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Drugs For Respiratory Disorders Bronchial Asthma & COPD Bronchial asthma It is a chronic inflammatory disease of airways where there is increased responsiveness of trachea & bronchi to various stimuli. It manifests by widespread inflammation & narrowing of the airways that chan...

Drugs For Respiratory Disorders Bronchial Asthma & COPD Bronchial asthma It is a chronic inflammatory disease of airways where there is increased responsiveness of trachea & bronchi to various stimuli. It manifests by widespread inflammation & narrowing of the airways that changes in severity either spontaneously or with treatment.  During an attack : 1. Contraction of airways smooth muscle (bronchospasm) During 2. Edema an infiltration & cellular attack :.  mucosal thickening 3. Thick viscid plugs of mucus 3) Thick mucus 2) Inflamed mucosa 1) Constricted hypertrophic muscle Normal airway Triggers of Asthmatic Symptoms Allergens - pollen, house dust, mites, animal fur, foods Respiratory infections Exercise Emotional stress Cold air Pollution - indoor and outdoor Drugs - NSAIDs, beta-blockers, Parasympathomimetics,…  Pathogenesis of asthma Edema, mucus hypersecretion, smooth muscle contraction& #bronchial reactivity Bronchoconstriction (Immediate response) (Late response) Drug Treatment of Bronchial Asthma Bronchodilators Anti-Inflammatory A. β- agonists. A. Corticosteroids. B. Methylxanthines. B. Leukotrienes C. Antimuscarinic antagonists. drugs= C. Mast cell stabilizers Anticholinergic D. MCA drugs =Muscarinic E. Alternative anti- antagonists. inflammatory drugs Bronchodilators *Mechanism Of Action: ↑Adenylate cyclase enzyme  cAMP : a- Bronchodilatation. b-  Bronchial secretion & Improve muco-cilliary clearance. c- Mast cell stabilization  Release of mediators  A- Short acting selective B2 B- Long acting selective agonists [SABA}: B2 agonists {LABA]: 1- Salbutamol. 1- Salmeterol inhalation. 2- Terbutaline. 2- Formoterol inhalation. - Used by inhalation as quick relief 3- Bambuterol oral. medications of acute attacks of - They are potent selective β2 asthma [asthma relievers]. agonists that achieve their action - - They are Given by inhalation (peak for a long duration (12 h) as a 30 min) and lasts for 3-4 hours. result of high lipid solubility. -Also, Salbutamol and Terbutaline can - Used with corticosteroids as long be given orally. term control medications of asthma [asthma controllers]. Adverse effects: 1. Tachycardia. 2. Tremors. 3. Nervous Tension. 4. Tolerance. 5. Hypokalemia due to K entery into skeletal muscles which may predispose to arrhythmias. 6. LABA may increase the risk of asthma-related death if used alone due to ischemia or arrhythmia. Therefore, they should be combined with inhaled corticosteroids. In general β2 adrenoceptor agonists are safe and effective bronchodilators when given in doses avoiding systemic adverse effects.  Ipratropium (SAMA) Tiotropium (LAMA) Atropine Derivatives  block muscarinic receptors in the airways  prevent bronchospasm & decrease mucus gland hypersecretion seen in asthma Inhaled ipratropium (atropine derivatives) is useful in patient who are unable to tolerate adrenergic agonist. Tiotropium is a long–acting antimascurinic, which is mainly used in the treatment of COPD. Provides additive benefit to in moderate or severe exacerbations in the emergency care setting  Adverse effects: bitter taste (this may compromise compliance); acute urinary retention (in patients with prostatic hypertrophy) acute glaucoma has been precipitated when nebulized doses are given via a face mask paradoxical bronchoconstriction due to sensitivity to benzalkonium chloride, which is used as a preservative They been largely replaced with 2 agonist and corticosteroids. Nonetheless Theophylline continues to have an important place in the therapy of asthma, because it appears to have anti-inflammatory as well as bronchodilator activity. Mechanism of action: 1- Inhibition of PDE-IV  cAMP & cGMP : a- Bronchodilatation. b- Mast Cell Stabilization  Release of Mediators 2- Block of Adenosine Receptors a- Bronchodilatation. b-  histamine release 3- Improve diaphragmatic contractility. Clinical use of methylxanthines: Aminophylline slowly IV relieves acute attacks of bronchial asthma and used in quick relief medications (asthma reliever). Sustained release [SR] theophylline reduces the severity and number of exacerbations in chronic asthma and used in long term control medications (asthma controller). It has a narrow therapeutic index, and overdose of drug may cause seizures or potentially fatal arrhythmia. It also interact with many drugs. Ciprofloxacin and Erythromycin should be avoided in patients who are taking theophylline, as concomitant use may result in elevated theophylline blood levels.  Anti-inflammatory I- Corticosteroids  C.O.X. Cell membrane PLA2 Arachidonic acid PG phospholipid L.O.X. LT R Bronchial asthma Inflammation * Mechanism of Action: 1-  Phospholipase A2  Arachidonic Acid (PG & LT) & PAF 2- Inhibit antibody formation & antigen/antibody reaction. 3- Inhibit the release of inflammatory cytokines as IL1,2,3,4 and TNF. 4- Anti-inflammatory &  Capillary Permeability  Inflammatory Edema of Bronchi  Airway caliber. 5- Potentiation of 2-agonists & prevents 2-receptors tolerance & tachyphylaxis.  Inhalation: For long-term control of bronchial asthma Recommended and the preferred method of administration as it avoids systemic adverse effects of corticosteroids. By inhalation of lipid soluble corticosteroids such as: (1) beclomethasone (cheapest and oldest), (2) budesonide, (3) fluticasone, (4) ciclesonide: (low molecular weight): enters small airways with high lung deposition. Is a prodrug activated by cleavage by esterases in bronchial espithelial cells. It causes less dysphonia and candidiasis than other costecosteroids. (5) Mometasone furoate. These inhalation preparations make it possible to deliver corticosteroids to the airway with minimal systemic absorption → no systemic side effects. Systemic: In acute severe asthma or when inhaled corticosteroids or other bronchodilators are not enough to control symptoms. Either oral or parenteral  Oral Prednisolone.  I.V. methylprednisolone sodium succinate or hydrocortisone sodium - Succinate. Systemic therapy can be discontinued in one week to 10 days to avoid systemic side effects.  To switch patients from oral to inhaled corticosteroid oral dose should be reduced gradually to avoid adrenal suppression. Adverse effects: Minimal with inhalation therapy (oral thrush, hoarse voice, Must wash mouth after use or use spacer with MDI High dose and Long-term adverse effects (specially with systemic use) include growth suppression in children, Hypothalamic- Pituitary-Adrenal (HPA) suppression (resembles Cushing’s syndrome), cataracts, dermal thinning, and osteoporosis (measure bone density every 3 years and consider bone protection with a bisphosphonate and calcium supplements)  Clinical use: The principal advantage of these drugs is that they are taken orally (i.e. easy to use). Montelukast is approved for children as young as 6 months: Zileuton may cause liver toxicity → least prescribed. Zafirlukast 20 mg/twice daily. Montelukast 4 mg/once daily for children, 10 mg/once daily for adults. Side effects: 1. Insomnia & Irritability 2. Vivid dreams 3. Vasculitic rash & eosinophilia (Chrug – strauss syndrome) - Prevent mast cell degranulation - Taken prophylactically - Used as aerosol - Effectively inhibit both antigen-and exercise-induced asthma - Also useful in reducing symptoms of allergic rhinoconjunctivitis - Side effect: throat irritation, cough, mouth dryness, chest tightness and wheezing, reversible dermatitis. Presentation of Asthma Acute severe Acute attack asthma Chronic BA -Patient presents -Patient presents -Mild intermittent with severe dyspnea, -Mild persistent with cough, dyspnea & wheezes. sweating, cyanosis, -Moderate persistent tachycardia. -Severe persistent  Mild Mild Moderate severe intermittent persistent persistent persistent Frequenc >twice a week Throughout once a Not >twice 7/week awakenin month, 3-4 week a month g times/mont h Management of Bronchial Asthma General measures: 1- Stop Smoking. 2- Identify the antigen 3- Treat upper respiratory tract Infection 4- Yearly administration of Influenza vaccine every winter. 5- Avoid Stress & Emotions. 6- Avoid severe muscle Exercise. 7- Avoid drugs that can precipitate asthma: NSAIDs, Non selective BB, ACEI, Parasympathomimetics, Morphine, Barbiturates   Stepwise treatment for managing asthma in Adults Maintenance and Reliever Therapy (MART): is a form of combined ICS and LABA treatment in which a single inhaler, containing both ICS and a fast-acting LABA, is used for both daily maintenance therapy and the relief of symptoms as required MART is only available for ICS and LABA combinations in which the LABA has a fast-acting component (for example, formoterol)  800 micrograms budesonide or equivalent= high dose.  Acute severe asthma Nebulized Beta 2-agonist: Repeat doses should be given at 15–30 minutes intervals, or continuous nebulization can be used where there is inadequate response to bolus therapy. Nebulized ipratropium bromide Oxygen should be given to maintain saturations at 94-98%. Patients with saturations less than 92% on room air should have an ABG to exclude hypercapnia. However, starting treatment should not be delayed to do the ABG. Steroids reduce mortality, relapses, subsequent hospital admission and requirement for β2-agonists. The earlier they are given in the attack, the better the outcome. A dose of 40-50mg should therefore be given once oxygen and nebulizer therapy has been established. This should be continued for 5 days, or until recovery, and can then be stopped abruptly unless the patient has taken long-term oral corticosteroids. Acute severe asthma Magnesium sulphate (MgSo4) IV recommended as next step for patients who are not responding to SOS (Salbutamol inhalation + Oxygen + Steroids) (e.g. 2g IV over 20 mins). The mechanism by which it has its effect is not fully understood, but it is thought that low magnesium levels in bronchial smooth muscle favour bronchoconstriction. Little evidence to support use of IV aminophylline (although still mentioned in management plans). If no response, consider IV salbutamol.  Acute severe asthma  Treatment of asthma in special populations Pregnancy and Breast Feeding:  Drugs for asthma should preferably be administered by inhalation to minimise exposure of the fetus.  β2-agonists, theophylline, and prednisolone can be taken as normal during pregnancy and breast- feeding.  Prednisolone is the preferred corticosteroid for oral administration since very little of the drug reaches the fetus.  An intravenous β2-agonists, aminophylline, or magnesium sulfate can be used in emergency during pregnancy if necessary.  Parenteral β2-agonists can affect the myometrium. Elderly:  Use of spacer with inhalers may be advised.  ICSs may have higher side effects, such as increased lower RT infections.  Avoid theophylline  Careful use of systemic β2-agonists (CV side effects)  Avoid anticholinergics (more risk of urine retention, gluacoma) Children:  Use of spacer with inhalers may be advised.  ICSs in high doses may have affect growth.  Avoid theophylline  Asthma vs COPD COPD is a chronic, irreversible obstruction of airflow. Smoking is the greatest risk factor.  Drugs for COPD Inhaled bronchodilators, such as anticholinergic agents plus 2 agonist are the foundation therapy of COPD. Longer-acting drugs combination, such as Salmeterol and Tiotropium has the advantage of less frequent dosing. Steroids: Using the inhaled anti-inflammatory steroids should be kept to the patients with moderate to sever reduction in airflow and the optimal bronchodilators has failed to improve symptoms. Oral theophylline: only recommended after trials of short and long-acting bronchodilators or to people who cannot used inhaled therapy. the dose should be reduced if macrolide or fluoroquinolone antibiotics are co-prescribed Mucolytics should be 'considered' in patients with a chronic productive cough and continued if symptoms improve   Drugs for COPD Roflumilast is a selective long-acting phosphodiesterase-4 inhibitor. It is recommended for patients who have suffered two or more exacerbations in a year, despite triple inhaled therapy, where FEV1 is less than 50% of predicted. It is orally administered. Roflumilast should be used in COPD for patients who are losing control on triple inhaled therapy Important Measures for COPD Patients: Smoking cessation advice Annual influenza vaccination Pneumococcal vaccination  COPD Chronic Management   COPD Chronic Management Factors which may improve survival in patients with stable COPD Smoking cessation - the single most important intervention in patients who are still smoking Long term oxygen therapy (LTOT; breathe supplementary oxygen for at least 15 hours a day.) LTOT is indicated in patients who fit criteria (A PO2 of < 7.3 kPa (55 mmHg) OR those with PO2 of 7.3 - 8 kPa (60 mmHg) and ONE of the following: secondary polycythaemia, pulmonary hypertension, nocturnal hypoxemia or peripheral oedema (Cor-pulmonale)). LTOT decreases secondary polycythaemia, sympathetic outflow, salt and water retention, cardiac arrhythmia and improves sleep quality due to reduced hypoxia-induced sleep arousals. Lung volume reduction surgery in selected patients Aerosol delivery devices used in asthma N.B. delivery rate of inhalations is 10-50% of labeled dose Inhaler (MDI) Spacer (to overcome dicoordination) Aerosol delivery devices used in asthma N.B. delivery rate of inhalations is 10-50% of labeled dose Nebulizer (solution for inhalation, by air jet or ultrasound) Aerosol delivery devices used in asthma N.B. delivery rate of inhalations is 10-50% of labeled dose Handihaler Diskus (DPI) Turbuhaler (dry powder for suction) Thank You 45