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Pharmacotherapy of asthma

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Pharmacotherapy of asthma

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Pharmacotherapy of asthma

  1. 1. Pharmacotherap y of Asthma 28/10/2012
  2. 2. What is Bronchial Asthma?  Chronic inflammatory airway disease associated with increased airway responsiveness and reversible airway obstruction.  It can present at any age; majority of cases diagnosed in childhood  Most of them become asymptomatic by adolescence  Disease severity rarely progresses; patients with severe asthma have it at the onset.
  3. 3. Clinical Features Recurrent episodes characterized by:  Breathlessness  Wheezing  Coughing- especially at night or early morning  Tightness in the chest  Hyperinflation  Increased mucus production
  4. 4. Risk factors Endogenous • Atopy • Genetic predisposition • Obesity • Early infections Environmental • Indoor allergens • Outdoor allergens • Occupational sensitizers • Passive smoking
  5. 5. Triggers  Allergens  Respiratory tract infection  Exercise  Stress  Cold Air  Drugs- Aspirin  Other irritants- SO2 , Household sprays
  6. 6. Pathophysiology
  7. 7. Pathophysiology
  8. 8. Diagnosis  Spirometry  Reduced FEV1, FEV1/FVC ratio, and PEF  Reversibility - >12% or 200 ml increase in FEV1 15 min after an inhaled short-acting beta 2-agonist  Airway Responsiveness - increased AHR measured by methacholine or histamine challenge - reduces FEV1 by 20%  Chest X ray- Usually normal; may show hyperinflation  Skin prick test – May be positive but not helpful in diagnosis
  9. 9. Drug Therapy • Beta 2 agonists • Anticholinergics • Methylxanthines Relievers • Corticosteroids • Mast cell stabilizers • Anti Leukotrienes • Biological Agents- Omalizumab Controllers
  10. 10. β2 Agonists Classified as:  SABAs(short acting)- Salbutamol, Terbutaline, Levalbuterol, Fenoterol, Pirbuterol, Metaproterenol  LABAs(Long acting) - Salmeterol, Formoterol  Ultra LABA: Indacaterol (as yet not approved for asthma)
  11. 11. Mechanism of action
  12. 12. Why are some β2 agonists long acting? DIFFUSION MICROKINETIC MODEL
  13. 13. Other actions  Acute anti-inflammatory effects by:  Inhibition of mast cell mediator release  Inhibition of plasma exudation and airway edema  Increased mucus secretion and enhanced mucociliary clearance  Reduction in airway cholinergic nerve transmission  Chronic inflammation not affected- Rapid downregulation of inflammatory cell β2 receptors No effect on airway hyper-responsiveness
  14. 14. SABAs  Albuterol, levalbuterol, terbutaline  Rapid onset of action with effects lasting for 3-6 hrs  Inhaled from pMDI or DPI; very few systemic ADRs  DOC for acute asthma symptoms and exacerbations and for preventing EIA  Regular, long-term use of SABA not recommended; used on ‘as required’ basis.  SABA >2 days a week indicates inadequate control
  15. 15. LABAs  Salmeterol, Formoterol  Formeterol: faster onset of action  Duration of action: 12 hrs; given BD  Do not control underlying inflammation and increase mortality in asthmatics  NOT TO BE USED AS MONOTHERAPY  Used as an adjunct to ICS therapy in persistent asthma  May be used before exercise to prevent EIA  Dose: Salmeterol- 50μg BD; Formeterol- 12μg BD
  16. 16. Safety issues of LABA  Trials comparing salmeterol with placebo found increased mortality and exacerbations in salmeterol group  Discontiuation of ICS after LABA results in increased markers of inflammation  Black box warning issued by FDA on all LABA  Postulated mechanisms are:  A direct deleterious effect on bronchial smooth muscle  Maintenance of lung function despite worsening inflammation; so that patients tend to delay seeking treatment for an exacerbation
  17. 17. Adverse Effects  Muscle tremor, palpitations- more common in elderly patients  Hypokalemia- clinically insignificant  Metabolic effects(hyperglycemia)- seen after large, systemic doses  Tolerance- Although downregulation is seen after chronic therapy, it does not affect efficacy due to large receptor reserve in airways
  18. 18. Recent Advances INDACATEROL:  Inhaled once-daily β2 agonist  Onset of action faster than salmeterol  Duration of action ~ 24 hrs  Has been approved only for COPD  Clinical trials in asthma underway to test safety and efficacy of once-daily combination of indacaterol with mometasone Cazzola M, Calzetta L, Matera MG. β(2) -adrenoceptor agonists: current and future direction. Br J Pharmacol. 2011 May; 163(1):4-17
  19. 19. Anticholinergics  Ipratropium  Tiotropium  Oxitropium M3 > M1 Prevent cholinergic-nerve induced: Broncho- constriction Mucus secretion
  20. 20. Contd…  Do not reduce mucociliary clearance  Less effective than beta-2 agonists as they inhibit only the cholinergic reflex component of bronchoconstriction  Hence used only as add-on drug  Combined with β2-agonists in treating acute severe asthma
  21. 21. Adverse effects  Bitter taste  Dryness of mouth  Glaucoma- due to direct effect of nebulized drug on the eye  Paradoxical bronchoconstriction- due to hypotonic nebulizer solution or additives like benzalkonium chloride/ EDTA  Urinary retention – common in elderly patients
  22. 22. Methylxanthines AC CAMP β2 AMP PDE Bronchial tone Contraction Relaxation Adenosine Methylxantines
  23. 23. Anti-inflammatory action  Increased secretion of IL-10  Inhibits the translocation of the pro-inflammatory transcription factor NK-κB into the nucleus  Promotes apoptosis in eosinophils(in-vitro)  Activates HDAC2 and enhances the effects of glucocorticoids  All these effects are seen at Cp < 10mg/L  Clinically, low oral doses reduce leukocytic infiltration into the airways and reduce the no. of eosinophils seen in BAL and induced sputum of asthmatic patients
  24. 24. Clinically available compounds  Theophylline  Doxofylline- less potent adenosine receptor antagonist  Enprofylline- no effect on adenosine receptors  Aminophylline- ethylenediamine salt; increases its solubility hence used for i.v. administration
  25. 25. Pharmacokinetics  Therapeutic range is 5-15 mg/L  Oral drug rapidly and completely absorbed  Metabolized in liver by CYP1A2  Dose has to be individualized because of:  Different patients respond differently to the drug  Clearance varies among patients due to the factors such as….
  26. 26. ….Factors affecting clearance Increased clearance Enzyme inducers- rifampin, barbiturates Smoking- which induces CYP1A2 High-protein, low-carb diet Barbequed meat In children Decreased clearance Enzyme inhibitors- emycin, ciprofloxacin CCF, liver disease, pneumonia Viral infection High-carb diet Old age Dose reduced to half
  27. 27. Route of administration Intravenous  Aminophylline is used in dose of 6mg/kg over 20 min f/b 0.5 mg/kg/hr maintenance dose  Indicated in acute severe asthma  Associated with many adverse effects  Hence, currently nebulized β2 agonists preferred over i.v. aminophylline
  28. 28. Oral Preparations  Immediate release formulations give wide fluctuations in plasma levels(Cp)- NOT RECOMMENDED  Sustained-release preparations: Absorbed at a constant rate and provide steady Cp  Twice daily therapy in dose of 8mg/kg is given  Once-daily release preparations now available  Single dose given at night for controlling nocturnal asthma symptoms
  29. 29. Indications  Steroid sparing effect: Addition of low dose theophylline to ICS improves symptom control compared to doubling the steroid dose  Nocturnal asthma  As add-on therapy: less effective than β2 agonists, but preferred when cost is a limiting factor  Acute asthma: Used only when patient not responding to β2 agonists
  30. 30. Adverse Effects  Plasma conc dependent; occur at Cp>15 mg/L  Headache  Nausea, vomiting  Increased gastric acid secretion  Diuresis  Cardiac arrythmias  Seizures Due to PDE4 inhibition Due to A1 receptor inhibition
  31. 31. Recent Advances  Most of the adverse effects of theophylline are due to systemic effects on PDE receptors.  Based on this, roflimilast, an oral PDE4 inhibitor, was tested in asthmatic patients but was associated with gastric side effects  Hence, inhaled selective PDE4 inhibitors are in development(phase 2) for asthma treatment Singh D, Petavy F, Macdonald AJ, Lazaar AL, O'Connor BJ. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res. 2010 Mar 1;11:26.
  32. 32. Corticosteroids
  33. 33. Mechanism of action
  34. 34. Anti-Inflammatory action  Reduce the number of inflm. cells in airway epithelium and submucosa  Induce eosinophil apoptosis  Prevent and reverse the increase in vascular permeability  Decease mucus secretion  Reduction in airway hyper-responsiveness and healing  Only suppress inflammation and do not cure underlying disease- recurrence seen after steroid withdrawal
  35. 35. Synergism between steroids and β2 agonists  They interact with each other to potentiate their actions  Steroids: a) Increase transcription of β2 receptor gene in airway mucosa b) Prevent uncoupling of β2 receptors to Gs c) Prevent downregulation of β2 receptors  β2 agonists: a) Enhance binding of GR to DNA b) Increase in translocation of liganded GR to the nucleus
  36. 36. Inhaled corticosteroids  Beclomethasone dipropionate  Budesonide  Fluticasone  Ciclesonide  Flunisolide  Mometasone furoate  Triamcinolone
  37. 37. Equipotent doses of ICS
  38. 38. Inhaled corticosteroids-PK
  39. 39. Adverse effects-Local  Hoarseness and weakness of voice(dysphonia)- due to atrophy of vocal cords  Oropharyngeal candidiasis  Cough- Common with MDI due to additives
  40. 40. How to reduce these?  Use a large-volume spacer device  Rinsing mouth after use of inhaler  Switch to DPI if cough is troublesome
  41. 41. Systemic ADRs  Adrenal suppression  Growth suppression  Dermal thinning and bruising  Osteoporosis  Cataract, glaucoma  Metabolic abnormalities
  42. 42. How to minimize these? Budesonide, Fluticasone High first-pass metabolism Reduced systemic bioavailability Ciclesonide Lung esterases Active metabolite Low oral bioavailability and less systemic ADRs
  43. 43. Indications  First line therapy for all patients of persistent asthma(mild, moderate, severe)  In intermittent asthma- use only when β2 agonist (SABA) use is more than twice weekly  Usually administered twice daily- maintain at lowest possible dose that controls symptoms  Dose: < 400 μg/d of beclomethasone or equivalent  If >800 μg/d is required, use spacer device  Growth suppression in children- usually not seen at doses < 400 μg/d
  44. 44. Systemic steroids  Oral steroids  For patients not controlled on ICS  Prednisolone: 30-40 mg/day usually gives maximal benefit  Maintenance dose: 10-15 mg/day  Given as single dose in the morning: produces less adrenal suppression (matches with diurnal variation)  Alternate day treatment: Control of asthma is suboptimal; hence not preferred
  45. 45. contd…  Intravenous steroids  In acute asthma where lung function is < 30% predicted  DOC: Hydrocortisone as it has rapid onset of action  Once control is achieved, switch over to oral prednisolone 40-60 mg/day
  46. 46. New developments  Transrepression – anti-inflammatory activity  Transactivation - Causes side effects  Classical steroids cause both activation and repression so that beneficial effects are accompanied by side effects  SEGRA(selective Glucocorticoid Receptor Agonists)- Less effective in transactivation; selective anti- inflammatory activity  Mapracorat- Undergoing preclinical studies
  47. 47. Mast Cell Stabilizers  Sodium cromoglycate, Ketotifen  Inhibit degranulation of mast cells by triggers such as exercise and pollen  Inhibit eosinophil recruitment and decrease inflammatory response  Well tolerated; hence widely used earlier for treatment of childhood asthma  Have short duration of action and hence given QID by inhalation  Less effective than ICS- Rarely used in current scenario
  48. 48. Anti-Leukotrienes
  49. 49. Indications  Orally administered  Improve lung function; however are less effective than ICS in mild asthma  Used as add-on therapy in patients not controlled on ICS  Can also be used in prophylaxis of exercise-induced and aspirin-induced asthma  Doses: a. Montelukast: 10 mg OD b. Zafirlukast: 20 mg BD
  50. 50. Adverse Effects  Well tolerated  Rarely can cause liver dysfunction: monitor liver enzymes  Churg-Strauss syndrome  Headache, rashes
  51. 51. FLAP inhibitors
  52. 52. Omalizumab
  53. 53. Indications  Reduces no. of exacerbations and improves control in severe asthma  Very expensive  Reserved for use only in patients not controlled on maximal doses of inhaled therapy and having serum IgE within a specified range  Administered as s.c. injection every 2-4 weeks  ADR- anaphylaxis
  54. 54. Types of Inhalers  Metered dose inhalers- use a pressurized inert gas (CFC used earlier now replaced by HFA)  “Metered“- amount of dose goes directly to the lungs  Coordination during inhalation may be difficult  Deposition of 50–80 % of actuated dose in oropharynx  Breath actuated MDI- useful for patients unable to coordinate inhalation  Most common patient errors: Forgetting to shake the canister, inhaling at the wrong time, or forgetting To hold their breath
  55. 55. Spacer devices/ Holding chambers Used with pMDIs that act as a reservoir or holding chamber for the drug Fitted with 1 way valve- to prevent medication escape At pateint end, mouthpiece can be attached- for use in children Advantages: Decrease oropharyngeal deposition and decreased risk of topical side effects No need for coordination with breathing
  56. 56. Dry Powder Inhalers  Delivers drug in the form of a dry powder  Contains no propulsion system/gas  Rely on force of patient’s inhalation to trigger delivery of a single dose(patient-activated)  Hence, insuficient inhalational flow rates may reduce drug delivery- used only in older children & adults  Different types are- Accuhaler DiskhalerTurbohaler
  57. 57. Nebulizer  Turn liquid form of the drugs into a fine mist like an aerosol  Done with the help of compressed oxygen/compressed air (Jet nebulizer/ Atomizer) OR ultrasonic waves(ultrasonic nebulizer)  Drug delivered during tidal breathing  Less dependent on patient coordination and effort  Method of choice – In patients with breating fatigue and in severe asthma where large doses of inhaled drugs need to be administered
  58. 58. Approach to Management of Asthma
  59. 59. Four pronged approach • Develop doctor-patient relationship1 • Identify and reduce exposure to risk factors2 • Assess, treat and monitor asthma3 • Manage asthma exacerbations4
  60. 60. Develop doctor-patient relationship  Asthma self-management education is essential  Begin at the time of diagnosis and continue through follow-up care  Involve all members of the health care team  Provide all patients with a written asthma action plan that includes two aspects:  daily management  how to recognize and handle worsening asthma
  61. 61. Identify and reduce exposure to risk factors  Clinician should evaluate potential role of allergens, particularly indoor inhalant allergens  Reduce, if possible, exposure to allergens to which the patient is sensitized  Avoid exposure to environmental tobacco smoke and other respiratory irritants  Avoid exertion outdoors when levels of air pollution are high
  62. 62. contd…  Avoid use of nonselective beta-blockers  H/o sensitivity to aspirin or NSAIDs should be counseled -risk of fatal exacerbations from these drugs  Consider inactivated influenza vaccination for adults and children more than 3 yrs of age who have severe asthma.
  63. 63. Asthma Treatment  In children upto 4 yrs of age:  Diagnosis is difficult  Long term therapy considered in patients who had 4 or more wheezing episodes alongwith atopic dermatitis/family h/o of asthma  Inhaled ICS(budesonide, fluticasone) in low doses are safe even for extended periods  LABA- Salmeterol is approved for use  Montelukast can be given as chewable tablets
  64. 64. contd..  Delivery devices  MDI plus valved holding chamber (VHC) with a face mask  Nebulizer with a face mask  Holding the mask or open tube near the infant’s nose and mouth, is not appropriate  If there is a clear and positive response for at least 3 months, step down in therapy should be attempted to identify the lowest dose  If clear benefit is not observed within 4–6 weeks the therapy should be discontinued and alternative diagnoses
  65. 65. In children 5-11 yrs of age  Physical activity at play is an essential part of a child’s life  Full participation in physical activities should be encouraged  Manage moderate or severe exacerbations due to viral RTI, with a short course of oral systemic corticosteroids
  66. 66. Patients > 12 yrs old and adults Achieving Control Of Asthma  Assess asthma severity  Select T/t that corresponds to the patient’s level of asthma severity  At a follow up visit after starting T/t, asthma is not well controlled ,then T/t should be advanced to the next step
  67. 67. Adjusting Therapy  Once therapy is selected T/t decisions are based on the level of the patient’s asthma control  Step up one step for pts whose asthma is not well controlled  Pts with very poorly controlled asthma, consider increasing by two steps, a course of oral corticosteroids, or both  Regular follow up visits (1-6 months) depending on severity
  68. 68. Special Considerations
  69. 69. Exercise-induced bronchospasm  Pretreatment before exercise-  Inhaled beta2-agonists- prevent EIB in more than 80 percent  SABA use may be helpful for 2–3 hours  LABAs can be protective up to 12 hours  LTRAs can attenuate EIB in up to 50 percent of patients  Cromolyn or nedocromil taken shortly before exercise is an alternative
  70. 70. Contd..  Frequent, severe EIB indicates poorly controlled asthma- Consider long-term control therapy  A warm up period before exercise may reduce the degree of symptoms  A mask or scarf over the mouth may attenuate cold- induced EIB
  71. 71. Surgery and Asthma  Attempts made to improve lung function preoperatively  Short course of oral systemic corticosteroids may be required  For patients who have received oral systemic corticosteroids during the past 6 months and for pts on a long-term high dose of ICS  100 mg hydrocortisone every 8 hours i.v during the surgical period & reduce dose rapidly within 24 hours after surgery
  72. 72. Pregnancy and Asthma  Asthma increases risk of preterm birth, IUGR and perinatal mortality.  NEVER WITHHOLD TREATMENT  Monitoring of asthma status during prenatal visits  Albuterol is the preferred SABA because it has an excellent safety profile  ICS are the preferred treatment for long-term control medication  Budesonide is the preferred ICS because more data are available
  73. 73. Bronchial Thermoplasty  Catheter introduced through a bronchoscope  It delivers thermal energy to the airway wall to reduce excess smooth muscle  Increases symptom-free days, improves PEFR and reduces the use of reliever medicines.  FDA approval obtained in 2010 for treatment of severe asthma. Cho JY. Recent Advances in Mechanisms and Treatments of Airway Remodeling in Asthma: A Message from the Bench Side to the Clinic. Korean J Intern Med 2011; 26:367-383
  74. 74. THANK YOU

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