Mark Duffy

Asthma Triggers

o Allergen exposure e.g. pets, 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).

What is it ?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 pathophysiologyKey features of its pathophysiologyo mucosal oedemao secretion of mucuso epithelial damageo bronchoconstriction

Therapy is therefore aimed atTherapy is therefore 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

Anti-Asthma Drugs: 2-ADR agonists

Short-acting (2-3h)Short-acting (2-3h)• salbutamol• terbutaline• fenoterol

Long-acting Long-acting (>12h)(>12h)• salmeterol• eformoterol( NB should not be used to relieve acute symptoms)

Side effects of 2-agonists• Tremor • Hypokalaemia • Tachycardia

Generally worse withoral administration

Anti-Asthma Drugs: Antimuscarinics

Example Ipratropium bromide (aerosol or nebulized)

Mechanism Vagodilatory action due to competitive inhibition of M3 receptors of bronchial SM cells

Side-effects Limited absorption but atropine-like effects at high doses e.g. dry mouth, mydriasis, urinary retention

Notes Generally less effective than agonists in chronic asthma – high vagal tone only in acute asthma

Anti-Asthma Drugs: Theophylline

• Weak bronchodilator• Prominent immunomodulatory/anti-inflammatory effects• Oral dosing

Problems with its useProblems 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 StatusCurrent Status

•Probably 4th line following introduction of LTRAs ?

Arachidonic Acid

LTC4 D4 E4 (SRSA)bronchoconstrictors

PGsTxA2

Lipoxygenase Cyclo-oxygenase

Phospholipid

Phospholipase A2

Montelukast

NSAIDsZileuton

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.

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. celecoxib.

Drug Delivery by an Inhaled Aerosol

Large particles (>10 Large particles (>10 m) deposit in the m) deposit in the mouth and small ones (<0.5 mouth and small ones (<0.5 m) fail to m) fail to deposit in the distal airways - deposit in the distal airways - SPACER SPACER devices increase the fraction of devices increase the fraction of droplets in the critical 1-5 droplets in the critical 1-5 m range.m range.

Effect of first-pass can be dramatic e.g. Effect of first-pass can be dramatic e.g. equiactive doses of oral and pMDI SALBUTAMOL equiactive doses of oral and pMDI SALBUTAMOL differ 40-fold (4000 vs 100 differ 40-fold (4000 vs 100 g) and g) and FLUTICASONE is inactive orally because of 100% FLUTICASONE is inactive orally because of 100% first-pass.first-pass.

NB there is no advantage (I.e. a ‘sparing effect’) in NB there is no advantage (I.e. a ‘sparing effect’) in delivering a GCC with delivering a GCC with lowlow first-pass by first-pass by aerosolisation e.g. hydrocortisone or prednisolone.aerosolisation e.g. hydrocortisone or prednisolone.

Drug Delivery Systems: Metered-dose Inhalers MDIs

Pressurised MDI (pMDI)Pressurised MDI (pMDI)• CFC (being replaced by HFA) propellant• Require co-ordinated activation/inhalation

Orange [fluticasone]

Blue [short acting 2 agonist]

Green [salmeterol]

Brown [BDP or budesonide]

Dry Powder MDIDry Powder MDI• No propellant• Require only priming then sucking• Low PEFR a problem (<60L/min)• Delivery humidity dependent ?

TurbuhalerTurbuhaler

DiskhalerDiskhaler

Anti-Asthma Drugs: Glucocorticoids (GCC)

SYSTEMICTOPICAL (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. >1000g/day

Problems with inhaled GCCProblems with inhaled GCC

2003 BTS Guidelines for Chronic Asthma

prnshort-acting

2 agonist

Step 1Step 1 prn (< once daily) short-acting 2*Step 2Step 2 Inhaled anti-inflammatory agent* ie GCC 400g/dayStep 3Step 3 ADD regular long-acting 2 agonist. If fails or inadequate increase inhaled GCC to 800g/day±long-acting 2. If inadequate, trial of methylxanthines or leukotriene antagonist Step 4 Step 4 Increase GCC to 2000g/day AND long-acting 2 agonist regularly, or methylxanthines ,or leukotriene antagonist, or oral 2 agonistStep 5Step 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 featuresLife-threatening features Silent chest Cyanosis Bradycardia Exhausted appearance PEFR <30% of predicted

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 Management of acute severe asthma in adults in A&E: PEF <33% predictedadults in A&E: PEF <33% predicted

Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92

TimeTime Measure PEF and arterial saturationsMeasure PEF and arterial saturationsPEF <33% best or predicted OR anyPEF <33% best or predicted OR any life threatening featureslife threatening features::• SpO2 <92%SpO2 <92%• Bradycardia, arrhythmia, hypotensionBradycardia, arrhythmia, hypotension

• Silent chest, cyanosis, poor respiratory effortSilent chest, cyanosis, poor respiratory effort• Exhaustion, confusion, comaExhaustion, confusion, coma

5 min5 min

15-30 min15-30 min

Obtain senior/ICU help now if any life-threatening features are presentObtain senior/ICU help now if any life-threatening features are presentIMMEDIATE IMMEDIATE MANAGEMENTMANAGEMENT

• High concentration oxygen (>60% if possible)High concentration oxygen (>60% if possible)• Give salbutamol 5mg plus ipratropium 0.5mg via oxygen-driven nebuliserGive salbutamol 5mg plus ipratropium 0.5mg via oxygen-driven nebuliser• AND prednisolone 40-50mg orally or IV hydrocortisone 100mgAND prednisolone 40-50mg orally or IV hydrocortisone 100mg

Measure arterial blood gasesMeasure arterial blood gasesMarkers of Markers of severity:severity:

• Normal or raised PaCONormal or raised PaCO22

(PaCO(PaCO22 >4.6 kPa; 35mm Hg) >4.6 kPa; 35mm Hg)• Severe hypoxiaSevere hypoxia (PaO (PaO22 <8 kPa; 60mm Hg) <8 kPa; 60mm Hg)• Low pHLow pH (or high H (or high H++))

60 min60 min • Give/repeat salbutamol 5mg Give/repeat salbutamol 5mg with ipratropium 0.5mg by with ipratropium 0.5mg by oxygen-driven nebuliser after oxygen-driven nebuliser after 15 minutes15 minutes

• Consider continuous salbutamol Consider continuous salbutamol nebuliser 5-10mg/hr nebuliser 5-10mg/hr

• Consider IV magnesium sulphate Consider IV magnesium sulphate 1.2-2g over 20 minutes1.2-2g over 20 minutes

• Correct fluid/ electrolytes, Correct fluid/ electrolytes, especially Kespecially K++ disturbances disturbances

• Chest X-rayChest X-ray

120 min120 min ADMIT – Patient should be accompanied by a nurse or doctor at all timesADMIT – Patient should be accompanied by a nurse or doctor at all times

Before discharge aim for the following: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

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?

• Inflammatory components in COPD airway distinct from asthma?• Does asthma predispose smokers to COPD? (Dutch hypothesis)

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!

Reversible airflow obstruction?Reversible airflow obstruction? • >15% rise (and >200ml) in FEV1 after GCC trial

TreatmentTreatment• Assess severity – Spriometry, 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• Consider pulmonary rehabilitation• Assess for home nebulizers/LTOT• Annual ‘Flu Vaccination’

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

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

Newer Therapeutic approaches

ImmunotherapyImmunotherapy

• 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 developmentsOther drug developments

• Magnesium – used IV in acute severe asthma.• 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

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