Respiratory Drugs


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Respiratory Drugs

  1. 1. RESPIRATORY DRUGS Florencia D. Munsayac, MD, MBA, RMT
  2. 3. Bronchial Asthma <ul><li>A disease of the airways </li></ul><ul><li>characterized by hyper-responsiveness of the tracheo-bronchial tree to a multiplicity of stimuli </li></ul><ul><li>Manifested: physiologically by widespread reversible narrowing of the air passages </li></ul><ul><li>: clinically by paroxysm of coughing, dyspnea, and wheezes </li></ul>
  3. 4. Pathogenesis of Asthma <ul><li>Exposure to allergen synthesis of IgE: binds to mast cells in the airway mucosa </li></ul><ul><li>Re-exposure to allergen/antigen Ag-Ab interaction on the surfaces of the mast cell triggers: </li></ul><ul><li>mediators of anaphylaxis: other mediators or a variety of histamine, tryptase, PGD 2 , cytokines: </li></ul><ul><li>leukotriene C 4 , PAF interleukines 4 & 5, GMCSF, </li></ul><ul><li> TNF, TGF </li></ul><ul><li> </li></ul><ul><li>contraction of the airway smooth muscle eosinophils & neutrophils </li></ul><ul><li> </li></ul><ul><li> ECP, MBP, Protease, PAF </li></ul><ul><li> edema, mucus hypersecretion </li></ul><ul><li> increase in bronchial reactivity </li></ul><ul><li> smooth muscle contraction </li></ul>
  4. 5. <ul><li>B. </li></ul><ul><li>Inhaled irritants afferent pathways in the vagus nerves travel to the CNS efferent pathways from the CNS travel to efferent ganglia postganglionic fibers release acetylcholine binds to muscarinic receptors on airway smooth muscle bronchoconstriction </li></ul><ul><li>C. </li></ul><ul><li>inhaled materials stimulate afferent receptors to initiate reflex bronchoconstriction or release of tachynins (substance P) directly stimulate smooth muscle contraction </li></ul>
  5. 6. Treatment of Asthma <ul><li>Aerosol delivery of drugs </li></ul><ul><ul><li>Should produce a high local concentration in the lungs with a low systemic delivery -> minimizing side effects </li></ul></ul><ul><ul><li>Size of the particles: critical determinant </li></ul></ul><ul><ul><ul><li>>10 um – deposited in the mouth & oropharynx </li></ul></ul></ul><ul><ul><ul><li> 0.5 um – inhaled, subsequently exhaled </li></ul></ul></ul><ul><ul><ul><li>1-5 um – allow deposition & most effective </li></ul></ul></ul>
  6. 7. Treatment of Asthma <ul><li>Aerosol delivery of drugs </li></ul><ul><ul><li>Recommendation: slow, deep breath & held for 5-10 seconds </li></ul></ul><ul><ul><li>2-10%: deposited in the lung </li></ul></ul><ul><ul><li>To minimize systemic effects: </li></ul></ul><ul><ul><ul><li>poorly absorbed from the GIT </li></ul></ul></ul><ul><ul><ul><li>Rapidly inactivated via first-pass hepatic metabolism </li></ul></ul></ul><ul><ul><ul><li>Use of a large-volume “spacer” </li></ul></ul></ul>
  7. 8. Treatment of Asthma <ul><li>Aerosol delivery of drugs </li></ul><ul><ul><li>2 types of devices: </li></ul></ul><ul><ul><ul><li>Metered dose inhalers </li></ul></ul></ul><ul><ul><ul><ul><li>Advantage: cheaper & portable </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Disadvantage: most contain hydroflourocarbons </li></ul></ul></ul></ul><ul><ul><ul><li>Nebulizers </li></ul></ul></ul><ul><ul><ul><ul><li>preferred for severe asthma exacerbations with poor inspiratory ability </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Advantage: not requiring hand-breathing coordination </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Can be delivered by face-mask to young children & elderly </li></ul></ul></ul></ul>
  8. 9. Treatment of Asthma <ul><li>Oral administration: Beta Adrenergic Receptor Agonists </li></ul><ul><ul><li>Has not gained wide acceptance </li></ul></ul><ul><ul><li>Side Effects: tremulousness, muscle cramps, cardiac tachyarrhythmias, metabolic disturbances </li></ul></ul><ul><ul><li>2 primary situations in which oral B adrenergic agonists are used: </li></ul></ul><ul><ul><ul><li>Brief courses of oral therapy are well tolerated & effective in young children who cannot manipulate metered-dose inhalers </li></ul></ul></ul><ul><ul><ul><li>Local irritation with the use of aerosol preparations </li></ul></ul></ul>
  9. 10. Treatment of Asthma <ul><li>Parenteral administration </li></ul><ul><ul><li>Indication: </li></ul></ul><ul><ul><ul><li>Severe asthma requiring emergency treatment (when aerosolized therapy is not available or has been ineffective) </li></ul></ul></ul>
  10. 11. I. Bronchodilators Sympathomimetic Agents <ul><li>Directly relax airway smooth muscle by activating G s adenylyl cyclase-cAMP in the airway tissues that results in bronchodilatation </li></ul><ul><li>Increase the conductance of large Ca+2-sensitive K+ channels in airway smooth muscle -> hyperpolarization & relaxation </li></ul><ul><li>Inhibit release of inflammatory mediators & cytokines from the mast cells, basophils, eosinophils, neutrophils, & lymphocytes </li></ul><ul><li>Increase mucociliary transport </li></ul>
  11. 12. a. Beta-2 Selective Agonists <ul><li>Short-acting: </li></ul><ul><ul><li>Used only for symptomatic relief of asthma </li></ul></ul><ul><ul><li>Terbutaline, albuterol, levalbuterol, metaproterenol, pirbuterol </li></ul></ul><ul><ul><ul><li>inhaled drugs: </li></ul></ul></ul><ul><ul><ul><ul><li>onset of action: 1-5 min., </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Peak effects: 15-30 min., </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Duration of action: 2 – 6 hours </li></ul></ul></ul></ul><ul><ul><li>Terbutaline, albuterol, metaproterenol </li></ul></ul><ul><ul><ul><li>oral form: </li></ul></ul></ul><ul><ul><ul><ul><li>DOA: 4-8 hrs. </li></ul></ul></ul></ul><ul><ul><li>Terbutaline </li></ul></ul><ul><ul><ul><li>parenteral form (0.25mg SC) </li></ul></ul></ul>
  12. 13. a. Beta-2 Selective Agonists <ul><li>Long acting: </li></ul><ul><ul><li>Salmeterol, formoterol </li></ul></ul><ul><ul><ul><li>Given by inhalation </li></ul></ul></ul><ul><ul><ul><li>DOA: 12 hours or more </li></ul></ul></ul><ul><ul><ul><li>Interact with corticosteroids to improve asthma control </li></ul></ul></ul><ul><ul><ul><ul><li>Salmeterol-fluticasone </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Formoterol-budesonide </li></ul></ul></ul></ul><ul><ul><ul><li>Not recommended as the sole therapy for asthma </li></ul></ul></ul><ul><ul><ul><li>Used prophylactically in the treatment of asthma </li></ul></ul></ul>
  13. 14. b. Non-selective Beta-Agonists: <ul><li>Epinephrine </li></ul><ul><ul><li>Rapid acting </li></ul></ul><ul><ul><li>Injected SC or inhalation </li></ul></ul><ul><ul><li>Onset: 15 minutes </li></ul></ul><ul><ul><li>DOA: 60-90 minutes </li></ul></ul><ul><ul><li>SE: tachycardia, arrhythmias, worsening of the angina pectoris </li></ul></ul><ul><li>Ephedrine </li></ul><ul><ul><li>Longer duration of action </li></ul></ul><ul><ul><li>Orally/parenterally administered </li></ul></ul><ul><ul><li>Lower potency </li></ul></ul><ul><ul><li>More pronounced central effects </li></ul></ul><ul><li>Isoproterenol </li></ul><ul><ul><li>Onset: 5 minutes </li></ul></ul><ul><ul><li>DOA: 60-90 minutes </li></ul></ul><ul><ul><li>SE: cardiac arrhythmias </li></ul></ul>
  14. 15. I. Bronchodilators Methylxanthine drugs <ul><li>Caffeine (1,3,7-trimethyxanthine) </li></ul><ul><li>Theobromide (3,7-dimethylxanthene) </li></ul><ul><li>Theophylline (1,3-dimethylxanthine) </li></ul><ul><ul><li>Most commonly used </li></ul></ul><ul><ul><li>Derivatives: </li></ul></ul><ul><ul><ul><li>Aminophylline </li></ul></ul></ul><ul><ul><ul><li>Dyphylline </li></ul></ul></ul><ul><ul><ul><li>oxtriptylline </li></ul></ul></ul>
  15. 16. I. Bronchodilators Methylxanthine drugs <ul><li>Mechanisms of action: </li></ul><ul><ul><li>inhibit cyclic nucleotide phosphodiesterases -> high </li></ul></ul><ul><ul><li>concentration of IC cAMP & cGMP -> smooth muscle relaxation </li></ul></ul><ul><ul><li>= Cilomilast, Roflumilast, Tofimilast: Selective PDE4 inhibitors </li></ul></ul><ul><ul><li>inhibition of cell surface receptors for adenosine </li></ul></ul><ul><ul><li> = Enprofylline: xanthine derivative devoid of adenosine antagonism </li></ul></ul><ul><ul><li>anti-inflammatory effect : inhibit synthesis & secretion of inflammatory mediators from mast cells & basophils </li></ul></ul>
  16. 17. I. Bronchodilators Methylxanthine drugs <ul><li>Pharmacodynamics: </li></ul><ul><ul><li>CNS : </li></ul></ul><ul><ul><ul><li>mild cortical arousal w/ increased alertness & deferral of fatigue </li></ul></ul></ul><ul><ul><ul><li>nervousness; insomnia </li></ul></ul></ul><ul><ul><ul><li>in high doses: medullary stimulation and convulsions </li></ul></ul></ul><ul><ul><ul><li>primary SE: nervousness and tremor </li></ul></ul></ul><ul><ul><li>CVS : </li></ul></ul><ul><ul><ul><li>have positive inotropic and chronotropic effects </li></ul></ul></ul><ul><ul><ul><li>Arrhythmia </li></ul></ul></ul><ul><ul><ul><li>sinus tachycardia and increased cardiac output </li></ul></ul></ul><ul><ul><ul><li>rises the PVR and BP slightly </li></ul></ul></ul><ul><ul><ul><li>decrease blood viscosity and may improve blood flow (pentoxifylline) </li></ul></ul></ul>
  17. 18. I. Bronchodilators Methylxanthine drugs <ul><li>Pharmacodymanics: </li></ul><ul><ul><li>GIT : </li></ul></ul><ul><ul><ul><li>stimulate secretion of gastric acid and digestive enzymes </li></ul></ul></ul><ul><ul><li>Kidneys : </li></ul></ul><ul><ul><ul><li>weak diuretics </li></ul></ul></ul><ul><ul><li>Skeletal muscles : </li></ul></ul><ul><ul><ul><li>have potent effects in improving contractility and in reversing fatigue of diaphragm in patient with COPD </li></ul></ul></ul><ul><ul><li>Smooth muscle : </li></ul></ul><ul><ul><ul><li>inhibit antigen-induced release of histamine from lung tissue </li></ul></ul></ul>
  18. 19. I. Bronchodilators Methylxanthine drugs <ul><li>Pharmacokinetics: </li></ul><ul><ul><li>Absorbed readily & completely </li></ul></ul><ul><ul><li>Food slows the absorption of theophylline </li></ul></ul><ul><ul><li>40% protein bound </li></ul></ul><ul><ul><li>Distributed into all body compartments </li></ul></ul><ul><ul><li>Cross the placenta & pass into breast milk </li></ul></ul><ul><ul><li>Metabolism: liver by CYP 1A2 enzyme </li></ul></ul><ul><ul><li>10% excreted unchanged </li></ul></ul><ul><ul><li>Half-life: 3.5 hrs – children; 8 or 9 hrs – adult </li></ul></ul><ul><ul><li>Usual dose: 3-4 mg/kg every 6 hours </li></ul></ul>
  19. 20. I. Bronchodilators Methylxanthine drugs <ul><li>Drug Interactions: </li></ul><ul><ul><li>Erythromycin, cimetidine, cirrhosis, CHF, acute pulmonary edema -  half-life </li></ul></ul><ul><ul><li>Phenytoin, barbiturates, cigarette smoking, rifampicin, oral contraceptives -  clearance </li></ul></ul>
  20. 21. I. Bronchodilators Methylxanthine drugs <ul><li>Toxicities: </li></ul><ul><ul><li>Sudden death </li></ul></ul><ul><ul><li>Headache, palpitation, dizziness, nausea, hypotension, precordial pain </li></ul></ul><ul><ul><li>Tachycardia, severe restlessness, agitation, emesis – plasma concentration of > 20 ug/ml </li></ul></ul><ul><ul><li>Focal & generalized seizures – 40 ug/ml </li></ul></ul>
  21. 22. <ul><li>Bronchodilators Anti-Muscarinic Agents </li></ul><ul><li>Competitively inhibits the effect of acetylcholine at muscarinic receptors -> effectively block the contraction of the airway smooth muscle and increase in secretion of mucus </li></ul><ul><li>Ipratropium bromide – a quarternary ammonium derivative of atropine </li></ul><ul><li>Tiotropium – structural analog of ipratropium, approved for COPD, permits once daily dosing </li></ul><ul><li>Delivered by aerosol (metered dose inhaler/nebulizer) </li></ul><ul><li>Slightly less effective than beta agonist </li></ul><ul><li>Effective in COPD </li></ul>
  22. 23. II. Anti-inflammatory Agents Corticosteroids <ul><li>Improving all indices of asthma: severity of symptoms, tests of airway caliber, bronchial reactivity, frequency of exacerbation and quality of life </li></ul><ul><li>Inhibiting airway inflammation: </li></ul><ul><ul><li>modulation of cytokine & chemokine production, </li></ul></ul><ul><ul><li>(-) of eicosanoid synthesis, </li></ul></ul><ul><ul><li>(-) of accumulation of basophils, eosinophils & other leukocytes in lung tissue, </li></ul></ul><ul><ul><li>decrease vascular permeability </li></ul></ul>
  23. 24. II. Anti-inflammatory Agents Corticosteroids <ul><li>Preparations: </li></ul><ul><li>a. oral: prednisone </li></ul><ul><li>b. IV: methylprednisolone </li></ul><ul><li>c. aerosol: beclomethasone, flunisolide, budesonide, triamcinolone, fluticasone, mometasone </li></ul><ul><li>SE : oral candidiasis, hoarseness, slow the rate of growth in children, decrease bone mineral density, cataract, mood disturbances,  appetite, & impaired glucose control in diabetics </li></ul><ul><li>- Ciclesonide </li></ul>
  24. 25. II. Anti-inflammatory Agents Cromolyn Sodium & Nedocromil <ul><li>MOA: alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation </li></ul><ul><ul><li>Inhibiting parasympathetic and cough reflexes </li></ul></ul><ul><ul><li>Inhibition of the early response to Ag challenge </li></ul></ul><ul><ul><li>Inhibition of the inflammatory response </li></ul></ul><ul><ul><li>inhibiting mediator release from bronchial mast cells </li></ul></ul><ul><ul><li>Suppressing the activating effects of chemotactic peptides on neutrophils, basophils & monocytes </li></ul></ul><ul><li>Taken prophylactically </li></ul><ul><li>Used as aerosol </li></ul>
  25. 26. II. Anti-inflammatory Agents Cromolyn Sodium & Nedocromil <ul><li>Effectively inhibit both antigen-and exercise-induced asthma & reducing symptoms of allergic rhinoconjunctivitis </li></ul><ul><li>SE : </li></ul><ul><ul><li>throat irritation, cough, mouth dryness, </li></ul></ul><ul><ul><li>chest tightness and wheezing, </li></ul></ul><ul><ul><li>reversible dermatitis, </li></ul></ul><ul><ul><li>myositis, </li></ul></ul><ul><ul><li>gastroenteritis, </li></ul></ul><ul><ul><li>pulmonary infiltration with eosinophils and anaphylaxis </li></ul></ul>
  26. 27. II. Anti-inflammatory Agents Leukotriene-Synthesis Inhibitors Leukotriene-Receptor Antagonists <ul><li>Block the action of leukotrienes by : </li></ul><ul><li>- inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis </li></ul><ul><li>- inhibition of the binding of leukotriene C4, D4, E4 to its cys-LT1 receptor on target tissues, thereby preventing its action </li></ul><ul><li>Drug categories </li></ul><ul><li>a. Zileuton – a 5-lipoxygenase inhibitor </li></ul><ul><li> - 600 mg QID </li></ul><ul><li> - may cause hepatotoxicity </li></ul><ul><li> - inhibits the formation of LTB4 </li></ul><ul><li>b. Zafirlukast – 20mg BID </li></ul><ul><li> Montelukast – 10mg OD </li></ul><ul><li>- are Leukotriene D4-receptor antagonists </li></ul>
  27. 28. II. Anti-inflammatory Agents Leukotriene-Synthesis Inhibitors Leukotriene-Receptor Antagonists <ul><li>Zileuton : absorbed rapidly </li></ul><ul><li>metabolized extensively by CYPs & by UDP- glucuronosyltransferases </li></ul><ul><li> short-acting drug </li></ul><ul><li> half-life: 2.5 hrs </li></ul><ul><li> 93% protein-bound </li></ul>
  28. 29. II. Anti-inflammatory Agents Leukotriene-Synthesis Inhibitors Leukotriene-Receptor Antagonists <ul><li>Zafirlukast : absorbed rapidly </li></ul><ul><ul><ul><ul><ul><li>90% bioavailability </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>99% protein-bound </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>metabolized extensively by hepatic CYP2C9 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>half-life: 10 hrs </li></ul></ul></ul></ul></ul>
  29. 30. II. Anti-inflammatory Agents Leukotriene-Synthesis Inhibitors Leukotriene-Receptor Antagonists <ul><li>Montelukast : absorbed rapidly </li></ul><ul><ul><ul><ul><ul><li>60 - 70% bioavailability </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>99% protein-bound </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>metabolized extensively by CYP3A4 & CYP2C9 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>half-life: 3 – 6 hrs </li></ul></ul></ul></ul></ul>
  30. 31. II. Anti-inflammatory Agents Leukotriene-Synthesis Inhibitors Leukotriene-Receptor Antagonists <ul><li>Other Effects: </li></ul><ul><li>Have demonstrated an important role for leukotrienes in aspirin-induced asthma </li></ul><ul><li>Their effect on symptoms, airway caliber, bronchial reactivity and airway inflammation are less marked than the effects of inhaled corticosteroids, but they are almost equally effective in reducing the frequency of exacerbations </li></ul>
  31. 32. Other Drugs in the Treatment of Asthma <ul><li>1. Anti-IgE Antibodies </li></ul><ul><li>- drugs that reduce the amount of IgE-bound to mast cells </li></ul><ul><li>- inhibits synthesis of IgE by B-lymphocytes </li></ul><ul><li>- Omalizumab (anti-IgE MAb) </li></ul><ul><li>= most important effect : reduction of the frequency & severity of asthma exacerbations </li></ul><ul><li>= delivered as a single SC injection q 2 – 4 weeks </li></ul><ul><li>= 60% bioavailability </li></ul><ul><li>= peak serum levels: 7 – 8 days </li></ul><ul><li>= half-life: 26 days </li></ul><ul><li>= elimination: liver reticuloendothelial system, bile </li></ul>
  32. 33. Other Drugs in the Treatment of Asthma <ul><li>2. Calcium channel Blockers </li></ul><ul><li>- inhibit airway narrowing induced by variety of stimuli </li></ul><ul><li>3. Nitric Oxide Donors </li></ul><ul><li>- relaxation of smooth muscle and vasculature </li></ul><ul><li>- very lipophilic drug, can be inhaled as a gas </li></ul><ul><li>- more useful in pulmonary hypertension </li></ul>
  33. 34. Possible Future Therapies <ul><li>Monoclonal antibodies directed against cytokines </li></ul><ul><li>Antagonist of cell adhesion molecules </li></ul><ul><li>Protease inhibitors </li></ul><ul><li>Immunomodulators </li></ul>
  34. 35. Other Respiratory Agents <ul><li>Mucolytic Agents </li></ul><ul><li>1. Acetylcysteine (mucomyst) </li></ul><ul><li>- reduce the thickness and stickiness of purulent and non-purulent pulmonary secretions </li></ul><ul><li>- antidote for paracetamol poisoning </li></ul><ul><li>2. Carbocysteine (SCMC) </li></ul><ul><li>- act by regulating and normalizing the viscosity of secretion from the mucus cell of respiratory tract </li></ul><ul><li>- decrease the size and number of mucus producing cells </li></ul><ul><li>3. Bromhexine </li></ul><ul><li>- depolymerization of mucopolysaccharides, direct effect on bronchial glands </li></ul><ul><li>- liberation of lysosomal enzymes producing cells which digest mucopolysaccharide fibers </li></ul>
  35. 36. <ul><li>Mucokinetic & Secretolytic </li></ul><ul><li> 1. Ambroxol </li></ul><ul><li>- increase respiratory tract secretions </li></ul><ul><li>- enhance pulmonary surfactant production </li></ul><ul><li>- stimulates cilia activity </li></ul><ul><li>Expectorant </li></ul><ul><li>1. Vagal stimulants: glyceryl guiacolate, salt solution </li></ul><ul><li>2. Direct stimulants: KISS, bromhexine, SCMC, ambroxol </li></ul><ul><li>Antitussives </li></ul><ul><li>1. Narcotic antitussives: heroin, codeine, morphine </li></ul><ul><li>2. Non-narcotic antitussive: Dextromethorphan </li></ul>