Adobe Systems Department of Pharmacology 1 Drugs used in diseases characterized by bronchial obstruction Adobe Systems 2 Bronchial asthma chronic inflammatory disease of airways affecting 300 million people all acros the globe prevalence in CZ: 8 %, in children over 10 % Characteristics: bronchial hyper-reactivity obstruction (often reversible) inflammation Symptoms: shortness of breath (bronchoconstriction, mucous plug, oedema, airway remodeling due to the inflammation) difficult and prolonged expiration → wheezing, whistling cough (especially at night or in early morning) Adobe Systems 3 Bronchial asthma ALERGIC ASTHMA NON-ALERGIC ASTHMA •allergy not present •excercire-induced, aspirin-sesitive, infectious, work-related, endogenous Adobe Systems 4 https://www.canstockphoto.com/anatomy-of-asthma-6231875.html Adobe Systems 5 Diagnose Anamnesis – personal, familiar Clinical examinations - auscultation, signs of atopy, eosinophilia, PEF – Peak Expiratory Flow FEV 1 – Forced Expired Volume Laboratory tests- eosinophilia, IgE Allergy testing Adobe Systems 6 Classification with regard to seriousness Intermittent – sign up to once a week, night symptoms up to twice a month, pulmonary function normal Mild persistent– signs no more than once daily, night symptoms up to twice a month, PEF at least 80 % Moderate persistent– signs once a day and are not permanent, night sign no more than once a week, PEF 60-80 % Severe persistent– permanent signs, daily, obstruction, PEF ≤ 60 % Adobe Systems 7 Managment of asthma the disease itself cannot be fully treated, the goal is to keep asthma under control Goals: minimalize both acute and chronic symptoms reduction of exacerbations (lessen SABA administration) improvement of the quality of life (physical activity) avoid adverse effects of the treatment Adobe Systems 8 Chronic obstructive pulmonary disease (COPD) affecting 600 million people all across the globe prevalence: 8 % risk factors: smoking, polluted air, dust and chemical vapors at workplace, genetic predisposition Characteristics: chronic inflammation caused and maintained by long-term exposure to harmful agents (irritating gases and particles) poorly reversible, progressing bronchial obstruction production of mucus Symptoms: cough (usually whole day, hardly ever only during night) expectoration shortness of breath Adobe Systems 9 Managment of COPD we can only slow the progression reduction of risk factors is necessary (mainly top quit smoking) Goals: symptom reduction improvement in physical condition and overall health state prevention of complications and exacerbations Adobe Systems 10 Administration oral, parenteral (injections, infusions) inhalation - local administration, high drug concentration at the site of action - fast onset of the effect - - minimal penetration to systemic circulation → ↓ risk of side effects Adobe Systems 11 - β2 sympathomimetics - parasympatholytics - glucocorticoids - methylxanthines - roflumilast (COPD only) - antileukotrienes - imunoprofhylactics - monoclonal antibodies - noselective sympathomimetics (epinephrine, life-saving medication) - adjuvant medication (antitussics, drugs facilitatong expectoration) BRONCHODILATATORS asthma only Drugs used in diseases characterized by bronchial obstruction Adobe Systems 12 β2 sympathomimetics MoA: selective β2 stimulants - inhibition of mediator release from mast cells + stimulation of ciliary beat frequency - diagnostics – post-bronchodilator test (salbutamol) - mostly inhaled, may be also given orally (mainly in kids) - not completely selective in their binding to β receptors long-term use = down-regulation of receptors Adobe Systems 13 β2 sympathomimetics Indication: asthma, COPD AE: nervousness, tremor, cephalgia, palpitation, hypokalemia (mainly when given orally) CI: hypertension, dysrhythmia, pregnancy Adobe Systems 14 β2 sympatomimetika Short-acting = SABA (also rapid-acting = RABA) fast onset of effect, which lasts 4 – 6 hours, inhalation salbutamol fenoterol Long-acting = LABA effect lasts for up to 12 hours, inhaled or administered orally salmeterol clenbuterol formoterol (RABA) indakaterol (U-LABA) vilanterol (U-LABA) Adobe Systems 15 Parasympatholytics MoA: competitive antagonism of M receptors - in a form of inhalation - can be combined with β2-sympathomimetics or glucocorticoids Indication: COPD, asthma AE: if entering the systemic circulation (low risk, they contain quaternary nitrogen in their structure) – anticholinergic effects CI: glaucoma, prostate hypertrophy, pregnancy Adobe Systems 16 Parasympatholytics ipratropium - used in asthma as well – in patients resistent to β2 sympathomimetic treatment (approx. 1/6 of patients) short acting (SAMA) aclidinium (LAMA) tiotropium (U-LAMA) glykopyrronium-bromide (U-LAMA) umeclidinium (U-LAMA) COPD only Adobe Systems 17 Glucocorticoids MoA: inhibition of phospholipase A2 by lipocortin Effects I: ↓ cytokine, PG a LT secretion ↓ lipolytic and proteolytic enzyme secretion ↓ endothelial permeability block of cell migration ↓ bronchial hyperreactivity, Adobe Systems 18 Glucocorticoids Effects II: reduction of edema prevention of chronic irreversible changes (hypertrophy and hyperplasia of bronchial smooth muscles, subendothelial fibrosis and thickening of mucous basal membrane) increase in sensitivity of β2 adrenergic receptors to β2-SM Adobe Systems 19 MoA at the cellular level glucocorticoid + cytoplasma receptor production of specific mRNA production of some proteins (lipocortins) Adobe Systems 20 MoA at the cellular level After entering the cell they bind to specific receptors in cytoplasm causing change of conformation = activation of receptors Complexes of corticoid + receptor are transported to cell nucleus and bind to DNA elements. The result is increased transcription of genes either inducing or inhibiting synthesis of other proteins GLC receptors are present in all tissues!!! Proteins called lipocortins are able to suppress phospholipase A Slide3 Adobe Systems 21 Antiinflammatory effect of GC AA cascade inhibition membrane phospholipids lipocortin glucocorticoids phospholipase A2 arachidonic acid Inh. 5-LOX lipooxygenase A-A NSAIDs LEUKOTRIENS cyclooxygenase PROSTAGLANDINE PROSTACYCLINES TROMBOXANES inflammation Mobilization of fagocytosis Changes in vessels permeability Inflammation Adobe Systems 22 Glucocorticoids given by inhalation lower risk of systemic adverse effects AE: affected vocal cords – croaky voice, oral candidiasis (thrush) beclomethasone budesonide fluticasone ciclesonide mometasone systemic administration orally, via injection – acute conditions, doses are gradually decreased, in severe persistent asthma – if nothing else is effective prednisone triamcinolone hydrocortisone (injection) Adobe Systems 23 Methylxanthines MoA: phosphodiesterase 1 – 4 inhibitors adenosine receptors antagonists sustained-release drug forms Effects: – bronchodilatation – cardiostimulation (+chrono, +inotropic eff. ) – diuretic eff. – CNS and respiratory center stimulation – stimulation of hydrochloric acid secretion Adobe Systems 24 Methylxanthines Effects: - substrates of CYP450 – be cautious if patient is a smoker! CI: pregnancy, epilepsy, cardiovascular disease AE: tachycardia, palpitations, sleeplessness Adobe Systems 25 Methylxanthines theophylline - combination therapy with β2 SM is convenient - becoming obsolent, therapeutic drug monitoring needed - variable pharmacokinetics, low therapeutic index aminophylline - a complex of theophylline and ethylendiamine (better solubility) - COPD, emphysema Adobe Systems 26 roflumilast selective long-acting inhibitor of phosphodiesterase 4 reduces the inflammation in bronchi in COPD Adobe Systems 27 Antileukotrienes MoA: antagonism of LT-receptors / inhibition of lipoxygenase LT receptor antagonists: treatment of persisting asthma, allows lowering of glucocorticoid dose 1-2x a day, orally montelukast Inhibitors of LOX: need for frequent application not registered in CZ (zileuton – USA) Adobe Systems 28 Imunoprophylactics (mast cells stabilizers) MoA: stabilisation of mast cell membrane → ↓ Ca2+ influx → ↓ degranulation of mast cells and thereby ↓ histamine release influence on lymphocyte function prevention of asthma attack, they do not affect already present bronchospasm Use: as preventive, long-term, maintenance therapy – mild and moderate asthma when combined with other antiasthmatics, they allow lowering of their dose CI: pregancy (1. trimester) nedokromil, ketotifen (H1 antihistamine), cromoglycate Adobe Systems 29 Monoclonal antibodies Anti-IgE omalizumab antibodies against a part of IgE, which binds to mast cells Indication: severe persistent allergic asthma, which cannot be otherwise controled administred subcutaneously in specialized centres only Adobe Systems 30 http://www.remedia.cz/Okruhy-temat/Respiracni-onemocneni/Omalizumab-terapeuticka-perspektiva-v-lecb e-tezkeho-bronchialniho-astmatu/8-1o-gD.magarticle.aspx vtextu20060906032727 Anti-IgE omalizumab Adobe Systems 31 Monoclonal antibodies Anti-IL-5 mepolizumab, reslizumab add-on treatment for severe refractory eosinophilic asthma in adult patients Adobe Systems 32 Other options Bronchial thermoplasty •bronchoskopic procedure, during which a therapeutic radiofrequency energy is delivered to the airway wall, resulting in reduction of smooth mucle cells Allergen immunotherapy •induces tolerance to the triggering allergen • • Adobe Systems 33 Devices for inhaled medications MDI = metered dose inhalers drugs as solutions, propellants BAI = breath-actuated inhalers DPI = dry powder inhalers spinhaler, diskhaler, turbohaler nebulizers (liquid → aerosol) Adobe Systems 34 Devices for inhaled medications spacers for children and elderly patient must be educated how to use their inhaler → up to 41 % of patients use incorrect technique inhalers often combine two drugs (bronchodilator + glucocorticoid or two bronchodilators) Adobe Systems 35 200905280912_meshcare_4 article_images main Adobe Systems 36 Adjuvant medication in diseases characterized by bronchial obstruction and another drugs affecting respiratory system antitussives drugs facilitating expectoration H1 antihistamines (mainly II. a III. generation)