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Recent advances in the management of bronchial asthma


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Advances in the pharmacotherapy of asthma

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Recent advances in the management of bronchial asthma

  1. 1. Recent Advances in the Pharmacotherapy of Bronchial Asthma Dr Pritam Biswas
  2. 2. As we go along • Introduction • Pathophysiology • Current Management Guidelines. • Recent Advances  Pharmacotherapy  Monoclonals & Anti cytokines  Immunotherapy  Non Pharmacological
  3. 3. Introduction • Asthma represents a global public health issue due to high prevalence rates in the general population( 1% to 18% of the population in different Countries), • Affects approximately 300 million people worldwide • Rising prevalence in developing countries which is associated with increased urbanization.
  4. 4. Asthma is defined as a chronic inflammatory disease  Airway hyper responsiveness  Recurrent symptoms such as wheezing, dyspnea (shortness of breath), chest tightness and coughing.  Episodes are associated with widespread ,variable, airflow obstruction within the lungs that is reversible spontaneously or with appropriate asthma treatment
  5. 5. Pathophysiology of Asthma
  6. 6. IMMEDIATE RESPONSE Eliciting agent: allergen or non-specific stimulus activates: Mast cells, platelets, alveolar macrophages, causing release of: Spasmogens: H, PAF, LTC4, LTD4, causing: Chemotaxins: LTB4, PAF, MNC, ECF-A which cause: BRONCHOSPASM Reversed by  agonists & Theophylline Aggregation & activation of platelets, infiltration & activation of neutrophils, eosinophils, monocytes/macrophages : PAF, LTB4, LTD4, platelet factors& susbstance P Neurotensin ODEMA, MUCOUS SECRETION & BRONCHOSPASM LATE-PHASE RESPONSE Bronchial hyper responsiven ess Endothelial damage & stimulation of C Fibes and irritant receptors
  7. 7. Inflammation  IgE  Histamine  Tryptase  Serotonin  Leukotrienes (LTC4, LTD4 LTB4)  Platelet activating factor (PAF)  Prostaglandins (PGD2)  Interleukins (IL-4, IL-5,IL- 9 ,IL- 13, IL-17 )  Granulocyte-macrophage colony stimulating factor (GM-CSF)  Tumor Necrosis Factor (TNF)  Major Basic Proteases (MBP)  Eosinophil Cationic Protein (ECP)  Eosinophil neurotoxin  Substance P  Neurotensin
  8. 8. Controller Medications  Inhaled Glucocorticosteroids  Leukotriene modifiers  Long acting inhaled β2 agonists  low dose sustained release Theophylline  Cromones  Long acting oral β2 agonists  Anti – Immunoglobin E  Systemic glucocorticosteroids Reliever Medications Rapid acting inhaled β2 agonists Systemic glucocorticosteroids  Anticholinergics Theophylline imediate release  Short acting oral β2 agonists
  9. 9. Current Management of Asthma . Short acting beta 2 agonist for symptom reliefStep 1 Mild intermittent asthma Mild Persistent asthma Moderate Persistent asthma Severe asthma ICS+ Leukotriene modifier add on Step 2 Step 3 Low dose ICS +LABA High dose ICS+ LABA Leukotriene modifier Step 4 Severe Persistent asthma Step 5 Oral steroid+ high dose ICS+ LABA
  10. 10. Inhalational corticosteroids & Advances in Steroid resistance Beta 2 agonists Phosphodiesterase Inhibitors Methyl xanthines Anticholinergics Anti IgE Anti cytokines Novel class of bronchodilators Immunomodulatory therapies Newer anti-inflammatory therapies Miscellaneous approaches CTRH Toll like receptors Marcolides Endothelin antagonists
  11. 11. Inhalational corticosteroids ICS Pharmacokinetics Safety Triamcinolone Greater systemic side effectsBeclomethasone Fluticasone High first Pass Metabolism (liver ) Fewer systemic side effects Safe at higher doses Budesonide Momethasone Ciclesonide Prodrug High First Pass metabolism High plasma protein binding Minimal systemic side effects
  12. 12. Ciclesonide Prodrug, converted to active ingredient des-ciclesonide by lung esterases Oral Bioavailability <1 % Highly Plasma protein bound 99% Half-life: 0.71 hr (ciclesonide); 6-7 hr (des-ciclesonide) Clearance: 152 ML/hr high Lipid Binding to fatty acids in lung Decreased systemic toxicity Increased Local action
  13. 13. Soft steroids They have improved local, topical selectivity and have much less steroid effect outside target area. Lactone GCS conjugate Glucocorticoid with a lactone ring Stable in the lung , not metabolized by lung esterases Metabolized quickly by plasma paraoxonase Soft steroids Loteprednol Approved for ophthalmic use Phase 2 development in Germany Lactone GCS Butixocort/ Tipredane Lack clinical efficacy Rofleponide Preclinical phase
  14. 14. SEGRA- Selective Glucocorticoid receptor agonist Desirable anti-inflammatory and immuno suppressive properties of classical glucocorticoids drugs but with fewer side effects . Transactivation annexin A1, angiotensin- converting enzyme, neutral endopeptidase Transrepression COX,NO synthase, TNF, TG F BETA, ICAM-1
  15. 15. Mapracorat ( SEGRA ) • Topical treatment of atopic dermatitis and inflammation following cataract surgery. • New frontier for asthma research .
  16. 16. Advances in Steroid resistance About 5-10% of asthmatics are resistant to steroids Definition Failure to improve baseline FEV1by more than 15% after treatment with prednisolone (30– 40 mg daily) for 2 weeks Type I Steroid Resistant Asthma Reduction in glucocorticoid receptor‐binding affinity High concentrations of IL‐2 and IL‐4 or by IL‐13 alone Type II Steroid Resistant Asthma Due to low numbers of glucocorticoid receptors
  17. 17. IV immunoglobulins: Steroid-sparing effect appears to be present but is not used, as it is prohibitively expensive. IL-2 & IL-4 levels can be lowered by IV immunoglobulins: 2-3 mg / kg / wk / 4wks Methotrexate: Methotrexate causes inhibition of T cell proliferation through inhibition of enzyme Amidophosphoribosyltransferase. Concomitant weekly methotrexate therapy causes clinically significant reduction in oral prednisolone doses 15mg/day to 5mg/day. Methotrexate therapy also increases peripheral blood T cell sensitivity to prednisolone inhibition.
  18. 18. Cyclosporine: selectively inhibits T lymphocyte proliferation, IL-2 and other cytokine production and response of inducer T cells to IL-1. It is used as a second line immunomodulator drug in steroid resistant asthma. Gold: Has been used in Japan, and isolated studies in Europe and America have shown decreased use of steroids, improved symptoms but no change in FEV 1 Leflunomide: A disease modifying agent for rheumatic diseases, it also causes selective suppression of Th cytokine expression. They have a steroid sparing effect.
  19. 19. Inhalers- Hydrofluroalkane HFA Breath actuated pMDI ( AUTOHALERS ) Multiple Dose Devices DPIUltrasonic Nebulizers Single dose DPI
  20. 20. SIT - Single Inhaler therapy • LABA monotherapy has been associated with an increased risk of asthma-related morbidity and mortality, • Should only be used along with an ICS Combination therapy Inhalational corticosteroid +LABA Maintenance
  21. 21. Rational of ICS + LABA Common combinations Beclomethasone+ salmeterol Fluticasone + salmeterol ICS 1. Prevents down regulation of Beta receptors 2. Prevents desensitization LABA Helps In enhancing the binding of Glucocorticoids to GCR Maintenance Levosalbutamol
  22. 22. SMART – Single Inhaler Maintenance and reliever therapy Formoterol has a fast onset of action <1min compared to other LABA like salmeterol with a onset of 30min Therefore ICS+ LABA Combinations that contain formoterol Budesonide + formoterol Fluticasone + formoterol Maintenance and reliever
  23. 23. Advances in Beta 2 agonists Ultra LABA’s Ultralong acting LABA . Duration > 24 hrs. Indacaterol Bambuterol carmoterol, vilanterol olodaterol, Indacaterol Initial trials Safe Improvements in FEV1 at 4 weeks , Long term studies – Not established the effect on asthma disease control Asthma exacerbations
  24. 24. Montelukast Zafirlukast Pranlukast Zileuton Leukotriene Modulators
  25. 25. CysLT 2 Receptor antagonists • Studies have revealed that Cyst LT2 mRNA is abundantly expressed on activated eosinophils. • Raised the possibility that Cyst LT2 antagonists would be more effective in ameliorating the LT’s response explaining the relative failure of the existing Cyst LT1 antagonists.
  26. 26. Methyl xanthines Low dose Sustained release theophylline Plasma values 5 to 10 mg/l – Anti-inflammatory / Less side effects . Mechanisms : Histone deacetylase activation- Steroid resistant asthma Effects on apoptosis Interleukin-10 Inhibition of NF-KB Indications Low dose sustained release theophyline as a add on to ICS in severe asthma
  27. 27. Doxofylline • Novel xanthine bronchodilator Mechanism of action • Inhibition of phosphodiesterase 4, • Decreased affinities towards adenosine A1 and A2 receptors, Comparative Safety Profile No CNS stimulation No cardiac arrhythmias
  28. 28. Phosphodiesterase Inhibitors PDE4 inhibition is thought to lead to elevated levels of intracellular cAMP, • suppression inflammatory cell function • inhibition of mucin production epithelial cells • alterations in airway smooth muscle tone Selective PDE inhibitors Roflumilast , Cilomilast, Rolipram, Ibudilast, Piclamilast, Luteolin
  29. 29. Roflumilast selective, long-acting inhibitor of the enzyme PDE-4 Reduces release of cytokines Reduces migration and activation of immune cells
  30. 30. Advances in use of Anticholinergics
  31. 31. Results Long acting Muscarinic Agonists ( Tiotropium ) 1. In moderate to severe asthma , as a add on when no response to ICS+ LABA 2. In mild persistent asthma as a add on to ICS . Important outcomes that are not evaluated in all studies published until now are the reduction of exacerbations and the anti-inflammatory effects of tiotropium Currently available data on the efficacy of tiotropium in asthmatic patients are not sufficient to recommend the use of this drug
  32. 32. Novel classes of bronchodilators Magnesium sulfate MOA • Reduces cytosolic calcium in airway smooth musclebronchodilatation USES : Useful as an additional drug to SABA in A/c severe asthma can be given by IV/nebulisation Side effects Include flushing and nausea Not suitable to be employed alone as clinical benefit is small
  33. 33. Potassium channel openers Potassium channel openers that open calcium activated large conductance K+ channels in smooth muscle Calcium channel blockers Nifedipine, verapamil -Prevent calcium entry into smooth muscle -Inhibit stimuli induced bronchoconstriction
  34. 34. VIP analogs - VIP binds to VPAC1(smooth muscles of blood vessels) & VPAC2(airway smooth muscle)couple to Gs adenylyl cyclase stimulated-smooth muscle relaxation - VIP potent bronchodilator in vitro studies but in patients it is rapidly metabolized and also has vasodilator Side effects Stable analog of VIP (RO 25-1533) selectively stimulate VPAC2-produces rapid bronchodilatation but effect is not prolonged .
  35. 35. ANP & related peptide Urodilatin - Activates membrane guanylyl cyclase cGMP bronchodilatation - Bronchodilator effects comparable to SABA. - Useful for additional bronchodilatation in Acute severe asthma
  36. 36. Anti IgE Omalizumab Humanized monoclonal antibody MOA: •Neutralizes IgE in circulation •Inhibits activation of IgE bound to mast cells •Down regulates IgE receptors on mast cells
  37. 37. Route : S/c or IV every 2- 4 weeks Use : severe persistent extrinsic asthma who are resistant to other forms of treatment. Reduces exacerbations and requirement of oral and inhaled steroids in them Drawback : high cost S/E : local reaction at inj. Site urticarial, rash, flushing rarely anaphylactic reaction
  38. 38. Anticytokines
  39. 39. Anti IL-5 IL-5 Anti IL-5 Antibodies Mepholizumab Humanized Monoconal antibody Phase 3 trials Reduced Eosinophil entry in the airways Decrease asthma exacerbation Reslizumab Phase 2 Pronounced in a subgroup of patients with highest blood &sputum eosinophils, IL5 Receptor antibodies Benralizumab Pre-clincial stage Decrease of circulating eosinophills
  40. 40. Anti IL-4 IL-4 Th2 differentiation Switching of B cells to IgE synthesis Eosinophil recruitment Development of mast cells Anti IL4 Pitrakinra ( s.c / inhaled ) Pascolizumab Dupilumab decrease in asthma exacerbation rate during withdrawal of inhaled therapy with corticosteroids and long-acting 𝛽2- adrenergic agonists, marked improvement of respiratory function TH2
  41. 41. Anti IL-13 Lebrikizumab ( PHASE 3) Improvement of lung function in patients with moderate-to severe asthma Improvement of FEV1 from baseline Tralokinumab ( s.c) -- Phase 3 Decrease need for rescue medication Anti IL-9 MEDI -528 Improved Asthma Symptom scores In Trial for exercise induced asthma TH2
  42. 42. Anti TNF alpha Th1 TNF alpha Recruitment neutrophils and eosinophils via upregulation of epithelial and endothelial adhesion molecule Anti TNF alpha Evidence from phase 2 trials Concern infliximab circadian oscillations in peak expiratory flow active tuberculosis, pneumonia, sepsis, and several different malignancies (breast cancer, B-cell lymphoma, metastatic melanoma, cervical carcinoma, renal cell carcinoma, basal cell carcinoma, and colon cancer) golimumab Not conclusive etanercept improve lung function, airway hyper- responsiveness, and quality of life
  43. 43. Anti IL-17 TH1 IL-17 Neutrophilic inflammation, airway remodeling, Steroid resistant Secukinumab Humanized anti IL17 antibody Brodalumab Il-17 receptor antibody On Going Phase 2 trials in severe asthma that is not adequately controlled by ICS+LABA IL-17 is also involved in immune protection against infectious and carcinogenic agents
  44. 44. In vitro studies human anti-GM-CSF monoclonal IgG1 antibody (MT203) has been developed, capable of significantly decreasing survival and activation of peripheral human eosinophils Anti GM-CSF GM-CSF is a growth factor over expressed in asthmatic airways
  45. 45. Th1 directed Serious infections Neoplastic disorders TH2 directed Autoimmune diseases Restricted to phenotype Needs evaluation of cytokines & markers Expensive add to the cost diagnosis and treatment Drawbacks
  46. 46. Toll like receptors
  47. 47. CRTH2 CRTH2 (Chemo attractant Receptor-homologous molecule expressed on Th2 cells) G-protein coupled receptor expressed by Th2 lymphocytes, eosinophils, and basophils. The receptor mediates the activation and chemotaxis of these cell types in response to prostaglandin D2 (PGD2), produced by mast cells. Contributes to the so-called “Th2 polarization”
  48. 48. CRTH2 antagonists Using indomethacin, a CRTH2 agonist, as a starting block and have prepared novel CRTH2 DP2-selective antagonists An oral CRTH2 antagonist (OC0000459) showed a 7.4% improvement in FEV1 at 28 days (p=0.037). led to a reduction in total IgE concentration and a trend toward decreasing sputum eosinophils
  49. 49. Macrolides Clarithromycin reported to be effective in many cases asthma. Causation of asthma linked to Chlamydia pneumonia or mycoplasma pneumonia
  50. 50.  Statins are now under evaluation in asthma therapy by AAAAI  It was observed that asthmatics with co-morbidities who are on statins have 30% lower risk for ER visits & hospitalizations due asthma than controls.
  51. 51. Miscellaneous approaches Endothelin antagonists may improve structural changes in asthma. However not tested. Antioxidants more potent than Vit C&E, N-Acetyl cysteine in development as oxidative stress important in asthma. Bitter taste receptors agonists ---chloroquine,saccharine
  52. 52. Bronchial thermoplasty Gene therapy T cell therapy Immunotherapy
  53. 53. Bronchial thermoplasty  Concept: Passing RF pulses through the airway tissues generates heat due to tissue resistance debulking of ASM  Devices : thermoplasty apparatus and RF compatible FOB
  54. 54. • In a double-blind, randomized, sham-controlled clinical study of bronchial thermoplasty • Improved Qol • Reduction in asthma attacks • Reduction in emergency room visits for respiratory symptoms • Reduction in days lost from work, school, • Reduction in hospitalizations for respiratory symptoms FDA approved 2010
  55. 55. Immunotherapy • Administration of increasing doses of allergen extracts to induce persistent immune tolerance in patients with allergen-induced symptoms • Recently SubLingual immunotherapy (SLIT) is preferred and claimed to be more effective in asthma
  56. 56.  Benefits include: ↓ in symptom scores, ↓ in medication usage and ↓ airway reactivity  Mechanism:  Increased regulatory T cell activity  Restoration of Th1- Th 2 balance  Switching of allergen-specific B cells towards IgG4 production.  Usual course:  3-5 years on maintenance therapy.
  57. 57. Allergen peptides: The active peptides of allergens are used → down regulation of T cells without co-stimulatory signals 1. Short T cell epitope peptides: induce tolerance without mediator release (no IgE binding) 2. B cell epitope derived peptides: stimulate B cells to produce blocking IgG 1 without IgE binding Recombinant allergens: Reconstructed with reduced allergenic activity
  58. 58. CpG-DNA based immunotherapy: • Giving cytosine guanine plasmid DNA with allergen extract produce a strong Th-1 response with increase of mucosal IF-ϒ and decrease IgE production
  59. 59. Is the insertion of a functional gene in a target cell to exert the gene function  Genes transferred to target cells by a viral vector or a liposome (? nanocarrier)  Target cells in the lungs are respiratory epithelium
  60. 60. Cytokine encoding genes:  Genes encoding for IL-12, IF-ϒ, IL-18: Cause marked reduction in eosinophilic inflammation, IgE production and airway hyper responsiveness  Genes encoding for IL-10 and TGF-β: Cause suppression of both Th-1&Th-2 response  β2 receptors encoding genes: To over express β2 receptors and potentiate bronchodilation  Glucocorticoid R genes: Over expression overcomes GCR resistance and decrease systemic SEs
  61. 61. Cloned Th -1 cells are now under Phase 2 trials Aim: correction of Th1-Th2 imbalance in asthma with correction of cytokine profile: ↑↑ IL-12, IF-ϒ & ↓↓ IL-4, IL-5, IL-13 T cell Therapy
  62. 62. Thank You