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DRUGS FOR THE RESPIRATORY SYSTEM Dr. Henri O. de la Cruz, M.D. G lobal INitiative for A Sthma, 2008 update GOLD, 2008 Four Components of COPD Management 1. Assess and monitor disease 2. Reduce risk factors 3. Manage stable COPD Education Pharmacologic Non-pharmacologic 4. Manage exacerbations Rank 1990 Percent of Total DALYs Rank 2020 Percent of Total DALYs Lower respiratory infections Diarrheal diseases Perinatal period conditions Unipolar major depression Ischemic heart disease 1 8.2 6 3.1 2 3 7.2 6.7 9 11 2.7 2.5 4 3.7 2 5.7 5 3.4 1 5.9 Cerebrovascular disease 6 2.8 4 4.4 Tuberculosis Measles Road traffic accidents 7 8 9 2.8 2.6 2.5 7 25 3 3.1 1.1 5.1 Congenital anomalies 10 2.4 13 2.2 Malaria COPD Trachea, bronchus, lung cancer 11 12 33 2.3 2.1 0.6 19 5 15 1.5 4.1 1.8 Disease or Injury Excerpted with permission from Murray and Lopez. Am. J. Respir. Crit. Care Med., Volume 163, Number 5, April 2001, 1256-1276 Which aspect of Airflow obstruction can be addressed by drug therapy? prolonged expiratory phase & wheezing mucus secretion smooth muscle constriction airway inflammation interstitial edema inflammatory cascade Goals of therapy? RELIEVERS Direct relaxation of airway smooth muscle Sympathomimetic drugs Theophylline Reduction of cholinergic influence from vagal motor nerves Antimuscarinic agents PREVENTERS Reduction of inflammatory mediator release Corticosteroids LT receptor antagonists Long acting Sympathomimetic drugs Anti IgE and PDE4 Reduction of mast cell degranulation Cromolyn / nedrocromil Commonly Used Medications Relievers =Bronchodilators Short-acting beta-agonists Fenoterol Salbutamol (albuterol) Terbutaline inhaled/oral inhaled/oral inhaled/oral Long-acting beta-agonists Formoterol Salmeterol inhaled inhaled Short-acting anticholinergics Ipratropium Oxitropium inhaled inhaled Long-acting anticholinergic Tiotropium inhaled Methylxanthines Aminophylline Theophylline oral oral Combination inhalers Fenoterol/Ipratropium Salbutamol/Ipratropium inhaled inhaled Control of airway diameter RELIEVER MEDICATIONS SYMPATHOMIMETIC AGENTS Non-selective : epinephrine / ethylnorepinephrine ephedrine Selective B2 adrenergic agonists Salbutamol (Ventolin) Terbutaline (Bricanyl) Levalbuterol Pirbuterol Bitolterol Isoproterenol Less-selective Beta1 & 2 adrenergic agents Metaproterenol Isoetharine BRONCHODILATORS Beta adrenergic drugs • MOA: Stimulates adenylyl cyclase = cAMP = smooth muscle relaxation • Benefits of Beta receptor agonism • Relaxation of airway smooth muscle • Inhibits mediator release • May increase mucociliary transport – increase ciliary beat frequency, enhance mucus secretion, and stimulate chlorideion secretion toward the lumen, suggesting enhanced water secretion onto the airway surface. • May inhibit microvascular leakage Classification of beta agonists Mixed Beta agonists: • isoproterenol HCl (Isuprel) • epinephrine chloride (Adrenalin) Beta1 agonist activity: • norepinephrine (Levophed) • dobutamine (Dobutrex) • dopamine HCl (Intropin; Dopastat) Beta2 agonists: • albuterol sulfate (Proventil;ventolin) • metaproterenol sulfate (Metaprel) • terbutaline sulfate (Bricanyl; Brethine) • ritodrine HCl (Yutopar) R isomer (levalbuterol) • GOLD 2008: • Albuterol is a racemic mixture : equal parts of R and S albuterol, • The S isomer may have some proinflammatory effects and binds to the ß2-receptor weakly, but for a longer period. S-isomer pharmacologically inert; may increase airway hyperreactivity, inc. in eosinophil activity and histamine production – There appears to be no advantage of single dose as needed levalbuterol over other short acting bronchodilators. Meta-analysis (2007) large multicenter trials are needed to prove its therapeutic superiority and cost-effectiveness in long term. • The R isomer, or levalbuterol, is more active and produces greater bronchodilation over a longer period in Donohue, J. F. Chest 2004;126:125Sboth adults and children in long-term– 137S dosing studies J Pediatr. 2007 Feb;74(2):161-7. Levalbuterol • Selective R-isomer activity responsible for cAMP activation – Cumulative effect: diminishing effect and shorter intervals between treatment Controversies on prolonged b2 agonist Con Regular Use Of Asthma Drugs Poses Respiratory, Cardiac Dangers ScienceDaily (June 18, 2004) — ITHACA, N.Y. -- Physicians who prescribe the regular use of beta-agonist drugs for asthma could be endangering their patients, two new studies by researchers at Cornell and Stanford universities find. One study compiles previously published clinical trials to conclude that patients could both develop a tolerance for beta-agonists and be at increased risk for asthma attacks, compared with those who do not use the drug at all. The second study shows that beta-agonist use increases cardiac risks, such as heart attacks, by more than twofold, compared with the use of a Pro • Previous literature indicates that confounding by poor asthma control may explain the apparent deleterious effects of inhaled beta2-agonists. • Tolerance to nonbronchodilator effects of beta2-agonists may account for the increase in reactivity to indirect bronchoconstrictor challenges and explain why some studies have demonstrated enhanced bronchoconstriction in patients with asthma after regular beta 2-agonist therapy. • despite all of the concerns raised by the SMART, inhaled beta2-agonists remain the most effective bronchodilators available for the immediate relief of asthma symptoms and, as such, remain an important component of asthma management. J Asthma. 2008 Jan-Feb;45(1):9-18. Ther Adv Respir Dis. 2007 Oct;1(1):35-46. 2 - Adrenoreceptor Polymorphism • 13 polymorphisms identified – Expression -receptor – Down Regulation – G-protein coupling The Arg16 polymorphism of the B 2adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature = increased asthma severity, reduced bronchodilator response, • the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. NEJM 2001;345:1030-5. Mechanisms of action • decreased plasma exudation • as well as inhibition of mediator release from smooth muscle cells, mast cells, eosinophils, monocytes,1 and lymphocytes. • inhibition of smooth muscle cell and fibroblast proliferationby ß2 agonists. Beta agonist and steroid interactions • Receptor cross-talk: – cAMP response binding element (CREB) ↓CBP ↓ GR function • ↑cAMP + GC receptor + transcription of GCR • cAMP can activate protein kinase A which is able to phosphorylate an important nuclear transcription factor called cAMP response element binding protein (CREB). Phosphorylated CREB is able to bind to segments of DNA and can thus influence gene transcription, Mechanisms of action • PKA by beta agonist = Gs sarcplasmic ret.: Ca –calmodulin interaction =MLCK • Lungs: β-arrestin in agonist-promoted internalization of the M2 mAChR • J. Biol. Chem., Vol. 276, Issue 45, 42509-42513, November 9, 2001 Mechanisms of action • beta 2-adrenoceptor agonists inhibit production of ET-1 from airway EpCs = increase cyclic AMP levels in the cells • ET-1 production was shown to be elevated in asthmatic subjects and in patients suffering from other inflammatory lung disorders • arterial oxygen tension may decrease after beta-agonist use Inflammation. 2007 Jul 10 Pharmacokinetics Short Acting Beta Agonist (SABA) is the primary treatment for bronchospasm & should be administered by inhalation repetitively or by continuous administration Onset of action <5min & repetitive administration produces incremental bronchodilation 2/3 of asthmatics respond well enough to albuterol to be discharged from ED after three 2.5mg doses of nebulized albuterol every 20minutes – Strauss & et al BRONCHODILATORS Beta adrenergic drugs ORAL INHALED • Peak effect 2-3 h 0.5-2 h • Duration 4-6 h 3-4 h • Half life 3.8 h 3.8-5 h • Metabolism: sulfide liver conversion to inactive Pharmacogenomic considerations in beta agonist use • Asthma Clinical Research Network has shown that persons with the arg/arg mutation at position 16 of the ß-receptor gene who regularly use SABAs such as albuterol have a decrease in lung function further exacerbated by withdrawal of the drug. • patients with the B16-Arg/Arg polymorphism may be at risk for adverse effects, or less of a salutary effect, when using -agonists regularly. Am J Respir Crit Care Med 2000;162,75-80 SALBUTAMOL BRONCHODILATORS Adverse effects TERBUTALINE > 10% > 10% tachycardia, palpitations, nervousness, restlessness, trembling GI upset nausea 1-10 % 1- 10 % tachycardia, hypertension, dizziness, drowsiness h/a insomnia; flushing of face, hpn, hypotn nervousness, CNS stimulation, hyperactivity, insomnia, dizziness muscle cramps, weakness xerostomia, N/V, bad taste; diaphoresis lightheadedness, drowsiness, h/a; tremors; weakness; muscle cramping <1% coughing; dysuria; diaphoresis; paradoxical bronchospasm; < 1% hypokalemia chest pain; loss of appetite; paradoxical bronchospasm; hypokalemia chest pain; loss of appetite; BRONCHODILATORS Beta adrenergic drugs • Drug interactions effects: TCAs; MAO inh.; sympathomimetics effects: Beta adrenergic blockers • Pregnancy risk factor C (risk cannot be ruled out) • Tolerance • downregulation of beta 2 receptors on chronic use; more on oral route • Duration of action more affected than peak effect Systemic beta agonists No advantage to subcutaneous epinephrine or terbutaline over inhaled albuterol in initial treatment of SAE Indications: Inability to comply with inhaled therapy because of altered mental status or near arrest situation Poor response to several hours of inhaled therapy, subcutaneous epinephrine maybe helpful Coronary artery disease relative contraindication IV administration is not recommended Combination of inhaled & parenteral treatment have not been adequately evaluated BRONCHODILATORS Beta adrenergic drugs Dose Preparations Salbutamol Aerosol 100 mcg/dose (200 doses) Rotacaps 200 mcg Terbutaline Injectable Aerosol 0.2 mg/dose Solution, inh.: 5 mg/ml Turbohaler 500mcg Syrup 2mg/ 5ml Tab 2.5, 5 mg Tab 2, 4 mg Tab, ext release 4, 8 mg BRONCHODILATORS Anticholinergics: IPRATROPIUM MOA: quaternary nitrogen blocks Ach at parasympathetic sites in bronchial smooth muscle causing bronchodilation Anticholinergic Mechanism of Bronchodilation • Competitive block of the M3 receptor subtype inhibits Gs protein, that in turn inhibits phospholipase C (PLC). – PLC causes a breakdown of phosphoinositides into inositol triphosphate (IP3) and diacyl glycerol (DAG). – This leads to an increase in cytoplasmic [Ca++] and smooth muscle contraction and glandular secretion. • Blockade of M1 receptors prevents transmission of nervous impulse to neuroeffector site. Responses to albuterol sulfate and ipratropium bromide Donohue, J. F. Chest 2004;126:125S-137S Clinical data supports adding ipratropium bromide to albuterol in the initial treatment of SAE Rodrigo & Rodrigo demonstrated combination albuterol & ipratropium had a 20.5%-48% improvement in FEV1 & PEF Rate of hospitalizations decreased significantly from 39% alone to 20% combination Clinical benefits May be sl. less effective than beta-agonist drugs in reversing bronchospasm Probably equally effective for COPD pts. In acute severe asthma: enhances effect of salbutamol Valuable in pts. Intolerant of inhaled beta-agonist drugs NIH: esp. effective in management of asthma in the elderly Treatment of choice for betablocker induced bronchospasm BRONCHODILATORS Anticholinergics: TIOTROPIUM • MOA: subtype-selective competitive binding of Ach receptors = antagonist of Ach; M3 & M1> M2 • Out of M1-M5 receptors in the body only M1-M3 are found in the lung • M3: mediate bronchoconstrictor and mucus secretory response to Ach IPRATROPIUM, TIOTROPIUM VS. LABA In head-to-head comparisons, short-acting anticholinergics such as ipratropium are less potent than LABAs and long-acting anticholinergics such as tiotropium.56 Anticholinergics in COPD are useful when combined with SABAs and/or theophyllines. Anticholinergics, particularly when administered by nebulized solution or by metered-dose inhaler and spacer in higher doses such as four puffs every 4 h, are useful in acute attacks of asthma and COPD. The longer-acting agents such as tiotropium are effective in stable patients with COPD for up to 24 h. In COPD, it appears that the longer-acting anticholinergic agents are superior to salmeterol, ipratropium, or placebo. In asthma, tiotropium bronchoprotects for up to 48 h. BRONCHODILATORS Anticholinergics: IPRATROPIUM Adverse effects 10 % Nervousness, dizziness, fatigue h/a Nausea, xerostomia, stomach upset 1-10 % Palpitations, hypotension, insomnia, trembling, blurred vision Urinary retention, nasal congestion <1% Rash, urticaria, stomatitis Pregnancy risk Factor B ( no evidence of risk in humans) BRONCHODILATORS Anticholinergics: IPRATROPIUM • Onset: 1-3 min after administration • Peak: 1.5-2 hrs • Duration: 4-6 hrs • Prep: inh 18 mcg/actuation nasal spray 0.03%, 0.06% nebulizing: 0.02 % / 2.5 ml BRONCHODILATORS Anticholinergics: TIOTROPIUM Adverse effects 3% dry mouth, dyspepsia, vomiting, abdominal pain, myalagia, pharyngitis, rhinitis, URTI; UTI; rash 1- 3 % allergic reaction leg pain, dysphonia, paresthesia, GERD, stomatitis, hypercholesterolemia, hyperglycemia, skeletal pain, angina, depression, laryngitis, cataract < 1% AF, SVT, angioedema BRONCHODILATORS Anticholinergics: TIOTROPIUM • Peak: 1.5 – 2 hrs • Duration: 540 hrs • Poorly absorbed thru GIT • Prep: Handihaler 18 ug/dose OD - BID BRONCHODILATORS THEOPHYLLINE MOA: - ?blocks phosphodiesterase inc. cAMP enhanced calcium influx = epi release bronchodilatation / gastric acid secretion / cardiac stimulation - low doses: inc. catecholamine release secondary to inhibition of presynaptic adenosine receptors prevents mooth muscle contraction & histamine release fr. Lung cells - anti-inflammatory action: low dose theophylline inhibits late response to antigenic challenge cAMP ATP Adenylyl Cyclase + Gs Gi AMP Phosphodiesterase - Theophylline Theophylline BRONCHODILATORS THEOPHYLLINE Adverse effects: 15 – 25 mcg/ml: GI upset, diarrhea, N/V, abdominal pain, nervousness, h/a, insomnia, agitation, dizziness, muscle cramp, tremor 25 – 35 mcg/ml: tachycardia, occasional PVC > 35 mcg : Vtach; frequent PVC, seizures Others: weak diuretic effect; unknown mechanism + reduced blood viscosity (e.g. pentoxifylline) Meta-analysis of 15 adult studies did not result in any additional bronchodilation compared with standard care with beta agonist Pregnancy risk factor C (risk cannot be ruled out) BRONCHODILATORS THEOPHYLLINE Drug interactions levels (induction of microsomal enzymes): barbiturates, carbamazepine, charcoal, high protein / low carbohydrate diet, hydantoins, isoniazid, rifamipicin, smoking, sympathomimetics, ketoconazole levels: allopurinol, beta blockers, calcium channel blockers, CS, hepatic cirrhosis, ciprofloxacin, cor pulmonale, macrolides, isoniazid, oral contraceptives, thyroid hormones BRONCHODILATORS THEOPHYLLINE • Preparations: • Aminophylline (IV): may be added after the first hr. if with no relief with beta blocker • Immediate release theophylline 100 mg, 200 mg • Timed release – 8-24 hrs (Theodur) 100 mg, 200 mg, 300 mg, 450 mg – 24 hrs (Unidur) 400 mg, 600 mg • Dietary precautions • Avoid caffeine containing food or beverages • Avoid extremes of dietary protein, carbohydrate, charcoal intake • Adm. with water 1 hr before or 2 hrs after meals Bronchodilators Epinephrine & Ephedrine • Epinephrine • Rapidly acting bronchodilator: SQ / IV / inhalation, intratracheal • Useful in asthma emergencies • Side-effects: B1 and B2 receptor activation: - tachycardia - other arrythmias - exacerbate angina • Ephedrine • Relative to Epi: - longer duration - orally active - more CNS effects - low potency • Infrequently used Risk Factors for Fatal or Near Fatal Asthma Frequent ED visits Frequent hospitalizations Intensive Care admissions Prior Intubation Hypercapnia Barotrauma Psychiatric Illness Medical Noncompliance Illicit drug use Low socioeconomic status Inadequate access to medical care Use of > 2 canisters of SABA/month Poor perception of airflow obstruction Comorbidities such as coronary artery disease PREVENTER MEDICATIONS PREVENTERS Corticosteroids Anti-leukotrienes Prednisolone, Betamethasone Montelukast, Zafirlukast Beclomethasone, Budesonide Fluticasone Xanthines Theophylline SR Long acting 2 agonists Mast cell stabilisers Bambuterol, Sodium cromoglycate Salmeterol Formoterol COMBINATIONS Salmeterol/Fluticasone Formoterol/Budesonide Salbutamol/Beclomethasone Asthma Inflammation: Cells and Mediators Source: Peter J. Barnes, MD Cigarette smoke Biomass particles Particulates Pathogenesis of COPD Host factors Amplifying mechanisms LUNG INFLAMMATION Anti-oxidants Oxidative stress Anti-proteinases Proteinases Repair mechanisms COPD PATHOLOGY Source: Peter J. Barnes, MD Oxidative Stress in COPD Macrophage Neutrophil Anti-proteases SLPI 1-AT NF-B Proteolysis IL-8 ↓ HDAC2 O2-, H202 OH., ONOO- ↑Inflammation Steroid resistance Isoprostanes Plasma leak TNF- Neutrophil recruitment Bronchoconstriction Mucus secretion Source: Peter J. Barnes, MD Asthma Pathways Environment Normal Airway Function Remodeling Genetic Predisposition Asthma Origins Epithelial Injury Injury Matrix Deposition Repair Angiogenesis Remission, Persistence Predisposition Progression or Regression?Genetic for Remodeling Smooth Muscle Hypertrophy/Hyperplasia Lazaar AL, Panettieri R. Am J Med. 2003;115:652-659. Models of Disease Progression from Childhood to Adulthood 100 A. Normal: remains normal FEV1 (% Predicted) 90 A B 80 C 70 D C. Begins normal: rapid decline early on resulting in severe obstruction 60 50 40 0 B. Begins normal: steep slope resulting in severe obstruction over time 5 10 15 20 30 40 50 60 70 Age (Years) Szefler SJ. J Allergy Clin Immunol. 2005;115:685-688. D. Begins with low values and continues with low lung function Inflammatory mechanisms in COPD Barnes, P. J. Chest 2000;117:10S-14S Levels of Asthma Control Characteristic Daytime symptoms Controlled Partly controlled (All of the following) (Any present in any week) None (2 or less / week) More than twice / week Limitations of activities None Any Nocturnal symptoms / awakening None Any Need for rescue / “reliever” treatment None (2 or less / week) More than twice / week Lung function (PEF or FEV1) Normal < 80% predicted or personal best (if known) on any day Exacerbation None One or more / year Uncontrolled 3 or more features of partly controlled asthma present in any week 1 in any week REDUCE LEVEL OF CONTROL TREATMENT OF ACTION maintain and find lowest controlling step partly controlled consider stepping up to gain control INCREASE controlled uncontrolled exacerbation step up until controlled treat as exacerbation REDUCE INCREASE TREATMENT STEPS STEP STEP STEP STEP STEP 1 2 3 4 5 Therapy at Each Stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe FEV1/FVC < 70% FEV1/FVC < 70% FEV1 > 80% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted FEV1/FVC < 70% 30% < FEV1 < 50% predicted FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long term oxygen if chronic respiratory failure. Consider surgical treatments Improving Asthma Control Goals of long-term control therapy Prevent symptoms Improve pulmonary function Reduce inflammation Resolve and prevent progression Airway inflammation Mast cells – Classic Model - IgA Ab bind to mucosal mast cells a. Ag-Ab interaction on mast cell surface b. release of mediators = early reaction Histamine Trytase / other neutral proteases Leukotrienes C4 and D4 PAF PG D2 RELIEVER MEDICATIONS CROMOLYN Na / Nedocromil Adverse effects: 10 % unpleasant taste; hoarseness; coughing 1-10% angioedema; xerostomia; dysuria; sneezing; nasal congestion < 1% dizziness, h/a, rash, urticaria, n/v, diarrhea, arthralgia, ocular stinging, lacrimation, wheezing, throat irritation, eosinophilic pneumonia, pulmonaryinfiltrates, nasal burning, anaphylactic reactions Pregnancy risk factor B (no evidence of risk in humans) Airway inflammation • Eosinophils • Impt. in infiltrative component • MBP and ECP: destroy airway epithelium cells • Lymphocytes • TH1 cytokines: IL-2 + IF B cell activation • TH2 cytokines: IL-4 and IL-5 eosinophil attraction & act. IgE production by B cells • IL-5 = eosinophil proliferation basophil granule release Airway inflammation Other cells: Neutrophils Macrophages Endothelial cells Epithelial cells Mediators (histamine; bradykinin; LT C, D, E; PAF; PGE2, PGF2a; PGD2): Bronchoconstriction Vascular congestion Edema mucus production / impaired mucociliary transport Reversible airflow limitation in COPD • Accumulation of inflammatory cells, mucus and plasma exudate • Smooth muscle contraction in peripheral and central airways • Dynamic hyperinflammation RELIEVER MEDICATIONS CORTICOSTEROIDS (CS) Mechanisms 1o Anti-inflammatory effect: prevents migration of eosinophils, PMN, fibroblasts Inh. of cytokine production Lysosomal stabilization at the cellular level Reverses capillary permeability 2o enhancement of beta-receptor agonist effects RELIEVER MEDICATIONS CORTICOSTEROIDS (CS) • BENEFICIAL EFFECTS • Diminish bronchial reactivity; Increase airway diameter in acutely ill pts. • In asthma - Reduced frequency of asthmatic exacerbations; - pts not adequately maintained or worsening on bronchodilator therapy • in COPD: - inhaled CS for symptomatic pts. with a documented spirometric response or with an FEV1 < 50% predicted with repeated exacerbations req. tx with oral steroids (Evidence B, GOLD) - chronic tx with systemic CS should be avoided because of an unfavorable risk-to-benefit ratio (Evidence A, GOLD) RELIEVER MEDICATIONS CORTICOSTEROIDS (CS) • In vitro effects of corticosteroids on remodelling processes • Decreased smooth muscle proliferation88–91 • Increased or decreased smooth muscle fibronectin production, depending on steroid92 • Decreased smooth muscle cytokine synthesis93,94 • Decreased fibroblast TGFß expression95 • Decreased fibroblast collagen gene expression96,97 Advantages of steroids in acute exacerbations • use of corticosteroids within 1 hr of arrival to ED reduces the need for hospitalization & benefits are greatest in pts with the more severe asthma & those not taking corticosteroids • Decrease the number of relapses in first 710days & number of asthma deaths • Speeds rate of recovery in hospitalized patients RELIEVER MEDICATIONS CORTICOSTEROIDS (CS) • Increased or decreased fibroblast proliferation98–104 • Increased expression of SLPI (secretory leukocyte protease inhibitor) by epithelial cells105 • Decreased VEGF expression by epithelial cells106 • Reduced adhesion molecule expression by endothelial cells, fibroblasts, and epithelial cells107–109 • Reconstitution of epithelial structure110 • Decreased mucus production111 • Decreased expression of cytokines and chemokines by a variety of cells87 IV vs. ORAL vs. INHALED NIH recommends 40-80 mg/day of either prednisone, methylprednisolone or prednisolone in 1 or 2 divided doses until PEF reaches 70% of personal best No known advantage for higher doses of corticosteroids in SAE, nor is there any advantage for IV over oral therapy provided GI absorption is not impaired Total course of corticosteriods for an asthma exacerbation may last from 3-10 days Corticosteroid courses < 1week, there is no need to taper the dose Slightly longer course (3-10 days) probably does not need to taper, especially if patient is taking ICS ICS can be started any point in treatment Estimate Comparative Daily Dosages for Inhaled Glucocorticosteroids by Age Drug Low Daily Dose (g) > 5 y Age < 5 y Medium Daily Dose (g) > 5 y Age < 5 y Beclomethasone 200-500 100-200 >500-1000 >200-400 Budesonide 200-600 100-200 600-1000 >200-400 Budesonide-Neb Inhalation Suspension Ciclesonide 250-500 80 – 160 High Daily Dose (g) > 5 y Age < 5 y >1000 >1000 >500-1000 >400 >400 >1000 80-160 >160-320 >160-320 >320-1280 >320 Flunisolide 500-1000 500-750 >1000-2000 >750-1250 >2000 >1250 Fluticasone 100-250 100-200 >250-500 >200-500 >500 >500 Mometasone furoate 200-400 100-200 > 400-800 >200-400 >800-1200 Triamcinolone acetonide 400-1000 400-800 >1000-2000 >800-1200 >2000 >400 >1200 Drug Equivalent Pharmalogic dose (mg) Biological Half life (hrs) Hydrocortisone (solucortef) 20 mg 8-12 hr Cortisone 25 mg 8-12 hr Prednisone 5 mg 24-36 hr Solumedrol methylprednislone 4 mg 24-36 hr Dexamethasone (decadron) 0.75 mg 36-54 hr Therapy at Each Stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe FEV1/FVC < 70% FEV1/FVC < 70% FEV1 > 80% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted FEV1/FVC < 70% 30% < FEV1 < 50% predicted FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long term oxygen if chronic respiratory failure. Consider surgical treatments RELIEVER MEDICATIONS CORTICOSTEROIDS (CS) • Advantages of inhaled CS - reduces / eliminates need for oral CS - improvement in pulmonary fcn in pts with mild to severe asthma - reduced bronchiole reactivity *- reduced risk of adrenal suppression & reduced risk of adverse effects RELIEVER MEDICATIONS CS Adverse effects >10% respiratory infection, rhinitis 1-10% Resp: bronchitis, bronchospasm, cough, epistaxis, nasal irritation, sinusitis, stridor; GI: oral candidiasis; taste perversion, weight gain, abdominal pain, anorexia, diarrhea, dry mouth, dyspepsia; bruising, Skin: c.dermatitis, eczema, pruritus, rash, CNS: insomnia, migraine, nervousness, emotional lability, migraine, back and chest pain, headache; Others: allergic rxn; flu-like syndrome; infection; voice alteration; cervical lymphadenopathy; arthralgia, fracture, hypertonia RELIEVER MEDICATIONS CORTICOSTEROIDS (CS) < 1% facial swelling, palpitations, aggressive reactions, anxiety, depression, irritability, angioedema, avascular necorsis of the femoral head, dyspnea, reduced sense of smell, hoarseness, osteoporosis, cataract formation May cause adrenal suppression: oral doses should be tapered May cause a reduction in growth velocity in pediatric pts. Immunosuppression risk shld be considered esp. in pts. with systemic infection Pregnancy category C (risk cannot be ruled out) ATS copd guidelines Chemical Structures Formoterol O HN O HO N H OH Salmeterol HO HO O N H OH BRONCHODILATORS Beta adrenergic drugs Formoterol • a long-acting beta-agonist with a shorter onset of action than salmeterol (3-5 minutes vs. 10-20 minutes). • The duration of action of formoterol is 12 hours. INDACATEROL: ultra-long acting beta agonist Eur Respir J. 2007 May;29(5):871-8. Epub 2007 Jan 24. β2 Receptor Binding for Formoterol and Salmeterol • Both molecules bind to the β2 adrenergic receptor active site, however – Prolonged salmeterol activity depends on binding with an exosite – Prolonged activity of formoterol is independent of exosite binding • Mutation in the exosite region (Ile 164) could affect duration of action of salmeterol Green SA, et al. J Biol Chem. 1996;271:24029-24035. Long acting beta agonists • Meta-analysis of 9 studies comparing salmeterol with doubling the dose of inhaled steroid showed that salmeterol improved symptoms and lessened the need for rescue medication. • Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma. BMJ 2000;320:1360-73. “Patients with moderate to severe symptoms of COPD require combination of bronchodilators” “Combining bronchodilators with different mechanisms and durations of actions may increase the degree of bronchodilation for equivalent or lesser side effects’’ GOLD Report 2008 Algorithm for the management of COPD Mild assess with symptoms and spirometry Short acting bronchodilator – as required Tiotropium Long acting beta agonist LABA + tiotropium Tiotropium+LABA Severe Add -Inhaled steroids -Theophylline LEUKOTRIENE PATHWAY INHIBITORS Factors involved in the pathophysiology of Salvi, S. S. et al. Chest 2001;119:1533-1546 Asthma Pathology Allergen Macrophage/ dendritic cell Th2 cell Mast cell Leukotrienes C4, D4 & E4 Neutrophil Eosinophil Mucus plug Nerve activation Epithelial shedding Subepithelial fibrosis Plasma leak Oedema Mucus hypersecretion Hyperplasia Barnes PJ Vasodilatation New vessels Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy/hyperplasia RELIEVER MEDICATIONS LEUKOTRIENE PATHWAY INHIBITORS Leukotriene mediators: Synthesized by inflammatory cells found in the airway: eosinophils macrophages mast cells basophils Effects of LT B4, C4 and D4: • Bronchoconstriction • mucosal edema • mucus hypersecretion • increase bronchial hyperreactivity Phospholipid Corticosteroids Phospholipase A2 5-lipoxyenase Arachidonic acid Cyclooxygenase (PGI2) Leukotriene PGE2 PGH2 PGF2 Diagrammatic representation of the steps involved Salvi, S. S. et al. Chest 2001;119:1533-1546 RELIEVER MEDICATIONS LEUKOTRIENE PATHWAY INHIBITORS • 5-Lipoxygenase inhibitors – Zileuton • Inhibitor of LT-D4 receptor binding – Zafirlukast – Montelukast – Pranlukast • pranlukast may inhibit NF-kappaB activation and MUC2 gene transcription through pathways distinct from cysLT(1) receptor antagonism in cultured human epithelial cells. (Pharmacology. 2005 Feb;73(2):89-96.) ZAFIRLUKAST MONTELUKAST PRANLUKAST RELIEVER MEDICATIONS LEUKOTRIENE PATHWAY INHIBITORS ZILEUTON 5 lipoxygenase inhibitor Use: prophylaxis and chronic tx of asthma in adults & pts > or = 12 yrs of age Not indicated for reversal of bronchospasm in acute exacerbations of asthma Peak: 1-2 hrs Half life: 2.5 hrs dose: 600 mg qid with meals and at bedtime RELIEVER MEDICATIONS LEUKOTRIENE PATHWAY INHIBITORS MONTELUKAST (Singulaire) inh. of LTD4 receptor binding Use: modestly effective for maintenance tx of adults & children with intermittent / persistent asthma; no use in acute exacerbations of asthma Less effective than inhaled steroids May be added to oral / inh. CS to improve asthma pts with aspirin intolerant asthma Only LT drug approved for use in children 6 – 12 yrs old RELIEVER MEDICATIONS LEUKOTRIENE PATHWAY INHIBITORS • Adverse effects > 10 % headache 1 – 10% dizziness, fatigue, fever; rash; Dyspepsia, dental pain, gastroenteritis; abd pain Weakness; Cough; Flu-like S/S Churg Strauss vasculitis • Pregnancy category B (no evidence of risk in humans What is the clinical efficacy of LEUKOTRIENE PATHWAY INHIBITORS • No evidence of benefit in COPD. GOLD 2008 • Alternative treatment for mild persistent asthma • Effect is generally less than that of low dose inhaled CS; Cannot be substituted for low dose CS therapy for those on inhaled CS therapy; • Requires monitoring for hepatic toxicity • Adverse effects: >10 % h/a; inc. ALT 1- 10% chest pain, dizziness, fever, insomnia, malaise, nervousness,dyspepsia, nausea, abd. pain, constipation, flatulence, myalgia, arthralgia, weakness, conjunctivitis, low white blood cell count RELIEVER MEDICATIONS CROMOLYN Na / Nedocromil • MOA: mast cell stabilizers by altering fcn of delayed chloride channels • Cl-mediated channel effects: - inhibition of cough - inhibition of early response to antigens (mast cells) - inhibition of late response to antigens (eos) RELIEVER MEDICATIONS CROMOLYN Na / Nedocromil Use: - prophylaxis with chronic tx = reduces need for bronchodilators in pts with perennial asthma = effective in reducing symptoms of allergic rhinitis/asthma & hay fever = prevention of exercise-induced asthma No direct effect on airway muscles; will not reverse bronchospasm Blocks bronchoconstriction due to Ag inhalatation or aspirin ingestion Anti-IgE antibodies Omalizumab • Addition of anti-IgE treatment to other controller medications improves control of allergic asthma when control has not been achieved on other medications (Evidence A) • Mech: inhibits the binding of IgE to the high-affinity IgE receptor (FceRI) on the surface of mast cells, basophils, and dendritic cells. – it cannot interact with IgE that is already bound to cell surfaces and thus cannot induce degranulation of mast cells or basophils.8,13 Instead, omalizumab binds to circulating IgE, regardless of allergen specificity, forming small, biologically inert IgE–anti-IgE complexes without activating the complement cascade.8,12,14 – An 89 to 99 percent reduction in free serum IgE (i.e., IgE not bound to omalizumab) occurs soon after the administration of omalizumab, and low levels persist throughout treatment with appropriate doses Anti-IgE antibodies Omalizumab • Indication: moderate-to-severe, persistent allergic asthma even with inhaled steroids • injectable dosage form, every 2 to 4 weeks • $4 000 to $20 000 per year (ave $12 000.00) Omaluzimab: Efficacy • Among patients in a clinical trial who had had a response to omalizumab by 16 weeks, 87 percent had done so by 12 weeks. • ¾ RCT trials, treatment with omalizumab as compared with placebo was associated with significantly fewer exacerbations of asthma per patient, and a significantly lower percentage of patients had an exacerbation. In addition, the dose of inhaled corticosteroids required to control symptoms was significantly less among patients treated with omalizumab than among those who received placebo. • no significant effect on the frequency of exacerbations was seen, although the dose of inhaled corticosteroids required to control symptoms was significantly lower among patients treated with omalizumab. • there is considerable variability of response to omalizumab therapy Strunk, NEJM, 2006Volume 354:2689-2695 Anti-IgE antibodies Omalizumab • Adverse effects: injection site reaction (45%), viral infections (23%), upper respiratory tract • infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). • an increased (0.5%) malignancies of various types, compared with patients who received the placebo drug (0.2%), possible induction of Churg-Strauss syndrome, nasal polyps and adrenal insufficiency Phosphodiesterase4 inhibitors Roflumilast • 4 form (PDE4). Inhibition of this enzyme prevents cAMP breakdown and thereby increases its intracellular concentration. • increased cAMP in smooth muscle causes relaxation • predominant isoenzyme in the majority of inflammatory cells, with the exception of platelets, implicated in inflammatory airways disease. It is expressed in the airways smooth muscle, brain and cardiovascular tissues Phosphodiesterase4 inhibitors • asthma, COPD, allergic rhinitis, psoriasis, multiple sclerosis, depression, Alzheimer's disease and schizophrenia. • roflumilast is equivalent to taking inhaled beclomethasone diproprionate in the treatment of mild to moderate asthma, suggesting that such drugs may prove to be a viable alternative therapy to inhaled glucocorticosteroids (reviewed by Lipworth, 2005). • ventricular arrhythmias in about 12% of patients, some of which may be life-threatening. Headaches and hypotension occur in about 3% of patients. Allergen-specific Immunotherapy The role of specific immunotherapy in asthma is limited Specific immunotherapy should be considered only after strict environmental avoidance and pharmacologic intervention, including inhaled glucocorticosteroids, have failed to control asthma Perform only by trained physician Component 1: Develop Patient/Doctor Partnership Key factors to facilitate communication: Friendly demeanor Interactive dialogue Encouragement and praise Provide appropriate information Feedback and review Component 2: Identify and Reduce Exposure to Risk Factors Measures to prevent the development of asthma, and asthma exacerbations by avoiding or reducing exposure to risk factors should be implemented wherever possible. Asthma exacerbations may be caused by a variety of risk factors – allergens, viral infections, pollutants and drugs. Reducing exposure to some categories of risk factors improves the control of asthma and reduces medications needs. SUMMARY Bronchoconstriction may be due to - direct mediator effects - activation of neuronal / humoral pathways The reversible components of COPD may respond to therapy BUT none of these will alter the long-term decline in lung function (Evidence A, GOLD) Pharmacological approaches must have multiple mechanisms In the pipeline … In the pipeline Mediator antagonists Leukotriene B4 (LTB4) antagonists: LY29311, SC-53228, CP105696, SB 201146, BIIL284 5'-lipoxygenase inhibitors: zileuton, Bay x1005 Chemokine inhibitors Interleukin-8 antagonists: CXCR2 antagonists, e.g. SB225002 Monocyte chemotactic protein (MCP) antagonists (CCR2 antagonists) Tumour necrosis factor (TNF) inhibitors: monoclonal antibodies, soluble receptors, TNF- converting enzyme inhibitors Antioxidants: e.g. stable glutathione analogues Inducible nitric oxide synthase (iNOS) inhibitors: e.g. L-N6-(1imminoethyl)lysine (L-NIL) The inflammatory cascade in asthma Salvi, S. S. et al. Chest 2001;119:1533-1546 Oxygen Low flow oxygen by nasal cannula is recommended to maintain arterial oxygen saturation >90% – >95% in pregnant women & coexistent heart disease Improves oxygen delivery to peripheral tissues, reverses hypoxic pulmonary vasoconstriction & may stimulate bronchodilation Antibiotics are not generally recommended for the treatment of acute asthma exacerbations Reserved for patients who have fever & purulent sputum & have strong evidence of pneumonia Presence of bacterial sinusitis Bacterial infections usually do not contribute to asthma exacerbations “The aim of (pulmo-active) therapy is to maintain control with the least amount of medication and hence minimal risk for adverse effects.” NHBLI Guidelines • Most men die of their remedies, not of their illnesses. - Moliere