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Respiratory Pharmacology Medications used for Asthma and COPD and more! By Tulika Nahar Queen’s University of Belfast 3 year Medical Student 18 February BRITISH INDIAN MEDICAL @ BRITISHINDIANMEDICASSOCIATION @BINDIANMEDICS ASSOCIATION @BIMA BIMA Preclinical seriesWHO AM I Third year medical student Interested in internal medicine and paediatrics Fun fact: I have changed schools almost seven times throughout my life and lived in India and Dubai and now Northern Ireland Your pictureTOPICS COVERED I. Short and long-acting bronchodilators II. Methylxanthines III. Corticosteroids IV. Leukotriene antagonists V. Mast cell stabilizers VI. SBAs asthma pulmonary fibrosis sarcoidosis COPD What are the most pulmonary embolism URTI common respiratory disorders? pneumothorax lung cancer pneumoniaRespiratory Tract Anatomy Airway smooth muscle tone: 1. Sympathetic innervation 2. Parasympathetic innervation 3. Non-adrenergic non-cholinergic nerves (NANC) Sympathetic = dilate the airways and pulmonary blood vessels Neurotransmitter: Adrenaline, Noradrenaline Receptor: b2, a1 Parasympathetic = constrict the airways, mucus secretion Neurotransmitter: Acetylcholine M1, M3or:Mechanism of Bronchoconstriction & BronchodilationAsthma pathophysiology Chronic inflammatory disorder that causes variable obstruction of the airways. Pathogenesis includes mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, epithelial cells 1. Vascular permeability Allergens cross-link IgEs on mast cells. 2. Goblet cell Early response Mast cells release histamine, hyperplasia leukotrienes, and other mediators. 3. Bronchial smooth muscle contraction Activated mast cells & helper T-cells 1. Bronchiole Delayed release cytokines which induce constriction response maturation of eosinophils which 2. Conjunctivitis migrate into airways, eyes, nose. 3. RhinitisCOPD pathophysiology Mixed Pathophysiology • Chronic Bronchitis – mucus oversecretion, inflammation, and bronchoconstriction • Emphysema – loss of elasticity and increased airway spaces Aim of anti-asthmatic drugs: 1. To relieve acute episodic attacks of asthma (bronchodilators – SABA, antimuscarinics, Xanthine) 2. To reduce the frequency of attacks (anti- inflammatory – corticosteroids, LABA, LTA, Mast- cell stabilizers, anti-IgE)Selective B2 agonists Examples: Short acting: Salbutamol, Terbutaline rapid onset of action (15-30 minutes) short duration of action (4-6 hours) used for symptomatic treatment of acute episodic attack of asthma Long acting: Salmeterol, Formoterol long duration of action (12 hours) not to relieve acute episodes but for decreasing the number of attacks MOA: Agonist at B2 receptor Overall affect: bronchial smooth muscle relaxation, bronchodilation, anti- inflammatory Adverse effects: Common Fine tremor, headache, muscle cramps, tolerance, dose dependent tachycardia Important Arrhythmias, myocardial ischaemia, hypokalaemia, lactic acidosis (overdose) Caution People with diabetes mellitus, hyperthyroidism, and cardiovascular diseaseMuscarinic antagonists Short acting: Ipratropium duration of action: 3-5 hours Long acting: Tiotropium [Umeclidinium, Aclidinium and Glycopyrronium] duration of action: 24 hours Does not diffuse into the blood MOA: Antagonist at M2, M3 receptor Do not enter CNS, minimal systemic side effects No inflammatory action Overall affect: Prevention of Ach-mediated constriction of the bronchi (bronchodilation) and mucus secretion Adverse effects: Common Anti-cholinergic (dry mouth), oral candidiasis Important Acute angle closure glaucoma, urinary retention Caution People with prostatic hyperplasia, high risk of acute angle glaucomaMethylxanthines Ex: Aminophylline MOA: They are phosphodiesterase inhibitors which increase cAMP resulting in bronchodilation Block adenosine receptors Prevent diaphragmatic fatigue Loads of systemic side effects , narrow therapeutic window, and many drug interactionsQuestion 1: A 23-year-old female patient with a history of persistent asthma is currently prescribed theophylline for maintenance therapy. She presents to the emergency department with complaints of palpitations and nausea. Upon further inquiry, she mentions recent initiation of a new medication. Which of the following medications is most likely to have precipitated these symptoms by interacting with theophylline? A) Salbutamol B) Ipratropium C) Carbamazepine D) Erythromycin E) PhenytoinQuestion 1: A 23-year-old female patient with a history of persistent asthma is currently prescribed theophylline for maintenance therapy. She presents to the emergency department with complaints of palpitations and nausea. Upon further inquiry, she mentions recent initiation of a new medication. Which of the following medications is most likely to have precipitated these symptoms by interacting with theophylline? A) Salbutamol B) Ipratropium C) Carbamazepine D) Erythromycin E) PhenytoinMethylxanthines Pharmacological effects: Lungs: Bronchial muscle relaxation Contraction of diaphragm which improve ventilation CVS: ↑ heart rate, ↑ force of contraction Arrhythmias, tachycardia, hypotension GIT: ↑ gastric acid secretions N&V Kidney: ↑renal blood flow, weak diuretic action CNS: stimulant effect: on respiratory center decrease fatigue & elevate mood overdose tremors, nervousness, insomnia, convulsion Inducers (decrease levels) Metabolised by CYP-450 Inhibitors CRAP GPS (increase levels)Glucocorticoids MOA: • Inhibition of phospholipase A2 (decrease prostaglandins and leukotrienes). • Mast cell stabilization (decrease histamine release, capillary permeability, and oedema) • Upregulate B2 receptors (have additive effect to B2 agonists) Used for prophylactic therapy, are not bronchodilators Have a delayed onset of action (effect usually attained after 2-4 weeks. Inhalation: Budesonide, fluticasone, beclomethasone Orally: Prednisone, methylprednisolone Injection: hydrocortisone, dexamethasoneQuestion 2: A 10-year-old child with moderate persistent asthma has been using an inhaled corticosteroid (ICS) with a spacer for symptom control. Despite proper inhaler technique, the child presents with a white coating on their tongue. Which of the following interventions is most appropriate to address this issue? A) Discontinue the ICS immediately and switch to a leukotriene receptor antagonist (LTRA) B) Increase the frequency of oral hygiene measures and continue the current ICS therapy C) Switch to a dry powder inhaler (DPI) for delivery of the ICS medication D) Prescribe an antifungal mouthwash and continue the current ICS therapy with the spacer E) Refer the child to a pediatric allergist for further evaluation and management, including consideration of immunotherapyQuestion 2: A 10-year-old child with moderate persistent asthma has been using an inhaled corticosteroid (ICS) with a spacer for symptom control. Despite proper inhaler technique, the child presents with a white coating on their tongue. Which of the following interventions is most appropriate to address this issue? A) Discontinue the ICS immediately and switch to a leukotriene receptor antagonist (LTRA) B) Increase the frequency of oral hygiene measures and continue the current ICS therapy C) Switch to a dry powder inhaler (DPI) for delivery of the ICS medication D) Prescribe an antifungal mouthwash and continue the current ICS therapy with the spacer E) Refer the child to a pediatric allergist for further evaluation and management, including consideration of immunotherapyGlucocorticoids – Continued Definition of low, moderate, and high-dose of ICS. Low = <400 micrograms budesonide or equivalent Moderate = 400-800 micrograms budesonide or equivalent High = >800 budesonide or equivalent Systemic corticosteroids are reserved for severe cases of asthma. Adverse effects: Local side effect: dysphonia, oropharyngeal candidiasis Systemic side effects: 1. MSK: osteoporosis, fat redistribution, wasting of muscles 2. Immune system: prone to infections 3. Skin: stria, bruising 4. Endocrine: hyperglycaemia, adrenal suppression, fluid retention, weight gain 5. Psychiatry: psychosis 6. CV: HTN Caution: Abrupt stop of oral corticosteroids (>2 weeks) should be avoided, and dose should be tapered (adrenal insufficiency syndrome). Modes of delivery: Nebulizers vs Inhalers Nebulizers Inhalers When is it Often preferred for severe asthma Regular use used? When the patient is unable to take For patients who can use them effectively. an inhaler Young children How do they Machine that sprays turns liquid Different types: metered-dose inhaler or work? medicine into a fine mist which is dry powder. delivered through a mask/mouthpiece. Advantages Easier to use. No need for strong Small and easy to carry. Handheld devices. inhalation. Can be used with Nebulizers take a couple of minutes, while supplemental oxygen. inhalers delivery medicine into lungs instantly. Can be used with a spacer.Leukotrienes Inhibitors Example: Montelukast, zafirlukast, pranlukast MOA: Leukotrienes are produced by the action of 5-lipoxygenase on arachidonic acid. Zileuton inhibits 5-lipoxygenase Leukotriene B4: chemotaxis of neutrophils Cysteinyl leukotrienes C4, D4 & E4: bronchoconstriction increase bronchial hyper-reactivity mucosal edema, mucus hyper-secretion Block leukotriene receptors (CysLT1). Overall effect: Bronchodilate, have anti-inflammatory action. Used prophylaxis. Special indication: good for aspirin induced asthma Adverse effect: Hepatotoxic, hypersensitivity reactions, headache, agrunlocytosisMast-cell stabilizer Eg: Cromolyn Stabilization of mast cell membrane preventing degranulation. Prevents acute asthma symptoms. Rarely used. Mode of delivery: inhalation, nebulizer, microfine powder Indications: asthma, allergic rhinitis, and other allergic conditionsIgE monoclonal antibodies Omalizumab binds mostly unbound serum IgE and blocks binding to Fc rector on B-cells, mast cells. Anti-IL5 monoclonal antibodies Mepolizumab, reslizumab—against IL-5. Benralizumab—against IL-5 receptor α Prevents eosinophil differentiation, maturation, activation, and survival mediated by IL-5 stimulation. For maintenance therapy in severe eosinophilic asthma.Question 3: You review a 60-year-old woman in the COPD clinic. She was diagnosed with COPD four years ago and is currently maintained on a salbutamol inhaler as required. Her latest FEV1 was 42% of predicted. Despite her current therapy she has frequent exacerbations. There is no history of asthma, eosinophilia or FEV1 variation. What is the most appropriate next step in her management? A) Salmeterol inhaler B) Increased dose of salbutamol C) Combined salmeterol and fluticasone inhaler D) Combined salmeterol and tiotropium E) Oral aminophyllineQuestion 3: You review a 60-year-old woman in the COPD clinic. She was diagnosed with COPD four years ago and is currently maintained on a salbutamol inhaler as required. Her latest FEV1 was 42% of predicted. Despite her current therapy she has frequent exacerbations. There is no history of asthma, eosinophilia or FEV1 variation. What is the most appropriate next step in her management? A) Salmeterol inhaler B) Increased dose of salbutamol C) Combined salmeterol and fluticasone inhaler D) Combined salmeterol and tiotropium E) Oral aminophylline COPD: still breathless despite using SABA/SAMA and no asthma/steroid responsive features which include wheeziness, eosinophils, signs of atopy, asthmatic features → add a LABA + LAMAManagement of COPDQuestion 4: An 18-year-old female comes to her GP for her annual asthma review. She reports a worsening of symptoms in the last few months requiring her blue inhaler three times a day. She currently only uses her blue inhaler. She is otherwise well, has no allergies, and is on no other medications What is the most appropriate next step in her management? A) Add a low dose budesonide inhaler B) Add a salmeterol inhaler C) Add a tiotropium inhaler D) Add oral montelukast and beclomethasone inhaler E) Add a medium dose budesonide inhalerQuestion 4: An 18-year-old female comes to her GP for her annual asthma review. She reports a worsening of symptoms in the last few months requiring her blue inhaler three times a day. She currently only uses her blue inhaler. She is otherwise well, has no allergies, and is on no other medications What is the most appropriate next step in her management? A) Add a low dose budesonide inhaler B) Add a salmeterol inhaler C) Add a tiotropium inhaler D) Add oral montelukast and beclomethasone inhaler E) Add a medium dose budesonide inhalerManagement of Asthma **Update on the BTS/SIGN/NICE Joint Guideline for the Diagnosis, Monitoring and Management of Chronic Asthma. May 2024.Question 5: A 23-year-old man attends the routine asthma review. He takes his SABA for his asthma during acute attacks but tells you that he currently has had no effect from his inhaler. Upon demonstration of his technique, you realize the problem. What advice can you give him on inhaler technique? A) After inhaling a dose of the medication, he should ideally hold his breath for 10 seconds B) After inhaling a dose of the medication, he should ideally hold his breath for 5 seconds C) After exhaling residual air from lungs, hold for 10 seconds, and then press down the cannister D) After exhaling residual air from lungs, hold for 5 seconds, and then press down the cannister E) Press down the cannister for 10 seconds while inhaling and exhaling for 10 secondsQuestion 5: A 23-year-old man attends the routine asthma review. He takes his SABA for his asthma during acute attacks but tells you that he currently has had no effect from his inhaler. Upon demonstration of his technique, you realize the problem. What advice can you give him on inhaler technique? A) After inhaling a dose of the medication, he should ideally hold his breath for 10 seconds B) After inhaling a dose of the medication, he should ideally hold his breath for 5 seconds C) After exhaling residual air from lungs, hold for 10 seconds, and then press down the cannister D) After exhaling residual air from lungs, hold for 5 seconds, and then press down the cannister E) Press down the cannister for 10 seconds while inhaling and exhaling for 10 secondsInhalation technique 1. Remove cap and shake 2. Breathe out gently 3. Put mouthpiece in mouth and as you begin to breathe in, which should be slow and deep, press canister down and continue to inhale steadily and deeply 4. Hold breath for 10 seconds, or as long as is comfortable 5. For a second dose wait for approximately 30 seconds before repeating steps 1-4. Only use the device for the number of doses on the label, then start a new inhaler.Summary SlideTHANK YOU FOR LISTENING ANY QUESTIONS BIMA Preclinical series