Respiratory Drugs for Asthma _ COPD

Respiratory Drugs (for Asthma & COPD) Phase III/Therapeutics Asthma is a Major Public Health Problem o 150 million sufferers Worldwide o Prevalence rising in most countries - up to 50%/decade o Large burden on health budgets o Major economic impact from lost days at work & school o Causes 100,000 deaths p.a. Worldwide Drug Treatment of Asthma What is it ? ‘A State of bronchial hyperreactivity resulting from a persistent inflammatory process in response to a number of stimuli in a genetically susceptible individual' Key features of its pathophysiology Airway inflammation o mucosal oedema Reflecting infiltration/activation of eosinophils, mast cells & Th2 cells o secretion of mucus o epithelial damage o bronchoconstriction Bronchial hyperreactivity Therapy is thus aimed at •Symptomatic relief - relieving bronchoconstriction •Disease modification - reducing inflammation and lung damage Asthma Triggers o Allergen exposure e.g. HDM, pet dander, pollens etc. o Exercise/cold-air - drying airway mucosa. o Drugs - Beta blockers, NSAIDs and anaphylactoids. o Food additives - tartrazines , sulphites etc. o Viral URTIs - especially rhinovirus. o Gastroesophageal reflux (GORD). NB a number of irritants can increase airway reactivity leading to deterioration of symptom control without necessarily being ‘triggers’ atmospheric pollutants (gases and particulates) are the best example. Anti-Asthma Drugs: 2-ADR agonists Short-acting (2-3h) • salbutamol • terbutaline • fenoterol Long-acting (>12h) • salmeterol • eformoterol ( NB should not be used to relieve acute symptoms) Side effects of  2-agonists • Tremor • Hypokalaemia • Tachycardia Generally worse with oral administration Using 2 or more canisters/month is marker of poor control (>10 puffs/day) Long acting beta agonists • Increased morbidity and mortality compared with placebo – Meta-analysis, Annals of Internal Medicine 2006 – Increased exacerbations requiring admission (OR 2.6) – Increased life threatening admissions (OR 1.8) – Increased asthma related deaths • OR 3.6, risk difference 0.07% over 6/12, I.e. 1 extra death per 1000 patientyears of use • Mechanism – Negative feedback with beta agonist use – Internalization of receptors and downregulation – Regular use increases bronchial hyperreactivity despite maintenance of some degree of bronchodilatation – These effects may worsen control without increased symptoms • Polymorphisms at human beta2-adrenoreceptor gene – Homozygous variant resulting in arginine at 16th position, Arg/Arg genotype – May experience decline in airflow when using beta-agonists, racial distribution Anti-Asthma Drugs: Antimuscarinics • Example Ipratropium bromide (aerosol or nebulized) • Mechanism Vagolytic action due to competitive inhibition of M3 receptors of bronchial SM cells • Slower and less intense than adrenergic agonists • Side-effects Limited absorption (quaternary N vs tertiary in atropine) but atropine-like effects at high doses e.g. dry mouth, mydriasis, urinary retention • Notes Generally less effective than 2 agonists in chronic asthma – high vagal tone only in acute asthma Tiotropium • Long-acting anticholinergic (once daily) • Reduced OR for exacerbation (0.73) and hospitalisation (0.68) but not pulmonary or all cause mortality compared to placebo and ipratropium • Greater increase in FEV1 and FVC compared to placebo and ipratropium (Meta-analysis, Thorax 2006) • Side-effects increased reports of dry mouth and UTI Anti-Asthma Drugs: Glucocorticoids (GCC) Problems with inhaled GCC TOPICAL (preventable by use of a spacer) SYSTEMIC • Easy Bruising • Adrenal suppression * • Growth retardation ? (pre-pubertal) • Increased bone catabolism * • Dysphonia • Oropharyngeal Candida * Typically a high-dose problem I.e. >1000g/day QVAR • Beclometasone dipropionate (BDP) • Utilizes a hydrofluoroalkane (HFA) not CFC propellant • delivered in smaller-sized particles • allows better penetration to small airways • In trials, the improvement in FEV1 across doses was greater for QVAR than for CFC-BDP, indicating a shift in the dose response curve for QVAR Problem: cost Anti-Asthma Drugs: Theophylline • Weak bronchodilator • Prominent immunomodulatory/anti-inflammatory effects • Oral dosing Problems with its use • Poorly tolerated (GI side-effects especially) in up to 1/3rd of patients • Narrow therapeutic range (10-20mg/L) • Biovailability varies widely between preparations • Extensive P450 metabolism - source of many interactions Current Status •Probably 4th line following introduction of LTRAs ? Magnesium • Evidence from meta-analysis for acute severe asthma where IV it may provide additional bronchodilatation (Cochrane, Annals of Emergency Medicine) • Improved PEFR and FEV1 (10%) • Reduced admission rates, NNT 8 • Single dose for - Acute severe asthma (FEV1 <30% predicted on arrival) who have responded poorly to inhaled bronchodilator therapy - Life threatening or near fatal asthma • 1.2 –2 g IV over 20 minutes NB Beware using in myasthenics … unless as a diagnostic test! Phospholipid Phospholipase A2 Arachidonic Acid Zileuton Lipoxygenase Cyclo-oxygenase NSAIDs LTC4 D4 E4 (SRSA) PGs TxA2 bronchoconstrictors Montelukast Anti-Asthma Drugs: LTRAs  Selective antagonists of CysLT1 receptor e.g. montelukast  Cysteinyl-LTs (LTC4, D4 & E4) are very potent airway spasmogens ~1000- fold > histamine.  Released by mast cells and influxing eosinophils.  improve lung function and symptoms, decrease in exacerbations  LTRAs are agents of choice for aspirin-induced asthma.  Role elsewhere still debated.  Advantage of better compliance (orally active); efficacy similar to low-dose inhaled GCC BUT without the side effects.  Churg-Strauss very rarely associated with their use - disease probably masked by previous GCC. Aspirin-Induced Asthma  Spirometric evidence in up to 20% of all asthmatics  COX-1 inhibition removes endogenous PGE2 inhibition of airway mast cells?  Why are a subpopulation of asthmatics affected?  ? LTC4 synthase polymorphism(s) predispose.  Paracetamol (AAP) safe alternative? - possibly NOT!  ? AAP-induced depletion of glutathione levels in the airway the problem.  Theoretical reasons for LTRAs as agents of choice for aspirin-induced asthma but little evidence  COX-2 selective NSAIDs are probably safe e.g. celecoxib. Drug Delivery by an Inhaled Aerosol Large particles (>10 m) deposit in the mouth and small ones (<0.5 m) fail to deposit in the distal airways - SPACER devices increase the fraction of droplets in the critical 1-5 m range. Effect of first-pass can be dramatic e.g. equiactive doses of oral and pMDI SALBUTAMOL differ 40-fold (4000 vs 100 g) and FLUTICASONE is inactive orally because of 100% first-pass. NB there is no advantage (I.e. a ‘sparing effect’) in delivering a GCC with low first-pass by aerosolisation e.g. hydrocortisone or prednisolone. Drug Delivery Systems: Metered-dose Inhalers MDIs Blue [short acting 2 agonist] Pressurised MDI (pMDI) • CFC (being replaced by HFA) propellant • Require co-ordinated activation/inhalation Green [salmeterol] Brown [BDP or budesonide] Orange [fluticasone] Turbuhaler Dry Powder MDI • No propellant • Require only priming then sucking • Low PEFR a problem (<60L/min) • Delivery humidity dependent ? Diskhaler 2005 BTS Guidelines for Chronic Asthma Step 1 prn (< once daily) short-acting  2* Step 2 Inhaled anti-inflammatory agent* ie GCC 200- 800 mcg/day (titrate) Step 3 ADD regular long-acting  2 agonist. If fails or inadequate increase inhaled GCC to 800g/day±long-acting  2. If inadequate, trial of other: e.g. leukotriene antagonist or SR theophylline prn short-acting  2 agonist Step 4 Increase GCC to 2000g/day Addtion of fourth drug:e.g. methylxanthines or leukotriene antagonist, or oral  2 agonist Step 5 Best of step 4 plus oral prednisolone * ‘reliever’ or ‘rescue’ medication vs. anti-inflammatory agents as ‘preventers’ Points to note: 1. Patient treatment should be reviewed/adjusted at least every 3-6 months. 2. Step down rapidly from high dose oral steroids if PEFR responds promptly i.e. within a few days, otherwise need to be stable for 1-3 months before attempting more gradual step down. MANAGEMENT OF ACUTE SEVERE ASTHMA Life-threatening features  Silent chest  Cyanosis  Bradycardia  Exhausted appearance  PEFR <33% of predicted  SpO2 <92%  Normal PaCO2  dysrhythmia, hypotension, exhaustion, confusion Arterial Blood Gases in Acute ASTHMA Mild  pH  PaO2  PaCO2  HCO3- Moderate  pH  PaO2  PaCO2  HCO3- Severe*  pH   PaO2  PaCO2  HCO3- * Beware the following: • Speechless patient • PEFR <50% • Resp Rate >25 • Tachycardia >110 (pre 2 agonist) Management of acute severe asthma in adults in A&E: PEF <33% predicted Time Measure PEF and arterial saturations PEF <33% best or predicted OR any life threatening features: • • 5 min SpO2 <92% Bradycardia, arrhythmia, hypotension • • Silent chest, cyanosis, poor respiratory effort Exhaustion, confusion, coma Obtain senior/ICU help now if any life-threatening features are present IMMEDIATE 15-30 min MANAGEMENT • High concentration oxygen (>60% if possible) • Give salbutamol 5mg plus ipratropium 0.5mg via oxygen-driven nebuliser • AND prednisolone 40-50mg orally or IV hydrocortisone 100mg • • Severe hypoxia (PaO2 <8 kPa; 60mm Hg) Low pH (or high H+) Measure arterial blood gases Markers of • Normal or raised PaCO2 severity: (PaCO2 >4.6 kPa; 35mm Hg) 60 min • Give/repeat salbutamol 5mg with ipratropium 0.5mg by oxygen-driven nebuliser after 15 minutes • • Consider continuous salbutamol nebuliser 5-10mg/hr Consider IV magnesium sulphate 1.2-2g over 20 minutes • • Correct fluid/ electrolytes, especially K+ disturbances Chest X-ray 120 min ADMIT – Patient should be accompanied by a nurse or doctor at all times Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92 Requirements for Discharge Before discharge aim for the following: • On discharge medication for 24 hrs • PEFR >75% predicted or best • <25% diurnal variability • Oral AND inhaled steroids – else risk early relapse when oral stopped • Give a PEFR meter for home use • Management plan based on home PEFR etc • GP follow up arranged Why do Asthma Deaths still occur? • • • • • • • Failure to recognize deterioration at home Underestimate severity – by patient, relatives or doctors Lack of objective measurements – PEFR, SaO2, ABG Under treatment with systemic steroids Inappropriate drug therapy Lack of monitoring Inadequate specialist input COPD What is it ? Airflow limitation that is not fully reversible Includes o Chronic bronchitis o Emphysema o Small airways disease Aetiology •Smoking!! •Alpha1 antitrypsin deficiency •Pollution, cadmium.. COPD Symptoms Cough, sputum production, wheeze, exertional dyspnoea Physical findings o Tar staining … o Hyperinflated chest, pursed lip breathing, paradoxical lower chest wall movement o Cyanosis o Signs of CO2 retention o Cor pulmonale Investigations • PFT • CXR • ABG, O2 Saturation COPD • According to NICE-British Thoracic Society Mild airflow obstruction Moderate Severe FEV1 50 – 80% predicted FEV1 30 – 49% predictetd FEV1 <30% predicted Drug Therapy for COPD: differences vs. Asthma • Inflammatory components in COPD airway distinct from asthma? • Does asthma predispose smokers to COPD? (Dutch hypothesis) Reversible airflow obstruction? • >15% rise (and >200ml) in FEV1 after GCC trial Treatment • Assess severity – Spirometry, reversibility, CXR, ABG • Stop smoking to decelerate loss of FEV1 • Use inhaled 2-agonist +/- IPRATROPIUM* • Trial of inhaled GCC, but use in the absence of reversibility ? . . . • Consider adding theophylline or oral steroid trial • if history of more purulent sputum • Consider pulmonary rehabilitation • Assess for home nebulizers/LTOT • Annual ‘Flu Vaccination’ , pneumococcal vaccination Pauwels et al (1999) - inhaled budesonide given in randomised fashion to 1000 smokers with COPD and FEV followed for 3 years. No significant effect! * effects of vagus more prominent than in chronic asthma Home Oxygen for COPD 15hrs/day O2 improves 5 year survival from 25 to 41% (MRC) Criteria for long-term home oxygen therapy • Two ABG readings when well (3 weeks apart) • PaO2<7.3, FEV1 <1.5 • Or PaO2 7.3-8 AND pulmonary HT, oedema, nocturnal hypoxia • STOP SMOKING • Oxygen concentrator and nasal prongs (PaO2 >8) • Minimum of 15 hrs per day Nonpharmacological Treatment • Pulmonary rehabilitation • Volume reduction surgery • NIV • Invasive ventilation • Lung transplantation • Treatment of Cor pulmonale, oxygen and diuretics for oedema Management of an Acute Exacerbation of COPD • Oxygen –24% Venturi mask - recheck ABG with an hour, monitor SaO2, aim for >90% • Nebulized salbutamol add Ipratropium if severe • Steroids – Prednisolone 30 mg for 7-14 days ? Osteoporosis prophylaxis • Antibiotics if more purulent sputum • If no improvement consider aminophylline and monitor levels • If deteriorating NIPPV, intubation, doxapram (?) • CXR, FBF, U&Es, PEFR Newer Therapeutic approaches Immunotherapy • Not recommended by the BTS in its ‘conventional’ form. • Significant risk of anaphylaxis. • Depletion of plasma IgE using rhuMab-E25 (Omalizumab) may be the way forward for a small number of subjects with difficult to control allergic asthma – but very expensive (~£10-20k/year). Other drug developments • More topically potent GCCs - mometasone more potent than fluticasone. • Single enantiomer salbutamol - (R)-salb is the active enantiomer; (S)-salb inactive, metabolised 10-fold slower than (R) and can increase airway hyperresponsiveness. • Type (4D) selective phosphodiesterase inhibitors - PDE4 is the predominant isoform in inflammatory cells. Potential for fewer side-effects vs theophylline. • Reproterol - monomolecular combination of orciprenaline ( 2-agonist) and theophylline. • Newer anti-T cell agents - FK506 and rapamycin PDE4 inhibitors • Cilomast, Roflumilast • Phosphodiesterases hydrolyse intracellular cyclic nucleotides (cAMP, cAMP into inactive 5’monophosphates • found in variety of cells • PDE4 inhibitors specifically prevent hydrolysis of cAMP leading to •Airway smooth muscle relaxation •inhibition of cellular inflammation and immune responses, cell trafficking and chemokine and cytokine release • Side effects – toxicity: Nausea and vomiting, arteritis • Disappointing phase III trials with Cilomast • Narrow therapeutic ratio Further Information • Full BTS guidelines for asthma management (pdf) • Full NICE guidelines for COPD management (pdf) • BTS (Brit Thoracic Society) web site Click on link to download