Antiasthmatics - drdhriti


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

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  • Eicosapentaenoic acid (EPA) is an omega-3 fatty acids; a fish oil.
  • Wheeze - A wheeze is a continuous, coarse, whistling sound produced in the respiratory airways during breathing. Dyspnoea – shortness of breath
    Wheeze - A wheeze is a continuous, coarse, whistling sound produced in the respiratory airways during breathing. Dyspnoea – shortness of breath
  • Atopy involves the capacity to produce IgE in response to common environmental proteins such as house dustmite, grass pollen, and food allergens. From the Greek atopos meaning out of place.
    A hereditary disorder marked by the tendency to develop immediate allergic reactions to substances such as pollen, food, dander, and insect venoms and manifested by hay fever, asthma, or similar allergic conditions. Also called atopic allergy.
    Atopy involves the capacity to produce IgE in response to common environmental proteins such as house dustmite, grass pollen, and food allergens. From the Greek atopos meaning out of place.
  • Found in coffee and tea, theophylline is closely related to caffeine, a molecule in which three methyl groups are bound to the nitrogen atoms of a xanthine ring. When caffeine is metabolized and loses a specific methyl group, theophylline is formed.  
  • 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