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Antiasthmatics - drdhriti

A power point presentation on drugs used in Bronchial asthma suitable for UG MBBS level students

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Antiasthmatics - drdhriti

  1. 1. DRUGS FOR BRONCHIAL ASTHMA Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Definition of Bronchial Asthma • Bronchial asthma is chronic respiratory condition characterized by – Hyper-responsiveness of tracheobronchial smooth muscles to a variety of stimuli ….
  3. 3. Results in … Narrowing of Air tubes …
  4. 4. … accompanied with ? 1. Increased secretion 2. Mucosal oedema 3. Mucus plugging All are Primarily due to Inflammation!
  5. 5. … resulting clinically as • Triad of asthma – Dyspnoea (shortness of breath) – Wheezing (additional sound) – Cough (persistent) – Additionally: limitation of activity • Clinical definition: Bronchial asthma (also called reversible airway obstruction) is a clinical syndrome characterized by recurrent bouts Bronchospasm. There is increased responsiveness of the tracheobronchial smooth muscles to various stimuli resulting in widespread narrowing of the airway • May be life threatening !!! - status asthmaticus • Basis: Allergic basis and non-allergic basis (triggering factors)
  6. 6. Classification - Etiological 1. Extrinsic or allergic: – History of `atopy` in childhood – Family history of allergies – Positive skin test – Raised IgE level – Below 30 years of age – Less prone to status asthmaticus 1. Intrinsic or Idiosyncratic: – No family history of allergy – Negative skin test – No rise in IgE level – Middle age onset – Prone to status asthmaticus Pollens Dust mite Mold Pet danders
  7. 7. … contd. What are the stimuli? (Triggers) • Tobacco smoke • Infections such as colds, flu, or pneumonia • Allergens such as food, pollen, mold, dust mites, and pet dander • Exercise • Air pollution and toxins • Weather, especially extreme changes in temperature • Drugs (such as aspirin, NSAID, and beta-blockers) • Food additives • Emotional stress and anxiety • Singing, laughing, or crying • Smoking, perfumes, or sprays • Acid reflux
  8. 8. Airway Inflammation in asthma • Airway inflammation presumably is triggered by innate and/or adaptive immune responses • Immediate release of mediators from granules: • Histamine, protease enzymes and TNF-alpha • Release of Mediators from cell membrane • PG, LT and PAF etc. • Gene activation (delayed): • Interleukins and TNF-alpha
  9. 9. The inflammatory response • Although there are subtypes of asthma (allergic vs. nonallergic), certain features of airway inflammation are common to all asthmatic airways • Although Multiple Trigger for inflammation (mast cell secretion) - there is consensus that a lymphocyte directed eosinophilic bronchitis is a hallmark of asthma • The lymphocytes that participate in asthma are of the T-helper type 2 (Th2) phenotype, leading to increases in production of interleukin 4 (IL- 4, IL-5, and IL-13). – IL- 4 promotes IgE synthesis in B cells, while IL-5 supports eosinophil survival • The innate or adapted immune response triggers the production of additional cytokines and chemokines, resulting in trafficking of blood-borne cells (i.e., eosinophils, basophils, neutrophils, and lymphocytes) into airway tissues; these cells further generate a variety of autacoids and cytokines
  10. 10. Bronchial Asthma – Airway Remodeling Textbook of Goodman Gillman
  11. 11. What is COPD? • COPD is characterized by airflow limitation caused by chronic bronchitis or emphysema often associated with long term tobacco smoking • This is usually a slowly progressive and largely irreversible process • Consists of increased resistance to airflow, loss of elastic recoil, decreased expiratory flow rate, and over inflation of the lung • COPD is clinically defined by a low FEV1 value that fails to respond acutely to bronchodilators, a characteristic that differentiates it from asthma - <15% in 1 sec FEV1
  12. 12. Pathology of Small Airways i.e. less then 2 mm in diameter Control Severe COPD
  13. 13. Treatment Strategy • Neutralize IgE • Prevent release of mediators • Antagonize mediators
  14. 14. Antiasthmatics - Classification 1. Bronchodilators: – ß2 sympathomimetics (agonists): salbutamol, salmeterol, fometerol, rimeterol, bitolterol and terbutaline (non specific – ephidrine, adrenaline and orciprenaline) – Methylxanthines: theophylline and derivatives aminophylline etc. – Anticholinergics: ipratropium bromide and tiotropium bromide 2. Mast cell stabilizers: sodium chromoglycate and ketotifen 3. Leukotriene antagonists: montelucast and zafirlucast 4. Corticosteroids: – Systemic: hydrocortisone and prednisolone – Inhalation: beclmethasone dipropionate, budesonide, fluticasone propionate, flunisolide etc. 2. Anti-IgE antibody: omalizumab
  15. 15. β-2 agonists – Recall • All adrenergic drugs act via alpha/beta receptors – Mainly, alpha -1 & 2 and Beta -1 & 2 (α1, α2 , ß1 and ß2) • Type β1: – These are present in heart tissue, JG cells - cause an increased heart rate by acting on the cardiac pacemaker cells • Type β2: – These are in the Bronchial smooth muscles and vessels of skeletal muscle and cause relaxation of smooth muscles and cause vasodilation • All β receptors activate adenylate cyclase, raising the intracellular cAMP concentration
  16. 16. Results of β-2 activation AND Tocolytic
  17. 17. ß2-sympathomimetics (agonists) - salbutamol and terbutaline etc. 1. Adrenergic drugs are mainstay in the treatment of Bronchial asthma • Bronchodilatation via beta-2 stimulation – increased cAMP production • Increased cAMP in mast cells – decreased mediator release 1. Adrenaline and Isoprenaline – not used frequently – WHY ? - (beta -1 receptor) 2. ß2-sympathomimetics are fastest acting bronchodilators when inhaled (5 minutes) – lasts 2 to 4 Hrs – hypertensives, digitalis & IHD
  18. 18. Clinical benefits of Beta-2 stimulation • Bronchodilatation without tachycardia (beta-1) • Inhibition of release of chemical mediators by stabilization of mast cell membrane (beta receptors) • Prevention of mucosal edema (vessels) • Increased ventilatory response to chemoreceptor stimuli (better exchange) • Restoration of mucocilliary transport mechanism in respiratory tract (result of reduction in secretion)
  19. 19. ß2-sympathomimetics - MOA MOA:  Stimulation of β2 receptor in bronchial smooth muscle cell membrane activation of adenyl cyclase →cAMP →Ca2+↓ →SM relaxation Drawbacks: • To abort or terminate attacks only • Not suitable for round-the clock prophylaxis – does not reduce bronchial hyperactivity - worsens • Down regulation of beta-2 receptors
  20. 20. Results of β2 stimulation
  21. 21. Salbutamol • Pharmacokinetics: – Undergoes metabolism in gut wall – Bioavailability is 50% – Duration of action: 4-6 Hrs • Salbutamol: preparation and doses – Available as 2, 4 and 8 mg tablets – reserved for patients who cannot correctly use inhalers – Syr. as 2 mg/5 ml – As metered dose inhaler – 100 μg – Preferred route – 200 μg as rotacaps • Adverse effects: – Muscle tremor, restlessness, palpitation and nervousness – Vasodilatation – reduction in mean arterial pressure with tachycardia and also exacerbate pulmonary hypoxia due to mismatched of ventilation and perfusion – Hyperglycaemia and hyperlacticacidemia – Worsening of asthma on prolong inhalation
  22. 22. Salmeterol • Long acting Beta-2 agonist (more lipophilic) • Available as inhaler: MDI and rotacaps (25 μg) • Weaker than salbutamol but more beta-2 selective • Duration of action is 3 Hrs to 12 hrs • Not useful for acute attacks, only for prophylaxis – maintenance therapy – twice daily • Usually combined with steroids • Bambuterol: Prodrug of terbutalin – hydrolysed in plasma by pseudocholinesterase to release active product – long acting – used in chronic bronchial asthma • Formeterol: Long acting and lasts for 12 Hrs
  23. 23. Metylxanthines • 3 Naturally occurring methylxanthines – caffeine, theophylline and theobromine • Theophylline and its derivatives are used in asthma – 3rd line --- in COPD • Chemically, they are purine structure and close to adenine and uric acid • Sources: – Thea sinensis: Caffeine (50 mg) & Theophylline (1 mg) – Coffea arabica: Caffeine (75 mg) – Theobroma cacao: Theobromine (200 mg) and caffeine (4mg) – Cola acuminata: caffeine (30 mg)
  24. 24. Metylxanthines - structures
  25. 25. Metylxanthines – Pharmacological actions • CNS: – Stimulation: improves performance, sense of well being and allays fatigue – thinking become clearer (caffeine:150-200 mg) – Higher doses – nervousness, insomnia and restlessness – High doses – tremor, convulsion • CVS: – Stimulation of heart – increase in heart rate, cardiac output • Vagal stimulation – TOTAL VARIABLE EFFECTS – Tachycardia – Theophylline, Caffeine – bradycardia – Cardiac output and Cardiac workload - increase – Higher doses – cardiac arrhythmia (above 9 cups); moderate drinking - beneficial – Dilatation of blood vessels including coronary – reduced peripheral resistance – But, constriction of cerebral vessels – migraine use
  26. 26. … contd. • BP: – Direct cardiac action – increased BP – Vagal action & vasodilatation – decreased BP – Overall: Rise in SBP and decrease in DBP • Kidney: mild diuretic (decrease in tubular reabsorption of Na+ and also increase in renal blood flow) • Stomach: increase in acid-pepsin secretion – even parenteral dose – gastric irritant • Smooth muscles: relaxed (theo – more potent) – all SM; bronchodilatation in asthmatics – Slow and sustained bronchodilatation – Biliary spasm relieved but no effect on intestine and urinary tract • Metabolic: Increase in BMR – plasma fatty acid level raised - release of endogenous catecholamines
  27. 27. Theophylline action - contd. • Skeletal muscles: – Caffeine increases contractile power – High doses – direct release of Ca++ from sercoplasmic reticulum – Facilitates NM transmission by increasing Ach release – Decreased fatigue by CNS action – relieves fatigue and increased muscular work – Enhanced diaphragmatic contraction
  28. 28. Metylxanthines - MOA • Blockade of adenosine receptors – no contraction of smooth muscles • Inhibition of Phosphodiesterase enzyme: ATP/GTP cAMP/cGMP 5-AMP/5-GMP (inhibit activity of PDE cAMP Ca2+ bronchial relaxation) • Higher doses - Release of Ca++ from sarcoplasmic reticulum PDE
  29. 29. Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by - adrenoceptor agonists, which increase the rate of its synthesis by adenylyl cyclase (AC); or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the rate of its degradation. Bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists.
  30. 30. Metylxanthines – contd. • Kinetics: – Absorbed orally, crosses placenta and secreted in milk – Protein bound, metabolized in liver - demethylation and oxidation – T1/2 is 6-12 Hrs, but faster in children: 3-5 Hrs, and slow in elderly & prematures; highly plasma protein bound – Saturation of metabolizing enzymes – On prolonged and high dose – elimination is zero order from first order • ADRs: – Low therapeutic index: Therapeutic range - 0.2 to 2 mg/100 ml, higher than 4 mg/100ml may cause arrhythmia, convulsion and coma • Insomnia, headache and nervousness Restlessness, palpitation vomiting etc. Tachycardia, flushing, hypotension Delirium, worsening of CVS status convulsion and shock death – Nausea and vomiting – common
  31. 31. Methylxanthines - Preparation and Dosage • Interindividual variation in plasma concentration • Rapid IV injection: Precordial pain, syncope and sudden death • Theophylline: (Unicontin/Theolong) – Poorly water soluble and cannot be injected – Available as tablets 100/200 mg SR • Aminophylline: 85% Theophylline – Water soluble and can be injected IV – Available as 100 mg tablets and 250 mg/ml injection • Hydroxyethyl theophylline: (Derriphylline) – Available as 100/300 mg tablets or 220 mg/2ml injection
  32. 32. Signal transduction pathway for Bronchodilatation
  33. 33. Anticholinergics – Ipratropium bromide and tiatropium bromide • Distinct muscarinic receptors exist within the airways are M1and M3 receptors • M1 – present in peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves • M3 are present on smooth muscle larger airways • Muscarinic receptor activation of these M3 receptors intracellular cAMP levels contraction of airway smooth muscle bronchoconstriction • Postganglionic fibers supply the smooth muscle and submucosal glands of the airways as well as the vascular structures • Motor nerves derived from the vagus form ganglia predominate in the large and medium-sized airways • Atropinic drugs block these cholinergic innervations and brings about bronchodilatation
  34. 34. Anticholinergics – contd. • Less efficacious than sympathomimetics • COPD, asthmatic bronchitis, psychogenic asthma – respond better • Drug of choice in COPD • Slower response – for prophylaxis (2-4 puffs 6 hrly) • IB + sympathomimetics = marked longer lasting bronchodilatation • Nebulized IB and Salbutamol – refractory asthma
  35. 35. Action of Bronchodilators Selective β2 agonist ATP cAMP Theophyline 5’-AMP Relaxation Ach Ipratopium Vagus nerve
  36. 36. Cromolyn sodium/Sodium cromoglycate • Synthetic compound and chemically benzopyrone • Stabilizes mast cells – inhibits degranulation of mast cells and other inflammatory cells • Mediator release is restricted • Also prevent chemotaxis of eosinophils and neutrophils – local inflammation is prevented • Basis of action may be due to delayed Cl- channel in the membranes • Long term use prevents hyperactivity of bronchial tree • No bronchodilatation or antagonism of constriction – no action on acute cases • Not absorbed orally, given via MDI – 1 mg/dose – 2 puffs 4 times daily • Uses: Prophylaxis of asthma, allergic rhinitis and allergic conjunctivitis (2%)
  37. 37. Leukotriene Antagonists Montelucast and zafirlucast: • Cysteinyl leukotrienes LT-C4, LT-D4 and LTE4 are important mediators of human asthma - Competitive antagonist of cysLT1 • Benefits – bronchodilatation, reduced eosinophil count, decreased vascular permeability and suppression of inflammation and hyperactivity • Used in mild to moderate asthma as alternative to inhaled glucocoticoides • Useful in children – reduces dose of steroids and beta agonists • Absorbed orally and highly plasma protein bound • Half life: montelucast (3-6 hrs), zafirlucast (8-12 Hrs) • Uses: Mild to moderate asthma as alternative to steroids – need of steroid is reduced and rescue with beta-2 reduced – Not suitable for termination of attack – useful in NSAID induced asthma • Safe drug, effective orally – only headache and rashes
  38. 38. Zileuton and Ketotifen • Zileuton: 5- LOX inhibitor, blocks LT-C4, LT-D4 and LTB4 synthesis – prevents all LT induced responses – Efficacy is similar to montelucast – Short duration of action and hepatotoxic • Ketotifen: H1 antihistaminic having Chromone like actions – Inhibits mediator release (mast cells, macrophages, eosinophils, lymphocytes and eosinophils) – Not bronchodilator – only sedation – 6-12 weeks therapy benefits 50% of patiens – Low improvement of lung function – Also used in atopic dermatitis, perennial rhinitis, conjunctivitis, urticaria and food allergy etc. – orally effective
  39. 39. Corticosteroids • 2 types - Glucocorticoids and Mineralocorticoids • Glucocorticoids – – In general: Suppress inflammatory responses to all noxious stimuli: Pathogens, chemical, physical and immune mediated stimuli, hypersensitivity – Antiinflammatory action – reduction in mediators IL, TNF and PAF etc. and reduction in exudate formation • Bronchial asthma is an inflammatory disease – Not Bronchodilator but - Reduce bronchial hyperactivity, mucosal oedema and suppress AG:AB reaction or other trigger stimuli – Reduction in cardinal signs of inflammation – Complete and sustained symptomatic relief than bronchodilators and chromones – improves airflow, reduce exacerbations and may retard airway remodeling and disease progression • Steroids act best in asthma than any other group of drugs - inhaled • But ??? remember – Adverse Effects of Prolonged therapy
  40. 40. Systemic corticosteroid therapy • Steroids are used as – inhaled, systemic (oral/parenteral) • Systemic steroid is useful in: – Acute asthma (status asthmaticus) – not relieved or worsening of obstruction in spite of bronchodilatator and inhaled steroid – hydrocortisone and prednisolone – Chronic asthma – failure of previously optimal regimen – frequent symptoms of progressive severity
  41. 41. Corticosteroids – contd. • Inhalation steroids – beclomethasone dipropionate, budesonide, fluticasone propionate and triamcinolone acetonide • Inhalation: high topical and low systemic activity – Due to poor absorption and marked 1st pass metabolism – Can be step one for all asthma cases – inflammation starts even in early cases – However, not used for mild and episodic asthma – Indicated when beta-2 agonists are required daily or disease not only episodic – Low dose starting 100 to 200 mcg BD – 3-5 days with max 400 qid – Suppress inflammation and prevents episodes of asthma – beta-2 agonist requirement lessens – No Role in acute attack – Peak effects starts after 4-7 days • To whom inhalation steroids can be given ? – Fresh patients as well as to those who had already required oral steroids – To be switched over from oral steroids – 1-2 weeks before tapering (precipitation of asthma, muscular pain, depression, hypotension)
  42. 42. Corticosteroids – contd. • COPD: high doses are required • Hoarseness of voice, soar throat, dysphonia and Oropharyngeal candidiasis • Minimized by use of spacer and gurgling • Side effects: Hoarseness of voice, dysphonia, sore throat, oropharyngeal candidiasis – Minimized by using spacers, gargling after the use – Topical Nystatin and clotrimazole • Systemic effects: Mood changes, osteoporosis, growth retardation, bruisig, petechiae, pituitary- adrenal- suppression etc.
  43. 43. Anti-IgE antibody - omalizumab • Humanized monoclonal antibody • Administered IV or SC • Neutralizes free IgE in circulation • Expensive • Reserved for resistant cases
  44. 44. Treatment - asthma • Seasonal: Chromones or low dose steroids (200-400 mcg/day) – plus beta-2 agonists if required • Step I: When symptoms are less than once daily - occasional inhalation of a short acting Beta-2 agonist – salbutmol, terbutaline. If used more than once daily – step II (Mild episodic asthma) • Step II: (Symptoms once daily or so) Regular inhalation of low-dose steroids. Alternatively, cromoglycates. Beta-2 agonist as and whenever required (Mild chronic asthma) • Step III: (Attack more than once a day) Inhalation of high dose of steroids (800 mcg) + Beta-2 agonist. Sustained release theophylline may be added. LT inhibitors may be tried instead of steroids (Moderate asthma with frequent exacerbations) - spacers • Step IV: Higher dose of steroid (800 to 2000 mcg) + regular beta-2 agonist twice daily (long acting salmeterol) Additional treatment with oral drugs – LT antagonist or SR theophylline or oral beat-2 agonist (Severe asthma) • Step V: Not controlled adequately – needing emergency care frequently – Oral Steroid therapy
  45. 45. Status asthmaticus • May be called acute severe asthma • Hydrocortisone hemisuccinate 100 mg stat IV and followed by 100-200 mg 4-8 hrly. Infusion • Nebulize Salbutamol (2.5 to 5 mg) + Ipratropium bromide (0.5 mg) intermittent inhalations with oxygen and nebulization • Humidified Oxygen inhalation • Salbutamol or terbutaline IM or SC (0.4 mg) • Intubation and Mechanical ventilation, if required • Antibiotics • IV saline – for dehydration and acidosis and sodibicarb if required
  46. 46. Aerosols • Solid and liquid dispersed particles of 1 to 5 micron in size suspended in gas • Do not coalesce and do not sink • Aim – to deliver to the alveoli without settling in bigger tubes – Particles > 10 micron are deposited primarily in the mouth & oropharynx. – Particles < 0.5 micron are inhaled to the alveoli and exhaled without being deposited in the lungs. • Aerosols are produced – In solution: MDI, nebulizers – Dry powder: Rotahaler and spinhaler etc.
  47. 47. Devices - Definition • A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a short burst of aerosolized medicine that is inhaled by the patient. ... • A Spinhaler/Rotahaler is a device used to deliver fine dry powered medications that are measured out in Rotacap capsules • An asthma Spacer is an add-on device used to increase the ease of administering aerosolized medication from a "metered-dose inhaler" (MDI)
  48. 48. Questions ??? • SAQs: – Bronchodilators – Pharmacotherapy (management) of status asthmaticus – Mechanism of action and Adverse effects of – Theophylline – Role of Salbutamol/Salmeterol in broncial asthma • Short Questions on: – Salbutamol, Salmeterol, Sodium chromoglycate, leukotriene antagonists and Ipratropium bromide
  49. 49. Thank You

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