Asthma and copd e000 1233730950067181-1


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Asthma and copd e000 1233730950067181-1

  1. 1. Respiratory Drugs (for Asthma & COPD) Phase III/Therapeutics
  2. 2. Asthma is a Major Public Health Problem <ul><li>150 million sufferers Worldwide </li></ul><ul><li>Prevalence rising in most countries - up to 50%/decade </li></ul><ul><li>Large burden on health budgets </li></ul><ul><li>Major economic impact from lost days at work & school </li></ul><ul><li>Causes 100,000 deaths p.a. Worldwide </li></ul>
  3. 3. Asthma Triggers <ul><li>Allergen exposure e.g. HDM, pet dander, pollens etc. </li></ul><ul><li>Exercise/cold-air - drying airway mucosa. </li></ul><ul><li>Drugs - Beta blockers, NSAIDs and anaphylactoids. </li></ul><ul><li>Food additives - tartrazines , sulphites etc. </li></ul><ul><li>Viral URTIs - especially rhinovirus. </li></ul><ul><li>Gastroesophageal reflux (GORD). </li></ul><ul><li>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. </li></ul>
  4. 4. <ul><li>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' </li></ul><ul><li>Key features of its pathophysiology </li></ul><ul><li>mucosal oedema </li></ul><ul><li>secretion of mucus </li></ul><ul><li>epithelial damage </li></ul><ul><li>bronchoconstriction </li></ul><ul><li>Therapy is thus aimed at </li></ul><ul><li>Symptomatic relief - relieving bronchoconstriction </li></ul><ul><li>Disease modification - reducing inflammation and lung damage </li></ul><ul><li>  </li></ul>Drug Treatment of Asthma Reflecting infiltration/activation of eosinophils, mast cells & T h2 cells
  5. 5. Anti-Asthma Drugs:  2 -ADR agonists <ul><li>Short-acting (2-3h) </li></ul><ul><li>salbutamol </li></ul><ul><li>terbutaline </li></ul><ul><li>fenoterol </li></ul><ul><li>Long-acting (>12h) </li></ul><ul><li>salmeterol </li></ul><ul><li>eformoterol </li></ul><ul><li>( NB should not be used to relieve acute symptoms) </li></ul>Side effects of  2 -agonists <ul><li>Tremor </li></ul><ul><li>Hypokalaemia </li></ul><ul><li>Tachycardia </li></ul>Generally worse with oral administration
  6. 6. <ul><li>Example Ipratropium bromide (aerosol or nebulized) </li></ul><ul><li>Mechanism Vagolytic action due to competitive inhibition of M3 receptors of bronchial SM cells </li></ul><ul><li>Side-effects Limited absorption (quaternary N vs tertiary in atropine) but atropine-like effects at high doses e.g. dry mouth, mydriasis, urinary retention </li></ul><ul><li>Notes Generally less effective than  agonists in chronic asthma – high vagal tone only in acute asthma </li></ul>Anti-Asthma Drugs: Antimuscarinics
  7. 7. Anti-Asthma Drugs: Theophylline <ul><li>Weak bronchodilator </li></ul><ul><li>Prominent immunomodulatory/anti-inflammatory effects </li></ul><ul><li>Oral dosing </li></ul><ul><li>Problems with its use </li></ul><ul><li>Poorly tolerated (GI side-effects especially) in up to 1/3rd of patients </li></ul><ul><li>Narrow therapeutic range (10-20mg/L) </li></ul><ul><li>Biovailability varies widely between preparations </li></ul><ul><li>Extensive P450 metabolism - source of many interactions </li></ul><ul><li>Current Status </li></ul><ul><li>Probably 4th line following introduction of LTRAs ? </li></ul>
  8. 8. Arachidonic Acid LTC 4 D 4 E 4 (SRSA) bronchoconstrictors PGs TxA 2 Lipoxygenase Cyclo-oxygenase Phospholipid Phospholipase A2 Montelukast NSAIDs Zileuton
  9. 9. Anti-Asthma Drugs: LTRAs <ul><li>Selective antagonists of CysLT1 receptor e.g. montelukast </li></ul><ul><li>Cysteinyl-LTs (LTC4, D4 & E4) are very potent airway spasmogens ~1000-fold > histamine. </li></ul><ul><li>Released by mast cells and influxing eosinophils. </li></ul><ul><li>LTRAs are agents of choice for aspirin-induced asthma. </li></ul><ul><li>Role elsewhere still debated. </li></ul><ul><li>Advantage of better compliance (orally active); efficacy similar to low-dose inhaled GCC BUT without the side effects. </li></ul><ul><li>Churg-Strauss very rarely associated with their use - disease probably masked by previous GCC. </li></ul>
  10. 10. Aspirin-Induced Asthma <ul><li>Spirometric evidence in up to 20% of all asthmatics </li></ul><ul><li>COX-1 inhibition removes endogenous PGE2 inhibition of airway mast cells? </li></ul><ul><li>Why are a subpopulation of asthmatics affected? </li></ul><ul><li>? LTC4 synthase polymorphism(s) predispose. </li></ul><ul><li>Paracetamol (AAP) safe alternative? - possibly NOT! </li></ul><ul><li>? AAP-induced depletion of glutathione levels in the airway the problem. </li></ul><ul><li>LTRAs are agents of choice for aspirin-induced asthma. </li></ul><ul><li>COX-2 selective NSAIDs are probably safe e.g. celecoxib. </li></ul>
  11. 11. 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.
  12. 12. Drug Delivery Systems: Metered-dose Inhalers MDIs <ul><li>Pressurised MDI (pMDI) </li></ul><ul><li>CFC (being replaced by HFA) propellant </li></ul><ul><li>Require co-ordinated activation/inhalation </li></ul><ul><li>Dry Powder MDI </li></ul><ul><li>No propellant </li></ul><ul><li>Require only priming then sucking </li></ul><ul><li>Low PEFR a problem (<60L/min) </li></ul><ul><li>Delivery humidity dependent ? </li></ul>Orange [fluticasone] Blue [short acting  2 agonist] Green [salmeterol] Brown [BDP or budesonide] Turbuhaler Diskhaler
  13. 13. Anti-Asthma Drugs: Glucocorticoids (GCC) SYSTEMIC TOPICAL (preventable by use of a spacer) <ul><li>Dysphonia </li></ul><ul><li>Oropharyngeal Candida </li></ul><ul><li>Easy Bruising </li></ul><ul><li>Adrenal suppression * </li></ul><ul><li>Growth retardation ? (pre-pubertal) </li></ul><ul><li>Increased bone catabolism * </li></ul><ul><li>* Typically a high-dose problem I.e. >1000  g/day </li></ul>Problems with inhaled GCC
  14. 14. 2003 BTS Guidelines for Chronic Asthma prn short-acting  2 agonist Step 1 prn (< once daily) short-acting  2 * Step 2 regular short-acting  2 inhaled + anti-inflammatory agent* ( low-dose GCC) 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 methylxanthines or leukotriene antagonist Step 4 Inhaled GCC to 800  g/day AND long-acting  2 agonist regularly, plus: increase GCC to 2000  g/day or 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.
  15. 15. MANAGEMENT OF ACUTE SEVERE ASTHMA <ul><li>Life-threatening features </li></ul><ul><li>Silent chest </li></ul><ul><li>Cyanosis </li></ul><ul><li>Bradycardia </li></ul><ul><li>Exhausted appearance </li></ul><ul><li>PEFR <30% of predicted </li></ul>
  16. 16. Arterial Blood Gases in Acute ASTHMA Mild  pH  PaO 2  PaCO 2  HCO 3 - Moderate  pH  PaO 2  PaCO 2  HCO 3 - Severe*  pH   PaO 2  PaCO 2  HCO 3 - <ul><li>* Beware the following : </li></ul><ul><li>Speechless patient </li></ul><ul><li>PEFR <50% </li></ul><ul><li>Resp Rate >25 </li></ul><ul><li>Tachycardia >110 (pre  2 agonist) </li></ul>
  17. 17. Immediate management · Oxygen therapy by tight fitting facemask (60%). · Nebulised  2 agonist eg salbutamol 2.5 +/- 0.5mg ipratropium* · Give Prednisolone 30-60mg p.o. or hydrocortisone 300mg i.v. · Urgent chest X-ray to exclude pneumothorax · Urgent blood gas** · Reassess in 15 min or if life-threatening features appear · Consider i.v. aminophylline if life-threatening features or fails to improve after 15-30 mins *** · Discuss all patients with ITU - ventilation needed if PEFR continues to fall despite medical therapy, patient becoming drowsy/confused/exhausted or deteriorating blood gases **. * Alternatively  2 agonist can be given s.c. ** Beware severe hypoxia (p0 2 <8.0 on high inspired O 2 ) or high/rising pCO 2 *** establish if patient on oral theophylline before giving any aminophylline IV. MANAGEMENT OF ACUTE SEVERE ASTHMA
  18. 18. <ul><li>Before discharge aim for the following: </li></ul><ul><li>On discharge medication for 24 hrs </li></ul><ul><li>PEFR >75% predicted or best </li></ul><ul><li><25% diurnal variability </li></ul><ul><li>Oral AND inhaled steroids – else risk early relapse when oral stopped </li></ul><ul><li>Give a PEFR meter for home use </li></ul><ul><li>Mx plan based on home PEFR etc </li></ul><ul><li>GP follow up arranged </li></ul>Requirements for Discharge
  19. 19. <ul><li>Failure to recognize deterioration at home </li></ul><ul><li>Underestimate severity – by patient, relatives or doctors </li></ul><ul><li>Lack of objective measurements – PEFR, SaO2, ABG </li></ul><ul><li>Under treatment with systemic steroids </li></ul><ul><li>Inappropriate drug therapy </li></ul><ul><li>Lack of monitoring </li></ul><ul><li>Inadequate specialist input </li></ul>Why do Asthma Deaths still occur ?
  20. 20. <ul><li>Inflammatory components in COPD airway distinct from asthma? </li></ul><ul><li>Does asthma predispose smokers to COPD? (Dutch hypothesis) </li></ul>Drug Therapy for COPD: differences vs. Asthma <ul><li>Reversible airflow obstruction? </li></ul><ul><li>>15% rise (and >200ml) in FEV1 after GCC trial </li></ul><ul><li>Treatment </li></ul><ul><li>Stop smoking to decelerate loss of FEV1 </li></ul><ul><li>Annual Flu vaccination </li></ul><ul><li>Use inhaled  2-agonist +/- IPRATROPIUM* </li></ul><ul><li>Use GCC in the absence of reversibility ? . . . </li></ul>* effects of X more prominent than in chronic asthma Pauwels et al (1999) - inhaled budesonide given in randomised fashion to 1000 smokers with COPD and FEV followed for 3 years. No significant effect!
  21. 21. Home Oxygen for COPD <ul><li>15hrs/day O 2 improves 5 year survival from 25 to 41% (MRC) </li></ul><ul><li>Criteria for long-term home oxygen therapy </li></ul><ul><li>Two ABG readings when well (3 weeks apart) </li></ul><ul><li>PaO 2 <7.3, FEV1 <1.5 </li></ul><ul><li>Or PaO 2 7.3-8 AND pulmonary HT, oedema, nocturnal hypoxia </li></ul><ul><li>STOP SMOKING </li></ul><ul><li>Oxygen concentrator and nasal prongs (PaO 2 >8) </li></ul><ul><li>Minimum of 15 hrs per day </li></ul>
  22. 22. Management of an Acute Exacerbation of COPD <ul><li>Oxygen –24% Ventimask </li></ul><ul><ul><li>- recheck ABG with an hour, monitor SaO 2 </li></ul></ul><ul><li>Nebulized salbutamol add Ipratropium if severe </li></ul><ul><li>If no improvement consider aminophylline </li></ul><ul><li>If deteriorating NIPPV, intubation, doxapram (?) </li></ul><ul><ul><li>- exercise tolerance, home O2, home nebulizers (?) </li></ul></ul><ul><li>CXR, FBF, U&Es, PEFR </li></ul><ul><li>Consider Abx, glucocorticoids, diuretics </li></ul>
  23. 23. Newer Therapeutic approaches <ul><li>Immunotherapy </li></ul><ul><li>Not recommended by the BTS in its ‘conventional’ form. </li></ul><ul><li>Significant risk of anaphylaxis. </li></ul><ul><li>Depletion of plasma IgE using rhuMab-E25 may be the way forward. </li></ul><ul><li>Other drug developments </li></ul><ul><li>Magnesium – used IV in acute severe asthma but not evidence based yet! </li></ul><ul><li>More topically potent GCCs - mometasone more potent than fluticasone. </li></ul><ul><li>Single enantiomer salbutamol - (R)-salb is the active enantiomer; (S)-salb inactive, metabolised 10-fold slower than (R) and can increase airway hyperresponsiveness. </li></ul><ul><li>Type (4D) selective phosphodiesterase inhibitors - PDE4 is the predominant isoform in inflammatory cells. Potential for fewer side-effects vs theophylline. </li></ul><ul><li>Reproterol - monomolecular combination of orciprenaline (  2 -agonist) and theophylline. </li></ul><ul><li>Newer anti-T cell agents - FK506 and rapamycin </li></ul>
  24. 24. Further Information <ul><li>Full BTS guidelines for asthma management (BTS website) </li></ul><ul><li>Full BTS guidelines for COPD management (BTS website) </li></ul><ul><li>NEJM review on Leukotrienes and LTRAs (pdf) </li></ul>Click on link