Respiratory system diseases: overview of national guidelines and clinical management of asthma and COPD in primary care. Roberta Luzzi, PharmD, MSc

Ischaemic heart disease, stroke, lower respiratory infections and chronic obstructive lung disease have remained the top major killers during the past decade. WHO Fact sheet N°310. Updated May 2014

Asthma is a syndrome characterised by airflow obstruction that varies from person to person. Narrowing of the airways is usually reversible but in some patients with chronic asthma there may be irreversible airflow obstruction. Asthmatics develop an inflammation in the airways that makes them more responsive than non asthmatic individuals to a wide range of triggers, leading to excessive narrowing with consequent reduced airflow and symptomatic wheezing and dyspnea. Asthma is a heterogeneous disease with interplay between genetic and environmental factors (allergens, diet, air pollution,occupational exposure..) Airway hyperresponsiveness (AHR) is the characteristic physiologic abnormality of asthma and describes the excessive bronchoconstrictor response to multiple inhaled triggers that would not have effect on normal airways. Asthma is one of the most common chronic disease globally and currently affects 300million people worldwide (approximately 10-12% adults and 15% children). It is rising in developing countries due to the increased urbanisation. L ongo et al. Harrisons’ principle of internal medicine ASTHMA

allergens virus infections Pharmacologic agents (Beta blocker; Non selective COX inhibitors) Exercise air pollution Food Occupational factors Hormonal factors Gastroesophageal reflux stress Asthma

Non pharmacologic approachPharmacologic approach TRIGGERS

Pharmacologic approach of asthma BRONCHODILATORS immediate relief of symptoms with relaxation of airway smooth muscles β2 agonists Anticholinergics Theophylline CONTROLLERS inhibit the underlying inflammatory process Inhaled corticosteroids Oral corticosteroids Antileuokotrienes (ICS) (OCS) Main drugs and most effective at present

β2 agonists Relax airway smooth-muscle cells Act as functional antagonists of all known bronchoconstrictors β2 agonists activate β2 receptors widely expressed in the airways Great efficacy as bronchodilators in asthma BRONCHODILATORS

Short acting β2 agonists (SABAs) Albuterol Terbutalin Duration of action 3-6hrs; Rapid onset of effect; MDI; DPI High doses via nebulizers Used as needed for symptom relief Prevention of exercised induced asthma Long acting β2 agonists (LABAs) Salmeterol Formoterol Duration of action > 12hrs; Twice a day MDI; DPI Used to improve control of symptoms ALWAYS combined with ICS (combined inhalers LABA/ICS achieve effective asthma control) BRONCHODILATORS

Side effects Not usually an issue when β2 agonists are given via inhalation. Most common are tremors and palpitations (especially in elderly patients) Tolerance: not an major problem due to the high presence of receptors in the airways Frequent use of SABAs indicates that asthma is NOT under control BRONCHODILATORS

Anticholinergics Ipratropium bromide (MDI, nebulisers) Muscarinic receptor antagonists prevent cholinergic nerve-induced bronchoconstriction and mucus secretion Not as effective as β2 agonists as they only act on the cholinergic reflex component of bronchocontriction. Used as additional bronchodilators when asthma not controlled Side effects: dry mouth; in elderly patients urinary retention, glaucoma (very little absorption systemically) BRONCHODILATORS

Theophylline It was widely prescribed as bronchodilator but now replaced by β2 agonists as more effective and for less incidence of side effects Inhibition of phosphodiesterases in smooth muscle cells SR formulation once or twice a day as additional bronchodilator in patients with severe asthma. Side effects are related to plasma concentration (it should be monitored). Side effects not common at concentrations below 10mg/L. Most common: nausea, vomiting, headaches, diuresis, palpitations. At high concentrations cardiac arrhythmias, epileptic seizures and death. Theophylline is metabolised by CYP450. BRONCHODILATORS

Increased clearance: Enzyme induction (rifampicin, phenobarbitone, ethanol) Smoking High-protein, low carbohydrate diet Barbecued meat Childhood Decreased clearance Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, zafirlukast) Congestive heart failure Liver disease Pneumonia Viral infection and vaccination High carbohydrate diet Old age Fauci et al. Harrison’s principles of internal medicine.18 th edition Factors affecting clearance of theophylline BRONCHODILATORS

Inhaled Corticosteroids Inhaled corticosteroids (ICS) are the most effective controllers of asthma They act reducing the number of inflammatory cells and their activation in the airways ICS chronic use leads to a reduction of AHR. Not a cure for the underlying condition! Generally used twice a day but could be used once a day in mild asthma. (MDI and DPI) Positive effects on symptoms after a few days and long term benefit in preventing symptoms recurrence. Chronic use prevents irreversible changes in airway function that occur in asthma CONTROLLERS

Local side effects: dysphonia and oral candidiasis Systemic side effects: many studies have demonstrated minimal side effects from lung absorption (high recommended doses and chronic use) LARGE VOLUME SPACER DEVICE ORAL HYGENE CONTROLLERS

Used to treat acute exacerbations of asthma (for 5-10 days) 1% of asthma patients needs maintenance treatment (lowest dose possible to maintain control should be determined) More incidence of systemic side effects: diabetes, hypertension, gastric ulceration, depression, cataracts… Oral corticosteroids CONTROLLERS

Antileukotrienes CONTROLLERS Cysteinyl-leukotrienes are inflammatory mediators mainly produced by mast cells and they induce bronchoconstriction activating cys-LT1-receptors. Montelukast, zafirlukast block cys-LT1-receptors inducing a modest clinical benefit. Used in the add-on therapy when low doses of ICS do not control symptoms (less effective thatn LABAs) Generally well tolerated

“ Stepwise approach” BTS/SIGN *guidelines have a stepwise approach to the management of asthma in both adults and children. The aim is to control early symptoms starting at the step most appropriate for the patient to achieve control when control is good STEP DOWN STEP UP * British Thoracic Society/Scottish Intercollegiate Guidelines Network

Stepwise management in adults Step 1-mild intermittent asthma Inhaled SABA when required Step 2-regular preventer therapy Step 3-initial add-on therapy ICS mcg/day Inhaled LABA Plus (if SABA more than twice a week or if night symptoms or exacerbation in the last 2 yrs) plus Good response: Continue LABA Benefit from LABA but no control yet: Continue LABA + ICS 800mcg/die No benefit from LABA: Stop LABA + ICS 800mcg/die + additional therapy in no control yet (leukotriene receptor antagonist or SR theophylline)

Step 4: persistent poor control Step 5: continuous or frequent use of oral steroids -Increasing ICS up to 2,000 mcg/die + SABA + LABA (if effective) -addition of a fourth drug: -leukotriene receptor antagonist -SR theophylline -β2 agonist tablet -Daily steroid tablet in lowest dose providing adequate control -Maintain high dose inhaled corticosteroid at 2,000mcg/die -Consider other treatments to minimise the use of steroid tablets -Refer patient for specialist care

Children aged 5-12 years Step 1-mild intermittent asthma Inhaled SABA when required Step 2-regular preventer therapy ICS mcg/day Inhaled LABA Good response: Continue LABA Benefit from LABA but no control yet: Continue LABA + ICS 400mcg/die No benefit from LABA: Stop LABA + ICS 400mcg/die + additional therapy in no control yet (leukotriene receptor antagonist or SR theophylline) Step 3-initial add-on therapy Plus (if SABA more than twice a week or if night symptoms or exacerbation in the last 2 yrs) plus

Step 4: persistent poor control -Increasing ICS up to 800 mcg/die -Daily steroid tablet in lowest dose providing adequate control -Maintain high dose inhaled corticosteroid at 800 mcg/die -Refer patient to respiratory paediatrician Step 5: continuous or frequent use of oral steroids

Children under 5yrs Step 2-regular preventer therapy Step 1-mild intermittent asthma Step 3-initial add-on therapy Step 4: persistent poor control Inhaled SABA when required ICS mcg/day Or leukotriene receptor antagonist if ICS cannot be used ICS + leukotriene receptor antagonist (if <2yrs go to step 4) Refer to respiratory paediatrician Plus (if SABA more than twice a week or if night symptoms or exacerbation in the last 2 yrs)

Existing therapy compliance Inhaler technique Presence of trigger factors Before stepping up… Step up People with asthma receive a structured review at least annually. Statement 5. NICE quality standard 25. February 2013

COPD (chronic obstructive pulmonary disease) COPD is a disease state characterised by AIRFLOW LIMITATION that is not fully reversible. Airflow limitation is the main physiologic change in COPD. COPD includes emphysema (anatomically condition characterised by destruction and enlargement of the lung alveoli), chronic bronchitis (condition with chronic cough and phlegm), small airways disease (condition where small bronchioles are norrowed). COPD is present only if chronic airflow obstruction occurs Persistent reduction in forced expiratory flow rates is the most typical finding in COPD. Longo et al. Harrison’s principles of internal medicine. 18 th edition. According to the latest WHO estimates (2004), currently 64 million people have COPD and 3 million people died of COPD.

Air pollution Occupational exposure COPD RISK FACTORS cigarette smoking Intensity of smoking exposure determines the effects on pulmonary function

COPD pharmacologic treatment SMOKING CESSATION BRONCHODILATORS: β2 agonists (SABAs, LABAs); anticholinergics (SAMAs as ipratropium bromide, LAMAs as tiotropium, aclidinium, glycopyrronium) INHALED CORTICOSTEROIDS ORAL CORTICOSTEROIDS (in exacerbations) THEOPHYLLINE: it should only be used after a trial of short and long acting bronchodilators or in patients unable to have inhaled therapy (MONITOR PLASMA LEVELS AND INTERACTIONS). OXYGEN: it is the only pharmacologic treatment that has demonstrated decrease of mortality rate in patients with COPD MUCOLYTICS: N-acetyl cysteine Patients should be clinically reviewed at least once a year in primary care. NICE clinical guideline 101

COPD management SABA or SAMA Exacerbations or breathlessness initial empirical treatment for breathlessness and exercise limitation LABALAMA (discontinue SAMA) FEV1≥ 50% FEV1 < 50% LABA + ICS LAMA (discontinue SAMA) Persistent exacerbations LABA + LAMA + ICS SABA + ICS

The spacer should be compatible with the pMDI being used. The drug should be administered by repeated single actuations of the metered dose inhaler into the spacer, each followed by inhalation. There should be minimal delay between pMDI actuation and inhalation. Spacers should be cleaned no more than monthly as more frequent cleaning affects their performance (because of a build up of static). They should be cleaned with water and washing-up liquid and allowed to air dry. The mouthpiece should be wiped clean of detergent before use. In children, pMDI and spacer are the preferred method of delivery of β2 agonists or inhaled corticosteroids. A face mask is required until the child can breathe reproducibly using the spacer mouthpiece. Where this is ineffective a nebuliser may be required. SIGN 141 British guideline on the management of asthma Spacer devices

The most common reason for poor control of asthma is non compliance with medications, in particular with ICS as patients do not feel immediate relief of symptoms. Longo et al. People with asthma and COPD are given specific training and assessment in inhaler technique before starting any new inhaler treatment. Statement 5. Nice quality standard 25 NICE clinical guideline 101 Ask opened questions when doing your clinical review!! Before we finish…

British National Formulary. 69th edition Longo et al. Harrison’s principles of internal medicine. 18 th edition NICE TA 10. Guidance on the use of inhaler systems (devices) in children under the age of 5 years with chronic asthma. August 2000 NICE TA 38. Inhaler devices for routine treatment of chronic asthma in older children (aged 5–15 years). March 2002 NICE CG 101. Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). June 2010 NICE TA 131. Inhaled corticosteroids for the treatment of chronic asthma in children under the age of 12 years. November 2007 NICE TA 138. Inhaled corticosteroids for the treatment of chronic asthma in adults and in children aged 12 years and over. March 2008 SIGN 141. British guideline on the management of asthma. October 2014 References

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Napp Pharmaceuticals, Christian Saunders LPC, Rita Bali Acknowledgments

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