persistent continuous <60% SABA high-dose ICS + LABA 59

60 60

61 Pharmacological markers for uncontrolled asthma acute SABA required >2/wk oral CS bursts required >2/yr 61

62 Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma Summary Report

63 COPD chronic obstructive pulmonary disease chronic, irreversible airflow obstruction two entities: - - slowly-progressive airway damage symptoms appear after years of exposure 63

64 COPD chronic obstructive pulmonary disease chronic, irreversible airflow obstruction 4 th leading cause of death (USA) deadlier than asthma morbidity and mortality rising estimated USA annual cost >$30,000,000,000 64

65 COPD chronic obstructive pulmonary disease chronic, irreversible airflow obstruction causes: 65

66 COPD chronic obstructive pulmonary disease chronic, irreversible airflow obstruction symptoms/diagnosis: chronic cough (productive/non-productive) excessive mucus production shortness of breath (mild exertion) frequent throat-clearing chest tightness respiratory function tests (spirometry) 66

67 COPD chronic obstructive pulmonary disease Non-pharmacological Tx avoid triggers smoking dust/chemicals air-pollution [get better genes] 67

68 COPD chronic obstructive pulmonary disease Pharmacotherapy non-curable, non-reversible: control symptoms 1 st -line: inhaled bronchodilators - SABAs/LABAs (LABAs advantageous for nocturnal episodes) - anticholinergic (tiotropium = Spiriva ) - combination 68 once-daily anticholinergic bronchodilator

69 COPD chronic obstructive pulmonary disease Pharmacotherapy non-curable, non-reversible: control symptoms 2 nd -line: ICS - moderate-severe COPD uncontrolled with 1st-line - modest effect in most COPD patients - differing efficacy in asthma vs. COPD related to different inflammatory mediators 69

70 COPD chronic obstructive pulmonary disease Pharmacotherapy non-curable, non-reversible: control symptoms 2 nd /3 rd -line: theophylline - past 1 st -line - presently lost favor (ADEs) - option for those unable to optimally operate inhalers 70

71 COPD chronic obstructive pulmonary disease Pharmacotherapy Severity mild moderate severe FEV 1 >80% 30-80% <30% Long-term Tx SABA, as needed SABA/LABA/anticholinergic ± ICS as in moderate, - antibiotics for acute exacerbations - O 2 71

72 COPD chronic obstructive pulmonary disease Pharmacotherapy 72

73 COPD chronic obstructive pulmonary disease COPD vs. asthma typical onset exacerbation Tx sequence Tx effect asthma childhood - young adulthood allergen, exercise, cold air ICS LABA symptom-free periods COPD adulthood (>40s) respiratory infections LABA ( ICS) nearly daily symptoms 73

74 Pharmacotherapy asthma/copd DRUGS FOR EXAM inhaled corticosteroids fluticasone beta-2 adrenergic agonists - short-acting: salbutamol - long-acting: salmeterol theophylline cromolyn ipratropium/tiotropium montelukast omalizumab 74