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Respiratory Pharmacology

Respiratory Pharmacology. Dr Mike Iredale October 2010. CASE PRESENTATION. 23 yr female; presents to A&E 5/7 URTI 3/7 cough + wheeze - waking at night - relief inhaler (Salbutamol) less effective - peak flow dropping. CASE PRESENTATION. Asthma for 10 years, 1 previous admission

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Respiratory Pharmacology

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  1. Respiratory Pharmacology Dr Mike Iredale October 2010

  2. CASE PRESENTATION 23 yr female; presents to A&E 5/7 URTI 3/7 cough + wheeze - waking at night - relief inhaler (Salbutamol) less effective - peak flow dropping

  3. CASE PRESENTATION Asthma for 10 years, 1 previous admission Best peak flow (when well): 350 l/min Rx: Fluticasone / Salmeterol combination MDI; bd Montelukast Salbutamol MDI; prn

  4. CASE PRESENTATION Ox: unable to complete sentences pulse: 110/min RR: 35/min Peak Flow: 150 l/min Bilateral polyphonic wheeze SaO2: 93% on high flow oxygen ABG: pO2 8.6 kPa; pCO2 4.7 kPa CXR: hyperinflation only

  5. CASE PRESENTATION Rx: High Flow Oxygen Nebulised Salbutamol Nebulised Ipratropium (as poor response) Hydrocortisone + Prednisolone prescribed Review: remains wheezy / distressed, peak flow 200/min

  6. CASE PRESENTATION Rx: IV Magnesium IV Aminophylline repeated nebulised bronchodilators admitted to HDU – for close monitoring

  7. CASE PRESENTATION Outcome: slow recovery over 5 days initial improvement in pm peak flow later improvement in am peak flow review of maintenance therapy + inhaler technique pre-discharge asthma clinic review after 4/52

  8. Drugs for Airway Disease • B2-agonist – short & long acting • Anticholinergic – Ipratropium / Tiotropium • Corticosteroids - inhaled • Leukotriene receptor antagonist • Theophylline • (Mucolytics) • Omalizumab

  9. B2-agonists Selective beta2-adrenoceptor agonists - bronchodilatation via cAMP dependent mechanism

  10. B2-agonists Short acting: Salbutamol / Terbutaline - rapid onset of action (within 5 min) - short duration (4 hours) - inhaled (100mcg / puff – Salbutamol) - nebulised (5mg) - IV or sub-cut (terbutaline) - oral (slow release preparations)

  11. B2-agonists Long acting: Salmeterol / Formoterol - salmeterol: slower onset of action (15min) - long duration of action (>12 hours) - used as maintenance therapy

  12. B2-agonists Side-effects: fine tremor palpitations headache / nervous tension hypokalaemia (high doses)

  13. Anticholinergics muscarinic receptor antagonists (parasympathetic) - bronchodilatation via cGMP mediated mechanism

  14. Anticholinergics Short-acting: Ipratropium: onset within 30 min duration 6 hours - inhaled (20mcg / puff) - nebulised (250 – 500 mcg)

  15. Anticholinergics Long Acting: Tiotropium: duration of action >24 hours once daily Handihaler: 18 mcg Respimat: 5 mcg

  16. Anticholinergics Side effects: dry mouth nausea / headache / palpitation urinary retention blurred vision angle-closure glaucoma Caution: prostatic hyperplasia / bladder outlet obstruction / glaucoma

  17. Inhaled Corticosteroids • Anti-inflammatory therapy • Transported into cell nucleus for effect • Influence transcription • Preventative / maintenance therapy • ‘topical therapy’ - clinical benefit, whilst minimising side- effects

  18. Inhaled Corticosteroids • Beclomethasone (BDP) • Budesonide • Fluticasone • Mometasone • Ciclesonide - numerous doses / devices - dose response curve not linear

  19. Inhaled Corticosteroids Common adult starting dose 400mcg BDP Top doses: 2,000mg Fluticasone (10x higher) Combinations (with LABA): Fluticasone / Salmeterol Budesonide / Formoterol (Beclomethasone / Formoterol)

  20. Inhaled Steroid Comparison Against Beclomethasone (BDP) (CFC) Budesonide 1:1 Fluticasone 1:2 Mometasone 1:2 Ciclesonide ? HFA BDP pMDI (QVAR) 1:2 Non-QVAR HFA BDP 1:1

  21. Inhaled Corticosteroids Side- Effects: - much less than oral steroid oral candidiasis dysphonia bruising osteoporosis ? growth retardation (children) (adrenal suppression)

  22. Leukotriene Antagonists • Competetive anataginist of leukotriene receptors (affect action of cysteinyl leukotrienes) • Mucosal oedema • Mucus production • Inflammatory cell recruitment • Used in addition to inhaled corticosteroid

  23. Leukotrienes Arachadonic acid 5-lipoxygenase cyclo-oxygenase Leukotriene A4 Prostaglandins Leukotriene B4 Leukotriene C4 Leukotriene D4 Leukotriene E4

  24. Leukotriene Antagonists Montelukast: 10 mg once daily (evening) Zafirlukast: 20mg twice daily Onset of action usually within a few days

  25. Leukotriene Receptor Antagonists • effective in asthma • improve lung function • reduce symptoms • reduce relief bronchodilator use • effective at all asthma severity • rapid onset of action • equivalent to 400 -500 mcg beclomethasone • effective in 73 % patients

  26. Leukotriene Antagonists Side-effects: Headache / GI disturbance ?? Churg-Strauss syndrome

  27. Theophylline Phosphodiesterase inhibitor (7 isoenzymes) - bronchodilatation - ? Anti-inflammatory - improve muscle strength

  28. Theophylline Theophylline: Nuelin / Slo-phyllin / Uniphyllin Aminophylline: Aminophylline SR / Phyllocontin IV: 250mg bolus / 0.5 mg / Kg / hr

  29. Theophylline Metabolism: hepatic, variable - variation in ½-life Narrow theraputic window: 10 – 20 mg/l Interaction: Erythromycin / Ciprofloxacin

  30. Theophylline Side-effects: nausea palpitation headache arrhythmias convulsions

  31. Mucolytics • Reduce sputum viscosity • Carbocysteine • Erdosteine • Mecysteine • Caution with Hx Peptic Ulcer

  32. Omalizumab – anti-IgE • humanised monoclonal IgG G1-blocking antibody against IgE • forms complexes with IgE without activation, so removes circulating and tissue IgE and promotes loss of high affinity receptors on effector cells • markedly reduces levels of free serum IgE

  33. Omalizumab UK Licence – adults & children >12 - Patients on high-dose inhaled steroid and long-acting B2-agonist who have impaired lung function, are symptomatic with frequent exacerbations, and have allergy as an important cause of their asthma.

  34. Omalizumab Dose: 0.016 mg / Kg / unit IgE - only effective if have high IgE (must be less than 700) - sub-cut injection every 2-4 weeks - takes up to 16 weeks for effect - local skin reaction - anaphylaxis has been reported (administer only under direct medical supervision) Cost: average £8,000 pa

  35. Omalizumab Benefits: 19% reduction in exacerbation needing oral steroid 26% reduction in severe exacerbation Minor increase in FEV1 and reduction in B2-agonist use 13% patients had significant improvement in health related QoL

  36. Emergency Oxygen • Must be prescribed • Target saturation range • 94-98% - acutely unwell • 88-92% - if risk of hypercapnic respiratory failure • Appropriate devices & flow rates • Assess response

  37. Emergency Oxygen • Is patient in Respiratory failure (pO2 < 8kPa)? • Oxygen saturation (< 92%) • Type 1 or Type 2? • ABG • What is the cause? • Treat or investigate if cause unknown • Prescribe oxygen appropriately

  38. Emergency Oxygen • Type 1: - high flow oxygen; target 94-98% • Venturi (35-60%) or reservoir mask • Type 2: without acidosis; target 88-92% • Venturi 24-28% • Type 2: with acidosis (pH < 7.35) • Consider augmented ventilation (NIV / IPPV) + target 88-92%

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