ANTIASTHMATICS This study material is exclusively for students of general medicine and stomatology in Pharmacology II course. It contains only basic notes of discussed topics, which should be completed with more details and actual information during practical courses to make a complete material for test or exam studies. Which means that without your own notes from the lesson this presentation IS NOT SUFFICIENT for proper preparation for neither tests in practicals nor the final exam. Asthma bronchiale l= chronic respiratory tract inflammation l l lprevalence in CZ: lchildren 10-15 %, adults 3-5 % l Asthma bronchiale •Constriction of bronchial smooth muscles •Edematous changes on bronchial mucosa •Increased mucus production and secretion Symptoms - breathlessness caused by bronchoconstriction, oedema, bronchial inflammation and mucus - difficult expiration, prolonged expiration, whistling, creaking. - cough Patophysiology Genetic predisposition Immune response deviation Early contact with allergens environmental factors diet, mother‘s health Early sensibilisation Inducers (allergens, viruses, irritants) INFLAMMATION airways remodelation Bronchial hyperreactivity Symptoms triggers Diagnose Anamnesis – personal, familiar Clinical examinations - auscultation, signs of atopy, eosinophilia, PEF – Peak Expiratory Flow FEV – Forced Expired Volume Laboratory tests- eosinophilia, IgE Allergy testing Asthma bronchiale classification allergic non-allergic inducer contact with allergen infection psychogennic phys. activity irritation aspirin ↑ of probability young patients older patients 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 % Administration of antiasthmatics •Peroral • •Injections • •Inhalation l benefits: high drug concentration on the site of action l fast onset of effect l minimal penetration to systemic circulation = low risk of systemic AE Inhalation preparation for antiasthmatics •Aerosol dispensers – meter dose dispensers •Aerosol dispenser + spacer – children elders •Powder (spinhaler, dischaler, turbohaler) •Nebulizer l astma atma2 nebulizer turbuhaler Asthma bronchiale pharmacotherapy •Quick relief drugs – acute attack • •Long-term control medicines – between attacks Pharmacotherapy l1. Bronchodilators •β-sympathomimetics •nonselective sympothomimetics •antimuscarinics •methylxanthines l2. Anti-inflammatory agents •Glucocorticoids •Immunoprophylactics l3. Adjuvant therapy and other drugs of respiratory system •Antileucotriens •leucotriens‘ receptors antagonists. •5-LOX inhibitors •Antighistamines •Expectorants •Antitussives l •Hyposensibilisation •Anti IgE monoclonal antibodies Bronchodilators target sites on smooth muscle cells mastocyte Histamine H1 receptor vagus ACH cholinergic rcp. α - receptor cAMP β2 adrenergics β2 rcp. PDE inhibitors (methylxanthines) α blockade Antimuscarinics cromolyn, ketotifen H1 antihistamines 1. Bronchodilators β- sympathomimetics •selective stimulation of β2-Rc • •adenylyl cyclase stimulation → ↑cAMP → bronchial smooth muscles relaxation • •decrease in inflammation mediators from mastocytes • •increase in cilliar activity •Short-acting (max. 4 - 6 hrs.) l salbutamol l fenoterol l terbutaline l hexoprenaline 1. Bronchodilators β- sympathomimetics •Long- acting (12 hrs.) l prokaterol l formoterol l salmeterol l clenbuterol l bambuterol l 1. Bronchodilators β- sympathomimetics •AE: l nervousness, tremor, cephalgia, palpitation l hypokalaemia l •CI: l dysrhythmia, hypertension l (pregnancy) 1. Bronchodilators β- sympathomimetics 1.Bronchodilators Nonselective sympathomimetics epinephrine– in life-threatening situations ephedrine orciprenaline More of AE tachycardia, palpitation, dysrhythmia, hyper/hypo tension, insomnia 1. Bronchodilators Antimuscarinics •for inhalation •blocks cholinergic M receptors •to increase the effect of β2-sympathomimetics • l ipratropium l tiotropium • latropine analogues, inhalation in combination with beta-mimetics – or administration after beta-mimetics l lwhen combined with corticoids, then administered after them • •AE: dry mouth, urine retention, constipation •CI: prostate hypertrophy, glaucoma, pregnancy 1. Bronchodilators Methylxanthines •phosphodiesterase inhibitors → ↓ cAMP degradation → smooth muscle relaxation •bronchodilators, cardiostimulants, diuretics • •retarded DDF (before going to bed) l theophylline l aminophylline l ethophylline • adenosine receptor antagonists (adenosine Þ contraction, His, LT, Pg) More effects: CNS stimulation; +chrono, +inotropic effect, ¯blood viscosity and hemoperfusion (pentoxiphillin) gastric acid secretion increase AE: similar to those of non-selective sympathomimetics 1. Bronchodilators Methylxanthines Pharmacotherapy 1. Bronchodilators •β-sympathomimetics •nonselective sympothomimetics •antimuscarinics •methylxanthines 2. Antiinflammatory agents •Glucocorticoids •Immunoprophylactics 3. Adjuvant therapy and other drugs of respiratory system •Antileucotriens •leucotriens‘ receptors antagonists. •5-LOX inhibitors •Antighistamines •Expectorants •Antitussives •Hyposensibilisation •Anti IgE monoclonal antibodies 2. Antiinflammatory agents Glucocorticoids lanti-inflammatory and immunosuppressant activity (PLA2 inhibition) l •↓ cytokines, prostaglandins and leukotrienes secretion • •↓ lipolytic and proteolytic enzymes secretion • •↓ endothelial permeability l •block cell migration and decrease bronchial hypereactivity, suppress oedema • •block chronic ireversible changes development (bronchial smooth muscles hypertrofia and hyperplasia, subendothelial fibrosis and thickening of mucous basal membrane) • •increase sensivity of b adrenergic receptors to beta mimetics l 2. Antiinflammatory agents Glucocorticoids lOrally or inhalation •Inhalation l beclomethasone l budesonide l fluticasone l flunisolide l dexamethasone l mometason l ciclesonide l l AE: hoarseness, cough, oral candidosis (wash out mouth after use) 2. Antiinflammatory agents Glucocorticoids •Orally lwhen inhalation are not sufficient lin challenge doses which are gradually decreased l l prednisone l triamcinolone l betamethasone 2. Antiinflammatory agents Glucocorticoids lAE: •candidosis, risk of systemic adverse effects • •systemic: Cushing‘s sy., DM, immunosuppresion, ostoporosis, hypertension, gastroduodenal ulcers... 2. Antiinflammatory agents Glucocorticoids •mast cells membrane stabilizers •inhibit histamine release •influence on lymphocytes • l in mild forms of asthma l prevention of asthma attacks, maintenance therapy l l cromones (cromoglycate, nedocromil) l ketotifen (H1 antagonist, anti-Ach effect) l lCI: 1. trimester of pregnancy 2. Antiinflammatory agents Immunoprophylactics Pharmacotherapy 1. Bronchodilators •β-sympathomimetics •nonselective sympothomimetics •antimuscarinics •methylxanthines 2. Antiinflammatory agents •Glucocorticoids •Immunoprophylactics 3. Adjuvant therapy and other drugs of respiratory system •Antileucotriens •leucotriens‘ receptors antagonists. •5-LOX inhibitors •Antighistamines •Expectorants •Antitussives •Hyposensibilisation •Anti IgE monoclonal antibodies 3. Adjuvant therapy lAntileucotriens l for mild forms of asthma l in serious asthma in combination with corticoids la) leucotrien receptor antagonists l montelukast l zafirlukast l lb) 5-lipoxigenase inhibitors(5-LOXi) l zileuton l piriprost l docebenone l lc) both effects (antag. rcp. + i 5-LOX) l tenidap 3. Adjuvant therapy Antihistamines l2nd generation antihistamines with minimal sedative and arrhythmogenic effects l ldesloratadine llevocetirizine lfexofenadine l lketotifen •Secretolytics lbronchial gland stimulation = liquid mucus l l ammonium chloride l potassium iodide l saponines – Primula, Verbascum 3. Adjuvant therapy Expectorants •Mucolytics- decrease of mucus viscosity l l N-acetylcysteine l carbocysteine l ambroxol l bromhexine (pro-drug) l erdosteine l 3. Adjuvant therapy Expectorants •Secretomotorics lincrease cilliar activity l l essential oils: oleum eucalypti, o. menthae piperitae l bromhexine (pro-drug) l ambroxol l lOthers l guaifenesine l emetine l l 3. Adjuvant therapy Expectorants lCough = reflexive activity produced to release or clean up airways l •symptomatic therapy of irritating and exhausting cough • •do not combine with expectorants, namely secretomotorics for antagonistic effects 3. Adjuvant therapy Antitussives •Block of cough center l codein l pholcodine l ethylmorphine l dextrometorphan l levopropoxyphen l lAE: respiratory center suppression → not for children! l 3. Adjuvant therapy Codiene antitussives •Block of sensitive neurons in submucosa l dropropizine l bezonatate • •Block of afferent pathways l prenoxdiazine l 3. Adjuvant therapy Non-codeine antitussives - peripheral •Block of cough cetre, but do not suppress respiratory center l butamirate l (clobutinol – withdrawn!!!) • •Block of efferent pathways l myorelaxants l ganglioplegics l lI: surgery 3. Adjuvant therapy Non-codeine antitussives - central Anti IgE monoclonal antibodies Omalizumab: monoclonal antibody used in bronchial asthma, that was unambiguously caused by IgE. Mechanism of action: it binds to IgE, which decreases amount of circulating IgE and thus IgE can not bind to their specific receptors and trigger the allergic reaction. It is administered subcutaneously. Intended for therapy of severe persisting allergic bronchial asthma, that can not be controlled with high doses of inhalational glucocorticoids and during therapy with long-term acting inhalational β2-sympatomimetics. Disadvantage: high price. Two independent groups of investigators demonstrated a short-term bronchodilator response in healthy male volunteers to inhalation of the smoke of marijuana in concentrations of 1.0% to 2.6% Δ9THC, that was not seen after inhalation of placebo. The bronchodilator rresponse to smoked marijuana was of greater magnitude than that observed after administration of a nebulized β-agonist. → THC (ane other CB1 receptor agonist) can have local bronchodilator effects in the airway through stimulation of CB1 receptors on efferent vagal nerve endings, leading to a parasympatholytic effect. Perspective use for athma therapy. !!! CAVE: THC in form of marihuana smoke: pulmonary toxicity risk of lung, neck and head cancer Ziment I., Tashkin DPT (2000): Alternative medicine for allergy and asthma. Journal of Allergy and Clinical Immunology, 106, 603-614. THC ?