INHALATION DRUG DELIVERY DEVICES: BRONCHODILATORS NATTAWAT NATPHOBSUK, MD

Transcription

1 INHALATION DRUG DELIVERY DEVICES: BRONCHODILATORS NATTAWAT NATPHOBSUK, MD

2 BACKGROUND SHORT-ACTING 2 -AGONISTS SHORT-ACTING 2 -AGONISTS (SABAS) USED EXTENSIVELY IN THE MANAGEMENT OF PULMONARY DISEASES SINCE THE 1960S MOST WIDELY USED BRONCHODILATOR MEDICATION FOR THE QUICK RELIEF OF ASTHMA (2 6 HOURS) SABAS USED FOR RELIEF OF ACUTE BRONCHOCONSTRICTION TREATMENT OF EXERCISE-INDUCED ASTHMA (EIA) GLOBAL INITIATIVE FOR ASTHMA (GINA) GUIDELINES RECOMMEND SABA USE AS RELIEVER THERAPY DURING ACUTE EPISODES OF BRONCHOCONSTRICTION, BUT THAT USE IS KEPT TO A MINIMUM Cockcroft DW J Clin Pharmacol 1999;39:

3 BACKGROUND LONG-ACTING 2 -AGONISTS LONG-ACTING 2 -AGONISTS (LABAS) INTRODUCED IN THE EARLY 1990S RELAX SMOOTH MUSCLE AND OPEN UP THE AIRWAYS USED AS SYMPTOM CONTROLLERS BECAUSE OF LONGER DURATION OF ACTION FOR UP TO ~12 HOURS WHEN USED AS MONOTHERAPY BRONCHODILATION AND BRONCHOPROTECTION LITTLE OR NO ANTI-INFLAMMATORY EFFECT Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention NHLBI/WHO Workshop Report, National Institutes of Health Publication No , Bethesda, MD, 2002.

4 BACKGROUND MECHANISMS OF ACTION OF 2 -AGONISTS G i protein b 2 -Agonists ATP Ca 2+ stores Adenylate cyclase - G s protein camp R E C E P T O R K + K + Ca 2+ release Sensitivity of contractile proteins + Membrane potential - RELAXATION

5 CARDIOVASCULAR

6 CARDIOVASCULAR CONCERNS WITH B 2 -AGONISTS META-ANALYSIS OF RANDOMISED PLACEBO-CONTROLLED TRIALS OBJECTIVE WAS TO EVALUATE THE CARDIOVASCULAR EFFECTS OF 2 -AGONIST USE IN PATIENTS WITH OBSTRUCTIVE AIRWAY DISEASE) PRIMARY ENDPOINTS FOR SINGLE-DOSE TRIALS: SHORT-TERM EFFECT ON MEAN HEART RATE AND POTASSIUM CONCENTRATIONS PRIMARY ENDPOINTS FOR LONGER DURATION TRIALS: LONG-TERM EFFECT ON ADVERSE CARDIOVASCULAR EVENTS RATE Salpeter SR et al Chest 2004;125:

7 Cardiovascular Meta-Analysis: Effect on Heart Rate Heart rate in single dose trials (beats per minute, treatment minus placebo) Favours -agonist Favours placebo -agonist n Placebo n Weight % Weighted mean difference (95% CI random) Bennett 1994 Braden 1998 Braun 1991 Buch 1984 Burgess 1998 Burggraaf 2001 Chan 1988 Jartti 1997 Marlin 1978 Vathenen 1988 Wong (2.12, 13.82) 5.00 (-2.00, 12.00) 0.70 (-4.20, 5.60) (16.47, 39.53) 4.30 (-0.32, 8.92) 5.20 (-2.40, 12.80) (1.54, 20.46) (6.93, 29.07) 8.00 (-2.06, 18.06) (7.51, 22.69) 9.90 (3.59, 16.21) Total (95% CI) (5.32, 12.92) Test for heterogeneity chi-square=30.62 df=10 p= Test for overall effect z=4.70 p< Weighted mean difference (95% CI random) Salpeter SR et al Chest 2004;125:

8 Cardiovascular Meta-Analysis: Cardiovascular Events Longer-duration studies cardiovascular events (treatment/placebo) Sinus tachycardia Aalbers 2002 Bensch 2001 Boyd 1995 Chapman 2002 Dahl 1991 Fitzpatrick 1990 Milgrom 2001 Nathan 1995 Pearlman 1999 Siegel 1985 Spector / / / 55 2 / / / / / / 46 7 / 24 7 / 24 -agonist n / N 0 / / / 64 4 / / / 20 4 / 65 0 / / 23 1 /12 0 / 24 Subtotal (95% 100 CI) / / 1083 Test for heterogeneity chi-square=7.11 df=10 p=0.71 Test for overall effect z=3.74 p= Placebo n / N Favours -agonist Favours placebo Weight % Relative risk (95% CI fixed) 5.74 (0.33, 99.00) 1.01 (0.04, 24.71) 1.60 (0.07, 18.17) 0.51 (0.10, 2.78) 2.99 (0.16, 55.23) 3.00 (0.13, 69.52) 3.81 (1.44, 10.08) 4.57 (0.25, 84.49) 1.53 (0.06, 36.20) 3.50 (0.48, 25.28) (0.90, ) 3.06 (1.70, 5.50) Major cardiovascular events Anderson 1979 D Urzo 2001 Dahl 2001 Donohue 2002 Nielson 1999 Rennard 2001 Richter 2000 Rossi 2002 Yates 1995 Subtotal (95% 15 / CI) / 17 1 / / /213 0 / 15 7 / / 80 2 / / 19 0 / 17 1 / / /201 1 / 19 3 / / 80 0 / / 19 7 / 1347 Test for heterogeneity chi-square=2.71 df=8 p=0.95 Test for overall effect z=1.27 p=0.2 Total (95% 115 CI) / / 2430 Test for heterogeneity chi-square =10.71 df=19 p=0.93 Test for overall effect z=3.91 p= Relative risk (95% CI fixed) (0.13, 68.85) 1.00 (0.06, 15.97) 1.56 (0.06, 38.08) 0.47 (0.04, 5.16) 0.42 (0.02, 9.55) 2.39 (0.63, 9.03) 3.00 (0.12, 72.56) 2.59 (0.13, 53.80) 3.00 (0.13, 69.32) 1.66 (0.76, 3.60) 2.54 (1.59, 4.05) Salpeter SR et al Chest 2004;125:

9 CARDIOVASCULAR META-ANALYSIS: SUMMARY SINGLE DOSES OF 2 -AGONIST VERSUS PLACEBO INCREASED HEART RATE BY 9.12 BEATS PER MINUTE, P< REDUCED POTASSIUM CONCENTRATION BY 0.36 MMOL/L, P= LONGER-TERM TREATMENT VERSUS PLACEBO INCREASED RISK OF CARDIOVASCULAR ADVERSE EVENTS RR 2.54, P= INCREASED RISK OF SINUS TACHYCARDIA RR 3.06 Salpeter SR et al Chest 2004;125:

10 BACKGROUND FIXED-DOSE COMBINATIONS OF LABA PLUS ICS COMBINATION TREATMENT WITH INHALED CORTICOSTEROID (ICS) PLUS LABA IS BELIEVED TO PROVIDE GREATER ASTHMA CONTROL THAN INCREASING THE ICS DOSE ALONE STUDIES HAVE SHOWN THAT REGULAR USE OF COMBINATIONS OF LABA PLUS ICS PROVIDED A SIMILAR REDUCTION IN EXACERBATIONS, WITH BETTER CONTROL OF SYMPTOMS AND LUNG FUNCTION, COMPARED WITH INCREASING DOSE OF ICS Nelson HS J Allergy Clin Immunol 2001;107: ;

11 ANTIMUSCARINICS INDIRECTLY RELAX AIRWAY SMOOTH MUSCLE BY BLOCKING THE EFFECT OF ACETYLCHOLINE ON M3 MUSCARINIC RECEPTORS CNS Antimuscarinics inhibit the bronchoconstrictor effect of the neurotransmitter acetylcholine (ACh) at M3 muscarinic receptors on airway smooth muscle Mucus gland Parasympathetic ganglia ACh ACh M2 ( ) M3 (+) M1 (+) M2 ( ) ACh M3 (+) M2 muscarinic receptors on postganglionic nerve terminals act as feedback inhibitors Smooth muscle Scullion. Int J Chron Obstruct Pulmon Dis 2007

12 Asthma

13 PHARMACOLOGICAL THERAPY Relievers inhaled fast-acting ß 2 -agonists inhaled anticholinergics Controllers inhaled corticosteroids inhaled long-acting ß 2 - agonists/anticholinergics oral anti-leukotrienes oral theophyllines oral corticosteroids

14 INHALED STEROIDS ARE FIRST LINE MAINTENANCE THERAPY Laitinen LA et al, J Allergy Clin Immunol 1992

15 LABA/ICS TARGET DIFFERENT COMPONENTS OF AIRWAY DISEASE Virus Adenosine Exercise Virusmicro Mast cell Bronchocontriction Macrophage Eosinophi l LABA Plasma leak Airway sensory nerve AIRWAY HYPERRESPONSIVENESS T-lymphocyte ICS Barnes PJ

16 STEPWISE MANAGEMENT - PHARMACOTHERAPY Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference Symptoms Exacerbations Side-effects Patient satisfaction Lung function Asthma medications Non-pharmacological strategies Treat modifiable risk factors STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE Other controller options RELIEVER STEP 1 STEP 2 Consider low dose ICS Low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta2-agonist (SABA) STEP 3 Low dose ICS/LABA** Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Med/high ICS/LABA Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS # For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5 (2/8) (upper part)

17 STEP 4 TWO OR MORE CONTROLLERS + AS-NEEDED INHALED RELIEVER STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 4 (7/8) Global Initiative for Asthma

18 STEP 4 TWO OR MORE CONTROLLERS + AS- NEEDED INHALED RELIEVER BEFORE CONSIDERING STEP-UP CHECK INHALER TECHNIQUE AND ADHERENCE ADULTS OR ADOLESCENTS: PREFERRED OPTION IS COMBINATION LOW DOSE ICS/FORMOTEROL AS MAINTENANCE AND RELIEVER REGIMEN*, OR COMBINATION MEDIUM DOSE ICS/LABA WITH AS-NEEDED SABA OTHER OPTIONS (ADULTS OR ADOLESCENTS) TIOTROPIUM BY MIST INHALER MAY BE USED AS ADD-ON THERAPY FOR PATIENTS AGED 12 YEARS WITH A HISTORY OF EXACERBATIONS TRIAL OF HIGH DOSE COMBINATION ICS/LABA, BUT LITTLE EXTRA BENEFIT AND INCREASED RISK OF SIDE-EFFECTS INCREASE DOSING FREQUENCY (FOR BUDESONIDE-CONTAINING INHALERS) ADD-ON LTRA OR LOW DOSE THEOPHYLLINE *Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol GINA 2016

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20 COPD

21 The main treatment goals of COPD are reduction of symptoms and future risk of exacerbations

22 GOLD 2017 Spirometry confirmed diagnosis Assessment of airflow limitation Assessment of symptoms/risk of exacerbations Exacerbation history Post bronchodilator FEV 1 /FVC < 0.7 FEV 1 (%predicted) GOLD 1 > 80 GOLD GOLD GOLD 4 < 30 > 2 or > 1 leading to hospital admission 0 or 1 (not leading to hospital admission) C A D B mmrc 0-1 mmrc >2 CAT <10 CAT >10 Symptoms

23 Pharmacological treatment algorithms by GOLD Grade [highlighted boxes and arrows indicate preferred treatment pathways] Group C LAMA + LABA LABA + ICS Group D consider roflumilast If FEV 1 < 50 pred. and pt has chronic bronchitis Consider macrolide (in former smoker) futher exacerbations LAMA futher exacerbations futher exacerbations LAMA + LABA + ICS Persistent symptoms/further exacerbations LAMA LAMA + LABA LABA + ICS Group A continue, stop or try alternative class of bronchodilator Evaluate effect A bronchodilator Group B LAMA + LABA Persistent symptoms A long-acting bronchodilator (LABA or LAMA)

24 AN ABRIDGED TIMELINE OF THE HISTORY OF AEROSOL THERAPY Nebulizer -jet -Ultrasonic MDI -Breath-actuated, spacer device, CFC/HFA DPI -passive/active, Single-dose/multiple dose

25 NEBULIZERS Liquid aerosol JET NEBULIZERS ULTRASONIC NEBULIZERS METER DOSE INHALER PRESSURIZED METERED-DOSE INHALERS DRY POWDER INHALERS CURRENT INHALER DEVICES ACCUHALER, HANDIHALER, EASYHALER, TURBUHALER, BREEZHALER MULTI-DOSE LIQUID INHALERS (RESPIMAT SOFT MIST INHALER) Liquid aerosol with propellant solid aerosol Liquid aerosol without propellant

26 MECHANISMS OF LUNG DEPOSITION particles > 3 μm particles < 2 μm Inertial impaction Gravitational sedimentation diffusion

27 FACTOR AFFECTING LUNG DEPOSITION Patients factors Inspiratory flow ( inspiratory muscle strength) Patient-device co-ordination Breath-holding (oropharyngeal anatomy) Devices factors Particle properties (size, shape, densities) Flow velocities, turbulence of flow Device resistance Drug stability, drug dispersion Adverse drug reaction, irritation

28 AEROSOL PARTICLE SIZE DETERMINE LUNG DEPOSITION Therapeutic aerosols deposition Drug deposition is directly influenced by the Mass Median Aerodynamic Diameter (MMAD) of the particles > 5µm : deposited into oropharynx and swallowed 1-5µm : optimal for delivery to the lower airways and parenchyma <1µm : likely to be exhaled by tidal breathing

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30 NEBULIZERS Bernoulli s principle the vibration of piezoelectric crystals at high frequency, creating crests that break the liquid into small droplets

31 PRESSURIZED METERED-DOSE INHALERS The structural components of the pmdi: canister, metering valve, actuator, and a mouth piece Constant vapor pressure throughout the product life

32 PRESSURIZED METERED-DOSE INHALERS contains the drug solution and formulated suspension Types of propellants chlorofluorocarbons (CFC) hydrofluoroalkanes (HFA) Varying particle sizes, high velocities Generate a percentage of lung deposition ranging from 10 to 20%.

33 LIMITATION OF PRESSURIZED METERED-DOSE INHALERS Need patient breath- coordination High velocity aerosols ( high inspiratory turbulent flow more upper airway deposit) Heterogeneous aerosol dispersion (variable sized particles)

34 SPACER DEVICES The advantages of spacers are: Eliminate the problem of handbreath coordination. Improve the delivery of medication and allows more medicine into the lungs. Reduce throat irritation and/or fungal growth in the upper airways (e.g. candidiasis, hoarseness and bad taste)

35 SPACER DEVICES

36 DRY POWDER INHALERS Formulation design for DPIs micronized drug particles (1 5 μm) blended with carries particles (lactose, mannitol, sucrose, sorbitol, glucose) of larger sizes (40 μm) Drug detachment from carries particles Aerodynamic based: direct interaction of flow stream with drug particle located on carrier surface Mechanical based: collisions between carrier particles and inhaler walls during transit through the devices Schematic-diagram-of-drugs-from-DPI-formulation [accessed 19 May, 2018]

37 DRY POWDER INHALERS American Journal of Health-System Pharmacy July 2011, 68 (13)

38 ACCUHALER

39 TURBUHALER Spiral channels Upper air inlet Air inlet

40 ACCUHALER VS TURBUHALER Resistance/ inspiratory effort Proper device handing position Accuhaler Lower Turbuhaler Higher Sensitive to humidify No Yes

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42 Suitability-of-inhaler-devices-according-to-the-patientsinspiratory-flow-and-ability-to_tbl2_ [accessed 20 May, 2018]

43 SUITABILITY OF INHALER DEVICES Good actuation- inhalation coordination > 30 l/min < 30 l/min > 30 l/min < 30 l/min pmdi pmdi pmdi + spacer pmdi + spacer DPI Inspiratory flow Nebulizer Nebulizer Nebulizer Nebulizer SMI SMI SMI poor actuation- inhalation coordination Inspiratory flow Suitability-of-inhaler-devices-according-to-the-patientsinspiratory-flow-and-ability-to_tbl2_ [accessed 20 May, 2018]

44 HANDIHALER

45 HANDIHALER

46 BREEZHALER cover mouthpiece button

47 BREEZHALER

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49 RESULT pmdi Accuhaler Turbuhaler Canister in the wrong position Lack of synchronization of hand actuation and breathing in Blowing into the device before inhalation Missing sliding the lever as far as possible Blowing into the device before inhalation Not holding inhaler upright for grip rotation (+-45) Missing rotate grip clockwise then counterclockwise until click

50 Percent patients who were scored No to key features of the nhalation technique checklist by inhaler

51 CONCLUSION The breath-actuated inhalers are not equal in real life in the frequency of device-dependent errors and critical errors The equivalence of efficacy demonstrated in controlled trial is unlikely to be transposable to real life

52 SOFT MIST DEVICES a spring-like mechanism to drive the liquid through its end Generating an aerosol cloud for 1 to 1.5 seconds (pmdis, sec) In adults, lung deposition with this device is around 40%

53 For each activation, 15µL of drug formation was forced through the micro-channels forming liquid jet from the nozzle opening (3-5µm) soft mist aerosol (majority of particles 1-5µm The 15µL formulation contains 2.5 µg tiotropium and was sprayed in 1.2 sec

54 COMPARISON OF THE AEROSOL VELOCITY OF RESPIMAT SOFT MIST INHALER AND PMDI

55 A SYSTEMATIC REVIEW OF COMPARATIVE STUDIES OF TIOTROPIUM RESPIMAT AND TIOTROPIUM HANDIHALER Published evidence from comparative studies suggests that tiotropium Respimat 5 μg and tiotropium HandiHaler 18 μg provide similar clinical outcomes in patients with COPD

56 SUITABILITY OF INHALER DEVICES Good actuation- inhalation coordination > 30 l/min < 30 l/min > 30 l/min < 30 l/min pmdi pmdi pmdi + spacer pmdi + spacer DPI Inspiratory flow Nebulizer Nebulizer Nebulizer Nebulizer SMI SMI SMI poor actuation- inhalation coordination Inspiratory flow Suitability-of-inhaler-devices-according-to-the-patientsinspiratory-flow-and-ability-to_tbl2_ [accessed 20 May, 2018]

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