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Drugs used in asthma
 

Drugs used in asthma

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    Drugs used in asthma Drugs used in asthma Presentation Transcript

    • Drugs Used In Asthma By M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science
    • Drugs Used In Asthma Introduction Classification Sympathomimetic Agents (beta agonists) Methylxanthines Antimuscarinic Agents Corticosteroids Cromolyn & nedocromil Leukotriene Pathway Inhibitors Anti-IgE Antibodies Treatment strategy Acute Asthma Drug delivery devices Drug Pictures
    • Introduction Asthma is characterized by:  Increased responsiveness of the bronchi  Contraction of airway smooth muscle  Mucosal thickening The most easily  Viscid plugs of mucusreversed pathology
    • The pathophysiology of asthma is complex, with participation of severalinflammatory cells, resulting in inflammatory effects on the airway.
    • Many cells and mediators are involved in asthma andlead to several effects on the airways.
    • Classification Asthma may be treated by different drugs. Drugs that reduce the amount of IgE bound to mast cells Anti-IgE antibody Prevent mast cell degranulation Block the action of the products released Cromolyn, Nedocromil Inhibit acetylcholine released from vagus nerve Antihistamines & Muscarinic antagonists antagonists Leukotriene Relax smooth muscle Sympathomimetics, Methylxanthines
    • Sympathomimetic Agents Along with corticosteroids, are the most widely used drugs for asthma. They relax smooth muscle and inhibit release of bronchoconstricting substances from mast cells. They also inhibit microvascular leakage, increase ciliary activity and increase cAMP. They cause tachycardia and tremor as side effects.
    • Sympathomimetic Agents (Cont’d) Adrenoceptor agonists are best delivered by inhalation for greatest effect and least systemic toxicity. Even in best conditions, 80-90% of the aerosol is deposited in the mouth or pharynx. Effectiveness can be increased by holding the breath in inspiration. Side effects include tremor and nervousness.
    • Sympathomimetic Agents (Cont’d) Short acting β2 selective drugs:  Albuterol (salbutamol)  Terbutaline  Metaproterenol  Pirbuterol Bronchodilation is maximal within 15-30 min. and persists for 3-4 hr. All can be diluted in saline for administration from a nebulizer.
    • Sympathomimetic Agents (Cont’d) Long-acting β2 selective agonists:  Salmeterol  Formoterol Their duration of action is ≥12 hr. They are usually used with other drugs (eg: inhaled corticosteroids)
    • Methylxanthines Methylxanthines:  Theophylline (tea)  Theobromine (cocoa)  Caffeine (coffee) Theophylline is most selective in its smooth muscle effects. Caffeine has the most marked CNS effects.
    • Methylxanthines Theophylline is not an ideal drug, but has a low cost. Aminophylline is an injectable derivative of theophylline. They Inhibit phosphodiesterase (PDE) and increase cAMP. Adenosine causes airway contraction and histamine release. Theophylline derivatives also nay inhibit adenosine receptors.
    • Methylxanthines (Cont’d) Theophylline also improves contractility and reverses fatigue of the diaphragm in patients with COPD. So theophylline can diminish dyspnea even in patients with irreversible airflow obstruction. Rate of metabolism: Children > adults > neonates and young infants Cigarette smoking induces metabolizing enzymes.
    • Methylxanthines (Cont’d) Theophylline has a narrow therapeutic window. Improvement in lung function is seen at 5-20 mg/L. Vomiting, abdominal discomfort, headache, and anxiety occur at 15 mg/L in some, and at >20 mg/L in all patients. Higher levels (> 40 mg/L) causes seizures or arrhythmias. These may NOT be preceded by GI or neurologic warning symptoms.
    • Methylxanthines (Cont’d) Methylxanthines stimulate secretion of both gastric acid and digestive enzymes. Even decaffeinated coffee has a potent stimulant effect on GI secretion. Methylxanthines decrease blood viscosity and may improve blood flow. For this reason pentoxifylline is used in the treatment of intermittent claudication.
    • Methylxanthines (Cont’d) Caffeine causes mild arousal with increased alertness and deferral of fatigue. Very high doses cause convulsions and even death. Caffeine has positive chronotropic and inotropic effects on the heart. In very sensitive individuals, consumption of a few cups of coffee may result in arrhythmias.
    • Caffeine Amount In Drinks Amount (gram) Caffeine (mg)CoffeeBrewed, regular 142–227 40–180Instant 142–227 30–120Espresso 57 120TeaBrewed, leaf or bag 227 80Instant 227 50Iced 340 70Soft DrinksPepsi, Diet Pepsi 340 38
    • Antimuscarinic Agents Involvement of parasympathetic system in respiratory diseases varies among individuals. Antimuscarinic agents are used:  Instead of inhaled β-agonists in asthmatics  In addition to inhaled β-agonists in asthmatics  In COPD patients Ipratropium is a polar drug used for asthma. Tiotropium is used for COPD.
    • M.H.Farjoo
    • Corticosteroids Their most important action is inhibition of airway mucosal inflammation. Inhalational therapy minimizes their adverse effects. Inhalational drugs include:  Beclomethasone  Budesonide  Fluticasone  Triamcinolone
    • Pharmacokinetics of inhaled corticosteroids
    • Corticosteroids (Cont’d) They do not relax airway smooth muscle directly. To prevent adrenal insufficiency they are used in the morning. If nocturnal asthma happens they have to be given in the afternoon.
    • Corticosteroids (Cont’d) Oropharyngeal candidiasis may occur which can be managed by gargling water and spit after each dose. Hoarseness happens by their effect on vocal cords. Chronic use of inhaled corticosteroids reduces bronchial reactivity. Corticosteroids are not curative, asthma returns after stopping them even if they have been taken for > 2 years.
    • Cromolyn & nedocromil They effectively inhibit both antigen and exercise induced asthma. Alter the function of delayed chloride channels in the cell membrane, inhibiting cellular activation. They inhibit cough and mast cell (but not basophil) degranulation in the lung. Are only of value when taken prophylactically.
    • Cromolyn & nedocromil (Cont’d) Young patients with extrinsic asthma are most likely to respond. A 4 weeks trial determines whether a patient will respond. Cromolyn solution is also useful for allergic rhinoconjunctivitis. Because the drugs are so poorly absorbed, adverse effects are minor and are.
    • Leukotriene Pathway Inhibitors LTC4 & LTD4 exert many effects known to occur in asthma There are two treatment strategy:  Inhibition of lipoxygenase and leukotriene synthesis Zileuton  Antagonizing leukotriene D4 receptor They are weaker than inhaled Zafirlukast, corticosteroids, but reducemontelukast the frequency of exacerbations.
    • Leukotriene Pathway Inhibitors (Cont’d) One advantage is that they are taken orally; children comply poorly with inhaled therapies. Montelukast is approved for children as young as 6 years of age. 5-10% of asthmatics are exquisitely sensitive to aspirin and other NSAIDs. It is thought to result from inhibition of cyclooxygenase. LT antagonists are useful for preventing this problem.
    • Anti-IgE Antibodies Omalizumab inhibits the binding of IgE to mast cells but does not activate IgE already bound. It also inhibits IgE synthesis by B lymphocytes. The murine antibody has been humanized and it does not cause sensitization. Omalizumabs effect is reduction of both the severity of asthma and corticosteroid dosage.
    • Anti-IgE Antibodies (Cont’d) Patients most likely to respond are those with the greatest need:  Patients with a history of repeated exacerbations  A high requirement for corticosteroid treatment  Poor pulmonary function Omalizumab treatment reduced exacerbations requiring hospitalization by 88%. These benefits justify the high cost of this treatment in severe disease.
    • Treatment strategy All asthmatics should be instructed for severe, attacks:  To take up to four puffs of albuterol every 20 minutes over 1 hour.  If they do not note clear improvement after the first four puffs, refer to emergency department. Children exposed to allergens (pets) may be protected from asthma in later stages of life.
    • Treatment strategy (Cont’d) Mild asthma Inhaled beta receptor In these cases inhaled corticosteroid is added: agonist (Albuterol) on an "as-needed" basis  Asthma attacks more than twice a week  Nocturnal symptoms more than twice a month  FEV1 less than 80% predicted Cromolyn or LT antagonist may be used alternatively, but inhalational steroids are superior.
    • Treatment strategy (Cont’d) If FEV1 is <50% predicted, oral corticosteroid is added to control the symptoms and then stopped. Anti-IgE antibody, is reserved for Patients :  Unresposive to long-acting β-agonist plus high-dose inhaled corticosteroid  With demonstrated IgE-mediated sensitivity
    • Approach to therapy.ICS, inhaled corticosteroid; LABA, long-acting beta agonists; OCS, oralcorticosteroid.
    • Acute Asthma In mild attacks subcutaneous epinephrine or inhalation of a β receptor agonist are equally effective. Both of them are superior to IV aminophylline. For severe attacks:  Oxygen  Frequent administration of aerosolized albuterol  Systemic treatment with corticosteroids. Patients should be closely watched.
    • Inhaler
    • Metered doseinhaler
    • nebulizer
    • nebulizer
    • Summary In English
    • Thank you Any question?
    • 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, antigen-antibody 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 inFEV1. 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.