Doxophylline and asthma


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Doxophylline and asthma

  1. 1. Doxophylline The safer methylxanthine Dr. B. K. Iyer
  2. 2. Topics for discussion <ul><li>Introduction to doxophylline & scope for it </li></ul><ul><li>Theophylline and limitations </li></ul><ul><li>Respiratory system </li></ul><ul><ul><li>Anatomy, </li></ul></ul><ul><ul><li>Physiology </li></ul></ul><ul><ul><ul><li>Innervation: </li></ul></ul></ul><ul><ul><ul><ul><li>autonomic nerves [paraysmpathetic, sympathetic, & NANC] </li></ul></ul></ul></ul><ul><ul><ul><li>Respiratory defense mechanism </li></ul></ul></ul>
  3. 3. Topics for discussion <ul><li>Pathophysiology of relevant diseases </li></ul><ul><ul><li>COPD </li></ul></ul><ul><ul><li>Asthma </li></ul></ul><ul><ul><li>Chronic bronchitis </li></ul></ul><ul><ul><li>Emphysema </li></ul></ul><ul><li>Anti-asthmatic Agents </li></ul><ul><li>Doxophylline data </li></ul><ul><li>Doxophylline studies </li></ul><ul><li>Summary </li></ul>
  4. 4. What is doxophylline? <ul><li>It is a Methylxanthine derivative </li></ul><ul><li>What does it do? </li></ul><ul><ul><li>It brings about bronchodilatation. </li></ul></ul><ul><li>How? </li></ul><ul><ul><li>Increases diaphragm contractility and mucociliary clearance </li></ul></ul><ul><ul><li>Relaxes bronchial musculature and thus causes bronchodilatation </li></ul></ul><ul><ul><li>Decreases the ability of eosinophils and T-lymphocytes to cause inflammation </li></ul></ul>
  5. 5. What are methylxanthines? <ul><li>Methylxanthines are a group of purine alkaloids </li></ul><ul><ul><li>Purines are crucially important compounds used in nature as the parent compound for formation of the nucleotides that form DNA and RNA </li></ul></ul><ul><ul><ul><li>The oxidation of purine by adding 2 oxygen atoms forms xanthine. </li></ul></ul></ul><ul><li>Examples of Methylxanthines: </li></ul><ul><ul><li>Caffeine </li></ul></ul><ul><ul><li>theophylline, </li></ul></ul><ul><ul><li>theobromine, and </li></ul></ul><ul><ul><li>Doxophylline </li></ul></ul>
  6. 6. Is there scope for doxophylline? <ul><li>Theophylline which is generally used in moderate to severe persistent asthma, as a long-acting bronchodilator, has decreased in usage over past decade </li></ul><ul><li>Besides, it is not recommended in acute exacerbations , as it is used only for </li></ul><ul><ul><li>Symptomatic relief, or </li></ul></ul><ul><ul><li>Prevention of bronchial asthma & reversible bronchospasm associated with chronic bronchitis and emphysema. </li></ul></ul>
  7. 7. Limitations to Theophylline <ul><li>Popular Bronchodilator with the oral form being most frequently used. </li></ul><ul><ul><li>Decreases the frequency and severity of asthma attacks </li></ul></ul><ul><ul><li>IV form in emergencies only (give slowly—death can result with rapid infusion) </li></ul></ul><ul><ul><ul><li>Aminophylline: Each molecule of Amino dissociates to yield two molecules of theophylline </li></ul></ul></ul><ul><ul><li>Narrow therapeutic range </li></ul></ul><ul><ul><ul><li>nausea, anxiety, palpitations, sleep disturbances, dysrhythmias, convulsions, death </li></ul></ul></ul>
  8. 8. Theophylline concentrations <ul><li>Therapeutic Range = 10-20 mg/L </li></ul><ul><li>Target 12 mg/L </li></ul><ul><li>ADRs increase at 20 mg/L </li></ul><ul><li>Lag time between serum concentrations and therapeutic effect in lung </li></ul><ul><ul><li>ranges from 14 to 70 minutes (mean 60 minutes), </li></ul></ul><ul><ul><li>maximal effect may take 48 hours. </li></ul></ul>
  9. 9. Mechanism of action [MOA] <ul><li>Theophylline and doxophylline have similar mechanism of action [ not completely understood ] </li></ul><ul><ul><li>Traditional theory </li></ul></ul><ul><ul><ul><li>Inhibition of phosphodiesterase which converts cAMP to AMP </li></ul></ul></ul><ul><li>We will look at it later, in details </li></ul>
  10. 10. Uses of doxophylline <ul><li>Bronchoconstriction makes breathing difficult and interferes with gas exchange. The problem is caused by: </li></ul><ul><ul><li>Airway inflammation </li></ul></ul><ul><ul><li>Bronchospasm </li></ul></ul><ul><ul><li>Excessive mucous secretion </li></ul></ul><ul><li>Doxophylline is useful in </li></ul>What is COPD, Asthma, chronic bronchitis and emphysema?
  11. 11. Respiratory system Physiology
  12. 12. Airway innervations <ul><li>ANS </li></ul><ul><ul><li>sympathetic – alpha and beta </li></ul></ul><ul><ul><ul><li>beta-2 causes bronchodilatation, </li></ul></ul></ul><ul><ul><ul><li>apha-1 constriction </li></ul></ul></ul><ul><ul><li>Parasympathetic provides basal tone (Ach) – bronchoconstriction. </li></ul></ul><ul><ul><li>Sympathetic NANC - Non adrenergic, non cholinergic </li></ul></ul><ul><li>Secondary messengers are: </li></ul><ul><ul><li>cAMP (NANC-i) and </li></ul></ul><ul><ul><li>cGMP (NANC-e) </li></ul></ul>
  13. 13. Respiratory defense mechanism Phagocyte system Muco- Ciliary clearance Goblet Cell function Cough / Sneeze Respiratory Defense mechanism
  14. 14. Respiratory defense mechanism <ul><li>No nervous control </li></ul><ul><ul><li>Beta-2 stimulation  ciliary movement </li></ul></ul><ul><li>Goblet cells </li></ul><ul><ul><li>secrete mucus, which lies over mucosa </li></ul></ul><ul><ul><li>They  in number during chronic airway disease </li></ul></ul><ul><ul><li>Submucosal glands secrete serous mucus </li></ul></ul><ul><li>Mucociliary clerance </li></ul><ul><ul><li>first major defense, </li></ul></ul><ul><ul><li>Cilia beat 1000/min and move gel layer (thick & sticky). </li></ul></ul>
  15. 15. Respiratory defense mechanism <ul><li>MonoNuclearPhagocyte system </li></ul><ul><ul><li>Alveolar macrophages & Pulmonary intravascular macrophages mediate actions via </li></ul></ul><ul><ul><ul><li>histamine, 5-Hydroxytryptamine, Prostaglandins, Leukotrienes, PAF and Nitric Oxide </li></ul></ul></ul><ul><ul><li>This causes </li></ul></ul><ul><ul><ul><li>bronchoconstriction, </li></ul></ul></ul><ul><ul><ul><li>oedema, </li></ul></ul></ul><ul><ul><ul><li>chemotaxis, </li></ul></ul></ul><ul><ul><ul><li> mucus and  Microvascular Permeability, </li></ul></ul></ul><ul><ul><ul><li>stimulated nerve endings (broncho-constriction) </li></ul></ul></ul>
  16. 16. Respiratory defense mechanism
  17. 17. Respiratory system Pathophysiology of diseases
  18. 18. Airway Inflammation [AI] <ul><li>Airway inflammation (AI) contributes to </li></ul><ul><ul><li>hyperresponsiveness, </li></ul></ul><ul><ul><li>airflow limitation, </li></ul></ul><ul><ul><li>symptoms & chronicity </li></ul></ul><ul><li>AI causes leads to: </li></ul><ul><ul><li>Bronchoconstriction, edema, mucus plug formation, airway wall remodeling </li></ul></ul><ul><li>Atopy is strongest predisposing factor for developing asthma </li></ul>
  19. 19. Receptors & mediators <ul><li>Pathogenesis: Airway caliber regulated by sensory receptors and mediators </li></ul><ul><li>Irritant receptors </li></ul><ul><ul><li>located beneath the airway epithelium </li></ul></ul><ul><ul><li>stimulation causes bronchoconstriction and cough </li></ul></ul><ul><li>Many chemical mediators are released during bronchoconstriction and airway infection. </li></ul><ul><li>Mucus and edema can occlude airways. </li></ul>
  20. 20. Receptors & mediators - outcomes
  21. 21. <ul><li>Chronic obstructive pulmonary disease (COPD) is an umbrella term used to describe airflow obstruction that is associated mainly with emphysema and chronic bronchitis. </li></ul>What is COPD?
  22. 22. What is COPD?
  23. 23. What is COPD? <ul><li>Chronic inflammatory disorder of the airways </li></ul><ul><li>Immunohistopathologic features </li></ul><ul><ul><li>Denudation of airway epithelium </li></ul></ul><ul><ul><ul><li>collagen deposition beneath basement membrane </li></ul></ul></ul><ul><ul><ul><li>edema </li></ul></ul></ul><ul><ul><ul><li>mast cell activation </li></ul></ul></ul><ul><ul><li>Inflammatory cell infiltration </li></ul></ul><ul><ul><ul><li>Neutrophils (sudden, fatal asthma) </li></ul></ul></ul><ul><ul><ul><li>Eosinophils </li></ul></ul></ul><ul><ul><ul><li>Lymphocytes </li></ul></ul></ul>
  24. 24. What is Asthma? <ul><li>Inflammatory response to allergen </li></ul><ul><li>Antibody binds with & ruptures mast cells </li></ul><ul><ul><li>Releases histamine, prostaglandins, leukotrienes </li></ul></ul><ul><li>2 primary issues </li></ul><ul><ul><li>Bronchoconstriction </li></ul></ul><ul><ul><li>Inflammation (mucous production) </li></ul></ul>
  25. 25. What happens in Asthma? <ul><li>Asthma = bronchoconstriction, mucus production & edema </li></ul><ul><ul><li>Bronchial tract becomes more sensitive </li></ul></ul><ul><ul><li>Mucociliary function will be inhibited </li></ul></ul><ul><ul><li>Mucous plugs clog parts of lung leading to collapse </li></ul></ul><ul><ul><li> epithelial permeability, chemotaxis, mucus production </li></ul></ul><ul><ul><li>Mediator reach submucosa, stimulate inflammatory cells </li></ul></ul><ul><ul><li>Stimulation of afferent nerve endings leads to bronchoconstriction </li></ul></ul><ul><ul><li>Cytotoxic proteins, toxic O2 radicals damage airway epithelium </li></ul></ul><ul><li>Chronic inflammation causes fibrosis and traps of air (emphysema) </li></ul>
  26. 26. How do you define Asthma? <ul><li>Working definition of asthma (1995, NHLBI) </li></ul><ul><ul><li>Asthma is a chronic inflammatory disorder of the airways in which many cells & cellular elements play a role (mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, & epithelial cells). </li></ul></ul><ul><ul><ul><li>In susceptible individuals , inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night / early morning . </li></ul></ul></ul><ul><ul><ul><li>These episodes are associated with variable airflow obstruction often reversible spontaneously/treatment </li></ul></ul></ul>
  27. 27. Severity classifications of asthma <ul><li>Mild intermittent </li></ul><ul><li>Mild persistent </li></ul><ul><li>Moderate persistent </li></ul><ul><li>Severe persistent </li></ul>
  28. 28. What is emphysema? <ul><li>Emphysema causes irreversible lung damage by weakening and breaking the air sacs within the lungs. As a result, elasticity of the lung tissue is lost, causing airways to collapse and obstruction of airflow to occur. </li></ul>
  29. 29. What is emphysema?
  30. 30. What is chronic bronchitis? <ul><li>Chronic Bronchitis is an inflammatory disease that begins in the smaller airways within the lungs and gradually advances to larger airways. It increases mucus in the airways and increases bacterial infections in the bronchial tubes, which, in turn, impedes airflow. </li></ul>
  31. 31. Principles of management of COPD
  32. 32. What is the therapeutic approach? <ul><li>Break inflammatory cycle& relieve bronchoconstriction </li></ul><ul><li>1 st step: </li></ul><ul><ul><li>To give oxygen by any of the methods: face mask, O 2 cage, nasal cannula, intubation & pump </li></ul></ul><ul><li>2 nd step </li></ul><ul><ul><li>To initiate treatment with bronchodilators </li></ul></ul><ul><ul><li>They increase cAMP, decrease cGMP, decrease Ca </li></ul></ul><ul><li>Anti-inflammatory : </li></ul><ul><ul><li>prevent mediator release from inflammatory cells </li></ul></ul>
  33. 33. Respiratory system Drugs
  34. 34. What are the therapy approaches? <ul><li>Relax bronchial smooth muscle [ bronchospasm ] </li></ul><ul><ul><li>Bronchodilators </li></ul></ul><ul><ul><li>Classifications: </li></ul></ul><ul><ul><ul><li>Sympathomimetics – adrenergic / nonadrenergic </li></ul></ul></ul><ul><ul><ul><li>Methylxanthines </li></ul></ul></ul><ul><ul><ul><li>Anticholinergics </li></ul></ul></ul><ul><li>Inhibit release of mediators </li></ul><ul><ul><li>Glucocorticoids </li></ul></ul><ul><ul><li>Mast cell stabilizers </li></ul></ul><ul><li>Block affects of mediators </li></ul><ul><ul><li>Leukotriene antagonists </li></ul></ul>
  35. 35. Bronchodilators Sympathomimetic Adrenaline Adrenergic Ipratropium bromide Anticholinergics Theophylline Aminophylline Doxophylline Methylxanthines Salmetrol, Salbutamol, Terbutaline Non adrenergic
  36. 36. Sympathomimetics <ul><li>Stimulate beta2 receptors to increase cyclic AMP production </li></ul><ul><ul><li>This relaxes bronchial smooth muscle, reducing airway resistance and improving airflow. </li></ul></ul><ul><ul><li>Classified as either: </li></ul></ul><ul><ul><ul><li>Catecholamines (Epinephrine) </li></ul></ul></ul><ul><ul><ul><ul><li>Affect both alpha and beta receptors, causing significant cardiovascular side effects </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Deactivated by first pass effects of the liver— oral doses are ineffective </li></ul></ul></ul></ul><ul><ul><ul><li>Noncatecholamines </li></ul></ul></ul><ul><ul><ul><ul><li>Beta2 stimulants are longer lasting, effective orally, evoke less side effects and are more resistant to liver degradation. </li></ul></ul></ul></ul>
  37. 37. Methylxanthines <ul><li>Methylxanthines: </li></ul><ul><ul><li>Provides mild-moderate bronchodilation </li></ul></ul><ul><ul><li>Sustained release form used as alternative but not preferred to long-acting beta2 agonists to control nocturnal symptoms </li></ul></ul><ul><li>Prototype: Theophylline </li></ul><ul><ul><li>CNS excitation (cardiac stimulation) </li></ul></ul>
  38. 38. Respiratory investigations… <ul><li>Assessment: </li></ul><ul><ul><li>Baseline: </li></ul></ul><ul><ul><li>Breath sounds, </li></ul></ul><ul><ul><li>laboratory data (sputum culture, blood gases, pulmonary function tests). </li></ul></ul><ul><ul><li>X-ray chest </li></ul></ul><ul><li>Cause for concern </li></ul><ul><ul><li>Ineffective airway clearance </li></ul></ul><ul><ul><li>Impaired gas exchange </li></ul></ul><ul><ul><li>Ineffective breathing pattern </li></ul></ul><ul><li>History </li></ul><ul><ul><li>Which drug and why? What other drugs is patient taking? </li></ul></ul>
  39. 39. Assessment / Monitoring measures <ul><li>Asthma diagnosis criteria </li></ul><ul><ul><li>+ episodic symptoms of airflow obstruction </li></ul></ul><ul><ul><li>Airflow obstruction partially reversible </li></ul></ul><ul><li>Techniques to establish diagnosis </li></ul><ul><ul><li>History </li></ul></ul><ul><ul><li>Physical exam (resp. tract, skin, chest) </li></ul></ul><ul><ul><li>Spirometry to demonstrate reversibility </li></ul></ul><ul><ul><li>Additional studies : </li></ul></ul><ul><ul><ul><li>Evaluate alternative differential diagnosis for precipitating factors </li></ul></ul></ul><ul><ul><ul><li>Assess severity for potential complications </li></ul></ul></ul>
  40. 40. Goals of Asthma Management <ul><li>Prevent symptoms </li></ul><ul><li>Maintain (near) “normal” PF </li></ul><ul><li>Maintain normal activity </li></ul><ul><li>Prevent exacerbations & minimize ER visits / hospitalizations </li></ul><ul><li>Optimal drug therapy, minimal problems </li></ul><ul><li>Patient / family satisfaction </li></ul>
  41. 41. Success of Asthma Management <ul><li>When evaluating the effectiveness of therapy, anticipate the following outcome: </li></ul><ul><ul><li>Wheezing will be absent from all lung fields </li></ul></ul><ul><ul><li>Respiratory rate and depth will increase </li></ul></ul><ul><ul><li>Blood gases will be within normal limits </li></ul></ul><ul><ul><li>Sputum clearance is increased </li></ul></ul>
  42. 42. Recommended monitoring <ul><li>Signs & Symptoms </li></ul><ul><li>Pulmonary Function Tests </li></ul><ul><li>Monitoring with clinician assessment & patient self-assessment for Quality of life and functional status </li></ul><ul><li>Exacerbations </li></ul><ul><li>Drugs </li></ul><ul><li>Spirometry tests </li></ul><ul><ul><li>Initial assessment </li></ul></ul><ul><ul><li>Post therapy after patient’s symptoms and PFT stabilize </li></ul></ul><ul><ul><li>Minimally Q 1-2 yrs </li></ul></ul>
  43. 43. Doxophylline Details
  44. 44. Doxophylline <ul><li>Differs from theophylline due to the presence of a dioxolane group in position 7 </li></ul>Dioxolane Ring CH 3 N O H 3 C N O N N CH 2 O O
  45. 45. Doxophylline <ul><li>Doxophylline produces stable serum concentrations with decreased affinities towards adenosine receptors, </li></ul><ul><li>Hence, plasma monitoring is required only in patients with hepatic insufficiency and intolerance to xanthine drugs. </li></ul>Reference: Cirillo R et al . Arch Int Pharmacodyn Ther 1988;295:221-237 . Interaction with A1 adenosine receptors:
  46. 46. Doxophylline - MOA <ul><li>Bronchodilatation is promoted by cAMP. </li></ul><ul><li>Intracellular levels of cAMP can be increased by: </li></ul><ul><ul><li>Beta-adrenoceptor agonists, which increase the rate of synthesis by adenyl cyclase, or by </li></ul></ul><ul><ul><li>Phosphodiesterase [PDE] inhibitors suchs as theophylline and doxophylline, which slow the rate of degradation . </li></ul></ul><ul><li>Bronchoconstriction can also be inhibited by muscuranic antagonists </li></ul>
  47. 47. Doxophylline and sleep <ul><li>Theophylline is known to alter sleep architecture because of its affinity to adenosine receptors. </li></ul><ul><ul><li>One of the consequences of disrupted sleep is impaired cognitive performance. </li></ul></ul><ul><li>In contrast to theophylline, doxophylline with decreased affinities towards adenosine A1 and A2 receptors, shows no disturbance in sleep rhythm and exhibits better safety profile. </li></ul>
  48. 48. Doxophylline studies <ul><li>Bronchodilating efficacy of doxophylline has been seen in various clinical studies involving patients with bronchial asthma and COPD. </li></ul><ul><ul><li>Dosage recommended for children >6 yrs of age is 6 mg/Kg/dose BID. </li></ul></ul>
  49. 49. Clinical studies <ul><li>Comparison between doxophylline and placebo as regards the effects on FEV1 in patients with exacerbation of COPD: </li></ul>Dolcetti A at al. J Int Med Res 1988;16:264-269 .
  50. 50. Comparative clinical studies in ADRs <ul><li>Percent of patients with one or more adverse reactions (ADR) during treatment with doxophylline and theophylline. </li></ul>Reference: Eandi M: Farmacoeconomia e Percorsi Terapeutici 2002;3:2. 3 ADR Doxophylline Theophylline 1 ADR 2 ADR
  51. 51. Comparative clinical studies in Asthma <ul><li>Reduction in the dyspnoea score in asthmatic patients treated with oral methylxanthines: </li></ul>Reference: Marino O et al. Uomo Med 1988;4:33-37.
  52. 52. Comparative clinical studies in COPD <ul><li>Effects on spirometric variables in COPD patients: </li></ul>Reference: Marino O et al. Uomo Med 1988; 4: 33-37 .
  53. 53. Comparative clinical studies in heart rate <ul><li>Comparative effects on heart rate in COPD pts treated with bronchodilators; </li></ul><ul><li>Theophylline significantly increased heart rate. </li></ul>Reference: Giorgi M et al. (Abstr) Eur Respir J 1993;6 (Suppl 17):417.
  54. 54. Doxophylline and heart <ul><li>Doxophylline does not cause stimulating effects at CNS or heart level, and it does not increase gastric secretion. </li></ul><ul><li>Doxophylline effect on cardiac rhythm has been investigated in a number of studies. </li></ul><ul><ul><li>In a series of 10 patients with COPD, no significant changes were noted in heart rate, compared with baseline values, during doxophylline use as assessed by 24-hour Holter monitoring. </li></ul></ul>
  55. 55. Doxophylline and ventilation <ul><li>Doxophylline is a rapid and efficient bronchodilator in mechanically ventilated patients with Acute Respiratory Failure and airflow obstruction. </li></ul><ul><li>With doxophylline, there is </li></ul><ul><ul><li>a decrease in the respiratory resistance </li></ul></ul><ul><ul><li>A decrease in PEEPi, </li></ul></ul><ul><ul><li>An improved mechanical efficiency of the respiratory muscles at a lower pulmonary volume, </li></ul></ul><ul><li>Thus, it provides better conditions for the patient- ventilator interaction and for weaning. </li></ul>
  56. 56. Doxophylline and chronic bronchitis <ul><li>Oral doxophylline in the treatment of patients with hypersecretive chronic bronchitis: </li></ul>Reference: Cogo R et al. Farmaci 1990; 14: 295-299 .
  57. 57. Doxophylline and histopathologic abnormalities <ul><li>Improvements in histopathologic abnormalities associated with the treatment with doxophylline </li></ul>Cogo R, Castronuovo A: Eur Rev Med Pharmacol Sci 2000;4:15-20. Basal 3 Months After Therapy Basal
  58. 58. Summary <ul><li>Lesser ADRs </li></ul>Safer No activity on adenosine receptors No side effects on heart No CNS / sleep disturbances Better functional improvement Better histological improvement Better tolerated