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 Best peak flow (when well): 350 l/min Rx: Fluticasone / Salmeterol combination MDI; bd Montelukast Salbutamol MDI; prn

CASE PRESENTATION Ox: unable to complete sentences pulse: 110/min RR: 35/min Peak Flow: 150 l/min Bilateral polyphonic wheeze SaO 2 : 93% on high flow oxygen ABG: pO kPa; pCO kPa CXR: hyperinflation only

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

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

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

Drugs for Airway Disease B 2 -agonist – short & long acting B 2 -agonist – short & long acting Anticholinergic – Ipratropium / Tiotropium Anticholinergic – Ipratropium / Tiotropium Corticosteroids - inhaled Corticosteroids - inhaled Leukotriene receptor antagonist Leukotriene receptor antagonist Theophylline Theophylline (Mucolytics) (Mucolytics) Omalizumab Omalizumab

B 2 -agonists Selective beta 2 -adrenoceptor agonists - bronchodilatation via cAMP dependent mechanism - bronchodilatation via cAMP dependent mechanism

B 2 -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)

B 2 -agonists Long acting: Salmeterol / Formoterol - salmeterol: slower onset of action (15min) - long duration of action (>12 hours) - used as maintenance therapy

B 2 -agonists Side-effects: fine tremor palpitations headache / nervous tension hypokalaemia (high doses)

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

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

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

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

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

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

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

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 BDP1:1

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

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

Leukotrienes Arachadonic acid 5-lipoxygenase 5-lipoxygenase cyclo-oxygenase Leukotriene A 4 cyclo-oxygenase Leukotriene A 4 ProstaglandinsLeukotriene B 4 Leukotriene C 4 Leukotriene D 4 Leukotriene E 4

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

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

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

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

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

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

Theophylline Side-effects:nauseapalpitationheadachearrhythmiasconvulsions

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

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

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.

Omalizumab Dose: 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

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

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

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

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