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RESPIRATORY PHARMACOLOGY. S+S OF RESPIRATORY CONDITIONS (ASTHMA AND COPD) SOB Cough Wheezing Tight chest.

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Presentation on theme: "RESPIRATORY PHARMACOLOGY. S+S OF RESPIRATORY CONDITIONS (ASTHMA AND COPD) SOB Cough Wheezing Tight chest."— Presentation transcript:

1 RESPIRATORY PHARMACOLOGY

2 S+S OF RESPIRATORY CONDITIONS (ASTHMA AND COPD) SOB Cough Wheezing Tight chest

3 Mechanism of action: Bronchodilator 1.Bind β 2 receptor 2.Activate adenylyl cyclase via GPCR ( α s subunit) 3.Increases cAMP levels 4.This activates PKA 5.Phosphorylates and hence inactivates myosin light chain kinase 6.This decreases smooth muscle cell contraction Short acting (e.g. salbutamol) and long acting (salmeterol)  Short acting go through the membrane channel  Long acting interact with (and are taken into) membrane therefore “hang around” for longer Side effects – think of too much dilation  Peripheral vasodilation, Headache, Tremor, Tachycardia Desensitisation:  Repeated over activation of β 2 receptors eventually leads to increased phosphodiesterase (PDE)  PDE inactivates cAMP so less cAMP and drugs will have less of an effect β 2 receptor AC ↑ cAMP Activates PKA P and decreases MLCK ↓ SMC contraction

4 ANTICHOLINERGICS Mechanism of action: Bronchodilator 1.Drug blocks M3 muscarinic receptor 2.This decreases PLC 3.PLC normally converts PIP2 into IP3 and DAG. Decreased PLC decreases this process 4.IP3 normally causes calcium induced calcium release from endoplasmic reticulum. Decreased IP3 decreases this process 5.Less calcium is released for use in muscle contraction therefore less contraction of smooth muscles occur * calcium causes contraction by binding to calmodulin and activating myosin light chain kinase Short term (e.g. ipratropium) and long acting (e.g. tiotropium) Side effects – ( think what blocking other cholinergic receptors will do. Decreased rest and digest)  Dry mouth, constipation, cough, headache, nausea, paradoxical bronchospasm, urinary retention, glaucoma M3 receptor ↑ PLC PIP2 → ↓ IP3 DAG M3 receptor ↓ PLC ↓ PIP2 → ↓ ↓ IP3 DAG No drug: With drug: CICR from E.R ↓ CICR from E.R

5 METHYXANTHINE Mechanism of action:  In normal functioning, phosphodiesterase breaks down cAMP into 5’AMP which contracts smooth muscle (less cAMP means less PKA so less phosphorylation of MLCK, hence myosin is active and causes contraction)  Methylxanthines act as phosphodiesterase inhibitors, increasing cAMP, increasing PKA, increasing phosphorylation of MLCK, less contraction. Therefore bronchodilation Oral tablets, or IV if acute asthma attack Side effects  Insomnia, nausea, vomiting, cardiac arrhythmias, seizures  Very severe so need to monitor serum levels  Therapeutic range – μg/ml  Need to consider what dose to start them on carefully (e.g. may need lower doses in heart failure, cirrhosis and older patients) β 2 receptor AC ↑ cAMP 5’ AMP PDE

6 LEUKOTRIENE ANTAGONISTS Mechanism of action  Leukotrienes contribute to airway inflammation and bronchospasm  Leukotriene antagonists oppose this  The cysteinyl-leukotrienes act at their cell-surface receptors CysLT1 and CysLT2 on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation. Used as a preventor Cysteinyl leukotriene receptors (CysLT1 & CysLT2) have been cloned Montelukast & Zafirlukast block CysLT1 receptors:  Reduces exercise-induced symptoms in asthma  Reduce inflammatory response in early & late phases of asthma  Additive effect with other drugs  No evidence of effect on remodelling (chronic asthma) Side effects:  Abdominal pain, headache, thirst, restlessness

7 GLUCOCORTICOIDS Mechanism of action  Corticosteroid. Diffuses across lipid membrane, bind receptor in cytoplasm and enters nucleus  Activated intracellular glucocorticoid receptor (GR) interacts with nuclear DNA and influences gene expression  Inhibition production of pro-inflammatory products (e.g. Th2 cytokines, IL-3, IL-5, vasodilators PGE2 and PGI2, LTs). They do this by interacting with transcription factors and therefore preventing transcription of targeted pro-inflammatory genes  Up-regulate expression of anti-inflammatory products (e.g. up-regulate beta2- adrenoceptors). They know where these genes because they recognise the GRE (glucocorticosteroid response element) in the promoter region Beclomethasone (inhaled), Fluticasone (inhaled), Prednisolone (oral), Hydrocortisone (IV, in emergency) Side effects  Cushingoid symptoms – central adiposity, moon face, buffalo hump  Ulcers  Skin: striae, thinning, bruising  Hypertension  Infections  Necrosis, avascular necrosis of the femoral head  Glycosuria  Osteoporosis  Immunosuppression  Diabetes Glucocorticoid cytoplasm

8 MAST CELL STABILISERS Mechanism of action  “Stabilise” membranes of mast cells, preventing histamine release  ?Suppress ‘irritant receptors’ on sensory C-fibres Only really used in children and in inhaler form Side effects  Bitter taste, paradoxical bronchospasm (rare)

9 IG-E ANTIBODIES Mechanism of action:  Monoclonal anti-IgE antibody  Competes with IgE to bind to mast cells  Prevent binding to mast cells therefore decrease the mediators released by mast cells Useful to prevent allergic asthma Omalizumab Very expensive NICE approved use (April 2013) in specific patients if:  continuous or frequent treatment with oral corticosteroids (defined as 4 or more courses in the previous year), and  only if the manufacturer makes it available with the discount agreed in the patient access scheme

10 OVERVIEW OF MAST CELL STABILISERS AND IG-E ANTIBODIES (REMEMBER THESE ARE ONLY USED IN ASTHMA) Allergen exposure Plasma cells activated – WBC that produce immunoglobulins IgE production Mast cell degranulation. Release histamines, prostaglandins and leukotrienes S+S of asthma Mast Cell Stabilisers IgE Antibodies IgE binds receptors on mast cells

11 ASTHMA TREATMENT Acute Management – think O SHIT O – high flow oxygen. Sufficient to maintain sats 94-98% S – Salbutamol. Nebulised, every minutes H – IV hydrocortisone. Move onto prednisolone QDS after initial attack I – Ipratropium bromide. Used normally if initial response to bronchodilators is poor T – Theophylline Chronic Management NICE guideline steps Step 1 – As needed short acting β agonists. Mild intermittent asthma Step 2 - Add low dose inhaled corticosteroids. Regular preventer therapy Step 3 – Add long acting β agonists. Initial add on therapy Step 4 – Increase dose of corticosteroids. Persistent poor control Step 5 – additional therapies to minimise steroid use. Constant use of steroid

12 COPD TREATMENT Smoking cessation advice – only real way to prolong life Bronchodilator therapy  short-acting ß2-agoinst (salbutamol)  short-acting anticholinergic (ipratropium) Combination therapy  long-acting ß2-agonist (salmeterol, formoterol)  inhaled steroid (beclomethasone, fluticasone)  long-acting anticholinergic (tiotropium) Oral theophylline  only if short and long-acting bronchodilators ineffective or inappropriate Home oxygen


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