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BRONCHIAL ASTHMA Pharmacology and Clinical Aspects DEFINITION AB Asthma bronchiale is chronic inflammatory disease of airways connected with bronchial hyperreactivity and totally or partially reversible obstruction of airways, which in the most cases dissapears spontaneously or with treatment. ASTHMA BRONCHIALE • • • • reversible obstruction daily symptom variability family history beginning at any age, most often – 10-15% children – 5-10% adults • no smoking • allergy, rinitis, eczema - may / may not ETIOPATOGENESIS • INFLAMMATION activation of mastocytes, macrophages, eosinophils, helper Th-lymfocytes => formed and released inflammatory mediators: histamine, leucotriens, prostaglandins, bradykinin bronchoconstriction, mucus secretion, plasma exudation and bronchial hyperreactivity, airway remodelation insufficient anti-inflammatory therapy => progressive destructive changes fixing of airway obstruction to emphysematous changes Triggers of Symptoms and Exacerbations • allergens • factors of air pollution (including cigarette smoke) • respiratory infections, particularly viral (RSV, rhinoviruses, influenza viruses, chlamydia) • physical activity and hyperventilation (by osmotic processes) • wheather changes • food and drugs (ASA, NSAID, -blockers) • emotional stress • gastroesophageal reflux CLINICAL SYMPTOMS OF AB • Emphasis on early diagnosis management begins with right analysis of symptoms - to them belong: • • • • dyspnoe cough chest tightness wheezing Clasification of Asthma according to clinical symptoms and lung function: GINA DEGREE OF SERIOUSNESS SYMPTOMS DURING DAY 2002 IV. severe persistent A III. moderate persistent II. mild persistent A I. mild intermittent A sy. continuously, attacks often, physical activity limited SYMPTOMS DURING NIGHT Often PEF 60%N variability of PEF 30% 1/week PEF = 60-80%N variability of PEF 30% 2/month PEF 80%N variability of PEF = 20-30% sy. daily, attacks 2/week, influencing activity sy. 2/week daily, attacks 2/week, changing activity sy. 2/week, only mild or no attacks, aktivity unchanged LUNG FUNCTION 2/month PEF 80%N variability of PEF 30% Levels of Asthma Control GINA 2011 Assessment of current clinical control (preferably over 4 weeks) Characteristics Controlled (all Partly Controlled (any of the following) measure presented) Daytime symptoms None (twice or less / week) More than twice / week Limitations of activities None Áno Nocturnal symptoms / awaking None Áno Need for reliever / rescue inhaler None (twice or less / week) More than twice / week Lung function / (PEF or FEV1) Normal < 80 % predicted or personal best (if known) Uncontrolled Three or more features of partly controlled asthma Assessment of future risk (risk of exacerbation, instability, rapid decline in lung function, side effects) Poor clinical control, frequent exacerbations in past year, ever admission to critical care for asthma, low FEV1, exposure to cigarette smoke, high dose medications GINA 2006 CLINICAL SIGNS OF AB • depends on the stage of asthma • intermittent attacks of expiration type dyspnoe, ich worsening at night and at dawn • wheezing: intermittent, more significant at expiration • cough: usually not productive, can be basic sign • anxiety, pressure, chest tightness, dyspnoe • sputum production usually little, if than väzký mucus • prodromal signs prior attack: itching under the chin, discomfort between shoulder blades, fear, anxiety • typical is vanishing of signs after b-dilatances or antiinflammatory therapy, unsuccessful ATB th. DIAGNOSIS • PRINCIPLE: simple examinations made repeatedly are more usefull than complete examinations made at one time or during long intervals limitation of expiratory flow at asthma has variable character findings may vary from completely normal to absolutely pathological • Functional diagnostics • Allergologic diagnostics • Specifying of inflammation markers EXAMINATIONS AT AB • SPIROMETRY • BRONCHODILATION TESTS (BDT) – it verifies the degree of obstruction reversibility • BRONCHOPROVOKING TEST (BKT) – BKT with histamine, ACh, adenosine, excercise, cold... – negative BKT excludes dg. of AB (absence of bronchial hyperreactivity...) • PEF variability by výdychomerom (self monitoring) • ARTERIAL BLOOD GASES (at exacerbation) • Determination of NO in exhaled air (early marker of asthmatic inflammation) • SPUTUM EXAMINATION – eosinophils and their effective products, Curshmann´s spirals, Charcot-Leyden´s crystalls SPIROMETRY • simple, reproductible • gives informations about restriction of air flow • – FVC (forced vital capacity) – FEV1 (sec. vital cap.) – FEV3 (forced expiratory flow at 50% expiration) – FEV1/VC – Tiffaneau´s index (FEV3/VC) – PEF (peak expiratory flow in l/min) DIFERENTIAL DIAGNOSIS • • • • • chronic obstructive pulmonary disease asthma cardiale at older adults viral bronchiolitis at children hyperventilatory syndrom fixed obstacles in the airways (tumors, extramural compression, foreign particles) • diffuse interstitial lung processes • pneumothorax • chest wall diseases (kyphoscoliosis, neuromuscular diseases) COPD Asthma Bronchiale Beginning in middle age Beginning in younger age Symptoms progress slowly Symptoms from day to day changing Long anamnesis of smoking Symptoms in the afternoon or early morning Dyspnoe at excercise Also allergy, rhinitis, eczema Larger irreversible restriction Usually reversible restriction of air flow of air flow bmedzenie Family history of asthma COPD Pulmonary functions Symptoms ASTHMA Symptoms Pulmonary functions GOALS of Optimal AB Control - elimination or significant reduction of symptoms - prevention of exacerbations - maintaining lung functions closest to physiological values - maintaining normal physical and living activity - absence of treatment adverse effects - prevention of irreversible bronchial obstruction (remodelation of lower airways) - preventing asthma mortality THERAPY OF AB • Nonpharmacological – Patients´ education – avoiding risk factors and triggers- • Pharmacological – ANTIINFLAMMATORY • • relieves inflammation and bronchial hyperreactivity regular, long-term use – B R O N CH O D I L A T O R Y • • eliminates the symptoms of expiratory flow limitation rescue therapy in exacerbation Administration of Drugs at AB peroral parenteral by inhalation directly to the site of action fast beginning of action maximum efficacy lower therapeutic doses = minimalise risk of AE limitations from the site of patient (technique of inhalation, cooperation...) inspiratory resistance, needs to be overcomed Inhalatory Systems Nowadays THERAPY OF AB A: CONTROLLERS – preventive drugs, controlling inflammation – are taken regularly,long time to maintain control antiinflammatory drugs long acting inhalatory bronchodilators B: RELIEVERS substances releasing bronchospasm relieving = fast acting bronchodilators C: OTHER ANTIASTHMATIC DRUGS – – – – Monoclonal Ab against IgE = omalizumab (50 pat. in SR) Monoclonal Ab against IL-5 = mepolizumab ketotifen Imunosupressives (MTX, CysA...) A: CONTROLLERS • inhalatory corticoids ICS • long-acting 2-sympathomimetics (long-acting betaagonists ) LABA, (8-15h.) • antileukotriens LTRAs – leukotriene receptor antagonists – inhibitors of 5-lipooxygenase (zileuton) • retard methylxanthines • cromones B: RELIEVERS • inhalatory short-acting 2-sympathomimetics (short-acting betaagonists ) SABA (till 4-6 h.) • inhalatory anticholinergics short-acting • systemic corticoids p.o./i.v. („rescue“ treatment) • some sources – controllers • fast acting methylxantines INHALATORY CORTICOIDS ICS the most effective antiinflammatory antiasthmatics • to long-term use at all forms of AB • Mechanism of action: 1. inhibition of cytokine transcription antiinflam. ef. 2. inhibition of mediators of inflam. release 3. decrease of airways reactivity 4. restriction of vasodilation antioedematic ef. 5. affect synthesis of eikosanoids 6. control activation of adhesive molecules 7. increase of susceptibility resp. protection of 2 receptors against down-regulation at long-term treatment with 2 mimetics ICS • AE locally can reduce with the use of attachments and rinsing the mouth with NaHCO3 – oropharyngeal candidosis – dysphonia – seldomly irritation to cough • risk of systemic AE is , depends on dose ,efficacy and pharmacokinetic of steroid • inflammation in airways, bronchial hyperreactivity and obstruction of airways • risk of AE (acute exacerbations) and control symptoms of disease ICS • • • • beclomethasone budesonide fluticasone ciclesonide – 1 times per day, minimal syst. AE, prodrug-activation dirrectly in lungs, the part resorbed is inactive => systemic ef. !!! • mometasone Principles of Treatment with ICS 1. ICS need to be administered at each new dg. AB 2. Treatment is essential to start early 3. We administer attack doses of ICS 4. Reduction of dose only after longer stabilisation (6 months) – than minimal effective dose 5. If not sufficient ICS, we add as the drug of the first choice LABA, alternatives are leucotriene modifiers ( the first choice add-on therapy for children younger than 5 years), methylxanthines, slow release β2-agonists tablets 6. To adult patients are administered max. 200-800 mcg BDP/day and to children max. 400 mcg BDP/day, than you should start on with add-on therapy ICS in the Treatment of AB – „exacerbations“ • the best to add high dose of ICS to regular maintenance therapy ICS+LABA • at severe AE systemic CS Adverse effects of systemically administered corticosteroids • • • • • • • • • • • Infections The long-term use may increase blood pressure, cause fluid retention and salt retention in the body (oedema), increased excretion of calcium and potassium Worse and longer wound healing Rash and acne Hyperglycaemia They increase the risk of gastrointestinal perforation Increased appetite and weight gain Osteoporosis (↓ absorption of calcium, ↑ its excretion) Muscle pain, muscle weakness and muscle cramps (especially ↑ loss of potassium, ↓ calcium level in the blood) Cataract, increased intraocular pressure, optic nerve damage, eye infections CNS: irritability, mood and personality changes, depression, headaches, dizziness Management control of asthma GINA 2011 (adults and children older than 5 years) STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 Asthma education. Enviromental control. As needed SABA CONTROLLER options As needed SABA Select one Select one Select one or more Add either Low-dose ICS Low-dose ICS + LABA Medium-dose or high-dose ICS + LABA Oral glucocorticosteroid (lowest dose) Leukotriene modifier Medium-dose or high-dose ICS Leukotriene modifier Anti – IgE treatment Low-dose ICS + leukotriene modifier Sustained release theophylline Low-dose ICS + sustained release theophylline ß2- SYMPATHOMIMETICS • Mechanism of action = agonistic, activating influence on ß2 receptors of sympathic NS 1. Long-acting ß2SM (long-acting betaagonists ) = LABA – Controllers – to long-term,regular bronchodilation 2. Short-acting ß2SM (short-acting betaagonists ) = SABA – Relievers – to short-term, acute management of exacerbation β2 –sympathomimetics (LABA and SABA) speed of effect beginning SLOW Fast beginning, short duration inhal. salbutamol, fenoterol Fast beginning, long duration inhal. formoterol Slow beginning, short duration oral salbutamol rtd. cps. Slow beginning, long duration inhal. salmeterol SHORT SABA LONG LABA maintanance therapy FAST rescue treatment duration of action β2 –sympathomimetics (LABA, SABA, ultraLABA) SABA LABA ultraLABA 2x per day 1x per day Fenoterol Formoterol Indacaterol Levalbuterol Salmeterol Vilanterol Salbutamol Abediterol Terbutaline Olodaterol ß2- sympatho MIMETICS = SM activate sympathic NS dilate bronchi Anti M cholinergic = PsL block parasympa thic NS dilate bronchi Localisation of Receptors cholinergic (parasympathic) adrenergic (sympathic) LABA the best, fast and intense acting b-dilatans duration of action >12 hours MA: Bronchodilation through β2 => relaxation of smooth muscle Improve mucociliar clearens Lower vascular permeability Modulate release of mediators from mastocytes a bazophils Provide long-term safety against bronchoconstriction Length of this bronchodilation effect at long-term regular administration decreases sign of tollerance for down regulation of β2 receptors => inhibition = concomitant administration of ICS LABA in long-term therapy of asthma never can administer lonely, without ICS! Molecular mechanism of positive interaction ICS and LABA Corticosteroid ß2-Agonist ß2-Adrenoceptor Glucocorticoid receptor Anti-inflammatory effect • • Bronchodilatation Effect of corticosteroids on ß2-adrenoceptors Effect of ß2-agonists on glucocorticoid receptors LABA: zlepšenie utilizácie KS a internalizácie GR do jadra (translokácia GR) ICS: prevencia desenzitizácie a znižovania expresie β2 receptora • formoterol • salmeterol LABA Monotherapy LABA: • effectivity of LABA vs. ICS • improving sleeping, but without effect to pulmonary functions • discontinuation ICS and adding LABA at persistent asthma loosing control • good controlled patient with asthma with persistent asthma at low dose ICS replacement by LABA loosing control ( eNo and Eo in sputum) • without effect on inflam. in airways (biopsia) FDA – LABA drug safety communication 2011 • In February 2010, the agency announced it was requiring manufacturers to revise their drug labels because of an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations, in pediatric and adult patients, as well as death in some patients using LABAs for the treatment of asthma. FDA – LABA drug safety communication 2011 • The new recommendations in the updated labels state: • • • • • Use of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated (absolutely advised against) in the treatment of asthma. LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid. Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure adherence with both medications. ANTILEUKOTRIENE DRUGS • controllers, for long-term control of symptoms • antagonists of leukotriene 1 (CysLT1) receptors – montelukast, zafirlukast, pranlukast • inhibitors of 5-lipooxygenase – zileuton • taken perorally • MA: - additive antiinflam. effect to ICS - reduce tissue eosinophilia - mild bronchodilation ef. - bronchoprotective ef. ANTILEUKOTRIENE DRUGS • role in therapy of AB - still unclear • are less effective than low doses of ICS • as additive drugs (in combination with ICS) reduce the need of steroid dose at severe asthma • again less effective than standard ICS+LABA • advantageous – aspirin asthma, by excercise induced asthma, „preschool wheezing“ • compliance at taking tablet form METHYLXANTHINES • controllers, to long-lasting control of symptoms • Improvement of clinical symptomatology – bronchodilation - without signif. increase of FEV1/ improvement of lung function parameters through inhibition of fosfodiesterase I. to IV. => cAMP – antiinflam., immunomodulatory effects – positive effect on phenomenon of „corticoid resist.“ • AE: cephalea, nausea, vomiting, tachycardia, palpitations, plasm. conc. (TDM) arrhytmias, epileptic spasms even death • potential toxicity, profile of AE bronchodilators of the third choice METHYLXANTHINES Proven benefit bring only drug forms providing longlasting action with controlled release –with controlled release - p.o. • aminophylline, theophylline for using during day time always + ICS – less effective than ICS+LABA – with short-lasting ef. - p.o., i.v. • aminophylline SABA basic relievers used ad hoc to relieve or to remove symptoms no reason for regular administration • salbutamol (Ventolin) • fenoterol /Australia – deregistered for AE CVS/ INHALATORY ANTICHOLINERGIC DRUGS Relievers of the second choice, at AE competitive antagonists on M1, M2 and M3 receptors of parasympathicus cholinergic tonus Division: • with short-lasting effect: ipratropium bromide • with long-lasting effect: tiotropium bromide Muscarinic receptorys in airways Pre-gangliový nerv Parasympatické ganglion Nicotinový receptor (+) M1 receptor (+) Post-gangliový nerv M2 receptor (–) ACh M3 receptor (+) Hladký sval Barnes PJ. Eur Respir Rev 1996 INHALATORY ANTICHOLINERGIC DRUGS • • • • decrease n. vagus tonus cause relaxation but no bronchoprotective action are in general less effective than β2– mimethics and have a little slower beginning of action • advantageous combinations v 1 inhalation system: • ipratropium • ipratropium+fenoterol INHALATORY ANTICHOLINERGIC DRUGS SAMA Ipratropium LAMA LAMA 2x per day 1x per day Aclidinium Tiotropium Glycopyrronium Umeclidinium Is this patient with asthma? 5th May, 2015