Asthma - Recent advances in treatment

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  • Asthma - Recent advances in treatment

    1. 1. 1 Recent advances in Asthma treatment Dr. Divya Krishnan Calicut medical college
    2. 2. 2 CONTENTSCONTENTS Introduction Etiology Pathogenesis Diagnosis Current management Recent advances in treatment Conclusion
    3. 3. 3 Common disease with enormous socioeconomic impact. Prevalent in 10% of the world population.  Can occur at any age with peak incidence in childhood. Males affected more(childhood), Females affected more in adults. Asthma……………Asthma……………
    4. 4. 4 Clinical syndrome characterised by airway inflammation and increased airway hyperresponsiveness that leads to recurrent episodes of wheezing, shortness of breath, chest tightness and cough. Symptoms are associated with widespread but variable bronchoconstriction that is at least partly reversible, either spontaneously or with treatment. Asthma……………….Asthma……………….
    5. 5. 5 Asthma-EtiologyAsthma-Etiology A Atopy Family history Prematurity, abnormal lung function at birth Aeroallergen exposures Viral respiratory tract infections Tobacco smoke Air pollutants Exercise Cold air Food additives Drugs ( Beta blockers, Aspirin, Bisphosphonates) T R I G G E R S
    6. 6. Etiological classification ofEtiological classification of asthmaasthma Extrinsic( atopic) asthma Intrinsic (non atopic)asthma - History of atopy - No allergen identified - Serum IgE raised - Serum IgE not raised - Onset in childhood - Onset in adulthood - Episodic type - Chronic type Classification not popular now as it fails to define treatment strategies 6
    7. 7. Pathogenesis of asthmaPathogenesis of asthma Immunological model of asthma pathogenesis 2 phases----early (bronchoconstriction) phase late (inflammation and hyper-reactivity) phase 7
    8. 8. Pathogenesis………Pathogenesis……… How it starts….? 8
    9. 9. PathogenesisPathogenesis Early phase reaction Bronchoconstriction start of late phase 9
    10. 10. Pathogenesis……Pathogenesis……
    11. 11. PathogenesisPathogenesis Role of neuronal pathways in asthma Bronchial tone results due to a balance between - Parasympathetic-bronchoconstriction - Sympathetic - bronchodilatation - NANC – releases neuropeptides (substance P, neurokinin A causing bronchoconstriction and nitric oxide causing bronchodilatation) (NO also produced by iNOS besides being a neuropeptide) Other mediators Adenosine causes bronchoconstriction (A1 receptors on smooth muscle) Endothelins, Bradykinins and many more………. 11
    12. 12. Pathogenesis………Pathogenesis……… AIRWAY REMODELING
    13. 13. DiagnosingDiagnosing AsthmaAsthma 13 Medical History -Wheezing, dyspnoea, chest tightness, coughing -Symptoms worse at night/early morning -Symptoms exacerbated by known triggers -Positive h/o atopy; family h/o asthma Physical examination -Rhonchi -Hyperexpansion of thorax -Associated atopic dermatitis/eczema
    14. 14. Diagnosing AsthmaDiagnosing Asthma 14 Spirometry - Decreased FEV1 , FEV1/FVC ratio, PEF -Reversibility after inhalation of beta 2 agonist ->20% diurnal variation in PEF Other tests - Methacholine/histamine challenge test - Total serum IgE levels/ blood eosinophils - Skin tests for common allergens - Exhaled NO test
    15. 15. Clinical classification ofClinical classification of AsthmaAsthma Mild intermittent Mild Persistent Moderate persistent Severe Persistent Symptoms ≤ 2 times a week Asymptomatic between exacerbations Brief exacerbations >2 times a week but <1 time a day Exacerbations affect activity Daily symptoms Exacerbations≥2 times a week & may last for days Daily symptoms Limited physical activity Frequent severe exacerbations Night time symptoms ≤ 2 times a month > 2 times a month > 1 per week Almost every night Lung function FEV1 PEF variability ≥80% predicted < 20% ≥80% predicted 20-30% >60-<80% predicted >30% ≤ 60% predicted >30% 15
    16. 16. AsthmaAsthma exacerbationsexacerbations Mild Moderate Severe Respiratory failure (Status asthmaticus) imminent - breathless at rest if - talks in words drowsy - respiratory rate >30/min - loud wheeze no wheeze - pulse >120/min bradycardia - PEF < 60% - Arterial O2 saturation<90% - PaO2 < 6O ; PaCO2 > 45 mm of hg 16
    17. 17. ManagementManagement ofof asthmaasthma 17
    18. 18. Asthma Management GoalsAsthma Management Goals Achieve & maintain symptom control Maintain normal activity including exercise Maintain pulmonary function as close to normal as possible Prevent asthma exacerbations Avoid adverse effects from asthma medications Prevent asthma mortality 18
    19. 19. Asthma managementAsthma management Pharmacological measures Non pharmacological measures - Patient education - Avoidance of triggers - Avoid smoking - Graded exercise training - Psychological treatment - Yoga, acupuncture, hypnosis 19
    20. 20. Targets of drug actionTargets of drug action 20 Suppression of inflammation and hyper-reactivity-steroids Prevention of release of mediators from mast cells-mast cell stabilizers Antagonism of released mediators- LTRA Blockade of constrictor neurotransmitter- anticholinergics Mimicking dilator neurotransmitter- beta 2 agonists Directly acting bronchodilator- methyl xanthines + new targets
    21. 21. Drugs for asthmaDrugs for asthma Short term relievers Long term controllers Immediate reversal of bronchospasm but no effect on underlying inflammation. Used at the time of acute attacks Short acting beta 2 agonists Anticholinergics Methyl xanthines Control degree of inflammation and bring about an improvement of overall asthma control Taken regularly on a long term basis. Corticosteroids Mast cell stabilizers Long acting beta 2 agonists Leukotriene modifiers Methyl Xanthines 21
    22. 22. Short term relieversShort term relievers Short acting beta 2 agonists(SABA) Salbutamol (albuterol), Terbutaline, Fenoterol, Remiterol, Pirbuterol, Levalbuterol - Beta 2 receptor agonism-bronchodilatation - Given by inhalation/oral/parenteral -S/E : Tachycardia, tremors, hypokalemia, decreased response on long term use ( at higher inhaled dose or with oral and parenteral dose) -Levalbuterol considered to be more potent with less side effects than racemic mixture – evidence from trials lacking 22
    23. 23. Short term relieversShort term relievers Anticholinergics Ipratropium, Tiotropium -Less effective than beta agonists -Used as additional to beta 2 agonists in severe asthma -S/E : Dry mouth, urinary retension -Tiotropium has longer duration of action and doesn’t inhibit M2 receptors 23
    24. 24. Long term controllersLong term controllers Corticosteroids Inhaled Corticosteroids: Beclomethasone, Budesonide, Fluticasone, Flunisolide, Ciclesonide - Have high topical to systemic activity -Reduce inflammation and hyperresponsiveness and improve all indices of asthma control -Peak effect seen after 5-7days. No role in acute episodes. -S/E : sore throat, hoarseness of voice, oropharyngeal candidiasis (local) Mood changes, osteoporosis, growth retardation, hyperglycemia, pituitary adrenal suppression(systemic effects a high doses) 24
    25. 25. Corticosteroids contd…… Fluticasone -higher potency - longer duration of action - negligible systemic bioavailability Ciclesonide – prodrug cleaved by esterases in bronchial epithelium - oral bioavailability < 1% - In circulation highly plasma bound thus decreasing exposure of tissue cells to free active drug Systemic steroids in asthma -In severe persistent asthma not controlled by other drugs(oral prednisolone) -Status asthmaticus (iv hydrocortisone) 25
    26. 26. Long term controllersLong term controllers Long acting beta 2 agonists (LABA) salmeterol, formoterol -Highly lipid soluble drugs with longer duration of action (>12hrs) than SABA. -Salmeterol has slow onset of action but formoterol’s onset of action is comparable to SABA. -They do not have anti-inflammatory actions. Their best use is as an add on to ICS in patients not controlled by ICS alone. The combination is better than increasing the dose of steroids in terms of symptom control and improvement of lung function 26
    27. 27. Long term controllersLong term controllers Leukotriene modifiers - lipoxygenase inhibitor- Zileuton (hepatotoxicity) - LTRA – Montelukast, Zafirlukast . Oral administration 27
    28. 28. Stepwise management ofStepwise management of asthmaasthma Step 1 Mild intermittent asthma Step 2 Mild persistent asthma Step 3 Moderate persistent asthma Step 4 Severe persistent asthma Step 5 Continuous use of oral steroids Inhaled short acting beta 2 agonist as and when needed As needed short acting beta 2 agonist with regular controller therapy Low dose inhaled steroid or LTRA Medium dose steroid Or Low dose steroid + LABA/LTRA/Su stained release theophylline Medium or high dose steroid + one or more of the following options:- LABA LTRA Sustained release theophylline To step 3, add oral steroids 28
    29. 29. Management of acute severeManagement of acute severe exacerbationsexacerbations Parenteral steroid(hydrocortisone) Nebulized salbutamol+ ipratropium High flow humidified oxygen Salbutamol/ terbutaline im or subcutaneously Intubation & mechanical ventilation if needed. Correct dehydration & acidosis with saline+ sodium bicarbonate infusion Antibiotics to treat chest infection 29
    30. 30. Recent Advances inRecent Advances in thethe treatment oftreatment of asthmaasthma 30
    31. 31. Why the search for newWhy the search for new drugs??drugs?? Asthma has a complex pathogenesis—many putative targets still remain to be explored Patients not controlled even by oral steroids need an alternative A drug which can reduce the dose of steroids/replace it without producing side effects of its own. Asthma still remains an incurable disease though it can be managed effectively. 31
    32. 32. Newer approaches toNewer approaches to treatmenttreatment Novel class of bronchodilators Immunomodulatory therapies Newer anti-inflammatory therapies Mediator antagonists Miscellaneous approaches 32
    33. 33. Novel class of bronchodilatorsNovel class of bronchodilators 1. Magnesium Sulphate -Reduces cytosolic calcium in airway smooth muscle- bronchodilatation -Can be given by IV/nebulisation -Useful as an additional drug to SABA in A/c severe asthma. (more studies needed to document this) - Not suitable to be employed alone as clinical benefit is small. -Cheap, well tolerated with minor S/E like nausea & flushing 33
    34. 34. Novel class of bronchodilatorsNovel class of bronchodilators 2. Potassium channel openers Potassium channel openers that open calcium activated large conductanceK+ channels in smooth muscles(maxi K+ channels) better tolerated. ( Potassium channel openers that open ATP dependent K+ channels donot produce bronchodilatation as expected and also produce CVS side effects) 3. Calcium channel blockers – Nifedipine, verapamil -Prevent calcium entry into smooth muscle -Inhibit stimuli induced bronchoconstriction but no effect on basal airway calibre. -Bronchodilator effect less than SABA. 34
    35. 35. 35 Novel class of bronchodilatorsNovel class of bronchodilators 5. ANP & related peptide Urodilatin -Activates membrane guanylyl cyclasecGMPbronchodilatation -Bronchodilator effects comparable to SABA. -Useful for additional bronchodilatation in A/c severe asthma 6. 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 metabolised and also has vasodilator S/E. -More stable analog of VIP (RO 25-1533) selectively stimulate VPAC2-produces rapid bronchodilatation but effect is not prolonged
    36. 36. Immunomodulatory therapiesImmunomodulatory therapies 1. Immunosuppressive therapy - Considered when other treatments are unsuccessful or to reduce the dose of oral steroids (in step 5) -Methotrexate, Cyclosporine, Gold salts, IV immunoglobulin -Not routinely employed due to greater side effects and lesser efficacy 2.Anti IgE therapy 3. Specific immunotherapy 36
    37. 37. Immunomodulatory therapiesImmunomodulatory therapies Anti IgE therapy - Omalizumab 37 - Humanized monoclonal antibody - MOA: Neutralises IgE in circulation Inhibits activation of IgE bound to mast cells Down regulates IgE receptors on mast cells -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 - rarely anaphylactic reaction
    38. 38. Immunomodulatory therapiesImmunomodulatory therapies Specific immunotherapy -Injection of low doses of allergen to cause desensitization -Benefit in asthma not well documented -Mechanism : induces secretion of anti-inflammatory cytokine(IL 10) from regulatory helper T cells. This blocks co-stimulatory transduction in T cells so that they are unable to react to allergens. -Drawback : risk of anaphylaxis and local reactions : time consuming therapy -Better specific immunotherapy developed with:- cloned allergen epitopes, T cell peptide fragments of allergens, DNA vaccines composed of allergen complement DNA. 38
    39. 39. Newer anti-inflammatoryNewer anti-inflammatory drugsdrugs NF-kB inhibitors -NF is a transcription factor regulating inflammatory genes in asthma. -NF degraded by inhibitory protein IkB. IkB is degraded by IB Kinase. -Inhibitors of IB kinase in clinical trials. -Drawback: susceptibility to infections when NF is inhibited. Mitogen activated protein kinase inhibitors -MAP kinase pathways involved in C/C inflammation -SB203580, RW567657 block p 38 MAP kinase pathways -These inhibit synthesis of inflammatory mediators but severe toxicity reported. 39
    40. 40. Newer mediator antagonistNewer mediator antagonist Several mediators involved. Inhibitors of bradykinin, PAF found to be disappointing in asthma No new mediator antagonists deserves mention 40
    41. 41. Miscellaneous approachesMiscellaneous approaches Cytokine modifiers -IL5 plays pivotal role in eosinophilic inflammation -Anti IL5 antibodies shown to decrease exacerbations in severe asthma with eosinophilia. -Antibodies against IL 4, 13 showed disappointing results Chemokine receptor antagonist -CCR3 antagonists tried in asthma expecting to block eosinophil recruitment in the airways -Results disappointing due to high degree of toxicity. 41
    42. 42. Miscellaneous approachesMiscellaneous approaches CRTH2 antagonists in development show promising results in asthma 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. Macrolide antibiotics like Clarithromycin reported to be effective in many cases of c/c asthma. Causation of c/c asthma linked to Chlamydia pneumonia or mycoplasma pneumonia 42
    43. 43. ConclusionsConclusions Newer drugs in the already available classes of drugs may be better in certain respects when compared to their predecessors. Among newer classes of drugs, none holds promise. - Among bronchodilators-MgSO4, ANP, VIP analogs may be used as additional drugs to SABA but seem to be less efficient than SABA. - Anti IgE therapy with Omalizumab holds promise but it is too costly for the majority of patients to afford. As of now, the drugs in current use are the possibly the best that can be offered to a asthma patient. 43
    44. 44. 44 Thank

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