respiratory pharmacology

Respiratory Respiratory PharmacologyPharmacology

Dr Mike IredaleDr Mike Iredale

October 2010October 2010

CASE PRESENTATIONCASE PRESENTATION

23 yr female; presents to A&E23 yr female; presents to A&E

5/7 URTI5/7 URTI

3/7 cough + wheeze 3/7 cough + wheeze

- waking at night- waking at night

- relief inhaler (Salbutamol) less - relief inhaler (Salbutamol) less effectiveeffective

- peak flow dropping- peak flow dropping

CASE PRESENTATIONCASE PRESENTATION

Asthma for 10 years, 1 previous admissionAsthma for 10 years, 1 previous admission

Best peak flow (when well): 350 l/minBest peak flow (when well): 350 l/min

Rx:Rx:

Fluticasone / Salmeterol combination Fluticasone / Salmeterol combination MDI; bdMDI; bd

MontelukastMontelukast

Salbutamol MDI; prnSalbutamol MDI; prn

CASE PRESENTATIONCASE PRESENTATION

Ox: Ox: unable to complete sentencesunable to complete sentencespulse: 110/minpulse: 110/minRR: 35/minRR: 35/minPeak Flow: 150 l/minPeak Flow: 150 l/minBilateral polyphonic wheezeBilateral polyphonic wheezeSaOSaO22: 93% on high flow oxygen: 93% on high flow oxygenABG: pOABG: pO22 8.6 kPa; pCO 8.6 kPa; pCO22 4.7 kPa 4.7 kPaCXR: hyperinflation onlyCXR: hyperinflation only

CASE PRESENTATIONCASE PRESENTATION

Rx: Rx: High Flow OxygenHigh Flow Oxygen

Nebulised SalbutamolNebulised Salbutamol

Nebulised Ipratropium (as poor Nebulised Ipratropium (as poor response)response)

Hydrocortisone + Prednisolone Hydrocortisone + Prednisolone prescribedprescribed

Review: Review: remains wheezy / distressed,remains wheezy / distressed,

peak flow 200/minpeak flow 200/min

CASE PRESENTATIONCASE PRESENTATION

Rx: Rx: IV MagnesiumIV Magnesium

IV AminophyllineIV Aminophylline

repeated nebulised bronchodilatorsrepeated nebulised bronchodilators

admitted to HDU – for close admitted to HDU – for close monitoringmonitoring

CASE PRESENTATIONCASE PRESENTATION

Outcome:Outcome:slow recovery over 5 daysslow recovery over 5 daysinitial improvement in pm peak initial improvement in pm peak

flowflowlater improvement in am peak flowlater improvement in am peak flow

review of maintenance therapy + review of maintenance therapy + inhaler inhaler technique pre-dischargetechnique pre-discharge

asthma clinic review after 4/52asthma clinic review after 4/52

Drugs for Airway DiseaseDrugs for Airway Disease

BB22-agonist – short & long acting-agonist – short & long acting Anticholinergic – Ipratropium / Anticholinergic – Ipratropium /

TiotropiumTiotropium Corticosteroids - inhaledCorticosteroids - inhaled Leukotriene receptor antagonistLeukotriene receptor antagonist Theophylline Theophylline

(Mucolytics)(Mucolytics) OmalizumabOmalizumab

BB22-agonists-agonists

Selective betaSelective beta22-adrenoceptor agonists-adrenoceptor agonists

- bronchodilatation via cAMP - bronchodilatation via cAMP dependent mechanismdependent mechanism

BB22-agonists-agonists

Short acting: Salbutamol / TerbutalineShort acting: Salbutamol / Terbutaline- rapid onset of action (within 5 min)- rapid onset of action (within 5 min)- short duration (4 hours)- short duration (4 hours)

- inhaled (100mcg / puff – Salbutamol)- inhaled (100mcg / puff – Salbutamol)- nebulised (5mg)- nebulised (5mg)- IV or sub-cut (terbutaline)- IV or sub-cut (terbutaline)- oral (slow release preparations)- oral (slow release preparations)

BB22-agonists-agonists

Long acting: Salmeterol / FormoterolLong acting: Salmeterol / Formoterol

- salmeterol: slower onset of action - salmeterol: slower onset of action (15min)(15min)

- long duration of action (>12 hours)- long duration of action (>12 hours)

- used as maintenance therapy- used as maintenance therapy

BB22-agonists-agonists

Side-effects:Side-effects:

fine tremorfine tremor

palpitationspalpitations

headache / nervous tensionheadache / nervous tension

hypokalaemia (high doses)hypokalaemia (high doses)

AnticholinergicsAnticholinergics

muscarinic receptor antagonists muscarinic receptor antagonists (parasympathetic)(parasympathetic)

- bronchodilatation via cGMP - bronchodilatation via cGMP mediated mechanismmediated mechanism

AnticholinergicsAnticholinergics

Short-acting:Short-acting:

Ipratropium: Ipratropium: onset within 30 onset within 30 minmin

duration 6 hoursduration 6 hours

- inhaled (20mcg / puff)- inhaled (20mcg / puff)

- nebulised (250 – 500 mcg)- nebulised (250 – 500 mcg)

AnticholinergicsAnticholinergics

Long Acting:Long Acting:

Tiotropium: Tiotropium: duration of action >24 duration of action >24 hourshours

once dailyonce daily

Handihaler: 18 mcgHandihaler: 18 mcg

Respimat: 5 mcgRespimat: 5 mcg

AnticholinergicsAnticholinergicsSide effects:Side effects:

dry mouthdry mouthnausea / headache / palpitationnausea / headache / palpitationurinary retentionurinary retentionblurred visionblurred visionangle-closure glaucomaangle-closure glaucoma

Caution:Caution:prostatic hyperplasia / bladder prostatic hyperplasia / bladder

outlet outlet obstruction / glaucomaobstruction / glaucoma

Inhaled CorticosteroidsInhaled Corticosteroids

Anti-inflammatory therapyAnti-inflammatory therapy Transported into cell nucleus for Transported into cell nucleus for

effecteffect Influence transcriptionInfluence transcription Preventative / maintenance therapyPreventative / maintenance therapy

‘‘topical therapy’topical therapy’- clinical benefit, whilst - clinical benefit, whilst

minimising side-minimising side- effects effects

Inhaled CorticosteroidsInhaled Corticosteroids

Beclomethasone (BDP)Beclomethasone (BDP) BudesonideBudesonide FluticasoneFluticasone MometasoneMometasone CiclesonideCiclesonide

- numerous doses / devices- numerous doses / devices- dose response curve not linear- dose response curve not linear

Inhaled CorticosteroidsInhaled Corticosteroids

Common adult starting dose 400mcg BDPCommon adult starting dose 400mcg BDP

Top doses: 2,000mg Fluticasone (10x Top doses: 2,000mg Fluticasone (10x higher)higher)

Combinations (with LABA):Combinations (with LABA):Fluticasone / SalmeterolFluticasone / SalmeterolBudesonide / FormoterolBudesonide / Formoterol

(Beclomethasone / Formoterol)(Beclomethasone / Formoterol)

Inhaled Steroid Inhaled Steroid ComparisonComparison

Against Beclomethasone (BDP) (CFC)Against Beclomethasone (BDP) (CFC)

Budesonide Budesonide 1:11:1Fluticasone Fluticasone 1:21:2Mometasone Mometasone 1:21:2Ciclesonide Ciclesonide ? ?

HFA BDP pMDI (QVAR)HFA BDP pMDI (QVAR) 1:21:2Non-QVAR HFA BDPNon-QVAR HFA BDP 1:11:1

Inhaled CorticosteroidsInhaled Corticosteroids

Side- Effects: - much less than oral Side- Effects: - much less than oral steroidsteroidoral candidiasisoral candidiasisdysphoniadysphonia

bruisingbruisingosteoporosis ?osteoporosis ?growth retardation (children)growth retardation (children)(adrenal suppression)(adrenal suppression)

Leukotriene AntagonistsLeukotriene Antagonists

Competetive anataginist of Competetive anataginist of leukotriene receptors (affect action of leukotriene receptors (affect action of cysteinyl leukotrienes)cysteinyl leukotrienes) Mucosal oedemaMucosal oedema Mucus productionMucus production Inflammatory cell recruitmentInflammatory cell recruitment

Used in addition to inhaled Used in addition to inhaled corticosteroidcorticosteroid

LeukotrienesLeukotrienesArachadonic acidArachadonic acid

5-lipoxygenase5-lipoxygenase

cyclo-oxygenasecyclo-oxygenase Leukotriene ALeukotriene A44

ProstaglandinsProstaglandins Leukotriene BLeukotriene B44

Leukotriene CLeukotriene C44

Leukotriene DLeukotriene D44

Leukotriene ELeukotriene E44

Leukotriene AntagonistsLeukotriene Antagonists

Montelukast: 10 mg once daily Montelukast: 10 mg once daily (evening)(evening)

Zafirlukast:Zafirlukast: 20mg twice daily20mg twice daily

Onset of action usually within a few Onset of action usually within a few daysdays

Leukotriene Receptor Leukotriene Receptor AntagonistsAntagonists

effective in asthmaeffective in asthma improve lung functionimprove lung function reduce symptomsreduce symptoms reduce relief bronchodilator usereduce relief bronchodilator use

effective at all asthma severityeffective at all asthma severity rapid onset of actionrapid onset of action equivalent to 400 -500 mcg equivalent to 400 -500 mcg

beclomethasonebeclomethasone effective in 73 % patientseffective in 73 % patients

Leukotriene AntagonistsLeukotriene Antagonists

Side-effects:Side-effects:

Headache / GI disturbanceHeadache / GI disturbance

?? Churg-Strauss syndrome?? Churg-Strauss syndrome

TheophyllineTheophylline

Phosphodiesterase inhibitor (7 Phosphodiesterase inhibitor (7 isoenzymes)isoenzymes)

- bronchodilatation- bronchodilatation

- ? Anti-inflammatory- ? Anti-inflammatory

- improve muscle strength- improve muscle strength

TheophyllineTheophylline

Theophylline:Theophylline:

Nuelin / Slo-phyllin / UniphyllinNuelin / Slo-phyllin / Uniphyllin

Aminophylline:Aminophylline:

Aminophylline SR / PhyllocontinAminophylline SR / Phyllocontin

IV: 250mg bolus / 0.5 mg / Kg / hrIV: 250mg bolus / 0.5 mg / Kg / hr

TheophyllineTheophylline

Metabolism: hepatic, variableMetabolism: hepatic, variable

- variation in ½-life- variation in ½-life

Narrow theraputic window: 10 – 20 Narrow theraputic window: 10 – 20 mg/lmg/l

Interaction: Erythromycin / Interaction: Erythromycin / CiprofloxacinCiprofloxacin

TheophyllineTheophylline

Side-effects:Side-effects:

nauseanausea

palpitationpalpitation

headacheheadache

arrhythmiasarrhythmias

convulsionsconvulsions

MucolyticsMucolytics

Reduce sputum viscosityReduce sputum viscosity

CarbocysteineCarbocysteine ErdosteineErdosteine MecysteineMecysteine

Caution with Hx Peptic UlcerCaution with Hx Peptic Ulcer

Omalizumab – anti-IgEOmalizumab – anti-IgE- humanised monoclonal IgG G1-blocking humanised monoclonal IgG G1-blocking

antibody against IgEantibody against IgE

- forms complexes with IgE without forms complexes with IgE without activation, so removes circulating and activation, so removes circulating and tissue IgE and promotes loss of high tissue IgE and promotes loss of high affinity receptors on effector cellsaffinity receptors on effector cells

- markedly reduces levels of free serum markedly reduces levels of free serum IgEIgE

OmalizumabOmalizumab

UK Licence – adults & children >12UK Licence – adults & children >12

- Patients on high-dose inhaled steroid - Patients on high-dose inhaled steroid and long-acting B2-agonist who have and long-acting B2-agonist who have impaired lung function, are impaired lung function, are symptomatic with frequent symptomatic with frequent exacerbations, and have allergy as exacerbations, and have allergy as an important cause of their asthma.an important cause of their asthma.

OmalizumabOmalizumabDose: 0.016 mg / Kg / unit IgEDose: 0.016 mg / Kg / unit IgE

- only effective if have high IgE (must - only effective if have high IgE (must be less than 700)be less than 700)

- sub-cut injection every 2-4 weeks- sub-cut injection every 2-4 weeks- takes up to 16 weeks for effect- takes up to 16 weeks for effect

- local skin reaction- local skin reaction- anaphylaxis has been reported - anaphylaxis has been reported

(administer only under direct medical (administer only under direct medical supervision)supervision)

Cost: average £8,000 paCost: average £8,000 pa

OmalizumabOmalizumab

Benefits:Benefits:

19% reduction in exacerbation needing oral steroid19% reduction in exacerbation needing oral steroid

26% reduction in severe exacerbation 26% reduction in severe exacerbation

Minor increase in FEV1 and reduction in B2-Minor increase in FEV1 and reduction in B2-agonist useagonist use

13% patients had significant improvement in health 13% patients had significant improvement in health related QoLrelated QoL

Emergency OxygenEmergency Oxygen

Must be prescribedMust be prescribed Target saturation rangeTarget saturation range

94-98% - acutely unwell94-98% - acutely unwell 88-92% - if risk of hypercapnic 88-92% - if risk of hypercapnic

respiratory failurerespiratory failure Appropriate devices & flow ratesAppropriate devices & flow rates Assess responseAssess response

Emergency OxygenEmergency Oxygen

Is patient in Respiratory failure Is patient in Respiratory failure (pO(pO22 < 8kPa)? < 8kPa)? Oxygen saturation (< 92%)Oxygen saturation (< 92%)

Type 1 or Type 2?Type 1 or Type 2? ABGABG

What is the cause?What is the cause? Treat or investigate if cause unknownTreat or investigate if cause unknown

Prescribe oxygen appropriatelyPrescribe oxygen appropriately

Emergency OxygenEmergency Oxygen

Type 1: - high flow oxygen; target Type 1: - high flow oxygen; target 94-98%94-98% Venturi (35-60%) or reservoir maskVenturi (35-60%) or reservoir mask

Type 2: without acidosis; target 88-Type 2: without acidosis; target 88-92%92% Venturi 24-28%Venturi 24-28%

Type 2: with acidosis (pH < 7.35)Type 2: with acidosis (pH < 7.35) Consider augmented ventilation (NIV / Consider augmented ventilation (NIV /

IPPV) + target 88-92%IPPV) + target 88-92%