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Asthma & COPD November 28, 2007 Frank F. Vincenzi Drug list for asthma & COPD • • • • • • • • • • * acetylcholine * adenosine * albuterol (Proventil®, Ventolin®) * aminophylline (theophylline ethylenediamine) * beclomethasone dipropionate (Vanceril®) * disodium cromoglycate cromolyn sodium (Intal®) * epinephrine (Adrenalin®) * histamine * ipratropium (Atrovent®) * isoproterenol (Isuprel®) • • • • • • • • • * leukotrienes * nedocromil (Tilade®) * prednisone (Deltasone®) * salmeterol (Serevent®) * terbutaline (Brethaire®, Brethine®, Bricanyl®) * theophylline (Theo-Dur®, SloPhyllin®, Somophyllin-T®, Somophyllin CRT®, Theobid®) * triamcinolone acetonide (Azmacort®) * zafirlukast (Accolate®) * zileuton (Zyflo®) Asthma, a disease of inflammation • Clinically intermittent wheezing &/or dyspnea &/or cough • Physiologically reversible obstructive airway disease • Pharmacologically obstructive airway disease reversed by beta agonists - or an appropriate course of anti-inflammatory drug Some mast cell triggers and products Drugs used in the treatment of asthma • Relievers Sympathomimetic bronchodilators (most) Injected methylxanthine, e.g., aminophylline • Controllers Theophylline (i.e., oral methylxanthine) Inhibitors of histamine release Anticholinergics Corticosteroids Certain sympathomimetics (e.g., salmeterol) Leukotriene synthesis inhibitors/antagonists Sympathomimetics used as relievers in the treatment of asthma • albuterol (Proventil®, Ventolin®) • epinephrine (Adrenalin®) • isoproterenol (Isuprel®) • terbutaline (Brethaire®, Brethine®, Bricanyl®) Beta-agonist bronchodilators compared Aer = aerosol, Inj. = injection, MDI = metered dose inhaler, PO = oral Mechanism of action of sympathomimetic amines in the treatment of asthma – Activate beta-2 receptors on bronchiolar smooth muscle • Beta-2 receptor /G-protein complex increases cAMP production • Increased cAMP activates protein kinase A (PKA) • PKA phosphorylates myosin light chain kinase (MLCK) • Phosphorylated MLCK; decreased affinity for (Ca)ncalmodulin • Less phosphorylation of myosin light chain • Decreased activity of smooth muscle actin/myosin • Bronchodilation Precautions when using beta-agonists in the treatment of asthma • Watch for non-improvement or paradoxical deterioration • Spacers to improve compliance and reduce systemic side effects (large droplets deposit in mouth, swallowed) • Avoid overuse; check number of MDIs used per month • Instruct patient on maximum number of puffs per day (usually 8-12) and on the number allowed during exacerbation (e.g., 12-24 over 3-4 hours) • If a long-acting agent is used, caution patient that frequent use must be avoided • “Home updraft nebulizers (pumps) that provide large doses are rarely needed……” Contraindication: beta-blockers in asthma • May precipitate acute attacks in asthmatics • Antagonize the most effective treatment for an acute attack • May precipitate asthma in patients not known to be asthmatic • Selectivity of beta-1 selective antagonists (such as atenolol or metoprolol) is only relative, not absolute Aminophylline (ethylenediamine salt of theophylline) • Soluble form of theophylline can be used for IV infusion • Rapid onset of action, can be effective in treating status asthmaticus - usually as an adjunct to an IV or inhaled sympathomimetic, typically albuterol or epinephrine • Seizures, a major limitation • ‘Therapeutic monitoring’ typically by nursing staff following patient symptoms Controller drugs: prevent asthma attacks and/or reduce severity • Methylxanthines (theophylline) • Inhibitors of histamine release (cromolyn) • Anticholinergics (ipratropium or tiotropium) [off label] (tiotropium, also off label) • Corticosteroids (inhaled or oral) • Certain sympathomimetics (e.g., salmeterol) • Leukotriene synthesis inhibitors (zileuton) • Leukotriene antagonists (zafirlukast) Methylxanthines (xanthines) • Theophylline (from Thea sinensis) (tea) (aminophylline = theophylline ethylenediamine) • Theobromine (from Theobroma cacao) (chocolate) • Caffeine (from Caffea arabica, etc.) (coffee) Xanthine pharmacology • Cellular antagonism of adenosine receptors inhibition of cyclic nucleotide phosphodiesterase release of calcium in muscle • Systemic CNS stimulation cardiac stimulation diuresis smooth muscle relaxation Concentration-effect curves for caffeine in vivo Cup of coffee Toxic dose 100 75 Block A2A Block A1 50 Inhibit PDE 25 Block GABAa Promote Ca release 0 -6 -5 -4 -3 -2 Caffeine (molar) -1 Adapted from Fredholm (1980) Theophylline: Potential mechanisms in asthma • Antagonism of adenosine receptors • Inhibition of cyclic nucleotide phosphodiesterase (could synergize sympathomimetics by sparing intracellular cAMP) • Increased Ca2+ release (increased contractility of diaghragmatic skeletal muscle) Increased bronchial smooth muscle sensitivity to adenosine: association with human asthma Adapted from Björck et al. (1991) NY Acad. Sci. 629: 458-459 Theophylline: adverse reactions • • • • • • • • • Anorexia Nausea & vomiting Anxiety Fever Tremors Dehydration Seizures Cardiac arrhythmias Cardiovascular & respiratory collapse Theophylline pharmacokinetics • Half life children adult smokers adult non-smokers ~ 200 min ~ 325 min ~431 min (P < 0.0001) • Therapeutic monitoring is a must • Therapeutic range is 10 - 20 µg/ml, t1/2 extremely variable • Dosage must be calculated based on ideal body weight (i.e., lean body mass) Theophylline as a controller for the treatment of asthma: trap for the unwary physician • • • • Rapid absorption Variable elimination (CYP1A2 and CYP3A4) Uncertain volume of distribution (ideal body weight) Interaction with many other drugs smoking viral infections Symptoms and theophylline levels of several young patients treated with theophylline before and during an influenza outbreak Adapted from Kraemer et al., Pediatrics 69: 476-480, 1982 Factors that decrease theophylline clearance • Minor changes verapamil, nifedipine, tetracycline, hydrocortisone, aluminum hydroxide, magnesium, thiabendazole • Major changes hepatic insufficiency, heart failure cor pulmonale, viral pneumonia, cimetidine, mexiletine, ciprofloxacin, allopurinol, erythromycin, propranolol*, oral contraceptives, zileuton Precautions when using theophylline • Initiate with a low dose, then adjust • Instruct patient to take drug at the same time each day with respect to meals • Reduce dose if clearance is likely to be impaired for ANY reason • Do not allow additional xanthines • If symptoms change, acute illness occurs, drugs are added (or removed), or symptoms suggest toxicity CHECK SERUM LEVEL • Aim for 8-12 µg/ml, adjust and follow serum level Controller drugs: prevent asthma attacks and/or reduce severity • Methylxanthines (theophylline) • Inhibitors of histamine release (cromolyn) • Anticholinergics (ipratropium or tiotropium) [off label] • Corticosteroids (inhaled or oral) • Certain sympathomimetics (e.g., salmeterol) • Leukotriene synthesis inhibitors (zileuton) • Leukotriene antagonists (zafirlukast) Inhibitors of histamine release • Chromones – Disodium cromoglycate (cromolyn sodium, Intal®, Nasalcrom®) – Nedocromil (Tilade®) • • • • Inhaled Inhibit the release of histamine Effective in some patients only Some local irritation, cough, rhinitis, sneezing, throat irritation Controller drugs: prevent asthma attacks and/or reduce severity • Methylxanthines (theophylline) • Inhibitors of histamine release (cromolyn) • Anticholinergics (ipratropium or tiotropium) [off label] • • • • Corticosteroids (inhaled or oral) Certain sympathomimetics (e.g., salmeterol) Leukotriene synthesis inhibitors (zileuton) Leukotriene antagonists (zafirlukast) Precautions when using ipratropium as a controller drug for the (off label) treatment of asthma or COPD (approved) • Use a spacer and avoid getting spray in the eyes • Be prepared to increase dose if necessary from 2-3 puffs 3-4 times per day to 6-8 puffs 3-4 times per day, if tolerated • Caution patients that the onset of effect is slow; additional doses should not be taken for acute relief of symptoms. • Monitor for systemic side effects; tachycardia, dry mouth, urinary retention, glaucoma Controller drugs: prevent asthma attacks and/or reduce severity • Methylxanthines (theophylline) • Inhibitors of histamine release (cromolyn) • Anticholinergics (ipratropium or tiotropium) [off label] • Corticosteroids (inhaled or oral) • Certain sympathomimetics (e.g., salmeterol) • Leukotriene synthesis inhibitors (zileuton) • Leukotriene antagonists (zafirlukast) Corticosteroids in the treatment of asthma • Inhaled beclomethasone dipropionate (Vanceril®) triamcinolone acetonide (Azmacort®) • Systemic prednisone (Deltasone®) …decrease inflammation and airway responsiveness. Systemic absorption occurs following inhalation. Long term steroid dosage is associated with substantial adverse reactions. Systemic corticosteroids: some adverse effects • Shapiro et al. (1976) J. Allergy Clin. Immunol. 57: 430-439. Steroid dependent asthmatic children daily prednisone or methylprednisolone or twice equivalent alternate-day methylprednisolone: abnormal growth, bone maturation and cataracts high incidence of disturbed pituitary and adrenal function (alternate-day therapy did not alter) Beclomethasone dipropionate (BDP): some pharmacokinetics • BDP has negligible oral and intranasal bioavailability. Similarly, inhaled BDP is extensively (95%) converted to B-17-MP [active metabolite] in the lung. • Bioavailability of B-17-MP is 41%, 44% and 62% for oral, intranasal and inhaled dosing. • When given IV, BDP [inactive] is rapidly (t1/2 = 0.5 h) converted to B-17-MP [active], which is eliminated more slowly (t 1/2 = 2.7 h) mainly by conversion to BOH [inactive]. Daley-Yates et al. (2001), Br.J.Clin.Pharmacol. 51: 400-409. Inhaled corticosteroids:some systemic effects • Skin thinning (striae) Skin thinning and purpura are associated with the use of oral or inhaled high dose steroids. Low dose inhaled steroids did not produce significant thinning of skin. Capewell et al. (1990) BMJ 300: 1548-1551. Inhaled corticosteroids:some systemic effects (continued) • Osteoporosis Inhaled corticosteroid therapy, unlike oral corticosteroid therapy may not induce bone loss at the doses used by our subjects. Wolff et al (1991) Ann. Allergy 67: 117-121. Although there was substantial interindividual variability in the responses, asthmatic patients receiving high dose inhaled beclomethasone and intermittent courses of systemic corticosteroids have reduced vertebral bone density Packe et al. (1992) Thorax 47: 414-417. Inhaled corticosteroids:some systemic effects (continued) • Cataracts All inhaled corticosteroid users are at a marginally increased risk of cataract (RR = 1.3). (Jick et al. (2001) Epidemiology 12: 229-234). Inhaled corticosteroid users are at increased risk of nuclear (RR = 1.5) and posterior subcapsular (RR = 1.9) cataracts. Risk of posterior subcapsular cataracts is greater (RR = 2.7) among users of systemic corticosteroids. (Cumming et al. (1997) NEJM 337: 8-14.) Precautions when using inhaled steroids • Confirm objective evidence of the value of this therapy which tends to decrease compliance with other aerosol usage • Standard dosing (2-4 puffs, 2-4 times per day) should not be exceeded • Use a spacer; monitor to minimize oral thrush and laryngeal dysfunction • Watch for systemic side effects • If replacing oral steroids, taper oral dosage Toxic effects of chronic glucocorticoids gluconeogenesis (liver)--hyperglycemia release of amino acids-catabolism (muscle)--muscle weakness release of fatty acids-lipolysis (fat)--together with increase in insulin, leads to inappropriate fat deposition, obesity insulin secretion (pancreas-in response to glucose) bone resorption--leading to osteoporosis, fractures fibroblast proliferation--thin skin, bruising, poor wound healing collagen synthesis growth (in children) changes in mood and excitability--euphoria, restlessness altered leukocyte functions (anti-inflammatory)--may mask underlying symptoms suppression of the HPA axis: acute withdrawal can lead to death Precautions when using oral steroids • Reduce to lowest daily or alternate day dosage as soon as symptoms allow • Monitor for hypertension, diabetes, weight gain, mental changes, infections, central polar cataracts, skin thinning, purpura, osteoporsis and osteonecrosis - administer prophylactic calcium • Monitor FEV1 for 2 weeks to establish objective evidence of benefit • Repeatedly evaluate patient to determine if steroid therapy can be discontinued….. November 17, 1998: Joint Public Statement • American Academy of Allergy Asthma and Immunology • American College of Allergy • American College of Chest Physicians • American Thoracic Society • American Academy of Pediatrics “Patients are advised not to stop using their inhaled or intranasal corticosteroids without first speaking to their health care providers about the benefits of these drugs compared to their risks.” (Prompted by new FDA warnings on rate of growth) Controller drugs: prevent asthma attacks and/or reduce severity • • • • Methylxanthines (theophylline) Inhibitors of histamine release (cromolyn) Anticholinergics (ipratropium or tiotropium) [off label] Corticosteroids (inhaled or oral) • Certain sympathomimetics (e.g., salmeterol) • Leukotriene synthesis inhibitors (zileuton) • Leukotriene antagonists (zafirlukast) Salmeterol: a unique beta-agonist with a very long duration of action (longer than plasma half life) (Probably works by an alternate or additional mechanism) • • • • • NOT for acute symptoms NOT for deteriorating asthma NOT a substitute for inhaled or oral corticosteroids Do not exceed recommended dosage Watch for: increasing use of short-acting beta agonists paradoxical bronchospasm immediate hypersensitivity (urticaria, angioedema, etc.) upper airway symptoms (laryngeal spasm, irritation) Salmeterol: an alternative and/or additonal mechanism? • Jeffery et al. (2002) Eur. Respir. J. 20: 1378-1385 A novel antineutrophilic effect of salmeterol? reduced numbers of neutrophils in bronchial lavage fluid Fluticasone decreased CD3+ T-lymphocytes, (CD4+) T-helper cells,CD45RO+) activated T-helper cells and eosinophils. Chronic clinical efficacy of salmeterol in two studies Controller drugs: prevent asthma attacks and/or reduce severity • • • • • Methylxanthines (theophylline) Inhibitors of histamine release (cromolyn) Anticholinergics (ipratropium or tiotropium) [off label] Corticosteroids (inhaled or oral) Certain sympathomimetics (e.g., salmeterol) • Leukotriene synthesis inhibitors (zileuton) • Leukotriene antagonists (zafirlukast) Arachidonic acid metabolism NSAIDS cyclooxygenase thromboxanes prostaglandins lipoxygenase Zileuton: Mechanism of Action • Zileuton (Zyflo®) is a highly selective inhibitor of 5-lipoxygenase • Inhibits the synthesis of leukotrienes (LTB4, LTC4*, LTD4* and LTE4) - potential for application in a variety of inflammatory diseases (e.g., colitis, rheumatoid arthritis) but currently only approved for asthma • Very short half life (~1-2 hours), given QID *Slow reacting substance of anaphylaxis, “SRS-A”, is a mixture of LTC4 and LTD4 Leukotrienes and asthma Arachidonic acid Zileuton (Zyflo®) 5-HPETE 5-lipoxygenase Leukotriene A4 Leukotriene B4 LTB4 receptor chemotaxis, immunomodulation Leukotriene C4 Leukotriene D4 Leukotriene E4 LT receptor (CYSLT1) bronchoconstriction, mucus secretion, hyperresponsiveness, eosinophilia Zileuton (Zyflo®) • Indicated for chronic treatment of asthma. Should be taken even during symptom-free periods. Zileuton is NOT a bronchodilator - it should NOT be used to treat acute episodes of asthma. • Reassess therapy if short-acting bronchodilators are needed more often than usual • Monitor patients on a regular basis - the most serious adverse reaction is elevation of liver enzymes. Zileuton: potential drug interactions • Zileuton decreases clearance of theophylline and increases AUC and Cmax. More adverse reactions to theophylline with zileuton. • Zileuton decreases clearance of propranolol and increases AUC and Cmax. There is increased beta-blockade and a greater decrease in heart rate when these drugs are combined. (Why is this a combination that should not happen??) Controller drugs: prevent asthma attacks and/or reduce severity • • • • • • Methylxanthines (theophylline) Inhibitors of histamine release (cromolyn) Anticholinergics (ipratropium or tiotropium) [off label] Corticosteroids (inhaled or oral) Certain sympathomimetics (e.g., salmeterol) Leukotriene synthesis inhibitors (zileuton) • Leukotriene antagonists (zafirlukast) Zafirlukast: Mechanism of Action • Zafirlukast (Accolate®) is a selective and competitive receptor antagonist of leukotrienes D4 and E4 (components of slowreacting substance of anaphylaxis [SRS-A]) Leukotrienes and asthma Arachidonic acid 5-HPETE 5-lipoxygenase Leukotriene A4 Leukotriene B4 Leukotriene C4 Leukotriene D4 Leukotriene E4 Zafirlukast (Accolate®) LTB4 receptor chemotaxis, immunomodulation LT receptor (CYSLT1) bronchoconstriction, mucus secretion, hyperresponsiveness, eosinophilia Zafirlukast: Selected adverse reactions Zafirlukast: potential drug interactions • Both terfenadine and erythromycin were reported to decrease bioavailability of zafirlukast, mechanism unknown • Zafirlukast inhibits CYP2C9 and CYP3A4 • No studies of interactions between zafirlukast and other CYP2C9 or CYP3A4 drugs (dihydropyridine Ca channel blkrs, cyclosporine, astemizole, etc.), but clearly best to avoid. • Reasonable to use therapeutic drug monitoring as appropriate…. COPD (often misdiagnosed as asthma): Approaches to treatment • Cessation of smoking !! • Oxygen therapy • Lung volume reduction surgery COPD (seventh most common reason for hospital admission in Canada): Physicians and patients view COPD differently. A 2002 study that showed that because combined therapy with inhaled corticosteroids and long-acting ßagonists produced a larger benefit than either therapy alone, it was easier to notice the difference in lung function and symptoms. • Each of these studies showed that the combination inhaler significantly reduced shortness of breath, reduced night awakenings, was associated with less use of ß-agonist reliever medications, and decreased symptom scores COPD • Mucolytics and combination inhaled corticosteroids/long acting beta-agonists • There may be a modest effect for some COPD patients - but the evidence is not strong • On the other hand, NNT was as low as 2.1 -2.4 for COPD patients treated with formoterol/budesonide to avoid one severe exacerbation over the course of one year. Tiotropium bromide (Spiriva®) HandiHaler • Recently approved for COPD • Six different phase 3 trials, over 2600 pts. • >40 y/0, >10 pack years, FEV1 < 60% predicted. • Overall, tiotropium once daily improved lung function, peak effect at about 3 hours after first dose Summary of mechanisms of drugs for asthma & COPD Limitations of drugs for asthma & COPD