Slide1: Clinical Pharmacology Unit Stage I seminars: Respiratory Drugs (for Asthma & COPD)


Slide2: Asthma is a Major Public Health Problem 150 million sufferers Worldwide Prevalence rising in most countries - up to 50%/decade Large burden on health budgets Major economic impact from lost days at work & school Causes 100,000 deaths p.a. Worldwide


Slide3: Asthma Triggers Allergen exposure e.g. HDM, pet dander, pollens etc. Exercise/cold-air - drying airway mucosa. Drugs - Beta blockers, NSAIDs and anaphylactoids. Food additives - tartrazines , sulphites etc. Viral URTIs - especially rhinovirus. 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.


Slide4: 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 mucosal oedema secretion of mucus epithelial damage bronchoconstriction Therapy is thus aimed at Symptomatic relief - relieving bronchoconstriction Disease modification - reducing inflammation and lung damage   Drug Treatment of Asthma Reflecting infiltration/activation of eosinophils, mast cells & Th2 cells


Slide5: Anti-Asthma Drugs: 2-ADR agonists Short-acting (2-3h) salbutamol terbutaline fenoterol Long-acting (>12h) salmeterol eformoterol (NB salmeterol should not be used to relieve acute symptoms due to slow onset action) Side effects of 2-agonists Tremor Hypokalaemia Tachycardia Generally worse with oral administration


Slide6: Anti-Asthma Drugs: Antimuscarinics Example Ipratropium bromide (aerosol or nebulized) Mechanism Vagolytic action due to competitive inhibition of M3 receptors of bronchial SM cells 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 b2 agonists in chronic asthma – high vagal tone only in acute asthma


Slide7: 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 ?


Slide8: Arachidonic Acid LTC4 D4 E4 (SRSA) bronchoconstrictors PGs TxA2 Lipoxygenase Cyclo-oxygenase Phospholipid Phospholipase A2 Montelukast NSAIDs Zileuton


Slide9: 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. 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.


Slide10: 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. LTRAs are agents of choice for aspirin-induced asthma. COX-2 selective NSAIDs are probably safe e.g. etoricoxib.


Slide11: 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.


Slide12: Drug Delivery Systems: Metered-dose Inhalers MDIs Pressurised MDI (pMDI) CFC (being replaced by HFA) propellant Require co-ordinated activation/inhalation Dry Powder MDI No propellant Require only priming then sucking Low PEFR a problem (<60L/min) Delivery humidity dependent ?


Slide13: Anti-Asthma Drugs: Glucocorticoids (GCC) SYSTEMIC TOPICAL (preventable by use of a spacer) Dysphonia Oropharyngeal Candida Easy Bruising Adrenal suppression * Growth retardation ? (pre-pubertal) Increased bone catabolism * * Typically a high-dose problem I.e. >1000g/day Problems with inhaled GCC


Slide14: 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 800mg/day±long-acting 2. If inadequate trial of methylxanthines or leukotriene antagonist Step 4 Inhaled GCC to 800mg/day AND long-acting 2 agonist regularly, plus: increase GCC to 2000mg/day or methylxanthines or leukotriene antagonist or oral b2 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.


Slide15: MANAGEMENT OF ACUTE SEVERE ASTHMA Life-threatening features Silent chest Cyanosis Bradycardia Exhausted appearance PEFR <30% of predicted


Slide16: 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 25 Tachycardia >110 (pre 2 agonist)


Slide17: 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 Give a one-off infusion of Magnesium Sulphate 1.2-2g over 20min (NOT evidence based) 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 (p02<8.0 on high inspired O2) or high/rising pCO2 *** establish if patient on oral theophylline before giving any aminophylline IV. MANAGEMENT OF ACUTE SEVERE ASTHMA


Slide18: 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 Mx plan based on home PEFR etc GP follow up arranged Requirements for Discharge


Slide19: 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 Why do Asthma Deaths still occur?


Slide20: Inflammatory components in COPD airway distinct from asthma? Does asthma predispose smokers to COPD? (Dutch hypothesis) Drug Therapy for COPD: differences vs. Asthma Reversible airflow obstruction? >15% rise (and >200ml) in FEV1 after GCC trial Treatment Stop smoking to decelerate loss of FEV1 Annual Flu vaccination Use inhaled 2-agonist +/- IPRATROPIUM* Use GCC in the absence of reversibility ? . . . * 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!


Slide21: 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) PaO28) Minimum of 15 hrs per day


Slide22: Management of an Acute Exacerbation of COPD Oxygen –24% Ventimask - recheck ABG with an hour, monitor SaO2 Nebulized salbutamol add Ipratropium if severe If no improvement consider aminophylline If deteriorating NIPPV, intubation, doxapram (?) - exercise tolerance, home O2, home nebulizers (?) CXR, FBF, U&Es, PEFR Consider Abx, glucocorticoids, diuretics


Slide23: Newer Therapeutic approaches Immunotherapy Not recommended by the BTS in its ‘conventional’ form. Significant risk of anaphylaxis. Depletion of plasma IgE using rhuMab-E25 may be the way forward. 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