Drugs and Asthma Lecture 2024 PDF

Drugs and Asthma Dr J Haylor School of Medicine, UCLan UM1011 2024 Asthma  1. Intermittent Reliever Therapy Short-acting β2-adrenoceptor agonists (inhaled SABA) Drug Treatment...

Drugs and Asthma Dr J Haylor School of Medicine, UCLan UM1011 2024 Asthma  1. Intermittent Reliever Therapy Short-acting β2-adrenoceptor agonists (inhaled SABA) Drug Treatment 2. Regular Preventer (maintenance) Therapy of Low dose corticosteroid (inhaled) Asthma 3. Initial Add - In Therapy Leukotriene Receptor Antagonist (oral) Long-acting β2-adrenoceptor agonist (inhaled LABA) 4. Additional Controller Therapy Theophylline (oral) Long-acting muscarinic antagonist (inhaled LAMA) 5. Continuous corticosteroid (oral) Prednisolone Inhalers, Spacers and Nebulisers  Drugs and Asthma 1. Intermittent Reliever Therapy  Short-acting β2-adrenoceptor agonists (SABA) Adrenaline (α/β) Catechol-o-methyl transferase Salbutamol (β2) Isoprenaline (β) (COMT) Terbutaline (β2)  SABA – Mechanism of Action Salbutamol Terbutaline Β2-adrenoceptor SABA - Metered Dose Aerosol Dilates bronchioles Immediate relief Maximum effect 30 min, duration 3-5 h Propellant (99%) – Hydrofluoroalkanes not CFC (boiling point upto 30C) In addition may:- I. Inhibit mediator release from mast cell II. Inhibit TNF-α release from monocytes III. Increases mucous clearance Inhaler vs Spacer spacer  Breath-activated Inhalers Autohaler Dry powder inhalers  SABA - Adverse Effects C16 Tolerance Tachycardia (Genetic Polymorphism) (care in CVS disease) Hypokalaemia (Na/K ATP-ase↑ C27 Drug binding site C16 Arg→Gly (tolerance ↑) K+ uptake into muscle) response to salbutamol ↓ Tremor (greater with oral dosing nocturnal asthma muscle spindles hypokalaemia) C27 Gln →Glu (tolerance ↓) Tolerance response to salbutamol ↑ (2-agonist down-regulates hypokalaemia 2-adrenoceptor) 2. Regular Preventer (Maintenance) Therapy Step 1 : Short acting B2 adrenoceptor agonist, as required (upto once a day) If needed more than twice a week or Night time symptoms more than once a week Step 2: Add inhaled corticosteroid (low dose)  Inhaled Corticosteroids beclometasone dipropionate fluticasone budesonide Inhaled steroids Problems Slow onset (3-7 days) - not bronchodilator, no acute relief Oral candidiasis - spacer less likely to give oral deposition Adrenal suppression - fluticasone has poor absorption from G/I tract and extensive first pass metabolism Immunosuppression – potential to develop pneumonia?  Step 3 Initial Add-In Therapy Leukotriene Receptor Antagonist (Oral) Long acting β2-adrenoceptor agonist (inhaled) A. An ORAL asthma agent - montelukast  Leukotrienes Cys-Gly Glu Cys-Gly Cys Cysteinyl Leukotriene LTC4 SRS-A = LTC4/LTD4/LTE4 (slow reacting substance of anaphylaxis)  Montelukast – A Leukotriene Receptor Antagonist Montelukast Adverse Effects CysLT-1 receptor antagonist (mainly LTC4/LTD4) Common - diarrhoea; gastrointestinal discomfort; nausea; and vomiting skin Inhibits lung inflammation in the asthmatic :- reactions; upper respiratory tract Airflow obstruction↓ infection; fever and headache Bronchoconstriction ↓ Inflammatory cell infiltration ↓ Risk of neuropsychiatric reactions Mucous secretion/accumulation ↓ Speech impairment and obsessive- compulsive symptoms, in adults, adolescents, and children. B. Long acting β2-adrenoceptor agonists (LABA) salmeterol (salbutamol analogue) formoterol fumarate Maintenance dosing (usually twice daily) – Not acute use Use with inhaled corticosteroids – increase in asthma related deaths when used alone Can induce muscle cramps  Maintenance and Reliever Therapy (MART) Beclometasone + Formoterol  4. Additional Controller Therapies Long-acting muscarinic cholinoceptor antagonist (inhalation) Theophylline (oral ) B. Long-acting muscarinic receptor antagonist (LAMA) Cholinoceptor (muscarinic type) Tiotropium  Openprescribing.net Muscarinic Antagonists Leukotriene Antagonist Theophylline Bronchodilator/respiratory stimulant Two central mechanisms Phosphodiesterase Inhibitor - cAMP↑ Adenosine receptor antagonist * Activates histone deacetylase (HDAC) – reverses resistance to corticosteroids induced by oxidative stress Extended release formulation to give twice daily dosing Therapeutic window - plasma levels 10-20 mg/L Can saturate liver metabolism Potential for convulsions/arrhythmia and drug interactions * Aminophylline - water soluble, injectable form  Step 5 : Continuous corticosteroid (oral) specialist therapies Effect at the level of transcription Anti-inflammatory Immunosuppressant prednisolone  Prednisolone Anti-inflammatory Immunosuppressant P Mechanisms Lipocortin inhibits IL-2 transcription ↓ P P Clonal expansion T cells ↓ lipocortin Mast cells↓ (IL-3 ↓) P P Vascular permeability ↓ β2-adrenoceptor ↑ Adverse Effects : Glucocorticoids  prednisolone Corticotrophin Releasing Adrenal Suppression Hormone (CRH) (Slow Withdrawal of Steroids) Adrenocorticotrophic Hormone (ACTH) cortisol  Severe Asthma and The Eosinophil Severe Asthma Constant breathlessness unable to perform simple tasks 100,000 adults in UK either many attacks or requiring oral steroids Asthma attacks can come without any warning so Eosinophil people often live in fear, afraid to go out and may lead to hospitalisation and in the worst cases death. Adults with severe asthma have had limited treatment options. Many end up taking oral corticosteroids for prolonged periods which can cause further complications such as diabetes, high blood pressure and mood swings. Mast cell activation of eosinophils  Interleukin IL-5 Inhibitors Monoclonal antibodies against Interleukin 5 (IL-5) IL-5 attracts asthma-causing eosinophils to airways mepolizumab (SC)/reslizumab (IV) bind to IL-5, neutralising its activity benralizumab is an IL-5 receptor antagonist Delivery is by SC injection or IV infusion every 4 weeks Major drugs to remember for the treatment of Asthma Salbutamol * Beclometasone* Montelukast Salmeterol* Tiotropium* Theophylline Prednisolone Mepolizumab * Delivered by inhalation Summary : Drug Treatment of Asthma 1. Intermittent Reliever Therapy Short-acting β2-adrenoceptor agonists (inhaled SABA) 2. Regular Preventer (maintenance) Therapy Low dose corticosteroid (inhaled) 3. Initial Add - In Therapy Leukotriene Receptor Antagonist (oral) Long-acting β2-adrenoceptor agonist (inhaled LABA) 4. Additional Controller Therapy Theophylline (oral) Long-acting muscarinic antagonist (inhaled LAMA) 5. Continuous corticosteroid (oral) Prednisolone