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

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.
  • Conceptual model for the immunopathogenesis of asthma. Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. On reexposure to allergen, antigenantibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene C4, and platelet-activating factor (PAF). These agents provoke contraction of airway smooth muscle, causing the immediate fall in FEV1. Reexposure to allergen also causes the synthesis and release of a variety of cytokines: interleukins 4 and 5, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. These cytokines in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor. These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the late asthmatic response, indicated by a fall in FEV1 2–8 hours after the exposure.
  • 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 Antiasthmatics - drdhriti Presentation Transcript

  • PHARMACOTHERAPY OF BRONCHIAL ASTHMA Department of Pharmacology NEIGRIHMS, Shillong
  • Definition of Bronchial Asthma
    • Bronchial asthma is chronic respiratory condition characterized by
      • Hyper-responsiveness of tracheobronchial smooth muscles to a variety of stimuli ….
  • … 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
  • Results in … Narrowing of Air tubes …
  • … accompanied with ?
    • Increased secretion
    • Mucosal oedema
    • Mucus plugging
    All are Primarily due to Inflammation!
  • … resulting in (clinically)
    • 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
  • Learning Objectives
    • To appreciate basic pathogenesis and therapeutic strategies for the management of asthma
    • To learn about the various drugs including their mechanism of action of the three major classes of bronchodilators
    • To learn about the management of acute asthmatic conditions
    • To learn about the various drugs used for prophylaxis
    • To appreciate prospects for new therapies for asthma
  • Classification - Etiological
    • 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
    • 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
  • 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
  • Cascade of Events From Textbook of Katzung
  • 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
  • Bronchial Asthma – Airway Remodeling Textbook of Goodman Gillman
  • 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.
  • Pathology of Small Airways i.e. less then 2 mm in diameter Control Severe COPD
  • CASE SCENARIO
    • Pankaj, a 14 years old boy came to your clinic c/o shortness of breath for one day duration
    • He is a known asthmatic patient for more than 8 years, he visited you frequently
    • His school performance is below average, with frequent absence from school due to his illness
    • HOW YOU WILL PROCEED DURING THIS CONSULTATION ?
  • Treatment Strategy
    • Neutralize IgE
    • Prevent release of mediators
    • Antaginize mediators
  • Antiasthmatics - Classification
    • Bronchodilators:
      • ß 2 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
    • Mast cell stabilizers: sodium chromoglycate and ketotifen
    • Leukotriene antagonists: montelucast and zafirlucast
    • Corticosteroids:
      • Systemic: hydrocortisone and prednisolone
      • Inhalation: beclmethasone dipropionate , budesonide, fluticasone propionate etc.
    • Anti-IgE antibody: omalizumab
  • What is a beta-2 agonist ?
    • 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, and 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
  • Results of beta- 2 activation AND Tocolytic
  • ß 2 -sympathomimetics (agonists)
      • salbutamol and salmeterol etc.
    • Adrenergic drugs are mainstay in the treatment of Bronchial asthma
    • Adrenaline and Isoprenaline – not used frequently – WHY ?
      • (beta -1 receptor)
    • ß2-sympathomimetics are fastest acting bronchodilators when inhaled (5 minutes) – lasts 2 to 4 Hrs
  • ß 2 -sympathomimetics - MOA
    • MOA:
    • Stimulation of β2 receptor in bronchial smooth muscle cell membrane activation of adenyl cyclase ->cAMP ->Ca2+↓ ->SM relaxation
    • Also activate β-receptor on mast cell membrane – decrease in mediator release
    • However, Βeta-receptors on mast cells are prone to desensitization – uncertain beneficial effect
  • Clinical benefits of Beta-2 stimulation
    • Bronchodilatation without tachycardia (beat-1)
    • Inhibition of release of chemical mediators by stabilization of mast cell membrane (beta receptors)
    • Prevention of mucosal edema (vessels)
    • Decreased microvascular permeability (vessels)
    • Increase ventilatory response to chemoreceptor stimuli (better exchange)
    • Restoration of mucocilliary transport mechanism in respiratory tract (result of reduction in secretion)
  • Results of β2 stimulation
  • 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
      • Syr. As 2mg/5 ml
      • As metered dose inhaler – 100 μ g
      • 200 μ g 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
  • Salmeterol
    • Long acting Beta-2 agonist (more lipophilic)
    • Available as inhaler: MDI and rotacaps (25 μ g)
    • 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
    • Usually combined with steroids
    • Formeterol: Long acting and lasts for 12 Hrs
  • Metylxanthines
    • 3 Naturally occurring methylxanthines – caffeine, theophylline and theobromine
    • Theophylline and its derivatives are used in asthma
    • Chemically, they are purine structured and close to adenine and uric acid
    • Many salts of theophylline have been marketed but the most common one is aminophylline is highly water soluble and a stable mixture of theophylline and ethylene diamine
    • Uses: Bronchial asthma and COPD and also in infantile apnoea
  • 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.
  • Metylxanthines - structures
  • Metylxanthines – Pharmacological actions
    • CNS:
      • Stimulation: improves performance, sense of well being and allays fatigue – thinking become clearer (150-200 mg)
      • Higher doses – nervousness, insomnia and restlessness
      • High doses – tremor, convulsion
    • CVS:
      • Stimulation of heart – increase in heart rate, cardiac output
      • Dilatation of blood vessels including coronary – reduced peripheral resistance
      • But, constriction of cerebral vessels – migraine use
      • Transient in normal individual but in cardiac insufficiency may remain long
      • Higher doses – cardiac arrhythmia
  • … contd.
    • Kidney: mild diuretic (decrease in tubular reabsorption of Na and also increase in renal blood flow)
    • Stomach: increase in acid-pepsin secretion
    • Smooth muscles: relaxed – bronchodilatation, but no effect on intestine and urinary tract
    • Metabolic: Increase in BMR – plasma fatty acid level raised
  • 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
  • Metylxanthines – contd.
    • Kinetics:
      • Absorbed orally, crosses placenta and secreted in milk
      • Metabolized in liver by demethylation and oxidation
      • T1/2 is 6-12 Hrs, but faster in children and slow in elderly (prematures – slow)
      • 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
  • Methylxanthines - Preparation and Dosage
    • Theophylline: (Unicontin/Theolong)
      • Poorly water soluble and cannot be injected
      • Available as tablets 100/200 mg SR
    • Aminophylline:
      • 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
  • Signal transduction pathway for Bronchodilatation
  • Anticholinergics
    • Atropine, Ipratropium bromide and tiatropium
    • Airways are innervated by a supply of efferent, cholinergic, parasympathetic autonomic nerves
    • Motor nerves derived from the vagus form ganglia predominate in the large and medium-sized airways
    • Postganglionic fibers supply the smooth muscle and submucosal glands of the airways as well as the vascular structures
    • Release of acetylcholine (ACh) at these sites results in stimulation of muscarinic receptors and subsequent airway smooth muscle contraction and release of secretions from the submucosal airway glands
    • ( Nicotinic receptors are present in NM junction, autonomic gnglia and adrenal medulla)
    Amanita muscaria
  • Anticholinergics – contd.
    • Distinct muscarinic receptors exist within the airways are M1, M2 and M3 receptors
    • M1 – present in peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves
    • M2 receptors are present on the postganglionic nerves - they are activated by the release of acetylcholine and promote its reuptake into the nerve terminal
    • M3 are present on smooth muscle larger airways
    • Muscarinic receptor activation of these M3 receptors
    • intracellular cAMP levels contraction of airway smooth muscle bronchoconstriction
  • Action of Bronchodilators Selective  2 agonist ATP cAMP Theophyline 5’-AMP Relaxation Ach Ipratopium Vagus nerve
  • Cromolyn sodium/Sodium cromoglycate
    • Synthetic compound and chemically benzopyrone
    • Stabilizes mast cells – inhibits degrannulation 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%)
  • Leukotriene Antagonists
    • Montelucast and zafirlucast:
    • Antagonist of cysLT1 - cysteinyl leukotrienes LT4, LTD4 and LTE4 are important mediators of human asthma
    • Benefits – bronchodilatation, reduced eosinophil count 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)
  • Corticosteroids
    • 2 types - Glucocorticoids and Mineralocorticoids
    • Glucocorticoids –
      • Suppress inflammatory response to all noxious stimuli: Pathogens, chemical, physical and immune mediated stimuli, hypersensitivity
      • Underlying cause of disease is not corrected
      • Reduction in cardinal signs of inflammation
    • MOA: Antiinflammatory action – reduction in mediators IL, TNF and PAF etc. and reduction in exudate formation
    • Bronchial asthma is an inflammatory disease
    • Steroids act best in asthma than any other group of drugs
    • But ??? remember – Adverse Effects of Prolonged therapy
  • Corticosteroids – contd.
    • Inhalation:
      • Not bronchodilator but reduces airway inflammation – anti inflammatory action
      • Topical action in lungs but low systemic absorption
      • Not used in mild episodic asthma
      • Used when regular beta-2 agonists are required
      • 100 – 200 mcg BD is starting dose and increased upto 400 mcg qid
      • Reduces the required dose of beta-2 agonists and prevents episodes of asthma
      • No role in acute attack
      • Given in patients who had taken oral steroids earlier
    • Inhalation steroids are used – beclomethasone dipropionate, budesonide, fluticasone propionate and triamcinolone acetonide
    • Adverse effects of long term steroids: M ood changes, osteoporosis, growth retardation, hyperglycaemia and adrenal crisis etc.
    • Doses:
      • Beclomethasone: available as 50, 100 and 1200 mcg/ml MDI – dose is 400 mcg/day
      • Budesonide: available as 100, 200, 400 mcg/ml MDI – dose is 200 mcg BD
  • Corticosteroids – contd.
    • 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
    • COPD: high doses are required
        • Hoarseness of voice, soar throat, dysphonia and Oropharyngeal candidiasis
        • Minimized by use of spacer and gurgling
  • Anti-IgE antibody - omalizumab
    • Humanized monoclonal antibody
    • Administered IV or SC
    • Neutralizes free IgE in circulation
    • Expensive
    • Reserved for resistant cases
  • Treatment - asthma
    • 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: Regular inhalation of low-dose steroids. Alternatively, cromoglycates. Beta-2 agonist as and whenever required (Mild chronic asthma)
    • Step III: 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 200 mcg) + regular beta-2 agonist (long acting salmeterol)
    • Additional treatment with oral drugs – LT antagonist or SR theophylline or oral beat-2 agonist
  • 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
  • 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.
  •  
  • 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 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 &quot;metered-dose inhaler&quot; (MDI)
  • Questions ???
    • SAQs:
      • Pharmacotherapy (management) of status asthmaticus
      • Steps of Management of Asthma
      • Mechanism of action and Adverse effects of – Theophylline
      • Management of Bronchial Asthma with COPD
      • Role of corticosteroids in asthma and COPD
    • Short Questions on:
      • Salbutamol, Salmeterol, Sodium chromoglycate, leukotriene antagonists and Ipratropium bromide
  • Thank You