Mark Duffy
Asthma Triggers <ul><li>Allergen exposure e.g. pets, pollens etc. </li></ul><ul><li>Exercise/cold-air - drying airway muco...
<ul><li>What is it ?   ‘A State of bronchial hyperreactivity resulting from a  persistent inflammatory process  in respons...
Anti-Asthma Drugs:   2 -ADR agonists <ul><li>Short-acting (2-3h) </li></ul><ul><li>salbutamol </li></ul><ul><li>terbutali...
<ul><li>Example  Ipratropium bromide (aerosol or nebulized) </li></ul><ul><li>Mechanism  Vagodilatory action due to compet...
Anti-Asthma Drugs:  Theophylline <ul><li>Weak bronchodilator </li></ul><ul><li>Prominent immunomodulatory/anti-inflammator...
Arachidonic Acid LTC 4  D 4  E 4  (SRSA) bronchoconstrictors PGs TxA 2 Lipoxygenase Cyclo-oxygenase Phospholipid Phospholi...
Anti-Asthma Drugs:  LTRAs <ul><li>Selective antagonists of CysLT1 receptor e.g. montelukast </li></ul><ul><li>Cysteinyl-LT...
Aspirin-Induced Asthma <ul><li>Spirometric evidence in up to 20% of all asthmatics </li></ul><ul><li>COX-1 inhibition remo...
Drug Delivery by an Inhaled Aerosol Large particles (>10   m) deposit in the mouth and small ones (<0.5   m) fail to dep...
Drug Delivery Systems: Metered-dose Inhalers MDIs <ul><li>Pressurised MDI (pMDI) </li></ul><ul><li>CFC (being replaced by ...
Anti-Asthma Drugs:  Glucocorticoids (GCC) SYSTEMIC TOPICAL   (preventable by use of a spacer) <ul><li>Dysphonia </li></ul>...
2003 BTS Guidelines for Chronic Asthma prn short-acting  2  agonist Step 1   prn (< once daily)  short-acting    2 * Ste...
MANAGEMENT OF ACUTE SEVERE ASTHMA <ul><li>Life-threatening features </li></ul><ul><li>Silent chest </li></ul><ul><li>Cyano...
Arterial Blood Gases in Acute ASTHMA Mild    pH    PaO 2    PaCO 2    HCO 3 - Moderate    pH    PaO 2    PaCO 2  ...
Management of acute severe asthma in adults in A&E: PEF <33% predicted Management of acute asthma. Thorax 2003; 58 (Suppl ...
<ul><li>Before discharge aim for the following: </li></ul><ul><li>On discharge medication for 24 hrs </li></ul><ul><li>PEF...
<ul><li>Failure to recognize deterioration at home </li></ul><ul><li>Underestimate severity – by patient, relatives or doc...
<ul><li>Inflammatory components in COPD airway distinct from asthma? </li></ul><ul><li>Does asthma predispose smokers to C...
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 l...
Management of an Acute Exacerbation of COPD <ul><li>Oxygen –24% Ventimask </li></ul><ul><ul><li>- recheck ABG with an hour...
Newer Therapeutic approaches <ul><li>Immunotherapy </li></ul><ul><li>Not recommended by the BTS in its ‘conventional’ form...
Further Information <ul><li>Full  BTS guidelines  for asthma management (pdf) </li></ul><ul><li>Full  NICE guidelines  for...
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Resp drugs presesntation

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Resp drugs presesntation

  1. 1. Mark Duffy
  2. 2. Asthma Triggers <ul><li>Allergen exposure e.g. pets, 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>
  3. 3. <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 therefore 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
  4. 4. 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
  5. 5. <ul><li>Example Ipratropium bromide (aerosol or nebulized) </li></ul><ul><li>Mechanism Vagodilatory action due to competitive inhibition of M3 receptors of bronchial SM cells </li></ul><ul><li>Side-effects Limited absorption 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
  6. 6. 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>
  7. 7. Arachidonic Acid LTC 4 D 4 E 4 (SRSA) bronchoconstrictors PGs TxA 2 Lipoxygenase Cyclo-oxygenase Phospholipid Phospholipase A2 Montelukast NSAIDs Zileuton
  8. 8. 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>
  9. 9. 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>
  10. 10. 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.
  11. 11. 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
  12. 12. 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
  13. 13. 2003 BTS Guidelines for Chronic Asthma prn short-acting  2 agonist Step 1 prn (< once daily) short-acting  2 * Step 2 Inhaled a nti-inflammatory agent* ie GCC 400  g/day 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 Increase GCC to 2000  g/day AND long-acting  2 agonist regularly, 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.
  14. 14. 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>
  15. 15. 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>
  16. 16. Management of acute severe asthma in adults in A&E: PEF <33% predicted Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92 Time Measure PEF and arterial saturations PEF <33% best or predicted OR any life threatening features : <ul><li>SpO2 <92% </li></ul><ul><li>Bradycardia, arrhythmia, hypotension </li></ul><ul><li>Silent chest, cyanosis, poor respiratory effort </li></ul><ul><li>Exhaustion, confusion, coma </li></ul>5 min 15-30 min Obtain senior/ICU help now if any life-threatening features are present IMMEDIATE MANAGEMENT <ul><li>High concentration oxygen (>60% if possible) </li></ul><ul><li>Give salbutamol 5mg plus ipratropium 0.5mg via oxygen-driven nebuliser </li></ul><ul><li>AND prednisolone 40-50mg orally or IV hydrocortisone 100mg </li></ul>Measure arterial blood gases Markers of severity: <ul><li>Normal or raised PaCO 2 (PaCO 2 >4.6 kPa; 35mm Hg) </li></ul><ul><li>Severe hypoxia (PaO 2 <8 kPa; 60mm Hg) </li></ul><ul><li>Low pH (or high H + ) </li></ul>60 min <ul><li>Give/repeat salbutamol 5mg with ipratropium 0.5mg by oxygen-driven nebuliser after 15 minutes </li></ul><ul><li>Consider continuous salbutamol nebuliser 5-10mg/hr </li></ul><ul><li>Consider IV magnesium sulphate 1.2-2g over 20 minutes </li></ul><ul><li>Correct fluid/ electrolytes, especially K + disturbances </li></ul><ul><li>Chest X-ray </li></ul>120 min ADMIT – Patient should be accompanied by a nurse or doctor at all times
  17. 17. <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
  18. 18. <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 ?
  19. 19. <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 * 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! <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>Assess severity – Spriometry, reversibility, CXR, ABG </li></ul><ul><li>Stop smoking to decelerate loss of FEV1 </li></ul><ul><li>Use inhaled  2-agonist +/- IPRATROPIUM* </li></ul><ul><li>Trial of inhaled GCC, but use in the absence of reversibility ? . . . </li></ul><ul><li>Consider adding theophylline or oral steroid trial </li></ul><ul><li>Consider pulmonary rehabilitation </li></ul><ul><li>Assess for home nebulizers/LTOT </li></ul><ul><li>Annual ‘Flu Vaccination’ </li></ul>
  20. 20. 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>
  21. 21. 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>
  22. 22. 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 . </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>
  23. 23. Further Information <ul><li>Full BTS guidelines for asthma management (pdf) </li></ul><ul><li>Full NICE guidelines for COPD management (pdf) </li></ul><ul><li>BTS (Brit Thoracic Society) web site </li></ul>Click on link to download

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