Teraputic consideration

• Asthma

  A common disease characterized by airway inflammation and episodic, reversible bronchospasm with severe shortness of breath
• COPD (Chronic Obstructive Pulmonary Disease)

  Characterized by airflow limitation that is less reversible than in asthma and usually follows a progressive course

  
• Many of the drugs used in asthma are also effective in COPD
• Drugs useful in classic allergic asthma

  • Bronchodilators (smooth muscle relaxants)
  • Anti-inflammatory

  
• Bronchodilators

  • Sympathomimetics: especially β2-selective agonists
  • Muscarinic antagonists
  • Methylxanthines
  • Leukotriene receptor blockers
• Anti-inflammatory

  • Corticosteroids
  • Mast cell stabilizers
  • Anti-IgE antibodies
  • Leukotriene antagonists (play a dual role)
• Pathophysiology of Asthma

  1. Release of several mediators from IgE-sensitized mast cells and other cells involved in immunologic responses

  2. Mediators include leukotrienes LTC4 and LTD4, tryptase, histamine and prostaglandin D2

  3. Mediators bring about the "early response" bronchoconstriction and increased secretions

  4. Chemotactic mediators such as LTB4 attract inflammatory cells to the airways and several cytokines and some enzymes are released "late response" inflammation

  
• Pathophysiology of COPD

  • Associated with neutrophilic rather than eosinophilic inflammation
  • Characterized by permanent structural damage to the airways and parenchyma
  • Exacerbation of symptoms often triggered by upper respiratory infection
  • Occurs mainly in older patients, especially long-term smokers
  • Poorly reversible with bronchodilators, and less responsive to corticosteroids than asthma

  
• Beta adrenoceptor agonist (sympathomimetics)

  • Selective β2-agonists used to reverse asthmatic bronchoconstriction
  • Nonselective agonist epinephrine is not recommended due to β1 and α-agonist effects
• Short-acting β2-agonists

  Albuterol (salbutamol), terbutaline and metaproterenol have a rapid onset of action (5 to 30 minutes) and duration of action of 4 hours or less
• Long-acting β2-agonists

  Salmeterol, formoterol, indacaterol, and vilanterol act for 12-24 hours
• Mechanism of action of β2-agonists

  1. Stimulate adenylyl cyclase (via the β2-adrenoceptor-Gs-coupling protein-adenylyl cyclase pathway) and increase cyclic adenosine monophosphate (cAMP) in smooth muscle cells

  2. Increase in cAMP leads to bronchodilation
• β2-agonists have no anti-inflammatory effects
• Therapeutic uses of sympathomimetics

  • Sympathomimetics are first-line therapy in acute asthma
  • Short-acting β2-agonists are the drugs of choice for acute episodes of bronchospasm
  • Short-acting not effective for prophylaxis
  • Long-acting agents used for prophylaxis
  • Long-acting not used for acute episodes due to slow onset of action
  • Long-acting drugs increase asthma mortality but are useful adjunctive therapy with corticosteroids
  • Many patients with COPD also benefit, although the risk of adverse effects is increased

  
• Adverse effects of β2-agonists

  • Skeletal muscle tremor
  • Significant β1-agonist effects at high clinical dosage
  • Tachycardia even when given by inhalation
  • Arrhythmias and tremor when used excessively
  • Tolerance and tachyphylaxis (loss of responsiveness) with prolonged use of short-acting
  • Patients with COPD often have concurrent cardiac disease and may have arrhythmia even at normal dosage
• Methylxanthines

  • Purine derivatives including caffeine, theophylline, and theobromine
  • Theophylline is the only member of this group important in the treatment of asthma
• Theophylline

  • Eliminated by P450 drug-metabolizing enzymes in the liver
  • Clearance varies with age, smoking status, and concurrent use of other drugs that inhibit or induce hepatic enzymes
  • Available in both immediate-release and slow-release forms
• Mechanism of action of methylxanthines

  1. Bronchodilator

  2. Non-selective phosphodiesterase (PDE) inhibitor, increasing cAMP

  3. Increased strength of contraction of the diaphragm, useful in COPD

  4. Inhibit adenosine receptors, leading to cardiac and CNS stimulant effects
• Therapeutic uses of methylxanthines

  • Major clinical use is in asthma and COPD
  • Slow-release theophylline is the most commonly used
  • Aminophylline is a salt for intravenous administration
  • Pentoxifylline is promoted as a remedy for intermittent claudication
  • Other effects: CNS stimulation, cardiac stimulation, vasodilation, diuresis, and increased gastrointestinal motility

  
• Adverse effects of methylxanthines

  • GIT distress
  • Tremor
  • Insomnia
  • Severe nausea, vomiting, hypotension, cardiac arrhythmias, and seizures in overdose
  • Beta blockers are useful in reversing severe cardiovascular toxicity
  • Drug interactions due to high protein binding
• Muscarinic antagonists

  • Atropine and other belladonna alkaloids replaced by ipratropium, a quaternary antimuscarinic agent designed for aerosol use
  • Tiotropium, aclidinium, umeclidinium, and glycopyrrolate are analogs approved for use in COPD
• Mechanism of action of muscarinic antagonists

  1. Competitively block muscarinic M3 receptors in the airways, preventing bronchoconstriction mediated by vagal discharge

  2. Reverse bronchoconstriction in some asthma patients and many COPD patients

  3. Have no effect on the chronic inflammatory aspects of asthma

  4. Less potent than β2 agonists

  
• Therapeutic uses of muscarinic antagonists

  • Useful in one third to two thirds of asthmatic patients, though β2 agonists are usually preferred
  • In COPD, may be more effective and less toxic than β2 agonists
• Adverse effects of muscarinic antagonists

  • Minor atropine-like effects e.g. dryness
• S.E.

  Lead to hyperreactivity (due to fide effect)
• COPD

  Benefit from Ms antagonist (⇒Baagonist)
• MB

  Less potent than Bz agonist
• Agonist

  Support effect, when block it ↑ action 132 agonist
• Mechanism of Action

  Competitively block muscarinic M3 receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge
• Muscarinic antagonists

  • Reverse bronchoconstriction in some asthma patients (especially children) and in many patients with COPD
  • Have no effect on the chronic inflammatory aspects of asthma

  
• Therapeutic uses of muscarinic antagonists

  • Useful in one third to two thirds of asthmatic patients; β2 agonists are effective in almost all, so are usually preferred
  • In COPD, which is often associated with acute episodes of bronchospasm, the antimuscarinic agents may be more effective and less toxic than β2 agonists
• Adverse effects of muscarinic antagonists

  • Minor atropine-like effects e.g. dry mouth (in high doses)
  • In contrast to the β2 agonists, do not cause tremor or arrhythmias
• All corticosteroids are potentially beneficial in severe asthma

  
• Inhaled corticosteroids

  Have become common first-line therapy for individuals with moderate to severe asthma

  
• Inhaled corticosteroids

  • Beclomethasone
  • Budesonide
  • Dexamethasone
  • Flunisolide
  • Fluticasone
  • Mometasone

  
• Systemic (oral) corticosteroids

  Usually prednisone, used chronically only when other therapies are unsuccessful due to their adverse effects
• Intravenous corticosteroids for status asthmaticus

  • Prednisolone (the active metabolite of prednisone)
  • Hydrocortisone (cortisol)

  
• Local, inhikers Parantral in sever status asthematicas
• For 5 days its safe
• Inhilar side effect is Candida Sis